Patent Grant
9682021
Petrolatum is used in dermatology to lubricate, protect, heal and medicate the skin and as a vehicle for topical drugs. Petrolatum is not suited to formation of foams. It is an unctuous solid and does not flow and is not shakable per se. Addition of large amounts of propellant to try and improve its flow is not desirable in general since the resultant material can have a cooling effect on application to the skin, mucosal cavity or body cavity. Addition of hydrophobic solvents can be useful to improve healing qualities of the formulation and to soften the petrolatum, but it can also significantly and substantially complicate or impede foam formation.
Foams are complex multi-ingredient systems which do not form under all circumstances. High quality foams are not at all easy to produce especially in a waterless environment. Yet, foams are easy to apply, use and spread and are a preferred mode of topical application. Changes in foam composition, such as, by the addition of active ingredients, may destabilize the foam. There is, therefore, a need for a foam composition, which provides desirable properties to the skin or body cavity and can be stable whilst accommodating a variety of active ingredients.
Petrolatum in its various forms has a number of useful attributes for use in topical foamable pharmaceutical and cosmetic compositions. They are inherently stable and inert, which are clearly desirable characteristics. They are also able to moisturize and soften the skin and in appropriate amounts can act as a protective or barrier layer and can form a barrier to water, which can, for example, solubilize or cause destabilization of some active ingredients. By careful design and appropriate formulation of petrolatum compositions they can act to improve drug delivery to the skin; provide a protective environment for the drug and yet remain resistant to being washed off unintentially. On the other hand petrolatums are by their nature greasy materials and can present a difficult challenge to formulate them into a topical non-aqueous or substantially so foamable composition that can deliver substantially uniform and stable foam that ameliorates and or overcomes the look and feel of a greasy material. It is further a problem to incorporate into such a vehicle pharmaceutically effective amounts of one or more active pharmaceutical ingredients such that they are uniformly present throughout the formulation and are effectively delivered especially without the use of an alcohol in the formulation.
Aliphatic alcohols in foam compositions promote fast drying and thereby attempt to address the sticky feeling left by many topical formulations after application; however, alcohols, and in particular short chain alcohols like methyl, ethyl and isopropyl alcohols are defatting agents and may cause skin to become dry and cracked. Also, the presence of such alcohols generates alcoholic foam that is thermal sensitive and quick breaking, e.g., it collapses readily upon contact with a surface upon exposure to body temperature environment. Although certain compositions based on petrolatum are known they are, for example, designed to form an occlusive layer in the presence of active pharmaceutical agents that are not soluble in the water or oil phase. Although some lipophillic compositions containing petrolatum and silicone oil are known, the silicone oil is an essential and main component and it is used to try and overcome the greasy feeling of petrolatum. Silicones can have substantial disadvantages in foamable compositions and foams especially in significant levels.
In the light of the unctuous, greasy, tacky, and heavy nature of petrolatum, there are problems in producing stable emulsion foams of good quality and texture from high levels of petrolatum and there is a real technical challenge of achieving inter alia a good bubble structure, texture, spreadability and look and feel. The presence of water is important in contributing to feel of the foam. Developing foams with such characteristics that are substantially free of water is a technical and inventive challenge. This challenge is increased where the formulations are to be substantially free of silicone oil and substantially free of lower alcohols.
Alcohol is known to impair the integrity of the skin barrier, dry the skin and cause skin irritation. The incidence skin irritation (burning, itching and stinging) can be very high. Thus, while alcohol is useful in solubilizing an active agent and enabling effective dermal penetration of an active agent, the development of a safe foam vehicle, which will overcome the evident skin drying and irritation caused by alcohol, is warranted, especially where sensitive skin, mucosa, or body cavity membranes are being targeted. Furthermore, foam compositions that possess a lesser degree of thermal sensitivity, thus being more useful for the treatment of large skin areas are desired.
Foamable compositions that produce foams, which are soft are desirable especially with improved stability.
It is particularly advantageous to have a foamable vehicle that is suitable for use as a base for delivery of not merely one type of active pharmaceutical ingredient (API) but is adaptable for use with one or more API's from a wide range of different types of API's with relatively minimal or minor adjustment to the vehicle. For example, by altering the amount of a component or by the addition of a buffer that provides a pH at which the API is stable as would be appreciated by a person skilled in the art.
This application relates to petrolatum-based foamable vehicles, pharmaceutical compositions and resultant foams. In one embodiment, the petrolatum-based foamable vehicles, pharmaceutical compositions and resultant foams are non-aqueous. In one embodiment, petrolatum-based foamable vehicles, pharmaceutical compositions and resultant foams have low water content. The application further relates to such compositions and to such resultant foams that are non-silicone and or are non-alcoholic or substantially so.
A prime concept covered herein is that petrolatum as a hydrophobic carrier is a main ingredient and is at least about 50% of the foamable carrier alone or in combination with a solvent substantially miscible therein for example a hydrophobic oil. In a preferred aspect the percentage of petrolatum is more than about 60%. In one aspect the foamable carrier is non-aqueous and the petrolatum is at least about 25% and is in combination with a solvent substantially miscible therein such that together they are at least about 80% and the carrier is substantially free of silicone oil. By substantially free it is meant that the silicone oil content in the composition is less than about 1%. In another aspect the foamable carrier is substantially non-aqueous or has low water content and the petrolatum is more than about 50% or more than about 55% and preferably more than about 60%. By substantially non-aqueous or low water content it is meant that the amount of water if present in the composition is small and is less than about 26%, preferably less than about 16% and more preferably less than about 13%. Although the proportion of water is relatively very small by selective use of appropriate and compatible surfactants it can be possible to produce both water in oil and also oil in water petrolatum emulsion compositions. Whilst these carriers are intended to be without lower or short chain alcohols, where an API is provided as an alcoholic extract, such small amount of alcohol is permitted in the compositions. In certain embodiments, such lower alcohol content is reduced or essentially eliminated by evaporation upon warming.
In an embodiment the petrolatum based carriers comprise one or more active pharmaceutical ingredients (API's). The formulations are designed to carry homogeneously large ranges of API's from microgram levels to up to about 33% of the composition. Some API's are stable in one kind of environment whilst others require a different environment. For example, many steroids are known to undergo rearrangement at high pH, and are more stable in acidic formulations whilst vitamin D and its derivatives fare better in a basic medium. So adding an acidic modulating agent such as an acidic buffer, or fatty acid helps prevent steroid degradation whilst the addition of a basic modulating agent, such as a basic buffer or triethanolamine is useful to maintain acceptable stability for vitamin D and derivatives. Other substances break down or react more rapidly in the presence of water and therefore are sustained better in a non-aqueous medium. The formulations described herein offer waterless and substantially waterless or low water content variations and an appropriate carrier may be selected for an API depending on its sensitivity and reactivity in the presence and absence of relatively small amounts of water. Whilst the carrier compositions described herein may be useful carriers for API's some are not compatible in the same formulations and may react or breakdown. The formulations described are suitable for use in dual or multi chamber foam delivery devices, where each chamber delivers an API which if stored with the API's in the other chamber(s) would have broken down. In one embodiment the carrier in the first chamber is substantially waterless and the carrier in the second chamber is waterless. In another embodiment the carrier is basically the same in each chamber although some minor variations such as to pH or artificial pH or in the presence of one or more preservatives, stabilizers, antioxidants, and the like may be made to reflect the specific requirements of the API.
To generate the good quality foams described herein the formulations contain a foam agent. In one or more embodiments the foam agent is selected from the group consisting of a surfactant, a surfactant combination, a foam adjuvant and combinations thereof. In one or more further embodiments the quality may be improved by addition of a polymeric agent. The polymeric agent may preferably have some surfactant-like properties or help to ameliorate the tacky greasy properties of petrolatum.
In one embodiment, the foamable composition is a non-aqueous, non-alcoholic foamable composition that includes a foamable carrier and at least one liquefied or compressed gas propellant. The foamable carrier includes (1) a petrolatum or mixtures thereof at a concentration of about 25% to about 95% by weight; (2) a solvent substantially miscible in the petrolatum at a concentration of about 0% to about 70% by weight; and (3) at least one foam agent selected from the group consisting of a surfactant, a surfactant system, a foam adjuvant and combinations thereof; at a concentration of about 0.1% to about 20% by weight. In the absence of the solvent, the petrolatum is present in the foamable carrier at a concentration of at least about 50% by weight. In the presence of the solvent, (i) the petrolatum is present in the foamable carrier at a concentration of at least about 25% by weight and the solvent and petrolatum are together present in the foamable carrier at a concentration of least about 55% by weight; or (ii) the amount of petrolatum is about the same as or in excess of the solvent and, together, the solvent and petrolatum are present in the foamable carrier at a concentration of at least about 80%. The ratio of the foamable carrier to the propellant is 100:10 to 100:35. The composition is substantially free of silicone. The composition is stored in a pressurized container or aerosol container and upon release expands to form a breakable foam.
In one embodiment, the foamable composition is a non-aqueous, non-alcoholic foamable composition that includes a foamable carrier and at least one liquefied or compressed gas propellant. The foamable carrier includes (1) a petrolatum or mixtures thereof at a concentration of about 50% to about 95% by weight; (2) a solvent substantially miscible in the petrolatum at a concentration of about 0% to about 45% by weight; (3) at least one foam agent selected from the group consisting of a surfactant, a surfactant system; a foam adjuvant and combinations thereof at a concentration of about 0.1% to about 20% by weight; and (4) an effective amount of an active pharmaceutical agent. The ratio of the foamable carrier to the propellant ranges from about 100:10 to about 100:35. The composition is substantially free of silicone. Moreover, the composition is resistant to centrifugation at 1000 rpm for about 10 minutes; is flowable or flowable to a degree and or is shakable or substantially so when stored in a pressurized container or an aerosol container and upon release expands to form a breakable foam having no substantial or sustained cooling affect and having a foam hardness in the range of about 5 g to about 100 g.
In one embodiment, the foamable composition is a low water content, non-alcoholic foamable composition that includes a foamable carrier and at least one liquefied or compressed gas propellant. The foamable carrier includes (1) a petrolatum or mixtures thereof at a concentration of about 25% to about 95% by weight; (2) a solvent substantially miscible in the petrolatum at a concentration of 0% to about 70% by weight; (3) at least one foam agent selected from the group consisting of a surfactant, a surfactant system, a foam adjuvant and combinations thereof; at a concentration of about 0.1% to about 20% by weight; and (4) water at a concentration of up to about 26% by weight. In the absence of the solvent, the petrolatum is present in the foamable carrier at a concentration of at least about 50% by weight. In the presence of the solvent: (i) the petrolatum is present in the foamable carrier at a concentration of at least about 25% by weight and the solvent and petrolatum are together present in the foamable carrier at a concentration of least about 55% by weight; or (ii) the amount of petrolatum is about the same as or in excess of the solvent and, together, the solvent and petrolatum are present in the foamable carrier at a concentration of at least about 80%. The ratio of the foamable carrier to the propellant ranges from about 100:10 to about 100:35. The composition is substantially free of silicone. The composition is stored in a pressurized container or aerosol container and upon release expands to form a breakable foam. In one embodiment, the foamable composition is a low water content, non-alcoholic foamable composition that includes a foamable carrier and at least one liquefied or compressed gas propellant. The foamable carrier includes (1) a petrolatum or mixtures thereof at a concentration of about 50% to about 95% by weight; (2) a solvent substantially miscible in the petrolatum at a concentration of about 0% to about 45% by weight; (3) at least one foam agent selected from the group consisting of a surfactant, a surfactant system; a foam adjuvant and combinations thereof at a concentration of about 0.1% to about 20% by weight; and (4) an effective amount of an active pharmaceutical agent. The solvent is water and is present in the carrier at a concentration of about 0.1% to about 26% by weight. The ratio of the foamable carrier to the propellant ranges from about 100:10 to about 100:35. The composition is substantially free of silicone. The composition is resistant to centrifugation at 1000 rpm for about 10 minutes and is flowable or flowable to a degree and or is shakable or substantially so when stored in a pressurized container or aerosol container and upon release expands to form a breakable foam having no substantial or sustained cooling affect and having a foam hardness in the range of about 5 g to about 100 g
In one or more embodiments there is provided a substantially non-aqueous, non-alcoholic, non-silicone foamable carrier composition comprising:
In one or more other embodiments the amount of petrolatum is in excess of about 50% and there is present an amount of solvent substantially miscible therein between about 0.1% to about 45%. Preferably it is in excess of about 55% and the range is about 0.1% to about 40% and more preferably in excess of about 60% and the range is about 0.1% to about 35%.
In one or more embodiments there is provided a substantially non-aqueous, non-alcoholic non-silicone foamable carrier composition comprising:
In one or more other embodiments the formulations and foams are non-aqueous, non-silicone and non-alcoholic (being in the absence of a lower alcohol). In one or more other embodiments the formulations and foams have at least two of the three features listed.
Non-Aqueous Formulations
Foamable non-aqueous compositions are described that are non-aqueous or essentially so, are stable and able to provide some of the main attributes of a petrolatum ointment or cream in a topical foamable formulation and which can deliver a substantially uniform and stable foam without the use of an alcohol in the formulation. By “non-aqueous” or “essentially non-aqueous” it is meant that the compositions contain at most incidental and trace amounts of water. In one embodiment, the water content is very small being about less than about 5%. By “without alcohol” or “non-alcoholic” it is intended to exclude the use of lower or short chain alcohols. These compositions comprise petrolatum. The petrolatum phase is the main phase or is a major element of the carrier. The formulations can also ameliorate or overcome to a degree the look and feel of a greasy material. These compositions can provide an improved delivery system over ointments and creams.
In one or more embodiments, the foamable non-aqueous compositions are flowable or flowable to a degree and or are shakable and can expand to produce a good quality foam without the propellant having a significant cooling effect.
In one or more embodiments, the foamable non-aqueous compositions produce foams that are soft or with an improved softness.
In one or more embodiments, pharmaceutically effective amounts of one or more active pharmaceutical ingredients are incorporated into the foamable non-aqueous composition.
In one or more embodiments an active ingredient is distributed homogeneously in the composition are described.
In one or more embodiments, substantial amounts of an active ingredient are distributed homogeneously in the composition.
In one or more embodiments, foamable non-aqueous compositions are provided without a co-solvent.
In one or more embodiments, foamable non-aqueous compositions are provided in which the solvent comprises a propellant, which evaporates on expansion to produce a foam.
In one or more embodiments, the foamable non-aqueous composition is suitable for use as a base for delivery for API's, which are by their nature emulsion destabilizers, micelle destabilizers or interphase destabilizers, with relatively minimal or minor adjustment to the vehicle or in the method of preparation. Pharmaceutical salts, for example, are in general emulsion destabilizers.
The foamable non-aqueous compositions are described that improve the solubility and/or deliverability of the active pharmaceutical to a target skin, mucosa or body cavity area and/or provide an improved delivery system over ointments and creams.
The present invention relates to non-aqueous, non-alcoholic, non-silicone, foamable carriers and pharmaceutical and cosmetic compositions comprising at least, a hydrophilic carrier comprising petrolatum or mixtures thereof with a solvent substantially miscible therein, a surfactant, and a propellant with and without the addition of an active agent.
The present invention relates to non-aqueous, non-alcoholic, non-silicone, foamable carriers and pharmaceutical and cosmetic compositions comprising at least, a hydrophilic carrier comprising petrolatum or mixtures thereof with a solvent substantially miscible therein, a surfactant, and a propellant, with and without the addition of an active agent, wherein the foam produced by the carrier or pharmaceutical composition when packaged in an aerosol container and released has a foam hardness in the range of about 5 g to about 100 g. Preferably, hardness level is towards the lower part of the range reflecting relative softness. Further, in an embodiment when the resultant foam is applied to a surface it does not have any cooling or significant cooling effect.
The present invention relates to non-aqueous, non-alcoholic, non-silicone foamable carriers and pharmaceutical and cosmetic compositions comprising a petrolatum or mixtures thereof with a solvent substantially miscible therein, a surfactant, and a propellant, which can hold substantial amounts of active agents and still produce a good quality stable breakable foam.
The present invention relates to non-aqueous, non-alcoholic, non-silicone foamable carriers and pharmaceutical and cosmetic compositions with relatively high viscosity prior to addition of the propellant. In some embodiments, relatively high viscosity is a viscosity from about 12,000 CPs to about 500,000 CPs. In some embodiments, relatively high viscosity is a viscosity from about 20,000 CPs to about 500,000 CPs. In some embodiments, relatively high viscosity is a viscosity from about 50,000 CPs to about 500,000 CPs. In some embodiments, relatively high viscosity is a viscosity from about 100,000 CPs to about 500,000 CPs. In some embodiments, relatively high viscosity is a viscosity of at least about 20,000 CPs. In some embodiments, relatively high viscosity is a viscosity of at least about 50,000 CPs. In some embodiments, relatively high viscosity is a viscosity of at least about 100,000 CPs.
The present invention also relates to non-aqueous, non-alcoholic, non-silicone, foamable carriers and pharmaceutical and compositions comprising a petrolatum or mixtures thereof with a solvent substantially miscible therein, a surfactant, a propellant, wherein the propellant dissolves in the composition.
The present invention also relates to non-aqueous, non-alcoholic, non-silicone, foamable carriers and pharmaceutical and cosmetic compositions comprising a petrolatum or mixtures thereof with a solvent substantially miscible therein, a surfactant, a propellant, wherein the propellant dissolves in the composition and which when stored in a pressurized canister rapidly expands on release to produce a breakable foam.
The present invention also relates to non-aqueous, non-alcoholic, non-silicone, foamable carriers and pharmaceutical and cosmetic compositions comprising a petrolatum or mixtures thereof with a solvent substantially miscible therein, a surfactant, a propellant, wherein the propellant dissolves in the composition.
The present invention also relates to non-aqueous, non-alcoholic, non-silicone, foamable based pharmaceutical compositions comprising petrolatum with a solvent substantially miscible therein, a surfactant, a propellant, and an active agent wherein the active agent is insoluble and is distributed uniformly in the composition or, wherein the composition or a phase thereof is able at least to a very limited degree to solubilize the active agent or wherein the composition or a phase of the composition is able to a degree to solubalize the active agent.
In certain embodiments where the composition is essentially non-aqueous but contains a small amount of water the hydrophobic carrier or composition does not in certain aspects contain a non-propellant organic co-solvent.
The present invention relates to non-aqueous, non-alcoholic, non-silicone, foamable compositions wherein each composition is flowable or flowable to a degree and or is shakable or substantially shakable when stored in an aerosol container and upon release expands to form a breakable foam that effectively delivers petrolatum with a solvent substantially miscible therein, at a concentration of from about 25% to about 95% by weight of the foam. Preferably the amount of petrolatum is about more than about 35% and more preferably the amount of petrolatum is more than about 50% or more than about 55% or more than about 60%.
The present invention relates to a non-aqueous, non-alcoholic, non-silicone, foamable carrier composition comprising:
In one or more embodiments the solvent substantially miscible in petrolatum is from about 1% to about not more than 68% by weight of the composition, preferably about not more than 55%, more preferably about not more than 45% by weight of the composition.
The present invention further relates to said compositions additionally comprising one or more additional active agents.
Thus, the present invention also relates to a non-aqueous, non-alcoholic, non-silicone, foamable pharmaceutical or cosmetic composition comprising:
In one or more embodiments the solvent substantially miscible in petrolatum or mixtures thereof is a hydrophobic solvent or an unctuous additive.
In a particular embodiment the solvent is an oil, preferably a therapeutically active oil. Thus, the present invention relates to said composition comprising one or more therapeutically active oils. The presence of oil on the one hand acts to soften and increase the fluidity of the petrolatum or mixtures thereof but on the other hand it significantly and substantially complicates the formulation and the selection of surfactants and other solvents and or foam adjuvants and or propellants appropriate to achieve a foam of quality.
In an embodiment the solvent comprises a mineral oil. In other embodiments the solvent comprises a therapeutic oil.
In an embodiment, the gas propellant and its amount can be significant in improving the characteristics of the foam. Indeed the propellant may itself be a solvent with respect to the foamable composition even though ultimately the propellant disappears from the composition upon release as it expands to form a breakable foam.
In an embodiment, the gas propellant comprises n butane.
In an embodiment, the gas propellant comprises a mixture of n-butane, isobutane and propane. The mixture may be varied as a man skilled in the art would appreciate.
In some embodiments, the foamable cosmetic or pharmaceutical composition is non-flammable, wherein said gas propellant contains hydrofluorocarbon.
Low Water Content Formulations
The aforesaid description of the non-aqueous formulations is also generally applicable to the low water content or substantially non-aqueous formulations herein with where necessary appropriate changes as would be appreciated by a man of the art. For example, where waterless is mentioned above the compositions further described below may also be waterless but without substantial amounts of a hydrophobic oil or where the compositions described below contain some small amount of water the compositions are formulated as an emulsion as opposed to a single phase. Similarly, where compositions above refer to a solvent which is substantially miscible in petrolatum, the compositions below are primarily concerned with hydrophilic or polar solvents. Thus, the previous section may be read and applied to these formulations with these points in mind. Other embodiments by way of example are specifically described below.
Petrolatum foamable compositions wherein the petrolatum phase is the main phase of the composition that are shakable and can expand to produce a good quality foam without the propellant having a significant cooling effect are described and can provide an improved delivery system over ointments and creams.
Petrolatum foamable and non-aqueous petrolatum foamable compositions in which the petrolatum phase is the main phase of the composition and contains an active ingredient distributed homogeneously in the composition are described. These compositions provide an improved delivery system over ointments and creams.
In one or more embodiments, petrolatum foamable compositions are provided without a cosolvent in which the petrolatum phase is the main phase of the composition and contains substantial amounts of an active ingredient distributed homogeneously in the composition.
In one or more embodiments, petrolatum foamable compositions are provided in which the solvent is a propellant, which evaporates on expansion to produce a foam. The petrolatum phase is the main phase of the composition and can contain substantial amounts of an active ingredient distributed homogeneously in the composition.
In one or more embodiments, a foamable petrolatum composition is suitable for use as a base for delivery of not merely one type of API but is adaptable for use with one or more API's from a wide range of different types of API's with relatively minimal or minor adjustment to the vehicle. For example, by altering the amount of a component or by the addition of a buffer that provides a pH at which the API is stable as would be appreciated by a person skilled in the art.
The present invention also relates to stable non-alcoholic foamable petrolatum based carriers and pharmaceutical and cosmetic compositions comprising a petrolatum or mixtures thereof, a surfactant, a propellant, with and without a solvent wherein the propellant dissolves in the composition and which when stored in a pressurized canister rapidly expands on release to produce a breakable foam.
The present invention also relates to stable non-alcoholic foamable petrolatum based carriers and pharmaceutical and cosmetic compositions comprising a petrolatum or mixtures thereof, a surfactant, a propellant, with and without a solvent wherein the propellant dissolves in the composition and which are resistant to creaming at 3000 rpm for at least 10 minutes.
The present invention also relates to stable non-alcoholic foamable petrolatum based pharmaceutical and cosmetic compositions comprising petrolatum mixtures.
The present invention also relates to stable non-alcoholic foamable petrolatum based pharmaceutical compositions comprising petrolatum, a surfactant, a solvent, a propellant, and an active agent wherein the active agent is insoluble and is distributed uniformly in the composition which does not contain a non propellant organic cosolvent.
The present invention also relates to stable non-alcoholic foamable pharmaceutical emulsion compositions comprising petrolatum, a surfactant, a solvent, a propellant, and an active agent, wherein the composition or a phase thereof is able at least to a very limited degree to solubilize the active agent; and or so that the composition does not comprise a non propellant organic cosolvent.
The present invention also relates to stable non-alcoholic foamable petrolatum based pharmaceutical compositions comprising a petrolatum or mixtures thereof, a surfactant, a solvent, a propellant, and an active agent wherein the composition or a phase of the composition is able to a degree to solubalize the active agent.
The present invention relates to stable non-alcoholic foamable petrolatum based compositions wherein each composition is shakable or substantially shakable stored in an aerosol container and upon release expands to form a breakable foam that effectively delivers petrolatum at a concentration of about 50% to about 95% by weight of the foam. Preferably petrolatum is delivered at a concentration of at least about 55%, and more preferably at least about 60%.
The present invention relates to stable non-alcoholic foamable petrolatum based compositions wherein each composition is flowable or flowable to a degree when stored in an aerosol container and upon release expands to form a breakable foam that effectively delivers petrolatum at a concentration of about 50% to about 95% by weight of the foam.
The present invention relates to a stable non-alcoholic foamable carrier composition comprising:
The present invention further relates to said compositions comprising in addition a solvent, preferably water or a hydrophilic solvent. In one or more embodiments the solvent is about not more than 40% by weight of the composition.
The present invention relates to a stable non-alcoholic foamable pharmaceutical or cosmetic composition comprising:
The present invention further relates to said composition comprising one or more additional therapeutically active oils.
In an embodiment the active agent is an alcoholic extract, an aqueous extract or an aqueous alcoholic extract. In such limited circumstances the amount of water or lower alcohol is permitted to the extent necessary to deliver an effective amount of the API.
In an embodiment these substantially non-aqueous formulations and foams are also non-silicone and or non-alcoholic or substantially so.
Methods of Treatment Using Non-Aqueous and Substantially Non-Aqueous Compositions
The present invention further provides a method of treating, alleviating or preventing a disorder of mammalian subject, comprising administering a therapeutically effective amount of the herein-mentioned compositions to an afflicted target site.
The present invention further provides a method of treating, alleviating or preventing a nappy rash of mammalian subject, comprising administering a therapeutically effective amount of the herein-mentioned compositions to an afflicted target site. In an embodiment the petrolatum based composition contains Zinc Oxide as an API for use against or to treat or prevent minor skin irritations (e.g., burns, cuts, poison ivy, rash, particularly diaper or nappy rash). The compositions described herein are ideal for carrying effective high concentrations of API.
The present invention further provides a use of any of the herein-mentioned compositions for the manufacture of a medicament for treating, alleviating or preventing a disorder of a mammalian subject in need thereof.
The present invention further provides a use of any of the herein-mentioned compositions for the manufacture of a medicament for treating, alleviating or preventing nappy rash of a mammalian subject in need thereof.
In one or more embodiments any of the foregoing methods of treatment may be applied by providing a first pharmaceutical composition in a first foam canister and a second pharmaceutical composition in a second canister. The contents of each canister may be applied individually in an appropriate sequence or at the same time. The canisters may be part of a dual or multi chamber foam delivery device.
Non-Aqueous Formulations
The present invention provides safe and effective foamable petrolatum based pharmaceutical and cosmetic vehicles and compositions. More particularly, it provides non-aqueous, non-alcoholic, non-silicone or essentially so, foamable petrolatum based pharmaceutical or cosmetic carriers and compositions in which a petrolatum or mixtures thereof is the largest single component or is a substantial or major component by weight in the carrier or composition. The present invention further provides low water content foamable petrolatum based pharmaceutical or cosmetic carriers in which a petrolatum or mixture thereof is the largest single component or is a substantial or major component by weight in the carrier or composition. The vehicle or composition further comprises at least one surfactant or surfactant system. The vehicle or composition further comprises at least one propellant wherein the composition is stored in an aerosol container and upon release expands to form a foam. In one or more embodiments the carrier or composition further comprises one or more active agents which may be insoluble, at least soluble to a very limited degree or soluble in the composition or a phase thereof.
By low water content or essentially non-aqueous it is intended the formulations may have present a small amount of water (i.e., incidental or trace amounts of water). In one embodiment, the formulations have less than about 5% water content. In one embodiment, the formulations have less than about 4% water content. In one embodiment, the formulations have less than about 3% water content. In one embodiment, the formulations have less than about 2% water content. In one embodiment, the formulations have less than about 1% water content. In one or more embodiments where the composition is has low water content or is essentially non-aqueous it may contain a small amount of water and in certain aspects the carrier or composition does not contain a non propellant organic co-solvent.
It was unexpectedly discovered that after dissolving the propellant into pre-foam formulations without solvent so that the viscosity is high that a change in the petrolatum formulation is observed such that it is shakable and flowable. It is believed that in certain embodiments some compositions may be marginally or apparently non-shakable and still have a degree of flowability such that a good quality foam can be expelled from the canister.
The present invention also relates to foamable petrolatum based pharmaceutical and cosmetic compositions comprising petrolatum mixtures. By combining appropriate amounts of different types of petrolatum with a solvent substantially miscible therein it is possible for example, to prepare foams which are able to mimic substantially barrier properties of petrolatum ointments and petrolatum based barrier creams for nappy rash. In one embodiment a low melting point petrolatum is mixed with a petrolatum with a higher melting point. In certain embodiments the major petrolatum is the lower molecular weight petrolatum. In other embodiments the petrolatum is mixed in a ratio for example, of about 5:1; 4:1; 3:1; 2:1; or 1:1 of lower melting point to higher melting point petrolatum. In some embodiments the ratio of mixture can be of higher melting point to lower melting point. In certain embodiments a softer type of petrolatum is utilized on its own or in a mixture.
In an embodiment it was surprisingly found that it was possible to exclude stabilizers other than a surfactant and still prepare a reasonable foam in the presence of ASOS, which whilst improving skin feel can ameliorate foam quality
In one or more embodiments it is possible to incorporate uniformly into a petrolatum based foamable vehicle, pharmaceutically or cosmetically effective amounts of one or more active cosmetic, therapeutic or pharmaceutical ingredients (agents).
In one or more embodiments it is possible to incorporate uniformly into a petrolatum based foamable vehicle, substantial amounts of one or more active ingredients.
In one or more embodiments it is possible to deliver uniformly in a foam produced from a petrolatum based foamable vehicle, an amount of active ingredients of up to about 33% preferably up to 20% by weight of the composition before addition of propellant.
In one or more embodiments, the foamable carriers described herein are suitable for use as a base for delivery of not merely one type of API but are adaptable for use with one or more API's from a wide range of different types of API's with relatively minimal or minor adjustment to the carrier, for example, by altering the amount of a component, as would be appreciated by a person skilled in the art. Although pH applies to aqueous environments in one or more embodiments the presence of a buffer or pH agent can also help to provide a stable environment for an active agent. In a preferred aspect the buffer or pH agent is provided in an effective amount that provides a pH at which the API is stable. Likewise chelating agents, antioxidants and anti-ionization agents may also be usefully added
In one or more embodiments there is provided a foamable vehicle or carrier that is suitable for use as a base for delivery for API's, which are by their nature destabilizes, with relatively minimal or minor adjustment to the vehicle or in the method of preparation. Pharmaceuticals that have a hydrophobic region may be absorbed at least partially by the hydrophobic carrier compositions. Thus, the identification of petrolatum based compositions that are effective in having anti destabilization properties in combination with at least one surfactant or surfactant system provides special advantages and is another embodiment.
In one or more embodiments there is provided a non-aqueous, non-alcoholic, non-silicone, foamable carrier composition comprising:
In certain embodiments the foamable carriers and compositions described herein are resistant to centrifugation at 1000 rpm for at least 10 minutes, for example, when the petrolatum concentration is relatively high.
In one or more embodiments there is provided a non-aqueous, non-alcoholic, non-silicone, foamable carrier composition comprising:
A breakable foam is thermally stable or substantially so, yet breaks under sheer force. The breakable foam is not “quick breaking”, i.e., it does not readily collapse upon exposure to body temperature environment. Sheer-force breakability of the foam is clearly advantageous over thermally induced breakability, (due to, for example, the presence of alcohol) since it allows comfortable application and well directed administration to the target area.
‘Shakability’ in the context herein means that the composition contains some or sufficient flow to allow the composition to be mixed or remixed on shaking. By shakable it indicates that some motion or movement of the formulation can be sensed when the canister containing the formulation is shaken or is firmly shaken.
In one or more embodiments there is provided a non-aqueous, non-alcoholic, non-silicone, foamable carrier composition comprising:
In one or more embodiments the foamable carriers and compositions described herein are stored in an aerosol container and upon release expands to form a breakable foam having a foam hardness in the range of about 5 g to about 100 g.
In a further embodiment the foam hardness is in the range of about 10 g to about 90 g or more preferably about 15 g to about 55 g.
In a further embodiment the petrolatum or mixture thereof influences foam hardness such that the foam produced is soft. Softness especially with stability improves usability. If the foam, for example, is intended upon application to form a barrier, the attribute of softness should be adjusted, balanced, increased or reduced with the need to provide an effective barrier. A little less softness can be achieved, for example, by adding a proportion of petrolatum with a higher melting point or increasing the amount of waxy or solid surfactant. Alternatively it may be achieved by reducing the amount of solvent or liquid surfactant. To the extent liquid surfactant is reduced it may be compensated by increasing solid or waxy surfactant or by addition of foam adjuvants.
In a further embodiment petrolatum or mixtures thereof is between about 57% to about 90% by weight of the foamable carrier (i.e., prior to the addition of propellant).
In a further embodiment petrolatum or mixtures thereof is preferably between about 57% to about 82% by weight of the foamable carrier.
In a further embodiment the surfactant or surfactant system is preferably between about 3% to about 15% by weight of the foamable carrier (i.e., prior to the addition of propellant).
The ratio between the petrolatum and solvent is determined according to the desirable level of petrolatum and the importance of the solvent from one or more non limiting aspects including, therapeutic effect, liquefying effect, hardness, resistance to centrifugation, enhancing solubility or penetration, and taking into account appropriate and desirable pharmacologic and safety properties of the product. Typically, the solvent to petrolatum ranges between about 3:1 and about 1:100, for example, about 3:1, about 2:1, about 1:1, about 1:2, about 1:3, about 1:4, about 1:5 about, about 1:10; about 2:25, about 1:15, about 2:35, about 1:20, about 2:45 and about 1:25, about 1:30; about 1:40 about 1:50; about 1:60; about 1:70; about 1:80; about 1:90; about 1:100 preferably between about 1:15 to about 1:60.
In one or more embodiments the solvent is a PPG alkyl ether, preferably PPG15 stearyl ether.
In one or more embodiments the solvent is a combination of an oil and a PPG alkyl ether. In a preferred embodiment the oil comprises a light mineral oil and the ether comprises PPG15 stearyl ether.
In one or more embodiments the surfactant or combination of surfactants is selected from one or more of the group consisting of ceteth 20, steareth 2, steareth 20, glucose methyl stearate, methyl glucose sesquistearate, Span 20, Span 80, Tween 20, and Tween 80.
In one or more embodiments the combination of surfactants is a complex emulgator.
In one or more embodiments the foam adjuvant is selected from one or more of the group consisting of oleyl alcohol, behenyl alcohol, and cetostearyl alcohol.
In one or more embodiments the foam adjuvant is selected from one or more of the group consisting of cetyl alcohol, and stearyl alcohol.
In a further embodiment the surfactant and its amount is selected so that the composition is sufficiently shakable so that substantially uniform foam extrusion is possible. In general terms, as the amount of solid or waxy surfactant is increased the shakability of the formulation reduces until a limitation point is reached where the formulation becomes non shakable and unsuitable. To this extent the maximum effective amount of surfactant that may be used may be limited by the need for shakability.
In a further embodiment the surfactant and its amount is selected so that the composition is sufficiently flowable so that substantially uniform foam extrusion is possible. In general terms, as the amount of solid or waxy surfactant is increased the flowability of the formulation reduces until a limitation point is reached where the formulation becomes non flowable and unsuitable To this extent, the maximum effective amount of surfactant that may be used may be limited by the need for some flowability.
In selecting a suitable surfactant or combination thereof it should be borne in mind that in certain exceptional embodiments the composition may be marginally shakable or apparently non shakable but nevertheless is flowable or flowable to a degree that it can flow under the pressure of the propellant through an aerosol valve to expand and form a good quality foam. This exception may be due to one or more of a number of factors such as, the high viscosity, the softness, the lack of crystals, the pseudoplastic or semi pseudo plastic nature of the composition and the dissolution of the propellant into the petrolatum. In such circumstances apart from using a standard dip tube aerosol system in certain embodiments an inverse canister system without a dip tube may be preferred and is ideal for formulations which are flowable to a degree but are apparently or marginally non shakable.
In a further embodiment the propellant or mixtures thereof and amounts thereof are selected so that the composition is sufficiently shakable so that substantially uniform foam extrusion is possible. An aspect of this embodiment is the property of the propellant to form a single phase with petrolatum.
In a further embodiment the propellant or mixtures thereof and amounts thereof are selected so that the composition is sufficiently flowable so that substantially uniform foam extrusion is possible. An aspect of this embodiment is the property of the propellant to form a single or homogeneous phase with petrolatum.
In a further embodiment the propellant and the surfactant or surfactant system and their amounts are selected so that the composition is sufficiently shakable so that substantially uniform foam extrusion is possible.
In a further embodiment the propellant and the surfactant or surfactant system and their amounts are selected so that the composition is sufficiently flowable so that substantially uniform foam extrusion is possible.
In a further embodiment the propellant is preferably between about 5% to about 30% by weight of the composition.
In a further embodiment the propellant is preferably between about 8% to about 20% by weight of the composition.
In a further embodiment the propellant is in a sufficient amount to expel the composition from the canister upon actuation to form a foam but is not sufficient to have a cooling effect on application of the foam to the skin.
In a further embodiment the foam produced from the composition or carrier is capable of remaining substantially unchanged after at least one freeze thaw cycle.
In a further embodiment the degree of solubility of the active agent is slightly, sparingly or more soluble.
In a further embodiment the degree of solubility of the active agent is very slightly soluble.
In certain embodiments where the composition has low water content or is essentially non-aqueous, the carrier or composition does not comprise a non propellant organic co-solvent.
In a further embodiment the active ingredient may be a cosmetic agent or a placebo. In which case, the carrier composition may itself be useful for the treatment prevention or amelioration of various general skin and cosmetic complaints such as aging, atopic dermatitis, contact dermatitis and radiation or burn injury and the like.
In one or more embodiments the composition further comprises one or more additional active agents. In a preferred embodiment the active agents compliment each other or may have a synergistic effect.
In one or more embodiments comprises one or more additional therapeutically active oils.
In some embodiments, the foamable cosmetic or pharmaceutical composition is non-flammable, wherein said gas propellant contains hydrofluorocarbon.
In one or more embodiments there is provided a method of treating, alleviating or preventing a disorder of mammalian subject, comprising administering a therapeutically effective amount of the above-mentioned compositions to an afflicted target site.
In one or more embodiments there is provided a method of treating, alleviating or preventing nappy rash in a mammalian subject, comprising administering a therapeutically effective amount of the above-mentioned compositions to an afflicted target site.
In one or more embodiments there is provided use of a therapeutically effective amount of the above-mentioned compositions in the manufacture of a medicament.
In one or more embodiments there is further provided a therapeutically effective amount of the above-mentioned compositions for use in the manufacture of a medicament.
In one or more embodiments the petrolatum may alone or in combination with a stabilizing agent or vica versa may help to ameliorate, counteract, or overcome undesirable effects and drawbacks of an API, such as destabilization, precipitation or breakdown.
In one or more embodiments the stabilizing agent can also assist or improve the skin feeling. Non limiting examples are polymeric agent such as ASOS, an alkyl lactate such as C-12 to C-15 alkyl lactate, a cellulose like carboxymethyl cellulose sodium and microcrystalline cellulose or methocel and xantham gum. In a preferred embodiment the polymeric agent comprises ASOS.
Additionally, in one or more embodiments there is provided foamable petrolatum based compositions that are stable and able to provide some of the main attributes of a petrolatum composition when delivered as a topical substantially uniform and stable foam and without the use of an alcohol in the formulation.
Additionally, in one or more embodiments there is provided foamable petrolatum based compositions that are stable and able to provide some of the main attributes of a petrolatum composition when delivered as a topical substantially uniform and stable foam with barrier properties and without the use of a volatile alcohol and or a volatile silicone in the formulation. In an embodiment the barrier properties are enhanced or improved by the refatting qualities of the solvent substantially miscible in the petrolatum.
In one or more embodiments a foamable pharmaceutical composition is provided also incorporating an added hydrophobic solvent, for example, as a look and feel enhancer, solubility enhancer or deliverability enhancer.
In one or more embodiments a foamable pharmaceutical composition is provided also incorporating an added polar solvent, for example, as penetration enhancer, solubility enhancer or deliverability enhancer. Preferably the enhancer is selected to be substantially miscible in the composition. In one or more embodiments the polar solvent or the potent solvent is in a small amount.
In one or more embodiments non limiting examples of other non-aqueous solvents, which preferably are added in small amounts are solvents such as polyethylene glycol (PEG), isosorbide derivatives, such as dimethyl isosorbide, propylene glycol (PG), hexylene glycol and glycerin, diethylene glycol monoethyl ether, a liquid polyethylene glycol, glycofurol, tetrahydrofurfuryl alcohol, polyethyleneglycol, ether, DMSO, a pyrrolidone, N-methylpyrrolidones, N-Methyl-2-pyrrolidone, 1-Methyl-2-pyrrolidinone, ethyl proxitol, dimethylacetamide, a PEG-type surfactant, an alpha hydroxy acid, lactic acid and glycolic acid, hexylene glycol, benzyl alcohol, DMSO, glycofurol and ethoxydiglycol (transcutol), butylene glycols, glycerol, pentaerythritol, sorbitol, mannitol, oligosaccharides, monooleate of ethoxylated glycerides having about 8 to 10 ethylene oxide units, and cyclodextrins, esters, such as ethyl propionate, tributylcitrate, acetyl triethylcitrate, acetyl tributyl citrate, triethylcitrate, ethyl butyrate, propylene glycol monoacetate, propylene glycol diacetate, .epsilon.-caprolactone and isomers thereof, .delta.-valerolactone and isomers thereof, .beta.-butyrolactone and isomers thereof; and other solubilizers known in the art, such as dimethyl acetamide.
In an embodiment the non-aqueous solvent is monooctanoin.
In one or more embodiments a foamable pharmaceutical composition is provided wherein the ratios of surfactant, petrolatum and added polar solvent as penetration enhancer are selected or adapted to provide a selected pharmacological or safety property.
In one or more embodiments a foamable pharmaceutical composition is provided also incorporating a polymeric agent. The polymeric agent whilst it is believed to be non essential can be useful in improving foam characteristics including hardness, viscosity, and feel.
In one or more embodiments the polymeric agent is selected from a bioadhesive agent, a gelling agent, a film forming agent and a phase change agent and can be from about 0.01% to about 5% by weight.
In one or more embodiments of the pharmaceutical or cosmetic foamable product is non-flammable.
According to one or more embodiments, the foamable composition is non-alcoholic or alcohol free, i.e., free of short chain alcohols. Short chain alcohols, having up to 5 carbon atoms in their carbon chain skeleton and one hydroxyl group, such as ethanol, propanol, isopropanol, butaneol, iso-butaneol, t-butaneol and pentanol, are considered less desirable solvents or polar solvents due to their skin-irritating effect. In one or more further embodiments, the composition is substantially alcohol-free and can includes less than about 5% final concentration of lower alcohols, preferably less than about 2%, more preferably less than about 1%. Where the active ingredient is provided in an alcoholic extract then in such limited circumstances the alcoholic content may be up to about 8%.
Non-limiting benefits include:
The ratio between the stabilizing agent or polymeric agent and petrolatum is determined according to the desirable level of petrolatum and taking into account appropriate and desirable pharmacologic and safety properties of the product. Typically, the stabilizing agent to petrolatum ranges between about 1:5 and about 1:100, for example, about 1:5, about 2:15, about 1:10, about 2:25, about 1:15, about 2:35, about 1:20, about 2:45 and about 1:25, about 1:30; about 1:40 about 1:50; about 1:60; about 1:70; about 1:80; about 1:90; about 1:100 preferably between about 1:15 to about 1:60.
Low Water Content Formulations
As indicated herein the aforesaid description of the non-aqueous formulations is also generally applicable to the low water content formulations herein with where necessary appropriate changes as would be appreciated by a man of the art. The non limiting examples given in the Summary also apply here. Thus, the previous section may be read and applied to these formulations with these points in mind. Other embodiments by way of example are specifically described below.
The present invention relates to stable non-alcoholic foamable petrolatum based carriers and pharmaceutical and cosmetic emulsion compositions comprising a petrolatum or mixtures thereof, a surfactant, and a propellant and in certain cases a solvent, with and without the addition of an active agent, wherein the foam produced by the carrier or pharmaceutical composition when packaged in an aerosol container and released has a foam hardness in the range of about 5 g to about 100 g. Unexpectedly some of the compositions show hardness measurements in the upper range and yet have a relatively soft feeling.
The present invention relates to stable non-alcoholic foamable petrolatum based carriers and pharmaceutical and cosmetic emulsion compositions with very high viscosity measurements prior to addition of the propellant. In one or more embodiments the pre foam formulation can have a wide range of viscosity from about 500,000 to about 12,000 CP or less. For example, from about 500,000 to about 300,000, from about 400,000 to about 150,000; from about 375,000 to about 225,000; from about 225,000 to about 75,000; from about 125,000 to about 12,000 or less.
It was unexpectedly discovered that after dissolving the propellant into pre foam formulations with such high viscosity that there is a change in the petrolatum such that it is shakable and flowable. It is believed that in certain embodiments some compositions may be marginally or apparently non shakable and still have a degree of flowability such that a good quality foam can be expelled from the canister.
The present invention also relates to stable non-alcoholic foamable petrolatum based pharmaceutical and cosmetic compositions comprising petrolatum mixtures. It was discovered that by combining appropriate amounts of different types of petrolatum foams which are able to mimic the barrier properties of petrolatum ointments and particularly petrolatum based barrier creams for nappy rash. In one embodiment a low melting point petrolatum is mixed with a petrolatum with a higher melting point. In certain embodiments the major petrolatum is the lower molecular weight petrolatum. In other embodiments the petrolatum is mixed in a ratio for example, of about 5:1; 4:1; 3:1; 2:1; or 1:1 of lower melting point to higher melting point petrolatum. In some embodiments the ratio of mixture can be of higher melting point to lower melting point.
In an embodiment it was surprising found that it was possible to exclude stabilizers other than a surfactant and still prepare a creamy stable foam without and with an active pharmaceutical ingredient.
In one or more embodiments there is provided a foamable vehicle that is suitable for use as a base for delivery of not merely one type of active pharmaceutical ingredient (API) but is adaptable for use with one or more API's from a wide range of different types of API's with relatively minimal or minor adjustment to the vehicle. For example, for compositions with a solvent, by altering the amount of a component or by the addition of a buffer that provides a pH in an aqueous environment or a postulated pH in a non-aqueous environment in which the API is stable and or by use of a chelating agent as is described below as would be appreciated by a person skilled in the art.
In one or more embodiments there is provided a stable non-alcoholic foamable carrier composition comprising:
In one or more embodiments there is provided a stable non-alcoholic foamable carrier composition comprising:
In one or more embodiments there is provided a stable non-alcoholic foamable carrier composition comprising:
In one or more embodiments there is provided a stable non-alcoholic foamable pharmaceutical or cosmetic composition comprising:
The present invention relates to a stable non-alcoholic foamable pharmaceutical or cosmetic composition comprising:
In one or more embodiments there is provided a stable non-alcoholic foamable pharmaceutical or cosmetic composition comprising:
In a further embodiment the foam hardness is in the range of about 10 g to about 90 g or more, preferably about 30 g to about 85 g.
In a further embodiment the surfactant or surfactant system is preferably between about 1% to about 10% by weight of the composition prior to the addition of propellant.
In a further embodiment the surfactant and its amount is selected so that the composition is sufficiently shakable so that substantially uniform foam extrusion is possible. To this extent the maximum effective amount of surfactant that may be used may be limited by the need for shakability.
In a further embodiment the surfactant and its amount is selected so that the composition is sufficiently flowable so that substantially uniform foam extrusion is possible. To this extent the maximum effective amount of surfactant that may be used may be limited by the need for some flowability.
In a further embodiment the propellant is preferably between about 10% to about 30% by weight of the composition.
In a further embodiment the propellant is preferably between about 14% to about 26% by weight of the composition.
In a further embodiment the active ingredient may be partially insoluble in a phase of the emulsion. In other embodiments it may be insoluble in a phase.
In one or more embodiments a stabilizing agent may alone or in combination with petrolatum help to ameliorate, counteract, or overcome undesirable effects and drawbacks of an API, such as destabilization, on an emulsion vehicle, on a phase, on micelles or on an interphase. In one or more embodiments the stabilizing agent comprises a polymeric agent such as ASOS, an alkyl lactate such as C-12 to C-15 alkyl lactate, carboxymethyl cellulose sodium and microcrystalline cellulose or methocel and xantham gum. For example, in preparing stable non-alcoholic petrolatum foamable pharmaceutical water in oil emulsion compositions suitable for delivery of an active pharmaceutical ingredient a combination of surfactants, a metal starch, and an alkyl lactate can be used to achieve a stable foam.
When water is present the foamable composition can be an emulsion, or microemulsion, or nanoemulsion.
In an embodiment these low water content formulations and foams are also non-silicone and or non-alcoholic or substantially so.
General
Solvent and optional ingredients are added to complete the total mass of the foamable carrier to 100%.
All % values are provided on a weight (w/w) basis. In the examples the components of the composition are added to a total of 100% exclusive of the propellant.
Aging
Formulation of foam is a very delicate balance between the functional inactive ingredients, excipients, which contribute to bubble size, viscosity, hardness look and feel and stability. In order to assure accurate and continuous foam actuation, the Foam Formulation should during its intended life or use period be liquid and shakable in the canister, otherwise it will not flow easily and completely towards and through the valve. In the context of high levels of petrolatum foamable formulations it is possible as an exception for the composition to be marginally or apparently non shakable whilst the composition has a sufficient degree of flowability under pressure of the propellant that it is possible to obtain a good quality of foam.
Stability of compositions of petroleum and solvents substantiality miscible therein together with surfactants and other additives is desired. Testing for aging as reflected by creaming or phase separation whilst normally considered in the realm of emulsions may also be used to explore waterless compositions. The concept of creaming in waterless single phase compositions may be artificial and not accurately applicable and requires investigation. Resistance to creaming or phase separation can be determined by taking a sample and subjecting it to a significant G force through centrifugation to simulate accelerated aging. Waterless compositions in which petrolatum is the main component may have some inherent resistant to “creaming” or phase separation because of the physical properties of petrolatum. In the context of foamable compositions improved physical stability may be obtained by an appropriate choice of product viscosity through use of different blends of petrolatum together with one or more solvents substantially miscible in petrolatum plus a surfactant or surfactant system optionally in combination with stabilizing agents and or viscoelastic agents, which can provide suitable rheology whilst retaining the requirements of shakability or at least flowability. In the context the solvents and the surfactants used can have a considerable influence on rheology, shakability and flowability.
Where there is an emulsion, for example, when water and surfactants are formulated with petrolatum stability of emulsions and resilience to creaming is desired. Emulsions in which petrolatum is the main single component or is the main component may be inherently resistant to creaming because of the physical properties of petrolatum. In the context of foamable emulsion compositions it has been discovered that improved physical stability is obtained by an appropriate choice of product viscosity through use of different blends of petrolatum plus a surfactant or surfactant system optionally in combination with stabilizing agents and or viscoelastic agents, which can provide suitable rheology whilst retaining the requirements of shakability or at least flowability and by controlling droplet size.
By creaming it is meant that an upper layer forms. The creaming value is defined as the relative volume of the creamed phase and the total volume the sample. The expression used for calculation of the creaming volume is as follows:
Creaming values are between 1% and 99%, accordingly. 100% means “no creaming” which is the desirable best score. 0% (Zero value) indicates phase separation and is the worst score.
By physically durable it is intended that the formulation is capable of physically withstanding to a substantial degree at least one of centrifugation at about 1000 rpm for non-aqueous formulations and at about 3000 rpm for emulsions for about 10 minutes in each case; or one, or possibly more freeze thaw cycles; or a period of time at an elevated temperature of say 30° C. or say 40° C. for say about one month; or a prolonged period of time at room temperature for say about three months. In preferred embodiments the formulations can withstand 3 months at 30 C or 40 C and or 6 months at room temperature.
In an embodiment the composition should exhibit pseudoplastic rheological behavior.
By selective use of appropriate stabilizing surfactant, co-surfactants and optionally stabilizing polymers and foam adjuvants the compositions can be stabilized.
By appropriate selection of agents, surfactants and solvent in a petrolatum base composition to facilitate biocompatibility and to achieve the appropriate balance of physical properties, it is possible to prepare formulations that are resilient to aging when subjected to centrifugation which could be extrapolated to reflect a reasonable stable shelf life.
Petrolatum
Petrolatum is known by various names including yellow soft paraffin, yellow petrolatum, mineral jelly; and petroleum jelly. Petrolatum is a purified mixture of semisolid saturated hydrocarbons having the general formula CnH2n+2, and is obtained from petroleum. The hydrocarbons consist mainly of branched and unbranched chains although some cyclic alkanes and aromatic molecules with paraffin side chains may also be present. Some forms may contain a suitable stabilizer (antioxidant). It is mainly used as an emollient and ointment base in topical pharmaceutical formulations creams and transdermal applications. Therapeutically, sterile gauze dressings containing petrolatum may be used for nonadherent wound dressings. Petrolatum is additionally widely used in cosmetics and in some food applications. It is odorless, and tasteless.
The rheological properties of petrolatum are determined by the ratio of the unbranched chains to the branched chains and cyclic components of the mixture. Petrolatum contains relatively high amounts of branched and cyclic hydrocarbons, in contrast to paraffin, which accounts for its softer character and makes it an ideal ointment base. In one or more embodiments, a petrolatum or a petrolatum mixture is selected such that it has a quality of relative softness.
Petrolatum is an inherently stable material. On exposure to light any impurities present may be Oxidation may be inhibited by the inclusion of a suitable antioxidant such as butylated hydroxyanisole, butylated hydroxytoluene, or alpha tocopherol.
In preparing Petrolatum compositions they should not be heated for extended periods above the temperature necessary to achieve complete fluidity (approximately 75° C.).
Various grades of petrolatum are commercially available, which vary in their physical properties depending upon their source and refining process. Petrolatum obtained from different sources may therefore behave differently in a formulation. White petrolatum is a preferred petrolatum for use in cosmetics and pharmaceuticals, Additives, such as microcrystalline wax, may be used to add body to petrolatum.
The petrolatum used in the present invention was examined microscopically and no wax crystallization was observed. Thus, in one or more embodiments the petrolatum selected shows no tendency to wax crystallization. In one or more further embodiments the petrolatum based foamable carriers and compositions are free or substantially free of wax crystallization. In one or more further embodiments the petrolatum based foamable carriers and compositions are free or substantially free of wax crystallization when the petrolatum level is about 50% to about 95% by weight in the composition before the addition of propellant.
MMP Inc state in their sales booklet on Sofmetic™ LMP (Rev 02/05 KVB) that they conducted studies with varying grades of petroleum USP to avoid formation of wax crystals in emulsions containing 20% petrolatum and that MMP's supersoft grade incorporated into low emulsifier content formulations containing 20% petroleum has been shown to eliminate undesirable crystallization of wax. They further state that when compared to similar compositions made with a higher melting point grade of petrolatum the Sofmetic™ LMP exhibited no tendency to wax crystallization.
In certain embodiments, in the context, the term petrolatum relates to any fatty substance, having rheological properties and meting temperature patterns in the same range as described above for petrolatum.
Unctuous Additives
A “unctuous additive” as used herein refers to a greasy, fatty, waxy or oily material, including liquids, semi solids and solids which can be mixed with petrolatum to alter refine or improve the petrolatum based compositions. In one or more embodiments a small, moderate medium or lager amount of one or more unctuous additive may be blended with petrolatum provided the petrolatum remains the single largest component of the composition. In one or more other embodiments the unctuous additive can be the major component of the blend with petrolatum. Even if not the main component the properties of petrolatum at the levels of about at least 25% in the present invention it may still have a major or dominating influence on the composition. In any event unctuous additives may also have a role in effecting the solubility of an API. Unexpectedly it has been noted that in certain cases where an oil is combined with petrolatum the resultant foam has a significantly lower density.
Non limiting examples of unctuous additives that may be used in the pharmaceutical composition may be natural or synthetic or a synthetic derivative and, include higher aliphatic hydrocarbons, animal or vegetable fats, greases and oils, waxes, and combinations thereof.
In one or more embodiments, specific non limiting examples are higher aliphatic hydrocarbons, mineral jelly and fractions thereof, paraffin, squalane, ceresin, mineral oil and the like.
In one or more embodiments, specific non limiting examples of the waxes include beeswax, carnauba wax, microcrystalline wax, candililla wax, berry wax, montan wax, polyethylene wax and ethylene vinyl acetate (EVA) copolymers spermaceti, lanolin, wool wax, wool fat, wax blend, solid paraffin, oxidized wax, waxy solids or waxy semi-solids, synthetic wax's and the like.
In one or more embodiments, non limiting specific examples of the animal or vegetable fats and oils include, triglycerides, olive oil, almond oil, avocado oil, borage oil, castor oil, cocoa butter, palm oil, turtle oil, cod-liver oil, whale oil, beef tallow, butter fat, shea butter, shorea butter, and the like.
In one or more embodiments, the above-described unctuous additive may be used alone or in combination with petrolatum.
The use of high melting point hydrocarbons, such as petrolatum can be occlusive when applied to the skin. In one or more embodiments, when an extensive refatting or moisturizing effect is required, then petrolatum in concentrations of more than 25% preferably more than 50% to about 95% prior to the addition of propellant is included in the compositions.
In order to derive, develop or optimize a composition, which is readily foamable upon release from a pressurized container, additional components may also be introduced, as provided herein below.
Hydrophobic Solvents
Further in one or more embodiments petrolatum and petrolatum mixtures may also be combined with one or more hydrophobic solvents or carriers, which are materials suitable for use to blend with or act as a carrier for the petrolatum emollients. They may also have a further role in effecting the solubility of an API.
In one or more other embodiments the hydrophobic solvents or carriers are ester oils. Specific non limiting examples of the ester oils include isopropyl myristate, isopropyl palmitate, butyl stearate, hexyl laurate, octyldodecyl myristate, di-isopropyl adipate, isocetyl myristate, di-isopropyl sebacate, and the like.
In one or more other embodiments the hydrophobic solvents or carriers are higher alcohols. Specific non limiting examples of the higher alcohols include cetyl alcohol, oleyl alcohol, isostearyl alcohol, octyldodecanol and the like.
According to one or more embodiments, hydrophobic solvents or carriers are liquid oils originating from vegetable, marine or animal sources. Suitable liquid oil includes saturated, unsaturated or polyunsaturated oils. By way of example, the unsaturated oil may be olive oil, corn oil, soybean oil, canola oil, cottonseed oil, coconut oil, sesame oil, sunflower oil, borage seed oil, syzigium aromaticum oil, hempseed oil, herring oil, cod-liver oil, salmon oil, flaxseed oil, wheat germ oil, evening primrose oils or mixtures thereof, in any proportion.
Suitable hydrophobic solvents or carriers also include polyunsaturated oils containing poly-unsaturated fatty acids. In one or more embodiments, the unsaturated fatty acids are selected from the group of omega-3 and omega-6 fatty acids. Examples of such polyunsaturated fatty acids are linoleic and linolenic acid, gamma-linoleic acid (GLA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Such unsaturated fatty acids are known for their skin-conditioning effect, which can contribute to the therapeutic benefit of the present foamable composition. Thus, the hydrophobic solvent can include at least 3% preferably at least 6% of an oil selected from omega-3 oil, omega-6 oil, and mixtures thereof.
In the context, oils that possess therapeutically beneficial properties are termed as “therapeutically active oil.”
Another class of hydrophobic solvents or carriers is the essential oils, which are also considered therapeutically active oils, and which contain active biologically occurring molecules and, upon topical application, exert a therapeutic effect. Non-limiting examples of essential oils include rosehip oil, which contain retinoids and is known to reduce acne and post-acne scars, and tea tree oil, which possess antibacterial, antifungal and antiviral properties. Other examples of essential oils are oils of anise, basil, bergemont, camphor, cardamom, carrot, canola, cassia, catnip, cedarwood, citronella, clove, cypress, eucalyptus, frankincense, garlic, ginger, grapefruit, hyssop, jasmine, jojova, lavender, lavandin, lemon, lime, mandarin, marjoram, myrrh, neroli, nutmeg, orange, peppermint, petitgrain, rosemary, sage, spearmint, star anise, tangerine, thyme vanilla, verbena and white clover.
Another class of therapeutically active oils is liquid hydrophobic plant-derived oils, which are known to possess therapeutic benefits when applied topically.
Silicone oils also may be used and are desirable due to their known skin protective and occlusive and antifriction properties. Moreover they may mask to some extent the tacky greasy feeling of petrolatum on the skin. Suitable silicone oils include non-volatile silicones, such as polyalkyl siloxanes, polyaryl siloxanes, polyalkylaryl siloxanes and polyether siloxane copolymers, polydimethylsiloxanes (dimethicones) and poly(dimethylsiloxane)-(diphenyl-siloxane) copolymers. Silicone oils are also considered therapeutically active oil, due to their barrier retaining and protective properties. However, silicone oils are not essential. They are foam defoamers and therefore if included are ideally used in relatively small amounts, such as less than about 5% if there is more than 50% petrolatum, and in other cases where the petrolatum is under about 50% then the silicones should be less than about 1%. To counteract to some extent the defoaming properties extra surfactant and or foam adjuvant may be usefully added. If volatile silicones are used they evaporate from the skin and effect the deposited composition and can interfere with its occlusive properties and may cause dryness. In a preferred embodiment there is no silicone or less than 1%. When the level of petrolatum is at least about 50% or more then higher levels of silicone may be used.
A further class of hydrophobic solvents or carriers includes hydrophobic liquids, selected from the family of organic liquids described as “emollients.” Emollients possess a softening or soothing effect, especially when applied to body areas, such as the skin and mucosal surfaces. Examples of suitable emollients include isopropyl myristate, isopropyl palmitate, isopropyl isostearate, diisopropyl adipate, diisopropyl dimerate, maleated soybean oil, octyl palmitate, cetyl lactate, cetyl ricinoleate, tocopheryl acetate, cetyl acetate, tocopheryl linoleate, wheat germ glycerides, arachidyl propionate, myristyl lactate, decyl oleate, propylene glycol ricinoleate, isopropyl lanolate, pentaerythrityl tetrastearate, neopentylglycol dicaprylate/dicaprate, isononyl isononanoate, isotridecyl isononanoate, myristyl myristate, octyl dodecanol, sucrose esters of fatty acids and octyl hydroxystearate.
In one or more embodiments the petrolatum based foamable carrier and composition comprises a hydrophobic solvent selected from the group consisting of:
In one or more embodiments the petrolatum based foamable carrier and composition comprises a hydrophobic solvent in a moderate or larger amount.
Polypropylene Glycol (PPG) Alkyl Ethers
In the context, a polypropylene glycol alkyl ether (PPG alkyl ether) is a liquid, water-insoluble propoxylated fatty alcohol, having the molecular formula of RO(CH2CHOCH3)n; wherein “R” is a straight-chained or branched C4 to C22 alkyl group; and “n” is in the range between 4 and about 50.
(PPG alkyl ethers), are organic liquids that function as skin-conditioning agent in pharmaceutical and cosmetic formulations. They possess exceptional emollient effect, side by side with enhanced solvency properties, which facilitates solubilization of active agents in a composition comprising a PPG alkyl ether. PPG alkyl ethers offer the following advantages when used as a component in the foamable composition:
Exemplary PPG alkyl ethers include PPG-2 butyl ether, PPG-4 butyl ether, PPG-5 butyl ether, PPG-9 butyl ether, PPG-12 butyl ether, PPG-14 butyl ether, PPG-15 butyl ether, PPG-16 butyl ether, PPG-17 butyl ether, PPG-18 butyl ether, PPG-20 butyl ether, PPG-22 butyl ether, PPG-24 butyl ether, PPG-26 butyl ether, PPG-30 butyl ether, PPG-33 butyl ether, PPG-40 butyl ether, PPG-52 butyl ether, PPG-53 butyl ether, PPG-10 cetyl ether, PPG-28 cetyl ether, PPG-30 cetyl ether, PPG-50 cetyl ether, PPG-30 isocetyl ether, PPG-4 lauryl ether, PPG-7 lauryl ether, PPG-2 methyl ether, PPG-3 methyl ether, PPG-3 myristyl ether, PPG-4 myristyl ether, PPG-10 oleyl ether, PPG-20 oleyl ether, PPG-23 oleyl ether, PPG-30 oleyl ether, PPG-37 oleyl ether, PPG-50 oleyl ether, PPG-11 stearyl ether. Preferred PPG alky ethers according to the present invention include PPG-15 stearyl ether (also known as Earlamol E®, Unichema), PPG-2 butyl ether, PPG-9-13 butyl ether and PPG-40 butyl ether. PPG alkyl ethers can be incorporated in the foamable composition in a concentration preferably between about 1% and about 20%, more preferably between about 3% and about 15%.
The sensory properties of foams containing PPG alkyl ethers are favorable, as revealed by consumer panel tests.
Surprisingly, it has been discovered that PPG alkyl ethers also reduce the degree of inflammability of a foam, as demonstrated in a standard inflammability test according to European Standard prEN 14851, titled “Aerosol containers. According to this standard, a product is considered inflammable if a stable flame appears following ignition, which is at least 4 cm high and which is maintained for at least 2 seconds. In an embodiment, the concentration of the PPG alkyl ether is sufficient to reduce the degree of inflammability, of a composition when compared with the same composition without the PPG alkyl ether.
Surface Active Agent
The composition further contains a surface-active agent. Surface-active agents (also termed “surfactants”) include any agent linking oil and water in the composition, in the form of emulsion. A surfactant's hydrophilic/lipophilic balance (HLB) describes the emulsifier's affinity toward water or oil. HLB is defined for non-ionic surfactants. The HLB scale ranges from 1 (totally lipophilic) to 20 (totally hydrophilic), with 10 representing an equal balance of both characteristics. Lipophilic emulsifiers form water-in-oil (w/o) emulsions; hydrophilic surfactants form oil-in-water (o/w) emulsions. The HLB of a blend of two emulsifiers equals the weight fraction of emulsifier A times its HLB value plus the weight fraction of emulsifier B times its HLB value (weighted average). In many cases a single surfactant may suffice. In other cases a combination of two or more surfactants is desired. Reference to a surfactant in the specification can also apply to a combination of surfactants or a surfactant system. As will be appreciated by a person skilled in the art which surfactant or surfactant system is more appropriate is related to the vehicle and intended purpose. In general terms a combination of surfactants is usually preferable where the vehicle is an emulsion. In an emulsion environment a combination of surfactants can be significant in producing breakable forms of good quality. In a waterless or substantially waterless environment it has been discovered that the presence of a surfactant or combination of surfactants can also be significant in producing breakable forms of good quality. It has been further discovered that the generally thought considerations for HLB values for selecting a surfactant or surfactant combination are not always binding for emulsions and that good quality foams can be produced with a surfactant or surfactant combination both where the HLB values are in or towards the lipophilic side of the scale and where the HLB values are in or towards the hydrophilic side of the scale.
It has been further discovered that the physical nature of the surfactant or combination thereof can affect the quality of foam produced. For example and in very general oversimplified terms the presence of a solid or waxy surfactant may help where the composition is more liquid or less viscous in nature and similarly where a formulation is less liquid and more viscous the presence of a liquid surfactant may help. More particularly a combination of a solid or waxy surfactant with a liquid surfactant may be of significance and the ratio between them may be adjusted to take into account to an extent whether the composition is otherwise more liquid or otherwise more viscous in nature. The position is more complex than this since the presence and interaction of other agents such as foam adjuvants, polymeric agents as well as unctuous additives and hydrophobic agents all have an influence on achieving a breakable foam of quality
According to one or more embodiments the composition contains a single surface active agent having an HLB value between about 2 and 9, or more than one surface active agent and the weighted average of their HLB values is between about 2 and about 9. Lower HLB values may in certain embodiments be more applicable.
According to one or more embodiments the composition contains a single surface active agent having an HLB value between about 7 and 14, or more than one surface active agent and the weighted average of their HLB values is between about 7 and about 14. Mid range HLB values may in certain embodiments be more suitable.
According to one or more other embodiments the composition contains a single surface active agent having an HLB value between about 9 and about 19, or more than one surface active agent and the weighted average of their HLB values is between about 9 and about 19. In a waterless or substantially waterless environment a wide range of HLB values may be suitable.
According to one or more embodiments a wide range of HLB values giving about an average mid range can be achieved with combinations of two, three or more surfactants. For example, the following provides an average of 9.36:
Preferably, the composition contains a non-ionic surfactant. Nonlimiting examples of possible non-ionic surfactants include a polysorbate, polyoxyethylene (20) sorbitan monostearate, sorbitan monostearate, polyoxyethylene (20) sorbitan monooleate, sorbitan laurate; a polyoxyethylene fatty acid ester, Myrj 45, Myrj 49, Myrj 52 and Myrj 59; a polyoxyethylene alkyl ether, polyoxyethylene cetyl ether, polyoxyethylene palmityl ether, polyethylene oxide hexadecyl ether, polyethylene glycol cetyl ether, steareths such as steareth 2, brij 21, brij 721, brij 38, brij 52, brij 56 and brij W1, behenyl alcohol; a sucrose ester, a partial ester of sorbitol and its anhydrides, sorbitan monolaurate, sorbitan monolaurate, a monoglyceride, a diglyceride, isoceteth-20 and mono-, di- and tri-esters of sucrose with fatty acids. In certain embodiments, suitable sucrose esters include those having high monoester content, which have higher HLB values.
In certain embodiments, surfactants are selected which can provide a close packed surfactant layer. To achieve such objectives combinations of at least two surfactants are selected. Preferably, they should be complex emulgators and more preferably they should both be of a similar molecular type; for example, a pair of ethers, like steareth 2 and steareth 21, or a pair of esters, for example, PEG-40 stearate and polysorbate 80. Ideally, the surfactants can be ethers. In certain circumstances POE esters cannot be used and a combination of sorbitan laurate and sorbitan stearate or a combination of sucrose stearic acid ester mixtures and sodium laurate may be used. All these combinations due to their versatility and strength may also be used satisfactorily and effectively with ether formulations, although the amounts and proportion may be varied according to the formulation and its objectives as will be appreciated by a man of the art.
It has been discovered also that by using a derivatized hydrophilic polymer with hydrophobic alkyl moieties as a polymeric emulsifier such as pemulen it is possible to stabilize the emulsion better about or at the region of phase reversal tension. Other types of derivatized polymers like silicone copolymers, derivatized starch [Aluminum Starch Octenylsuccinate (ASOS)]/[DRY-FLO AF Starch], and derivatized dexrin may also a similar stabilizing effect.
A series of dextrin derivative surfactants prepared by the reaction of the propylene glycol polyglucosides with a hydrophobic oxirane-containing material of the glycidyl ether are highly biodegradable. [Hong-Rong Wang and Keng-Ming Chen, Colloids and Surfaces A: Physicochemical and Engineering Aspects Volume 281, Issues 1-3, 15 Jun. 2006, Pages 190-193].
Non-limiting examples of non-ionic surfactants that have HLB of about 7 to about 12 include steareth 2 (HLB˜4.9); glyceryl monostearate/PEG 100 stearate (Av HLB˜11.2); stearate Laureth 4 (HLB˜9.7) and cetomacrogol ether (e.g., polyethylene glycol 1000 monocetyl ether). More exemplary stabilizing surfactants which may be suitable for use in the present invention are found below.
PEG-Fatty Acid Monoester Surfactants
PEG-Fatty Acid Diester Surfactants:
Transesterification Products of Oils and Alcohols
Polyglycerized Fatty Acids, Such as:
PEG-Sorbitan Fatty Acid Esters
Polyethylene Glycol Alkyl Ethers
Sugar Ester Surfactants
Sorbitan Fatty Acid Ester Surfactants
In one or more embodiments the surface active agent is a complex emulgator in which the combination of two or more surface active agents can be more effective than a single surfactant and provides a more stable emulsion or improved foam quality than a single surfactant. For example and by way of non-limiting explanation it has been found that by choosing say two surfactants, one hydrophobic and the other hydrophilic the combination can produce a more stable emulsion than a single surfactant. Preferably, the complex emulgator comprises a combination of surfactants wherein there is a difference of about 4 or more units between the HLB values of the two surfactants or there is a significant difference in the chemical nature or structure of the two or more surfactants.
Specific non limiting examples of surfactant systems are, combinations of polyoxyethylene alkyl ethers, such as Brij 59/Brij 10; Brij 52/Brij 10; Steareth 2/Steareth 20; Steareth 2/Steareth 21 (Brij 72/Brij 721); combinations of polyoxyethylene stearates such as Myrj 52/Myrj 59; combinations of sucrose esters, such as Surphope 1816/Surphope 1807; combinations of sorbitan esters, such as Span 20/Span 80; Span 20/Span 60; combinations of sucrose esters and sorbitan esters, such as Surphope 1811 and Span 60; combinations of liquid polysorbate detergents and PEG compounds, such as Tween 80/PEG-40 stearate; methyl glucaso sequistearate; polymeric emulsifiers, such as Permulen (TRI or TR2); liquid crystal systems, such as Arlatone (2121), Stepan (Mild RM1), Nikomulese (41) and Montanov (68) and the like.
In certain embodiments the surfactant is preferably a combination of steareth-2 and steareth-21; in certain other embodiments the surfactant is a combination of polysorbate 80 and PEG-40 stearate. In certain other embodiments the surfactant is a combination of glyceryl monostearate/PEG 100 stearate.
In one or more embodiments the stability of the composition can be improved when a combination of at least one non-ionic surfactant having HLB of less than 9 and at least one non-ionic surfactant having HLB of equal or more than 9 is employed. The ratio between the at least one non-ionic surfactant having HLB of less than 9 and the at least one non-ionic surfactant having HLB of equal or more than 9, is between 1:8 and 8:1, or at a ratio of 4:1 to 1:4. The resultant HLB of such a blend of at least two emulsifiers is preferably between about 9 and about 14.
Thus, in an exemplary embodiment, a combination of at least one non-ionic surfactant having HLB of less than 9 and at least one non-ionic surfactant having HLB of equal or more than 9 is employed, at a ratio of between 1:8 and 8:1, or at a ratio of 4:1 to 1:4, wherein the HLB of the combination of emulsifiers is preferably between about 5 and about 18.
In certain cases, the surface active agent is selected from the group of cationic, zwitterionic, amphoteric and ampholytic surfactants, such as sodium methyl cocoyl taurate, sodium methyl oleoyl taurate, sodium lauryl sulfate, triethanolamine lauryl sulfate and betaines.
Many amphiphilic molecules can show lyotropic liquid-crystalline phase sequences depending on the volume balances between the hydrophilic part and hydrophobic part. These structures are formed through the micro-phase segregation of two incompatible components on a nanometer scale. Soap is an everyday example of a lyotropic liquid crystal. Certain types of surfactants tend to form lyotropic liquid crystals in emulsions interface (oil-in-water) and exert a stabilizing effect. Non limiting examples of surfactants with postulated tendency to form interfacial liquid crystals are: phospholipids, alkyl glucosides, sucrose esters, sorbitan esters. In certain embodiments surfactants which tend to form liquid crystals may improve the quality of foams produced.
In one or more embodiments the surfactant is a surfactant or surfactant combination is capable of or which tends to form liquid crystals.
In one or more embodiments the at least one surface active agent is liquid.
In one or more embodiments the at least one surface active agent is solid, semi solid or waxy.
It should be noted that HLB values may not be so applicable to non ionic surfactants, for example, with liquid crystals or with silicones.
In one or more embodiments the surfactant can be, a surfactant system comprising of a surfactant and a co surfactant, a waxy emulsifier, a liquid crystal emulsifier, an emulsifier which is solid or semi solid at room temperature and pressure, or combinations of two or more agents in an appropriate proportion as will be appreciated a person skilled in the art. Where a solid or semi solid emulsifier combination is used it can also comprise a solid or semi solid emulsifier and a liquid emulsifier.
In one or more embodiments, the surface-active agent includes at least one non-ionic surfactant. Ionic surfactants are known to be irritants. Therefore, non-ionic surfactants are preferred in applications including sensitive tissue such as found in most mucosal tissues, especially when they are infected or inflamed. Non-ionic surfactants alone can provide formulations and foams of good or excellent quality in the carriers and compositions described herein.
Thus, in a preferred embodiment, the surface active agent, the composition contains a non-ionic surfactant. In another preferred embodiment the composition includes a mixture of non-ionic surfactants as the sole surface active agent. Yet, in additional embodiments, the foamable composition includes a mixture of at least one non-ionic surfactant and at least one ionic surfactant in a ratio in the range of about 100:1 to 6:1. In one or more embodiments, the non-ionic to ionic surfactant ratio is greater than about 6:1, or greater than about 8:1; or greater than about 14:1, or greater than about 16:1, or greater than about 20:1. In further embodiments, surface active agent comprises a combination of a non-ionic surfactant and an ionic surfactant, at a ratio of between 1:1 and 20:1.
In one or more embodiments, a combination of a non-ionic surfactant and an ionic surfactant (such as sodium lauryl sulphate and cocamidopropylbetaine) is employed, at a ratio of between 1:1 and 20:1, or at a ratio of 4:1 to 10:1; for example, about 1:1, about 4:1, about 8:1, about 12:1, about 16:1 and about 20:1 or at a ratio of 4:1 to 10:1, for example, about 4:1, about 6:1, about 8:1 and about 10:1.
In selecting a suitable surfactant or combination thereof it should be borne in mind that the upper amount of surfactant that may be used may be limited by the shakability of the composition. In general terms, as the amount of non liquid surfactant is increased the shakability of the formulation reduces until a limitation point is reached where the formulation becomes non shakable and unsuitable. Thus in an embodiment any effective amount of surfactant may be used provided the formulation remains shakable. In other certain exceptional embodiments the upper limit may be determined by flowability such as in circumstances where the composition is marginally or apparently non shakable. Thus in an embodiment any effective amount of surfactant may be used provided the formulation remains flowable.
In certain embodiments the amount of surfactant or combination of surfactants is between about 0.05% to about 20%; between about 0.05% to about 15%. or between about 0.05% to about 10%. In a preferred embodiment the concentration of surface active agent is between about 0.2% and about 8%. In a more preferred embodiment the concentration of surface active agent is between about 1% and about 6%.
If the composition as formulated is a substantially non shakable composition it is nevertheless possible as an exception in the scope for the formulation to be flowable to a sufficient degree to be able to flow through an actuator valve and be released and still expand to form a good quality foam. This surprising and unusual exception may be due one or more of a number of factors such as the high viscosity, the softness, the lack of crystals, the pseudoplastic or semi pseudo plastic nature of the composition and the dissolution of the propellant into the petrolatum.
In one or more embodiments, the surface-active agent includes mono-, di- and tri-esters of sucrose with fatty acids (sucrose esters), prepared from sucrose and esters of fatty acids or by extraction from sucro-glycerides. Suitable sucrose esters include those having high monoester content, which have higher HLB values.
Single Phase Compositions and Solvents; Emulsions ((a) w/o; o/w (b) Non-Aqueous)
In one or more embodiments the carrier or composition is non-aqueous or essentially so and comprises a single phase.
In one or more embodiments the carrier or composition comprises a solvent substantially miscible in petrolatum.
In one or more non-aqueous embodiments the carrier or composition comprises a hydrophobic solvent in petrolatum wherein preferably the solvent is an unctuous additive or an oil.
In one or more embodiments the solvent is a PPG alkyl ether, preferably PPG15 stearyl ether.
In one or more embodiments the solvent is a combination of an unctuous additive and or an oil and or a PPG alkyl ether. In a preferred embodiment the combination is of an oil and a PPG alkyl ether. Preferably the oil comprises a light mineral oil and the ether comprises PPG15 stearyl ether.
In one or more embodiments of the present invention the carrier or composition comprises a single phase.
In one or more embodiments of the present invention the carrier or composition comprises an emulsion.
In one or more embodiments of the present invention the carrier or composition comprises a solvent in petrolatum emulsion.
In one or more embodiments of the present invention the carrier or composition comprises a solvent in petrolatum emulsion wherein the solvent is selected from water or a non-aqueous solvent
In one or more embodiments of the present invention the carrier or composition comprises water in petrolatum emulsion.
In one or more embodiments of the present invention the carrier or composition comprises a unique solvent in petrolatum emulsion wherein the solvent is a non-aqueous solvent.
In one or more embodiments of the present invention the carrier or composition comprises a unique hydrophillic solvent in petrolatum emulsion.
In one or more embodiments of the present invention non limiting examples of the non-aqueous solvent are solvents such as polyethylene glycol (PEG), isosorbide derivatives, such as dimethyl isosorbide, propylene glycol (PG), hexylene glycol and glycerin, diethylene glycol monoethyl ether, a liquid polyethylene glycol, glycofurol, tetrahydrofurfuryl alcohol, polyethyleneglycol, ether, DMSO, a pyrrolidone, N-methyl pyrrolidones, N-Methyl-2-pyrrolidone, 1-Methyl-2-pyrrolidinone, ethyl proxitol, dimethylacetamide, a PEG-type surfactant, an alpha hydroxy acid, lactic acid and glycolic acid, hexylene glycol, benzyl alcohol, DMSO, glycofurol and ethoxydiglycol (transcutol), butylene glycols, glycerol, pentaerythritol, sorbitol, mannitol, oligosaccharides, monooleate of ethoxylated glycerides having about 8 to 10 ethylene oxide units, and cyclodextrins, esters, such as ethyl propionate, tributylcitrate, acetyl triethylcitrate, acetyl tributyl citrate, triethylcitrate, ethyl butyrate, propylene glycol monoacetate, propylene glycol diacetate, .epsilon.-caprolactone and isomers thereof, .delta.-valerolactone and isomers thereof, .beta.-butyrolactone and isomers thereof; and other solubilizers known in the art, such as dimethyl acetamide.
In an embodiment of the present invention the non-aqueous solvent is monooctanoin.
In one or more embodiments of the present invention the carrier or composition comprises a unique hydrophillic solvent in petrolatum emulsion, wherein the hydrophilic solvent is selected from a liquid polyethylene glycol, a propylene glycol or dimethyl isosorbide.
Stabilizing Agent
A stabilizing agent is an agent that may have to some extent one or more of the properties of foam adjuvant, friction ameliorator, gelling agent, look and feel ameliorator, lubricant, stabilizer, anti-destabilizer, surfactant, thickener and viscosity modifier or enhancer.
In one embodiment the stabilizing agent may help to ameliorate, counteract, or overcome undesirable effects and drawbacks of using an petrolatum emollient.
In one or more embodiments, the stabilizing agent can be, a polymer or a polymeric agent; more specifically it can be an alkyl lactate for example a C12-15 alkyl lactate, a metal starch for example ASOS or similar polymeric derivatives; a hydrophobic starch; a microcrystalline cellulose; a cellulose ether and or long chain polysaccharide; a (alpha-tocopheryl polyethylene glycol succinate); polyoxyethylene alkyl ethers and crosslinked polyacrylic acid polymers and the like.
Modulating Agent
The term modulating agent is used to describe an agent which can improve the stability of or stabilize a foamable carrier or composition and or an active agent by modulating the effect of a substance or residue present in the carrier or composition.
In one or more embodiments the modulating agent is used in a water in oil (petrolatum) emulsion. In one or more other embodiments the modulating agent is used in a unique waterless emulsion.
In certain embodiments the substance or residue may for example be acidic or basic and potentially alter pH in an emulsion environment or it may be one or more metal ions which may act as a potential catalyst in an emulsion environment.
In certain other embodiments the substance or residue may for example be acidic or basic and potentially alter an artificial pH in a waterless or low water content environment or it may be one or more metal ions which may act as a potential catalyst in a waterless or low water content environment.
In one or more embodiments the modulating agent is used to describe an agent which can affect pH in an aqueous solution. The agent can be any of the known buffering systems used in pharmaceutical or cosmetic formulations as would be appreciated by a man of the art. It can also be an organic acid, a carboxylic acid, a fatty acid an amino acid, an aromatic acid, an alpha or beta hydroxyl acid an organic base or a nitrogen containing compound. In certain cases the API, can also affect pH.
In one or more further embodiments the modulating agent is used to describe an agent, which is a chelating or sequestering or complexing agent that is sufficiently soluble or functional in the solvent to enable it to “mop up” or “lock” metal ions.
In an embodiment modulating agent is used to describe an agent which can effect pH in an aqueous solution the term modulating agent more particularly means an acid or base or buffer system or combinations thereof, which is introduced into or is present in and acts to modulate the ionic or polar characteristics and any acidity or basesity balance of (i) a waterless or low water content or (ii) an emulsion carrier, composition, foamable carrier or foamable composition or resultant foam described herein.
The substance or residue can be introduced into the formulation from any one or more of the ingredients, some of which themselves may have acidic or basic properties. For example the polymer or solvent may contain basic residues in which case it may be desirable or beneficial to add an acid. Alternatively the surfactant may contain some acid residues in which case the addition of a base may be desirable and beneficial. In some cases more than one ingredient may contain residues which may ameliorate or compound their significance. For example, if one ingredient provided weak acid residues and another ingredient provided stronger acid residues, the pH in an emulsion environment should be lower. In contrast, if one residue was acidic and the other basic the net effect in the formulation maybe significantly reduced. In some circumstances the active ingredient may favor an acidic pH or more significantly may need to be maintained at a certain acidic pH otherwise it may readily isomerize, chemically react or breakdown, in which case introducing acidic components such as an acidic polymer might be of help. In an embodiment of the present invention sufficient modulating agent is added to achieve a pH in which the active agent is preferably stable. In another embodiment of the present invention sufficient modulating agent is added to achieve an artificial pH in which the active agent is preferably stable.
The terms pH, pKa, and pKb, buffers and the like are used in classical measurements of an aqueous solution. Such measurements are artificial in a waterless environment. Nevertheless, reference to and description below of such terms are made for convenience and clarity, since such terms are well defined and understood with reference to aqueous solutions and further due to the lack of an appropriate uniform way of describing and identifying the artificial or virtual pH, pK etc in a waterless environment in relation to the present invention. Although predictions of artificial pH can be made using dilution techniques of measurements of waterless formulations diluted in water they are formulation sensitive and specific and have to be carefully calibrated with complex formulas.
Waterless medium can be polar and protic yet it does not conform to classical ionic behavior.
In one or more embodiments of the present invention the modulating agent comprises an organic compound.
In one or more preferred embodiments of the present invention the chelating agent is selected from the group consisting of ethylenediaminetetraacetic acid (EDTA), diethylenetriaminepentaacetic acid (DTPA), hydroxyethylenediaminetriacetic acid (HEDTA), nitrilotriacetic acid (NTA), O,O′-bis(2-aminoethyl)ethyleneglycol-N,N,N′,N′-tetraacetic acid (EGTA), trans-1,2-diaminocyclohexane-N,N,N′,N′-tetraacetic acid (CyDTA) or a pharmaceutically acceptable salt thereof (normally as a sodium salt), more preferably EDTA, HEDTA and their salts; most preferably EDTA and its salts.
In one or more embodiments of the present invention a preferred non limiting example of the chelating agent is EDTA. Typically, the chelating and sequestering agent is present in the composition at a level of up to about 5.0%, preferably 1.0 percent, by weight, of the composition.
In one or more embodiments of the present invention the modulating agent may also be a preservative or an antioxidant or an ionization agent. Any preservative, antioxidant or ionization agents suitable for pharmaceutical or cosmetic application may be used. Non limiting examples of antioxidants are tocopherol succinate, propyl galate, butylated hydroxy toluene and butyl hydroxy anisol as well as a whole range of flavanoids such as quercitin and rutin. Ionization agents may be positive or may be negative depending on the environment and the active agent or composition that is to be protected. Ionization agents may for example act to protect or reduce sensitivity of active agents. Non limiting examples of positive ionization agents are benzyl conium chloride, and cetyl pyridium chloride. Non limiting examples of negative ionization agents are sodium lauryl sulphate, sodium lauryl lactylate and phospholipids.
Humectant
A humectant is a substance that helps retain moisture and also prevents rapid evaporation. Non limiting examples are propylene glycol, propylene glycol derivatives, glycerin, hydrogenated starch hydrosylate, hydrogenated lanolin, lanolin wax, D manitol, sorbitol, sodium 2-pyrrolidone-5-carboxylate, sodium lactate, sodium PCA, soluble collagen, dibutyl phthalate, and gelatin. Other examples may be found in the Handbook of Pharmaceutical Additives published by Gower. In the present invention the humectant is preferably a hydrophobic humectant.
Moisturizers
A moisturizer, is a substance that helps retain moisture or add back moisture to the skin. Examples are allantoin, petrolatum, urea, lactic acid, sodium PCV, glycerin, shea butter, caprylic/capric/stearic triglyceride, candelilla wax, propylene glycol, lanolin, hydrogenated oils, squalene, sodium hyaluronate and lysine PCA. Other examples may be found in the Handbook of Pharmaceutical Additives published by Gower. In the present invention the moisturizer is preferably a hydrophobic moisturizer.
Pharmaceutical compositions may in one or more embodiments usefully comprise in addition a humectant or a moisturizer or combinations thereof.
Polar Solvent
A “polar solvent” is an organic solvent, typically soluble in both water and oil. Certain polar solvents, for example propylene glycol and glycerin, possess the beneficial property of a humectant.
In one or more embodiments, the polar solvent is a humectant.
In one or more embodiments, the polar solvent is a polyol. Polyols are organic substances that contain at least two hydroxy groups in their molecular structure.
In one or more embodiments, the polar solvent contains an diol (a compound that contains two hydroxy groups in its molecular structure), such as propylene glycol (e.g., 1,2-propylene glycol and 1,3-propylene glycol), butaneediol (e.g., 1,4-butaneediol), butaneediol (e.g., 1,3-butaneediol and 1,4-butenediol), butynediol, pentanediol (e.g., 1,5-pentanediol), hexanediol (e.g., 1,6-hexanediol), octanediol (e.g., 1,8-octanediol), neopentyl glycol, 2-methyl-1,3-propanediol, diethylene glycol, triethylene glycol, tetraethylene glycol, dipropylene glycol and dibutylene glycol.
In one or more embodiments, the polar solvent contains a triol (a compound that contains three hydroxy groups in its molecular structure), such as glycerin and 1,2,6-Hexanetriol.
Other non-limiting examples of polar solvents include pyrrolidones, (such as N-methyl-2-pyrrolidone and 1-methyl-2-pyrrolidinone), dimethyl isosorbide, 1,2,6-hexapetriol, dimethyl sulfoxide (DMSO), ethyl proxitol, dimethylacetamide (DMAc) and alpha hydroxy acids, such as lactic acid and glycolic acid.
According to still other embodiments, the polar solvent is a polyethylene glycol (PEG) or PEG derivative that is liquid at ambient temperature, including PEG200 (MW (molecular weight) about 190-210 kD), PEG300 (MW about 285-315 kD), PEG400 (MW about 380-420 kD), PEG600 (MW about 570-630 kD) and higher MW PEGs such as PEG 4000, PEG 6000 and PEG 10000 and mixtures thereof.
Polar solvents are known to enhance the penetration of active agent into the skin and through the skin, and therefore, their inclusion in the composition can be desirable, despite their undesirable skin drying and irritation potential. There is at one level a commonality between the different polar solvents and their penetration enhancement properties. Lower molecular weight alcohols can sometimes be more potent as a solvent, for example by extracting lipids from the skin layers more effectively, which characteristic can adversely affect the skin structure and cause dryness and irritation. Therefore the selection of lower molecular weight alcohols is ideally avoided.
Potent Solvent
In one or more embodiments, the foamable composition includes a potent solvent, in addition to or in place of one of the hydrophobic solvents, polar solvents or emollients of the composition. A potent solvent is a solvent other than mineral oil that solubilizes a specific active agent substantially better than a hydrocarbon solvent such as mineral oil or petrolatum. For example, a potent solvent solubilizes the active agent 5 fold better than a hydrocarbon solvent; or even solubilizes the active agent 10-fold better than a hydrocarbon solvent.
In one or more embodiments, the composition includes at least one active agent in a therapeutically effective concentration; and at least one potent solvent in a sufficient amount to substantially solubilize the at least one active agent in the composition. The term “substantially soluble” means that at least 95% of the active agent has been solubilized, i.e., 5% or less of the active agent is present in a solid state. In one or more embodiments, the concentration of the at least one potent solvent is more than about 40% of the at least one solvent of the composition; or even more than about 60%.
Non-limiting examples of pairs of active agent and potent solvent include: Betamethasone valerate: Practically insoluble in mineral oil (<0.01%); soluble more than 1% in glycofurol; Hydrocortisone butyrate: Practically insoluble in mineral oil (<0.01%); soluble more than 1% in glycofurol; Metronidazole: Practically insoluble in mineral oil (<0.01%); soluble more than 1% in dimethyl isosrbide; Ketoconazole: Practically insoluble in mineral oil (<0.01%); soluble more than 1% in glycofurol, propylene glycol and dimethyl isosrbide; Mupirocin: Practically insoluble in mineral oil (<0.01%); soluble more than 1% in glycofurol, hexylene glycol, dimethyl isosorbide, propylene glycol and polyethylene glycol 400 (PEG 400); Meloxicam, a nonsteroidal anti-inflammatory agent: Practically insoluble in mineral oil (<0.001%); soluble in propylene glycol: 0.3 mg/mL; and in PEG 400: 3.7 mg/mL; and Progesterone: Practically insoluble in mineral oil (<0.001%); soluble in PEG 400: 15.3 mg/mL.
A non-limiting exemplary list of solvents that can be considered as potent solvents includes polyethylene glycol, propylene glycol, hexylene glycol, butaneediols and isomers thereof, glycerol, benzyl alcohol, DMSO, ethyl oleate, ethyl caprylate, diisopropyl adipate, dimethylacetamide, N-methylpyrrolidone, N-hydroxyethylpyrrolidone, polyvinylpyrrolidone, isosorbide derivatives, such as dimethyl isosorbide, glycofurol and ethoxydiglycol (transcutol) and laurocapram.
In another aspect, the present invention provides a method of designing a stable petrolatum foamable composition by selecting at least one active agent; and identifying a solvent that solubilizes the active agent substantially better than mineral oil or petrolatum, for example, solubilizes the active agent 5-fold better or even 10-fold better than a hydrocarbon solvent such as mineral oil or petrolatum. The method may further include adjusting the type and concentration of surfactant and gelling agent to provide a foamable composition.
In another aspect, the active agent has a degree of solubility in solvent, in petrolatum, in the emulsion or a phase thereof and a potent solvent is used to increase the solubility, in one or both phases, in the interphase or in the foam.
In another aspect, the active agent has a limited degree of solubility in solvent, in petrolatum, in the emulsion or a phase thereof and a potent solvent is used to increase the solubility, in one or both phases, in the interphase or in the foam.
The use of a potent solvent in a foam composition provides an improved method of delivering poorly soluble therapeutic agents to a target area. It is known that low drug solubility results in poor bioavailability, leading to decreased effectiveness of treatment. Foam compositions, for which the solvent includes a potent solvent, increase the levels of the active agent in solution and thus, provide high delivery and improved therapy.
Potent solvents, as defined herein, are usually liquid. Formulations comprising potent solvents and active agents are generally disadvantageous as therapeutics, since their usage involves unwanted dripping and inconvenient method of application; resulting in inadequate dosing. Surprisingly, the foams, which are drip-free, provide a superior vehicle for such active agents, enabling convenient usage and accurate effective dosing.
In one or more embodiments the present invention the foamable pharmaceutical composition may additionally include a potent solvent or a mixture of two or more of the above solvents selected from the group of hydrophobic solvents, silicone oils, emollients, polar solvents and potent solvents in an appropriate proportion as would be appreciated to a person skilled in the art and preferably in relatively small amounts.
Polymeric Agent
In one or more embodiments, the foamable composition contains a polymeric agent. The polymeric agent serves to stabilize the foam composition and to control drug residence in the target organ.
In one or more specific non limiting embodiments, the polymeric agent is ASOS, carboxymethyl cellulose/microcrystalline cellulose, Arlacel 2121, or methocel and xantham gum.
More exemplary polymeric agents are classified below in a non-limiting manner. In certain cases, a given polymer can belong to more than one of the classes provided below.
In one or more embodiments, the composition includes a gelling agent. A gelling agent controls the residence of a therapeutic composition in the target site of treatment by increasing the viscosity of the composition, thereby limiting the rate of its clearance from the site. Many gelling agents are known in the art to possess mucoadhesive properties.
The gelling agent can be a natural gelling agent, a synthetic gelling agent and an inorganic gelling agent. Exemplary gelling agents that can be used in accordance with one or more embodiments include, for example, naturally-occurring polymeric materials, such as locust bean gum, sodium alginate, sodium caseinate, egg albumin, gelatin agar, carrageenin gum, sodium alginate, xanthan gum, quince seed extract, tragacanth gum, guar gum, starch, chemically modified starches and the like, semi-synthetic polymeric materials such as cellulose ethers (e.g. hydroxyethyl cellulose, hydroxypropyl cellulose, methyl cellulose, carboxymethyl cellulose, methylhydroxyethylcellulose, methylhydroxypropylcellulose, hydroxypropylmethyl cellulose, hydroxyethylcarboxymethylcellulose, carboxymethylcellulose and carboxymethylhydroxyethylcellulose), guar gum, hydroxypropyl guar gum, soluble starch, cationic celluloses, cationic guars, and the like, and synthetic polymeric materials, such as carboxyvinyl polymers, polyvinylpyrrolidone, polyvinyl alcohol, polyacrylic acid polymers, polymethacrylic acid polymers, polyvinyl acetate polymers, polyvinyl chloride polymers, polyvinylidene chloride polymers and the like. Mixtures of the above compounds are also contemplated.
Further exemplary gelling agents include the acrylic acid/ethyl acrylate copolymers and the carboxyvinyl polymers. Non-limiting examples include Carbopol® 934, Carbopol® 940, Carbopol® 950, Carbopol® 980, Carbopol® 951 and Carbopol® 981. Such agents can function as stabalisers in one or more embodiments and as delivery enhancers in one or more other embodiments.
Yet, in other embodiments, the gelling agent includes inorganic gelling agents, such as silicone dioxide (fumed silica).
Mucoadhesive/bioadhesion has been defined as the attachment of synthetic or biological macromolecules to a biological tissue. Mucoadhesive agents are a class of polymeric biomaterials that exhibit the basic characteristic of a hydrogel, i.e. swell by absorbing water and interacting by means of adhesion with the mucous that covers epithelia. Compositions may contain a mucoadhesive macromolecule or polymer in an amount sufficient to confer or partially to confer bioadhesive properties, although these substances may by their nature, increase the tackiness of a composition so this will be taken into account in preparing compositions. The bioadhesive macromolecule can enhance delivery of biologically active agents on or through the target surface. The mucoadhesive macromolecule may be selected from acidic synthetic polymers, preferably having an acidic group per four repeating or monomeric subunit moieties, such as poly(acrylic)- and/or poly(methacrylic) acid (e.g., Carbopol®, Carbomer®), poly(methylvinyl ether/maleic anhydride) copolymer, and their mixtures and copolymers; acidic synthetically modified natural polymers, such as carboxymethylcellulose (CMC); neutral synthetically modified natural polymers, such as (hydroxypropyl)methylcellulose; basic amine-bearing polymers such as chitosan; acidic polymers obtainable from natural sources, such as alginic acid, hyaluronic acid, pectin, gum tragacanth, and karaya gum; and neutral synthetic polymers, such as polyvinyl alcohol or their mixtures. An additional group of mucoadhesive polymers includes natural and chemically modified cyclodextrin, especially hydroxypropyl-β-cyclodextrin. Such polymers may be present as free acids, bases, or salts, usually in a final concentration of about 0.01% to about 0.5% by weight. Many mucoadhesive agents are known in the art to also possess gelling properties.
In one or more embodiments, the polymeric agent contains a film-forming component, although these substances may also by their nature, increase the tackiness of a composition so this will be taken into account in preparing compositions. The film-forming component may include a water-insoluble alkyl cellulose or hydroxyalkyl cellulose. Exemplary alkyl cellulose or hydroxyalkyl cellulose polymers include ethyl cellulose, propyl cellulose, butyl cellulose, cellulose acetate, hydroxypropyl cellulose, hydroxybutyl cellulose, and ethylhydroxyethyl cellulose, alone or in combination. In addition, a plasticizer or a cross-linking agent may be used to modify the polymer's characteristics. For example, esters such as dibutyl or diethyl phthalate, amides such as diethyldiphenyl urea, vegetable oils, fatty acids and alcohols such as oleic and myristyl acid may be used in combination with the cellulose derivative.
In one or more embodiments, the polymeric agent includes a phase change polymer, which alters the composition behavior from fluid-like prior to administration to solid-like upon contact with the target mucosal surface. Such phase change results from external stimuli, such as changes in temperature or pH and exposure to specific ions (e.g., Ca2+). Non-limiting examples of phase change polymers include poly(N-isopropylamide) and Poloxamer 407®.
The polymeric agent is present in an amount in the range of about 0.01% to about 5.0% by weight of the foam composition. In one or more embodiments, it is typically less than about 1 wt % of the foamable composition.
Preferably, a therapeutically effective foam adjuvant is included in the foamable compositions to increase the foaming capacity of surfactants and/or to stabilize the foam. In one or more embodiments, the foam adjuvant agent includes fatty alcohols having 15 or more carbons in their carbon chain, such as cetyl alcohol and stearyl alcohol (or mixtures thereof). Other examples of fatty alcohols are myristyl alcohol (C14), arachidyl alcohol (C20), behenyl alcohol (C22), 1-triacontanol (C30), as well as alcohols with longer carbon chains (up to C50). Fatty alcohols, derived from beeswax and including a mixture of alcohols, a majority of which has at least 20 carbon atoms in their carbon chain, are especially well suited as foam adjuvant agents. The amount of the fatty alcohol required to support the foam system is inversely related to the length of its carbon chains. Foam adjuvants, as defined herein are also useful in facilitating improved spreadability and absorption of the composition.
In one or more embodiments, the foam adjuvant agent includes fatty acids having 16 or more carbons in their carbon chain, such as hexadecanoic acid (C16) stearic acid (C18), arachidic acid (C20), behenic acid (C22), octacosanoic acid (C28), as well as fatty acids with longer carbon chains (up to C50), or mixtures thereof. As for fatty alcohols, the amount of fatty acids required to support the foam system is inversely related to the length of its carbon chain.
In one or more embodiments, a combination of a fatty acid and a fatty ester is employed.
Optionally, the carbon atom chain of the fatty alcohol or the fatty acid may have a double bond. A further class of foam adjuvant agent includes a branched fatty alcohol or fatty acid. The carbon chain of the fatty acid or fatty alcohol also can be substituted with a hydroxyl group, such as 12-hydroxy stearic acid.
A property of the fatty alcohols and fatty acids used in context of the composition is related to their therapeutic properties per se. Long chain saturated and mono unsaturated fatty alcohols, e.g., stearyl alcohol, erucyl alcohol, arachidyl alcohol and behenyl alcohol (docosanol) have been reported to possess antiviral, antiinfective, antiproliferative and anti-inflammatory properties (see, U.S. Pat. No. 4,874,794). Longer chain fatty alcohols, e.g., tetracosanol, hexacosanol, heptacosanol, octacosanol, triacontanol, etc., are also known for their metabolism modifying properties and tissue energizing properties. Long chain fatty acids have also been reported to possess anti-infective characteristics.
In one or more embodiments, the active agent is encapsulated in particles, microparticles, nanoparticles, microcapsules, spheres, microspheres, nanocapsules, nanospheres, liposomes, niosomes, polymer matrix, nanocrystals or microsponges.
The composition may further optionally include a variety of formulation excipients, which are added in order to fine-tune the consistency of the formulation, protect the formulation components from degradation and oxidation and modify their consistency. Such excipients may be selected, for example, from stabilizing agents, antioxidants, humectants, moisturizers, preservatives, colorant and odorant agents and other formulation components, used in the art of formulation.
Propellants
Aerosol propellants are used to generate and administer the foamable composition as a foam. The total composition including propellant, foamable compositions and optional ingredients is referred to as the foamable carrier. The propellant makes up about 3% to about 25% (w/w) of the foamable carrier or composition. Examples of suitable propellants include volatile hydrocarbons such as butane, propane, isobutane, and fluorocarbon gases or mixtures thereof. In an embodiment the propellant is 1681, which is a mixture of three gas propellants propane, isobutene and butane. In another embodiment it is AP 70, which is a mixture of propane, isobutene and butane with a higher pressure. In some circumstances the propellant may be up to 35%. The total composition including propellant, foamable compositions and optional ingredients is referred to as the foamable composition. However, for the purposes of calculating the percentage of each component and thereby the amount present in the resultant foam the propellant is not included in the 100% but is instead added to the 100% since the propellant is essentially discharged into the atmosphere upon expulsion of the formulation.
Non-Flammable Stable Foam Compositions
Alcohol and organic solvents render foams inflammable. It has been surprisingly discovered that fluorohydrocarbon propellants, other than chloro-fluoro carbons (CMOs), which are non-ozone-depleting propellants, are particularly useful in the production of a non-flammable foamable composition. A test according to European Standard prEN 14851, titled “Aerosol containers—Aerosol foam flammability test” revealed that compositions containing an organic carrier that contains a hydrophobic organic carrier and/or a polar solvent, which are detected as inflammable when a hydrocarbon propellant is used, become non-flammable, while the propellant is an HFC propellant.
Such propellants include, but are not limited to, hydrofluorocarbon (HFC) propellants, which contain no chlorine atoms, and as such, fall completely outside concerns about stratospheric ozone destruction by chlorofluorocarbons or other chlorinated hydrocarbons. Exemplary non-flammable propellants according to this aspect include propellants made by DuPont under the registered trademark Dymel, such as 1,1,1,2 tetrafluorethane (Dymel 134), and 1,1,1,2,3,3,3 heptafluoropropane (Dymel 227). HFCs possess Ozone Depletion Potential of 0.00 and thus, they are allowed for use as propellant in aerosol products.
Notably, the stability of foamable emulsions including HFC as the propellant can be improved in comparison with the same composition made with a hydrocarbon propellant.
In one or more embodiments foamable compositions comprise a combination of a HFC and a hydrocarbon propellant such as n-butane or mixtures of hydrocarbon propellants such as propane, isobutane and butane.
Additional Components
In an embodiment, a composition includes one or more additional components. Such additional components include but are not limited to anti perspirants, anti-static agents, buffering agents, bulking agents, conservational agents, chelating agents, cleansers, colorants, conditioners, deodorants, diluents, dyes, emollients, fragrances, hair conditioners, humectants, pearlescent aids, perfuming agents, permeation enhancers, pH-adjusting agents, preservatives, protectants, skin penetration enhancers, softeners, solubilizers, sunscreens, sun blocking agents, sunless tanning agents, viscosity modifiers, ionization agents, and antioxidants like flavonoids and phenolics. As is known to one skilled in the art, in some instances a specific additional component may have more than one activity, function or effect.
In an embodiment, the additional component is a pH adjusting agent or a buffering agent. Suitable buffering agents include but are not limited to acetic acid, adipic acid, calcium hydroxide, citric acid, glycine, hydrochloric acid, lactic acid, magnesium aluminometasilicates, phosphoric acid, sodium carbonate, sodium citrate, sodium hydroxide, sorbic acid, succinic acid, tartaric acid, and derivatives, salts and mixtures thereof.
Sodium Metabisulfite (Disodium Metabisulfite) and Derivatives
Sodium metabisulfite is used as an antioxidant in (primarily acidic) pharmaceutical formulations, at concentrations of 0.01-1.0% w/v., preparations and can also be used as a preservative having some antimicrobial activity at though for alkaline preparations, sodium sulfite is usually preferred
Active Agents
It is to be understood that the active agents useful herein can in some instances provide more than one benefit or operate via more than one mode of action. Therefore, classifications herein are made for the sake of convenience and are not intended to limit the active agent to that particular application or applications listed.
The composition comprises an active agent that provides therapeutic or cosmetic activity.
Non-limiting examples of active agents include an anti-infective, an antibiotic, an antibacterial agent, an antifungal agent, an antiviral agent, an antiparasitic agent, a steroidal anti-inflammatory agent, a nonsteroidal anti-inflammatory agent, an immunosuppressive agent, an immunomodulator, an immunoregulating agent, a hormonal agent, a steroid, a vasoactive agent, a vasoconstrictor, a vasodilator, vitamin A, a vitamin A derivative, a retinoid, vitamin B, a vitamin B derivative, vitamin C, a vitamin C derivative, vitamin D, a vitamin D derivative, vitamin E, a vitamin E derivative, alpha-tocopheryl polyethylene glycol succinate, vitamin F, a vitamin F derivative, vitamin K, a vitamin K derivative, a wound healing agent, a burn healing agent, a disinfectant, an anesthetic, an antiallergic agent, an alpha hydroxyl acid, lactic acid, glycolic acid, a beta-hydroxy acid, a protein, a peptide, a neuropeptide, an allergen, an immunogenic substance, a haptene, an oxidizing agent, an antioxidant, a dicarboxylic acid, azelaic acid, sebacic acid, adipic acid, fumaric acid, an insecticide, an antiproliferative agent, an anticancer agent, a photodynamic therapy agent, an anti-wrinkle agent, a radical scavenger, a metal oxide (e.g., titanium dioxide, zinc oxide, zirconium oxide, iron oxide), silicone oxide, talc, an anti-acne agent, a skin whitening agent, a self tanning agent, an anti-cellulite agent, a skin protective agent, a masking agent, an anti-wart agent, a refatting agent, a lubricating agent and mixtures thereof at any proportion. The concentration of the active agent can be adapted to exert a therapeutic effect on a disease when applied to an afflicted area.
In one or more embodiments the active agent may be vitamin D or a derivative such as calcipotriol or calcitriol. In one or more other embodiments the vitamin D or derivative is used in combination with a steroid. Due to the different environmental requirements of the two types of API's it is very difficult to produce formulations that are both chemically and physically stable. In certain embodiments there are provided chemically and physically stable formulations containing one or both active agents. Nevertheless, in certain other preferred embodiments the active agents are in separate formulations and are delivered by means of a multichamber or dual chamber device. Alternatively they can be expelled manually simultaneously or consecutively from two separate canisters directed to the same target site.
In one or more embodiments the active agent may be an extract or tincture of one or more beneficial agents that have beneficial properties, for example, when applied to the skin, a body surface, a body cavity or a mucosal surface. The extract can be, for example, alcoholic, hydroalcoholic, propelyne glycol, glycerine, dry, press, cold, hot, liquid carbon dioxide, oil or other process known in the art. The extract or tincture may comprise of substances of animal, plant, (such as herb, fruit, vegetable) mineral or other origin. Nonlimiting examples are proteins, polypeptides, sugars, hyularonic acid, and coal tar. Herbal extracts may be from any known therapeutic herb, as listed for example in Herbal Medicines, London: Pharmaceutical Press Electronic Version 2006 or in the American Herbal Association electronic publication Herbal gram or in German Commission E., such as, angelica, calendula, celery, coltsfoot, comfrey, dandelion, jamaica dogwood, kava, marshmallow, prickly ash, northern prickly ash, southern senna, valerian, agrimony, aloe vera, alfalfa, artichoke, avens, bayberry, bloodroot, blue flag, bogbean, boldo, boneset, broom, buchu, burdock, burnet, calamus, calendula, cascara, centaury, cereus, chamomile, german chamomile, roman chamomile, cinnamon, clivers, cohosh, black, cohosh, blue, cola, corn silk, couchgrass, cowslip, damiana, devil's claw, drosera, echinacea, elder, elecampane, euphorbia, eyebright, figwort, frangula, fucus, fumitory, garlic, golden seal, gravel root, ground ivy, guaiacum, hawthorn, holy thistle, hops, horehound black, horehound white, horse chestnut hydrangea, ispaghula, juniper, lady's lipper, liferoot, lime flower, liquorice, lobelia, mate, meadowsweet, mistletoe, motherwort, myrrh, nettle, parsley, parsley piert, passionflower, pennyroyal, pilewort, plantain, pleurisy root, pokeroot, poplar, pulsatilla, queen's delight, raspberry, red clover, rosemary, sage, sarsaparilla, sassafras, scullcap, senega, shepherd's purse, skunk cabbage, slippery elm, squill, St. John's wort, stone root, tansy, thyme, uva-ursi, vervain, wild carrot, wild lettuce, willow, witch hazel, yarrow and yellow dock. The extract may contain, for example, an aqueous, polar, hydrophobic or potent solvent as will be appreciated by a person of ordinary skill in the art.
In one or more embodiments, the active agent is an anti-infective agent, selected from an antibiotic agent, an antibacterial agent, an anti-fungal agent, an anti-viral agent and an anti-parasite agent.
The antibacterial drug can be active against gram positive and gram-negative bacteria, protozoa, aerobic bacteria and anaerobic ones.
In one or more embodiments, the antibiotic agent is selected from the classes consisting of beta-lactam antibiotics, synthetic and semi-synthetic penicillin's, aminoglycosides, ansa-type antibiotics, anthraquinones, antibiotic azoles, antibiotic glycopeptides, macrolides, antibiotic nucleosides, antibiotic peptides, antibiotic polyenes, antibiotic polyethers, quinolones, fluoroquinolnes, antibiotic steroids, cyclosporines, sulfonamides, tetracycline, chloramphenicol, dicarboxylic acids, such as azelaic acid, salicylates, antibiotic metals, oxidizing agents, substances that release free radicals and/or active oxygen, cationic antimicrobial agents, quaternary ammonium compounds, biguanides, triguanides, bisbiguanides and analogs and polymers thereof and naturally occurring antibiotic compounds.
Additional antibacterial agents, which are non-specific, include strong oxidants and free radical liberating compounds, such as hydrogen peroxide, bleaching agents (e.g., sodium, calcium or magnesium hypochloride and the like), iodine, chlorohexidine and benzoyl peroxide.
The antifungal agent can be an azole compound. Exemplary azole compounds include azoles selected from the group consisting of azoles, diazoles, triazoles, miconazole, ketoconazole, clotrimazole, econazole, mebendazole, bifonazole, butoconazole, fenticonazole, isoconazole, oxiconazole, sertaconazole, sulconazole, thiabendazole, tiaconazole, fluconazole, itraconazole, ravuconazole and posaconazole.
Additional exemplary antifungal agents include griseofulvin, ciclopirox, amorolfine, terbinafine, Amphotericin B, potassium iodide, flucytosine (5FC) and any combination thereof at a therapeutically effective concentration.
In one or more embodiments, the active agent is an anti-viral agent. Any known antiviral agent, in a therapeutically effective concentration, can be incorporated in the foam composition. Exemplary antiviral agents include, but not limited to, acyclovir, famciclovir, gancyclovir, valganciclovir and abacavir.
In another embodiment according to the present invention, the active agent is an anti-inflammatory or anti-allergic agent. Anti-inflammatory agents can be selected from the group of corticosteroids, non-steroidal anti-inflammatory drugs (NSAIDs), anti-histamines, immunosuppressant agents, immunomodulators; and any combination thereof at a therapeutically effective concentration.
Non-limiting examples of corticosteroids include hydrocortisone, hydrocortisone acetate, desonide, betamethasone valerate, clobetasone-17-butyrate, flucinonide, fluocinolone acetonide, alcometasone dipropionate, mometasone furoate, prednicarbate, triamcinolone acetonide, betamethasone-17-benzoate, methylprednisolone aceponate, betamethasone dipropionate, halcinonide, triamcinolone acetonide, halobetasol and clobetasol-17-propionate.
A second class of anti-inflammatory agents, which is useful in the foam, includes the nonsteroidal anti-inflammatory agents (NSAIDs). The variety of compounds encompassed by this group is well known to those skilled in the art. Specific non-steroidal anti-inflammatory agents useful in the composition invention include, but are not limited to, oxicams, such as piroxicam, isoxicam, tenoxicam, sudoxicam; salicylates, such as salicylic acid, ethyl salicylate, methyl salycilate, aspirin, disalcid, benorylate, trilisate, safapryn, solprin, diflunisal, and fendosal; scetic acid derivatives, such as diclofenac, fenclofenac, indomethacin, sulindac, tolmetin, isoxepac, furofenac, tiopinac, zidometacin, acematacin, fentiazac, zomepirac, clindanac, oxepinac, felbinac, and ketorolac; fenamates, such as mefenamic, meclofenamic, flufenamic, niflumic, and tolfenamic acids; propionic acid derivatives, such as ibuprofen, naproxen, benoxaprofen, flurbiprofen, ketoprofen, fenoprofen, fenbufen, indopropfen, pirprofen, carprofen, oxaprozin, pranoprofen, miroprofen, tioxaprofen, suprofen, alminoprofen, and tiaprofenic; and pyrazoles, such as phenylbutazone, oxyphenbutazone, feprazone, azapropazone, and trimethazone.
Any further steroidal and nonsteroidal compounds, having the capacity to prevent, alleviate the symptoms of, treat or cure inflammation processes, are generally included, as possible anti-inflammatory agents, according to the present invention.
Antiallergic active agents include antihistamine compounds, including, in a non limiting manner, thylenediamines, such as pyrilamine (mepyramine), antazoline and methapyrilene; tripelennamine phenothiazines, such as promethazine, methdilazine and trimeprazine; ethanolamines, such as diphenhydramine, bromodiphenhydramine, carbinoxamine, clemastine, dimenhydrinate, diphenylpyraline, doxylamine and phenyltoxamine; piperazines, such as cyclizine, buclizine, chlorcyclizine, hydroxyzine, meclizine and thiethylperazine; alkylamines, such as brompheniramine, pyrrobutamin, desbrompheniramine, tripolidine, dexchlorpherniramine, chlorpheniramine; dimethindene and pheniramine; and piperidines, such as cyproheptadine and azatadine. These active agents, as well as additional antihistamines can also be incorporated in the composition.
The composition may also comprise an anti-inflammatory or antiallergic agent, wherein said agent reduces the occurrence of pro-inflammatory cytokines or inhibits the effect of pro-inflammatory cytokines.
Immunosuppressant agents, immunoregulating agents and immunomodulators are chemically or biologically derived agents that modify the immune response or the functioning of the immune system (as by the stimulation of antibody formation or the inhibition of white blood cell activity). Immunosuppressant agents and immunomodulators include, among other options, cyclic peptides, such as cyclosporine, tacrolimus, tresperimus, pimecrolimus, sirolimus (rapamycin), verolimus, laflunimus, laquinimod and imiquimod.
In one or more embodiments, the active agent is a topical anesthetic. Examples of topical anesthetic drugs include, but not limited to, benzocaine, lidocaine, bupivacaine, chlorprocaine, dibucaine, etidocaine, mepivacaine, tetracaine, dyclonine, hexylcaine, procaine, cocaine, ketamine, pramoxine, and phenol. Mixtures of such anesthetic agents may be synergistically beneficial.
In one or more embodiments, the active agent is a “keratolytically active agent.” The term “keratolytically active agent” refers herein to a compound, which loosens and removes the stratum corneum of the skin, or alters the structure of the keratin layers of the skin.
Suitable keratolytically active agents include phenol and substituted phenolic compounds. Such compounds are known to dissolve and loosen the intracellular matrix of the hyperkeratinized tissue. Dihydroxy benzene and derivatives thereof have been recognized as potent keratolytic agents. Resorcinol (m-dihydroxybenzene) and derivatives thereof are used in anti-acne preparations. Hydroquinone (p-dihydroxybenzene), besides its anti-pigmentation properties, is also keratolytic.
Vitamin A and its derivatives, such as retinoic acid, isoretinoic acid, retinol and retinal are another preferred class of keratolytically active agents.
Another group of keratolytically active agents include alpha-hydroxy acids, such as lactic acid and glycolic acid and their respective salts and derivatives; and beta-hydroxy acids, such as Salicylic acid (o-hydroxybenzoic acid) and its salts and pharmaceutically acceptable derivatives, which typically possess anti-inflammatory, as well as keratolytic, activity. Yet, another class of preferred keratolytically active agents includes urea and its derivatives.
In one or more embodiments, the active agent is a retinoid. Retinoids include, for example, retinol, retinal, all-trans retinoic acid and derivatives, isomers and analogs thereof. Etretinate, actiretin, isotretinoin, adapalene and tazarotene are further examples of said retinoid isomers and analogs.
In one or more embodiments, the active agent is a vitamin D3 analogue such as calcipotriol, tacalcitol, maxacalcitol, and calcitriol with calcipotriol being especially preferred. Vitamin D3 analogues and derivatives are known to degrade at low pH levels. The waterless compositions can protect against or retard such degredation. In certain embodiments where the active agent is vitamin D3 or an analogue or a derivative thereof, and there is a concern that there are some potential residues which could effect the agent in the composition or following application to the skin or a body cavity could cause breakdown a neutralizing or stabilizing agent might additionally be added which could be a suitable pH adjuster or buffer. Note where calcipotriol and a steroid like betmethasone diproprionate are in the same composition the waterless compositions are ideal to protect from degradation. In an aqueous environment they have opposing pH requirements for stability with the steroid favoring an acidic environment and the vitamin favoring a basic environment.
In one or more embodiments, the active agent is an insecticide or an insect repellent agent.
In one or more embodiments, the active agent is an anti cancer agent.
In one or more embodiments, the active agent is a photodynamic therapy (PDT) agent. By way of example, such PDT agents can be modified porphyrins, chlorins, bacteriochlorins, phthalocyanines, naphthalocyanines, pheophorbides, purpurins, m-THPC, mono-L-aspartyl chlorin e6, bacteriochlorins, phthalocyanines, benzoporphyrin derivatives, as well as photosensitizer precursors, such as aminolevulinic acid (ALA).
In one or more embodiments, the active agent is an agent useful in the treatment of burns, wounds, cuts and ulcers. The foam compositions may comprise a combination of anti-infective agents (against bacteria, fungi and/or viruses), anti-inflammatory agents (steroidal and/or NSAIDs) and pain relieving components.
In one or more embodiments, the active agent can also be used as an absorption and bioavailability enhancer for other drugs and vitamins, for example TPGS that forms its own micelles can aid e.g. amprenavir and vitamin D respectively.
In one or more embodiments the active agent has some degree of solubility in water. By the phrase some degree of solubility it is understood to include API's that are described by the US or European Pharmacopoeia as being slightly soluble, sparingly soluble, soluble, freely soluble or very soluble. Both describe the approximate ranges of parts of solvent (volume) required for 1 part (per gram) of solute as less than 1 for very soluble; from 1-10; for freely soluble, from 10-30 for soluble; from 30 to 100 for sparingly soluble; and from 100 to 1000 for slightly soluble. Additionally, the phrase may include the terms partly soluble and miscible. Non limiting examples of substances that have some degree of solubility in water are acyclovir, azelaic acid, allantoin, ammonium lactate, benzoyl peroxide, caffeine, calcipotriol, ciclopirox olamine, clindamycin hydrochloride, clindamycin phosphate, clindamycin palmitate hydrochloride, coal tar, cyanocobalamine, diclofenac sodium, gentamycin sulphate, lactic acid, glycyrrhizinic acid, map (magnesium ascorbyl phosphate), minoxidil, mupirocin, salicylic acid, terbinafine, urea, fusidic acid, a hydrocortisone, hydrocortisone sodium phosphate, hydrocortisone sodium succinate, a clobetasol, a halobetasol, a batamethsone; halobetasol and clobetasol-17-propionate or -17-butyrate; ketoconazole, lidocaine hydrochloride, metronidazole, tetracycline, tetracycline hydrochloride, meclocycline sulfosalicylate, resorcinol, chloramphenicol, erythromycin, acriflavinium monochloride, ethacridine lactate, dibrompropamidine isetionate, chlorhexidine acetate, chlorhexidine gluconate, chlorhexidine hydrochloride, hexamidine isetionate, phenol, povidone-iodine, dequalinium chloride, hydroxyquinoline sulfate, potassium hydroxyquinoline sulphate, benzalkonium chloride, cetrimonium bromide, cetylpyridinium chloride, cetrimide, phenylmercuric acetate, phenylmercuric borate, mercuric chloride, silver nitrate, potassium permanganate, tosylchloramide sodium, prednisolone sodium phosphate, betamethasone sodium phosphate, demeclocycline, demeclocycline hydrochloride, chlortetracycline hydrochloride, oxytetracycline hydrochloride, neomycin sulfate, bacitracin zinc, gentamicin sulphate, amikacin, amikacin sulphate, sulfathiazole sodium, mafenide acetate, idoxuridine, fumaric acid, mepyramine maleate, tripelennamine hydrochloride, promethazine hydrochloride, dimetindene maleate, diphenhydramine hydrochloride, cinchocaine hydrochloride, oxybuprocaine hydrochloride, benzocaine, tetracaine hydrochloride, pramoxine hydrochloride, panthenol, dexpanthenol, calcium pantothenate, hyaluronic acid, trypsin, aminobenzoic acid, methylrosanilinium chloride, sodium butyl hydroxybenzoate, sodium ethyl hydroxybenzoate, sodium methyl hydroxybenzoate, sodium propyl hydroxybenzoate, flucytosine and fluconazole.
In one or more embodiments the active agent has a limited degree of solubility in water. By a limited degree of solubility it is understood to include API's that are described by the US or European Pharmacopoeia as being very slightly soluble. The approximate range of parts of solvent (volume) required for 1 part (per gram) of solute is from 1000 to 10000 for very slightly soluble.
In one or more embodiments the active agent has some degree of solubility in an petrolatum emollient. So any agent that by its nature is hydrophobic may qualify, such as permethrin and tetracaine.
In one or more embodiments the active agent has some degree of solubility in a composition in one or more of the water phase, the oil phase, or the interphase or the foam. For example, beamethasone valerate has been stated to be practically insoluble in water. However, it has been surprisingly found that it is soluble in the water phase of a foamable composition in a pharmaceutically effective amount for topical application.
The foam compositions, with or without further active ingredients, are suitable for the further application as “cosmeceutical” preparation (cosmetic products with therapeutic benefit), to treat “cosmetic” skin disorders, such as aging skin, wrinkles, hyperpigmentation (melasma, chloasma, freckles, etc.), scaly skin and other skin undesirable properties.
Any cosmetically active agent is considered an active agent in the context. The CTFA Cosmetic Ingredient Handbook describes a wide variety of non-limiting cosmetic and pharmaceutical ingredients commonly used in the skin care industry, which are suitable for use in the compositions. Examples of these ingredient classes include: abrasives, absorbents, aesthetic components such as fragrances, pigments, colorings/colorants, essential oils, astringents, etc. (e.g., clove oil, menthol, camphor, eucalyptus oil, eugenol, menthyl lactate, witch hazel distillate), anti-acne agents, anti-caking agents, antifoaming agents, anti-microbial agents (e.g., iodopropyl butylcarbamate), antioxidants, binders, biological additives, buffering agents, bulking agents, chelating agents, chemical additives, colorants, cosmetic astringents, cosmetic biocides, denaturants, drug astringents, external analgesics, film formers or materials, e.g., polymers, for aiding the film-forming properties and substantivity of the composition (e.g., copolymer of eicosene and vinyl pyrrolidone), opacifying agents, pH adjusters, propellants, reducing agents, sequestrants, skin bleaching and lightening agents (e.g., hydroquinone, kojic acid, ascorbic acid, magnesium ascorbyl phosphate, ascorbyl glucosamine), skin-conditioning agents (e.g., humectants, moisturizers, etc.), skin soothing and/or healing agents (e.g., panthenol and derivatives (e.g., ethyl panthenol), aloe vera, pantothenic acid and its derivatives, allantoin, bisabolol, and dipotassium glycyrrhizinate), skin treating agents, and vitamins and derivatives thereof.
In one or more embodiments, the active agent is an agent useful in the treatment of acne, wrinkles and scars. Examples of useful anti-acne actives include resorcinol, sulfur, salicylic acid and salicylates, alpha-hydroxy acids, nonsteroidal anti-inflammatory agents, benzoyl peroxide, retinoic acid, isoretinoic acid and other retinoid compounds, adapalene, tazarotene, azelaic acid and azelaic acid derivatives, antibiotic agents, such as erythromycin and clyndamycin, zinc salts and complexes, and combinations thereof, in a therapeutically effective concentration. Exemplary anti-wrinkle/anti-atrophy active agents suitable for use in the compositions include sulfur-containing D and L amino acids and their derivatives and salts, particularly the N-acetyl derivatives; thiols; hydroxy acids (e.g., alpha-hydroxy acids such as lactic acid and glycolic acid and their derivatives and salts; or beta-hydroxy acids such as salicylic acid and salicylic acid salts and derivatives), urea, hyaluronic acid, phytic acid, lipoic acid; lysophosphatidic acid, skin peel agents (e.g., phenol, resorcinol and the like), vitamin B3 compounds (e.g., niacinamide, nicotinic acid and nicotinic acid salts and esters, including non-vasodilating esters of nicotinic acid (such as tocopheryl nicotinate), nicotinyl amino acids, nicotinyl alcohol esters of carboxylic acids, nicotinic acid N-oxide and niacinamide N-oxide), vitamin B5 and retinoids (e.g., retinol, retinal, retinoic acid, retinyl acetate, retinyl palmitate, retinyl ascorbate). In the case of dry, scaly skin (xerosis) and ichthyosis such agents can alleviate the symptoms by temporary relief of itching associated with these conditions.
In one or more embodiments, the active agent is an anti-oxidant or a radical scavenger. Anti-oxidants/radical scavengers such as ascorbic acid (vitamin C) and its salts, ascorbyl esters of fatty acids, ascorbic acid derivatives (e.g., magnesium ascorbyl phosphate, sodium ascorbyl phosphate, ascorbyl sorbate), tocopherol (vitamin E), tocopherol sorbate, tocopherol acetate, other esters of tocopherol, butylated hydroxy benzoic acids and their salts, 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid, gallic acid and its alkyl esters, especially propyl gallate, uric acid and its salts and alkyl esters, sorbic acid and its salts, lipoic acid, amines (e.g., N,N-diethylhydroxylamine, amino-guanidine), sulfhydryl compounds (e.g., glutathione), dihydroxy fumaric acid and its salts, lycine pidolate, arginine pilolate, nordihydroguaiaretic acid, bioflavonoids, curcumin, lysine, methionine, proline, superoxide dismutase, silymarin, tea extracts, grape skin/seed extracts, melanin, and rosemary extracts may be used.
It is further pointed out that polyunsaturated fatty acids, containing omega-3 and omega-6 fatty acids (e.g., linoleic and linolenic acid, gamma-linoleic acid (GLA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)) are beneficial in the treatment of psoriasis and other skin inflammation conditions. Likewise, emollients and silicone oils exert moisture-retaining and skin protective effects on the skin. Thus, in a preferred embodiment, a skin protective foam is provided, wherein the hydrophobic carrier comprises in full or in part, an organic liquid selected from the group consisting of emollients, silicone oil and oils rich in unsaturated fatty acids.
In one or more embodiments, the active agent is a self-tanning active Agent, such as dihydroxyacetone.
According to another embodiment, the active agent comprises solid matter or particulate matter, i.e., material that is not soluble in the liquid carrier composition of the foamable composition. For definition purposes, solid matter shall mean material that is not soluble in the foamable composition more than 10% of the concentration intended to be included in said foamable composition. By way of example, the following classes of solid matter substances are presented: metallic oxides, such as titanium dioxide, zinc oxide, zirconium oxide, iron oxide; silicon containing materials such as silicone oxide and talc; carbon, for example in the form of amorphous carbon or graphite; insoluble oxidizing agents, such as benzoyl peroxide, calcium and magnesium hypochlorite; metallic Silver; cosmetic scrub materials, including, for example meals of strawberry seeds, raspberry seeds, apricot seeds, sweet almond, cranberry seeds; and pigments.
In an embodiment the solid is substantially uniformly dispersed as a suspension in the composition, wherein the composition is formulated so that the resultant foam when applied topically to a target will form an effective barrier and the composition does not comprise a non propellant organic cosolvent.
According to certain embodiments, the active agent is selected from the group of solvent, surface active agent, foam adjuvant and gelling agent, which are, on a case-by-case basis, known to possess a therapeutic benefit.
In one or more embodiments at least one or at least two active agents are included in the composition.
Whenever there is reference to an active agent and or derivatives the reference includes, derivatives, conjugates, analogues, prodrugs, chelates, complexes, ions, isomers, enantimers, and salts thereof.
Composition and Foam Physical Characteristics and Advantages
A pharmaceutical or cosmetic composition manufactured using the foamable carrier is very easy to use. When applied onto the afflicted body surface of mammals, i.e., humans or animals, it is in a foam state, allowing free application without spillage. Upon further application of a mechanical force, e.g., by rubbing the composition onto the body surface, it freely spreads on the surface and is rapidly absorbed.
The foamable composition can be in the state of (1) solutions; (2) a readily dispersible suspension; or (3) an emulsion. It is stable, having an acceptable shelf life of a year, or at least two years at ambient temperature, as revealed in accelerated stability tests. Polar solvents, hydrophobic carriers and propellants, which are a mixture of low molecular weight hydrocarbons, tend to impair the stability of emulsions and to interfere with the formation of a stable foam upon release from a pressurized container. It has been observed, however, that the foamable compositions according to the present invention are surprisingly stable. Following accelerated stability studies, they demonstrate desirable texture; they form fine bubble structures that do not break immediately upon contact with a surface, spread easily on the treated area and absorb quickly.
The composition should also be free flowing, to allow it to flow through the aperture of the container, e.g., and aerosol container, and create an acceptable foam. Compositions containing semi-solid hydrophobic solvents, e.g., white petrolatum, as the main ingredients of the oil phase of the emulsion, exhibit high viscosity and reduced or poor flowability and are not ideal candidates for a foamable composition. It has been found that despite the aforesaid in the compositions s the produce foams, which are surprisingly soft, or with improved stability.
Where the petrolatum emollient is provided in large quantities sufficient to produce an effective occlusion the foam can act as a barrier to water soluble irritants and air borne bacteria whilst also providing a vehicle for water soluble active agents. However, there is a potential downside of anaerobic bacteria growing under the barrier. Depending on the nature of the emulsion formulation an petrolatum emollient can aid API transport through the skin or retard penetration prolonging thereby its action. Accordingly a pharmaceutical formulation for example with petrolatum can be designed to improve or prolong delivery as is required as will be appreciated by a person skilled in the art.
Foam quality can be graded as follows:
Topically administrable foams are typically of quality grade E or G, when released from the aerosol container. Smaller bubbles are indicative of more stable foam, which does not collapse spontaneously immediately upon discharge from the container. The finer foam structure looks and feels smoother, thus increasing its usability and appeal. Achieving G or E, where petrolatum. a heavy, greasy, tacky substance, is the main or major component is a challenge and achievement. As a consequence of the high levels of petrolatum and its nature, the density of the resultant foams can be significantly higher than with non or low petrolatum foams. With high petrolatum a density of the order of about 0.5 g to about 0.4 g is acceptable. Nevertheless, in certain other embodiments relatively low density petrolatum foams can be achieved having a density below about 0.4 g and preferably with a density of less than about 0.2 g.
A further aspect of the foam is breakability. The breakable foam is thermally stable, yet breaks under sheer force. Sheer-force breakability of the foam is clearly advantageous over thermally induced breakability. Thermally sensitive foams immediately collapse upon exposure to skin temperature and, therefore, cannot be applied on the hand and afterwards delivered to the afflicted area.
In one or more embodiments there is provided a composition, wherein the foam demonstrates at least eighteen of the following properties:
In a preferred embodiment it demonstrates one or more of the following: nineteen; twenty; twenty one; twenty two properties and in a more preferred embodiment it demonstrates all of the properties.
In one or more embodiments there is provided a composition, wherein the foam provides at least two of the following traits:
In one or more embodiments there is provided a composition, wherein the foam provides at least two of the following traits:
Dual and Multi Chamber devices and heads suitable for use with the formulations described herein where a first formulation is stored in a first canister and a second formulation is stored in a second canister are described in U.S. Pat. No. 6,305,578 entitled DEVICE FOR MIXING, FOAMING AND DISPENSING LIQUIDS FROM SEPARATE COMPRESSED-GAS CONTAINERS and in U.S. Publication 2007-0069046 and entitled APPARATUS AND METHOD FOR RELEASING A MEASURE OF CONTENT FROM A PLURALITY OF CONTAINERS all of which are incorporated herein by reference in their entirety. More particularly any of the devices and uses described are applicable herein and are incorporated by reference.
In an embodiment the dual chamber device is as described in U.S. Pat. No. 6,305,578 for example,
a compressed gas container apparatus, having
In an embodiment the dual dispenser head is as described in U.S. Publication 2007-0069046 for example:
a dispenser head for use with a plurality of containers, comprising:
In one or more embodiments there is provided a kit comprising a dual chamber device or dual dispenser head, a first canister comprising a first foamable formulation comprising a first API and a second canister comprising a second foamable formulation comprising a second API wherein each canister is connectable to the said device or head. The first foamable formulation may be any of the stable petrolatum formulations described herein and the second foamable formulation may also be any of the stable petrolatum formulations described herein. In an embodiment the first API is a steroid and the second API is a vitamin D derivative and the each formulation is adapted to carry an effective amount of steroid and vitamin D derivative, respectively, such that each formulation and API is sufficiently chemically and physically stable for pharmaceutical use.
Other foamable compositions are described in: U.S. Publication No. 05-0232869, published on Oct. 20, 2005, entitled NONSTEROIDAL IMMUNOMODULATING KIT AND COMPOSITION AND USES THEREOF; U.S. Publication No. 05-0205086, published on Sep. 22, 2005, entitled RETINOID IMMUNOMODULATING KIT AND COMPOSITION AND USES THEREOF; U.S. Publication No. 06-0018937, published on Jan. 26, 2006, entitled STEROID KIT AND FOAMABLE COMPOSITION AND USES THEREOF; U.S. Publication No. 05-0271596, published on Dec. 8, 2005, entitled VASOACTIVE KIT AND COMPOSITION AND USES THEREOF; U.S. Publication No. 06-0269485, published on Nov. 30, 2006, entitled ANTIBIOTIC KIT AND COMPOSITION AND USES THEREOF; U.S. Publication No. 07-0020304, published on Jan. 25, 2007, entitled NON-FLAMMABLE INSECTICIDE COMPOSITION AND USES THEREOF; U.S. Publication No. 06-0193789, published on Aug. 31, 2006, entitled FILM FORMING FOAMABLE COMPOSITION; U.S. patent application Ser. No. 11/732,547, filed on Apr. 4, 2007, entitled ANTI-INFECTION AUGMENTATION OF FOAMABLE COMPOSITIONS AND KIT AND USES THEREOF; U.S. patent application Ser. No. 11/732,547, filed on Apr. 4, 2007, KERATOLYTIC ANTIFUNGAL FOAM; U.S. patent application Ser. No. 11/767,442, filed on Jun. 22, 2007, entitled FOAMABLE COMPOSITIONS AND KITS COMPRISING ONE OR MORE OF A CHANNEL AGENT, A CHOLINERGIC AGENT, A NITRIC OXIDE DONOR, AND RELATED AGENTS AND THEIR USES; U.S. patent application Ser. No. 11/825,406, filed on Jul. 5, 2007, entitled DICARBOXYLIC ACID FOAMABLE VEHICLE AND PHARMACEUTICAL COMPOSITIONS THEREOF; U.S. patent application Ser. No. 11/900,072, filed on Sep. 10, 2006, entitled FOAMABLE VEHICLE AND VITAMIN AND FLAVONOID PHARMACEUTICAL COMPOSITIONS THEREOF; and U.S. patent application Ser. No. 11/947,751, filed Nov. 29, 2007, entitled COMPOSITIONS WITH MODULATING AGENTS, all of which are incorporated herein by reference in their entirety. More particularly any of the active ingredients; the solvents; the surfactants; foam adjuvants; polymeric agents, penetration enhancers; preservatives, humectants; moisturizers; and other excipients as well as the propellants and methods listed therein can be applied herein and are incorporated by reference.
A “stable foam” is defined herein as a composition, which upon release from an aerosol can, creates a foam mass, which is sustained on a surface for at least one minute, more preferably at least two minutes, and yet more preferably for at least 5 minutes. A period of minutes is regarded as a short term, but nevertheless it allows a good and more than sufficient period of time for a subject to receive foam dispensed on a body surface and to spread it or to transfer it to another region and to spread it.
In terms of spreadability and absorption an acceptable foam is one, that does not readily collapse upon dispensing on the skin; spreads easily on a skin surface; at least partially absorbed following rubbing onto the skin, and more preferably, substantially absorbed following rubbing on the skin.
In terms of tactile properties, an acceptable foam is one, that: creates a pleasant feeling after application; leaves minimal oily residue; and leaves minimal shiny residual look.
Skin drying and skin barrier function. Short chain alcohols are known to dry the skin and impair the integrity of the skin barrier. By contrast, including a film forming agent in the composition of the present invention Does not cause unwanted skin barrier damage.
Irritability. Due to the lack of lower alcohols (C1-C5) and improvement in skin barrier function, skin irritability is eliminated.
The petrolatum foam described herein has several advantages, when compared with hydroalcoholic foam compositions.
In terms of usability, the foamable composition is most advantageous, as revealed by clinical trials:
(i) Ease of Application.
(ii) the Foam is Drip-Free
For the purpose of the specification the external limits of the various ranges given are approximate as will be appreciated by those skilled in the art. Therefore, for the purpose of interpreting the outer limits of the range the limits shall be deemed to include up to a 20% leeway outside the range, and preferably about at least a 10% leeway.
Fields of Applications
According to one or more embodiments, the foamable carrier and the foamable pharmaceutical or cosmetic composition are intended for administration to an animal or a human subject. In one or more embodiments, the composition is intended to treat the skin, a body surface, a body cavity, a deep body cavity, or a mucosal surface, e.g., the mucosa of the nose, mouth, eye, ear, respiratory system, vagina, rectum or colon.
By including an appropriate active agent in the compositions, the composition are useful in treating a patient having any one of a variety of dermatological disorders, which include inflammation as one or their etiological factors (also termed “dermatoses”), such as classified in a non-limiting exemplary manner according to the following groups:
The same advantage is expected when the composition is topically applied to a body cavity or mucosal surfaces, including, but not limited to the cranial cavity, the thoratic cavity, the abdominal cavity, the venteral cavity, the vagina, the rectum and penile cavities, the urinary tract, the nasal cavity, the mouth, the eye, the ear the peritoneum, the large and small bowel, the caecum, bladder, and stomach, the cavity between the uterus and the fallopian tubes, the ovaries and other body areas, which may accept topically-applied products. The composition is suitable to treat conditions of a body cavity and a mucosal membrane, such as post-surgical adhesions, chlamydia infection, gonorrhea infection, hepatitis B, herpes, HIV/AIDS, human papillomavirus (HPV), genital warts, bacterial vaginosis, candidiasis, chancroid, granuloma Inguinale, lymphogranloma venereum, mucopurulent cervicitis (MPC), molluscum contagiosum, nongonococcal urethritis (NGU), trichomoniasis, vulvar disorders, vulvodynia, vulvar pain, yeast infection, vulvar dystrophy, vulvar intraepithelial neoplasia (VIN), contact dermatitis, pelvic inflammation, endometritis, salpingitis, oophoritis, genital cancer, cancer of the cervix, cancer of the vulva, cancer of the vagina, vaginal dryness, dyspareunia, anal and rectal disease, anal abscess/fistula, anal cancer, anal fissure, anal warts, Crohn's disease, hemorrhoids, anal itch, pruritus ani, fecal incontinence, constipation, polyps of the colon and rectum.
According to one or more embodiments, the compositions are also useful in the therapy of non-dermatological disorders by providing transdermal or trans-mucosal delivery of an active agent that is effective against non-dermatological disorders.
In one or more embodiments, the disorder is a health abnormality that responds to treatment with a hormone. A typical example of such abnormality is sexual dysfunction in men and women whereby androgen therapy is successfully used to restore sexual function. Other non-limiting examples of disorders/medical indications that are in the scope of treatment with a hormone according to the present invention are androgen deficiency, estrogen deficiency, growth disorders, hypogonadism, cancer, vasomotor symptoms, menopausal disorders, vulvar and vaginal atrophy, urethritis, hypoestrogenism, osteoarthritis, osteoporosis, uterine bleeding, Hirsutism, Virilization, ovarian tumors, hypothalamic pituitary unit diseases, testicular tumors, prostate cancer, hypopituitarism, Klinefelter's syndrome, testicular feminisation, orchitectomy, vasomotor symptoms (such as “hot flashes”) associated with the menopause, metabolic abnormalities and mood disturbances.
Methodology
A general procedure for preparing foamable compositions is set out in WO 2004/037225, which is incorporated herein by reference.
Waterless Foam
Step 1: Preparation of Water Phase
The water is heated to 70° C.
Step 2: Preparation of Oil Phase
The Oil Phase is prepared by mixing together of all ingredients and heat up to 70° C. Continue mixing until full melting for solid ingredients.
Step 3: PFF Formation
Step 3-a: Emulsification
The Water phase at 70-75° C. is added to the Oil phase in small portions at 70° C. The emulsification is performed in presence of vigorous agitation continues until PFF uniformity is reached for at least 20 min.
Step 4: Addition of Zinc Oxide
Stop heating the PFF and slow addition of Zinc Oxide at 40-50° C. during vigorous mixing. Continue mixing for at lease 30 min.
Petrolatum API (Water/Oil) Emulsion
The procedure is as above with API replacing or in addition to the Zinc oxide. For sensitive ingredients cool to below 40° C. and add them with mild mixing.
Petrolatum Zinc Oxide (Solvent/Oil) Emulsion
The procedure is as above for water in petrolatum emulsion, but, DMI, or PG, or PEG 400 replaces the water.
Petrolatum API (Solvent/Oil) Emulsion
The procedure is as above with API replacing or in addition to the Zinc oxide. For sensitive ingredients cool to below 40° C. and add them with mild mixing.
Petrolatum Zinc Oxide (Waterless)
Step 1: Preparation of Oil Phase
The Oil Phase is prepared by mixing together of all ingredients and heat up to 65° C. Continue mixing until full melting for solid ingredients.
Step 2: Addition of Zinc Oxide
Stop heating the oil phase and slow addition of Zinc Oxide at 40-50° C. during vigorous mixing. Continue mixing for at lease 30 min.
Production Under Vacuum
Optionally, the foamable formulation may be produced under nitrogen and under vacuum. Whilst the whole process can be carried out under an oxygen free environment, it can be sufficient to apply a vacuum after heating and mixing all the ingredients to obtain an emulsion or homogenous liquid. Preferably the production chamber is equipped to apply a vacuum but if not the formulation can be for example placed in a dessicator to remove oxygen prior to filing and crimping.
Loading and Testing of Canisters
By way of non limiting example the objectives of hardness, collapse time tests and aging are briefly set out below as would be appreciated by a person of the art.
Hardness
LFRA100 instrument is used to characterize hardness. A probe is inserted into the test material. The resistance of the material to compression is measured by a calibrated load cell and reported in units of grams on the texture analyzer instrument display. Preferably at least three repeat tests are conducted. The textural characteristics of a dispensed foam can effect the degree of dermal penetration, efficacy, spreadability and acceptability to the user. The results can also be looked at as an indicator of softness. Note: the foam sample is dispensed into an aluminum sample holder and filled to the top of the holder.
Collapse Time
Collapse time (CT) is examined by dispensing a given quantity of foam and photographing sequentially its appearance with time during incubation at 36° C. It is useful for evaluating foam products, which maintain structural stability at skin temperature for at least 1 minute. Thus foams which are structurally stable on the skin for at least one minute are termed “short term stable” compositions or foams.
Viscosity
Viscosity is measured with Brookfield LVDV-II+PRO with spindle SC4-25 at ambient temperature and 10, 5 and 1 RPM. Viscosity is usually measured at 10 RPM. However, at about the apparent upper limit for the spindle of ˜>50,000 CP, the viscosity at 1 RPM may be measured, although the figures are of a higher magnitude.
FTC
FTC (Freeze Thaw Cycles)To check the foam appearance under extreme conditions of repeated cycles of cooling, heating, (first cycle) cooling, heating (second cycle) etc., commencing with −10° C. (24 hours) followed by +40° C. (24 hours) measuring the appearance and again repeating the cycle for up to three times.
Chemical Stability
The amount of active agent present is analyzed in foam expelled from various pressurized canisters containing foam formulations using HPLC. Analysis is carried out at zero time and at appropriate time intervals thereafter. The canisters are stored in controlled temperature incubators at 5° C., at 25° C., at, 40° C. and sometimes at 50° C. At appropriate time intervals canisters are removed and the amount of active agent in the foam sample is measured.
Focus Group
Five healthy volunteers selected at random were give a sample of foam formulation and applied it to the skin on their forearm and were asked to complete a questionnaire.
Corneometer
Skin hydration is measured using a Corneometer® CM 825 instrument. (Courage+Khazaka, Koln, Germany). The measuring principle of the Corneometer® CM 825 is based on capacitance measurement of dielectric medium. Any change in the dielectric constant due to skin surface hydration alters the capacitance of a measuring capacitor. It can detect even slight changes in the skin hydration level.
Bubble Size
Foams are made of gas bubbles entrapped in liquid. The bubble size and distribution reflects in the visual texture and smoothness of the foam. Foam bubbles size is determined by dispensing a foam sample on a glass slide, taking a picture of the foam surface with a digital camera equipped with a macro lens. The diameter of about 30 bubbles is measured manually relatively to calibration standard template. Statistical parameters such as mean bubble diameter, standard deviation and quartiles are then determined. Measuring diameter may also be undertaken with image analysis software. The camera used was a Nikon D40X Camera (resolution 10MP) equipped with Sigma Macro Lens (ref: APO MACRO 150 mm F2.8 EX DG HSM). Pictures obtained are cropped to keep a squared region of 400 pixels×400 pixels.
The light microscope enables observing and measuring particles from few millimeters down to one micron. Light microscope is limited by the visible light wavelength and therefore is useful to measuring size of particles above 800 nanometers and practically from 1 micron (1,000 nanometers).
“Shakability” represents the degree to which the user is able to feel/hear the presence of the liquid contents when the filled pressurized canister is shaken. Shaking is with normal mild force without vigorous shaking or excessive force. When the user cannot sense the motion of the contents during shaking the product may be considered to be non shakable. This property may be of particular importance in cases where shaking is required for affecting proper dispersion of the contents.
Shakability Scoring:
Aging by Centrifugation:
Non-limiting examples of how stock solutions are made up with and without API. Other stock solutions may be made using the same methodology by simply varying adding or omitting ingredients as would be appreciated by one of the ordinary skills in the art.
The following examples further exemplify the stable non-alcoholic foamable pharmaceutical carrier, pharmaceutical compositions thereof, methods for preparing the same, and therapeutic uses of the compositions. The invention is described with reference to the following examples. For the purpose of the Examples below it was sufficient to apply a vacuum only at the crimping stage although for long term stability preferably any vacuum should be applied during manufacture as well at a sufficient pressure so that any oxygen remaining in the formulation is virtually negligible. The examples are for the purposes of illustration only and are not intended to be limiting. Many variations may be carried out by one of ordinary skill in the art and are contemplated within the full scope the description herein.
Section A—Non-Aqueous Formulations with at Least about 60% to about 91% Petrolatum but without Oil and without Silicone
Comments: The formulations of example 2 are waterless ointment foam, without polymers, main hydrophobic petrolatum types are the Sofmetic™ LMP which is characterized in the lowest range of melting point for petroleum jelly USP and Petrolatum white. The ratio of Sofmetic™ and Petrolatum white is balanced to obtain excellent foam yet shakable non washable and heavy occlusive skin cover and greasy skin feeling.
2a. Stock Waterless
Comments: This formula was prepared in a pressurized glass bottle and a translucent single phase was observed with the propellant being dissolved in the petrolatum. See
2b. Stock Waterless+API's
2c. Stock Waterless+API's
3a. Stock Waterless with Zinc Oxide
3b. Stock Waterless with Zinc Oxide+API's
3c. Stock Waterless with Zinc Oxide+API's
Examples 9, 10 and 11 are waterless emulsions of liquid hydrophilic solvents: DMI, PEG 400 or Propylene glycol, stabilized in petrolatum base. It has been unexpectedly observed that replacing the water in above water in petrolatum emulsions, yielded high quality foams.
Part A—Minimal Ingredients of 60% Petrolatum a Foam Adjuvant a Polymer and API
Part B—72% Petrolatum, an Oil, a Surfactant, a Foam Adjuvant, a Polymer and API with different propellants
Part C—61% to 81% Petrolatum Formulations with and without Alkyl Lactate and DMI with API. Formulation 47 is with Different Propellants.
Part D—71% to 77% Petrolatum Formulations with and without Alkyl Lactate and DMI with API. Formulation 49 is with Different Propellants.
Part E—Focus Group
Comments: Each individual applied the foam to their skin and completed a questionnaire when they gave a mark for each foam trait between 1 and 5 for each trait where 5 is excellent and 1 is poor. A preferred formulation is one with an average score eg about 60 or more.
Part F—A Study of Skin-Hydration Effect of Petrolatum Vehicle of Example A9
The study is single blind (study recipient is blinded). Healthy subjects are applied with single dose of formulations as shown in Example A9. Skin hydration is measured using a Corneometer® CM 825 instrument. (Courage+Khazaka, Koln, Germany). The measuring principle of the Corneometer® CM 825 is based on capacitance measurement of dielectric medium. Any change in the dielectric constant due to skin surface hydration alters the capacitance of a measuring capacitor. It can detect even slight changes in the skin hydration level.
Skin hydration level is assessed at baseline with the Corneometer® CM 825. The formulations (about 0.075 g) is applied. Corneometers tested skin hydration after 15 mins following application. The skin was then washed and the hydration again measured.
Four circles of the same size are drawn on the forearms (applying area), two on each side and will be numbered from 1 to 4: The measurements were taken from marked areas only, since those the areas that were exposed to treatment.
Comments: After washing a protective layer was still felt on the skin but the corneometer was able to detect about a 50% improvement in skin hydration as a result of the presence of the occlusive Zinc Oxide formulations even after a short period of 15 mins suggesting utility for example for nappy use.
Exemplary concentrations of active agents in foamable compositions are set out in Table 2. Each active agent is added into, for example, any of the carriers listed in any of the above Examples in a therapeutically effective concentration and amount. The methodology of addition is well known to those of the art. The composition is adjusted in each case so that it is made up to 100% w/w as appropriate by solvent or petrolatum.
Note, all the above active agents have a degree of solubility in water or petrolatum or the composition other than clobestol proprionate, which is practically insoluble; tacrolimus, which is insoluble in water; and betamethasone valerate which although has very limited solubility is nevertheless, surprisingly soluble at least to a degree in the compositions, in the water phase. Note, for example, calcipotriol solubility in water is 0.6 μg/mL.
The above examples represent different drug classes and it is to be understood that other drugs belonging to each of the classes represented above or described elsewhere in the specification may be included and used in the compositions in a safe and effective amount.
Section B—Formulations with in Excess of 50% Petrolatum and Oil, without Silicone and with No Water
atowards excellent
Comments: This formula (having an average HLB of 9.36) was prepared in a pressurized glass bottle and a milky homogenous single phase was observed with the propellant being dissolved in the petrolatum (see
bOne sample showed an almost good foam.
Comments: In these experiments formulations containing liquid surfactants of varying HLB values were prepared by modifying the ratio between Tween 20, a liquid surfactant having an HLB of 16.7, and Span 80, a liquid surfactant having an HLB of 4.3. No significant changes were observed between the various formulations and resulting foams. A different mixture of propellant was tried at 11.5%. Foam quality observed in all three cases was fairly good. In addition, two formulations containing no surfactant (one with aluminum starch octenyl succinate and the other without) were prepared but were not able to produce anything like a viable or usable foam.
Comments: High and relatively Low petrolatum formulations appear to be good waterless carriers for active ingredients. The hardness results observed indicates that both the high and relatively low petrolatum concentrations produce soft foams. The results with active ingredients can be readily extrapolated to apply to the carrier without any active ingredient since the amount of active agent is well below 0.1% and therefore any effect on hardness is anticipated to be negligible. The vitamin D derivative may easily be replaced by an effective amount of another such as calcitriol. Likewise the steroid may be replaced by an effective amount of another steroid such as BMV. Although a combination of API's is exemplified the formulation may alternatively contain only one of them.
Comments: The addition of sorbitan stearate or of polysorbate surfactants enhanced the foam quality. The formulations without sorbitan stearate were less stable physically and chemically. Vehicles 27 and 30 displayed physical and chemical stability for three months at 40 C. It is possible that the polysorbate surfactant may effect stability. Although combined herein in one carrier the active ingredients may in an alternative embodiment be presented in two separate canisters in the same or different carriers adapted to maximize the stability of the active ingredients. For example, the steroid formulation may have a modulating agent present such that the formulation is at an artificial acid pH. Likewise the vitamin D derivative may have a modulating agent present such that the formulation is at an artificial basic pH. The vitamin D derivative may easily be replaced by an effective amount of another such as calcitriol. Likewise the steroid may be replaced by an effective amount of another steroid such as BMV. Although a combination of API's is exemplified the formulation may alternatively contain only one of them.
A) Betamethasone Valerate
B) Betamethasone Dipropionate
C) Clobetasol Propionate
D) Triamcinolone Acetonide
Comments: The lecicthin vehicle showed good foam quality and a collapse time in excess of 300 secs and was found to be stable at 40 C for several months with BMV. Preliminary accelerated stability tests for two weeks with other steroids indicated that the vehicle can be stable with other steroids. It is predicted that if the lecithin carrier were to be stability tested with an effective amount of other steroids for example halobetasol propionate or hydrocortisone butyrate, the formulations would also show stability.
Part A Wherein the Petrolatum Mineral Oil Combination is about at Least 75% and the Petrolatum is in Excess of 50%.
Part B Wherein the Petrolatum Mineral Oil Combination is about at Least 65% and the Petrolatum is in the Majority.
Part C Wherein the Petrolatum Mineral Oil Combination is about at Least 78% and the Petrolatum is in Excess of 50%.
Part C—Results at Zero Time, for FTC (4 Cycles), and after Two Weeks at 40 C
Comments: Formulations 39 and 40 appeared to be the most stable. FTC was four cycles.
Exemplary concentrations of active ingredients in foamable compositions are set out in Table 1. Each active ingredient is added into, for example, any of the carriers listed in any of the above Examples in a therapeutically effective concentration and amount. The methodology of addition is well known to those of the art. The composition is adjusted in each case so that it is made up to 100% w/w by either a solvent or petrolatum.
The above examples represent different drug classes and it is to be understood that other drugs belonging to each of the classes represented above or described elsewhere in the specification may be included and may be used in the compositions in a safe and effective amount.
Section C—Formulations with in Excess of 80% Combinations of Petrolatum and Oil, without Silicone and with No Water
atowards excellent;
Comments: This formula (having an average HLB of 8.56) was prepared in a pressurized glass bottle and a milky homogenous single phase was observed with the propellant being dissolved in the petrolatum (see
Comments: The formulation appears to be a good waterless carrier for active ingredients. The hardness results observed indicates that the high oil petrolatum combination concentrations produce soft foams. The results with active ingredients can be readily extrapolated to apply to the carrier without any active ingredient since the amount of active agent is well below 0.1% and therefore any effect on hardness is anticipated to be negligible. The vitamin D derivative may easily be replaced by an effective amount of another such as calcitriol. Likewise the steroid may be replaced by an effective amount of another steroid such as BMV. Although a combination of API's is exemplified the formulation may alternatively contain only one of them.
Section D—Formulations with in Excess of 50% Petrolatum without Oil, without Silicone and with Up to about 26% Water
1a. Formulation Contain Polymer
1b. Formulation without Polymer
Comments: Example one, table 1a, shows formulations comprising polymers whereas 1b polymer-less foams. It should be noted, that good foams and desired properties are obtained with and without polymers.
2a. Stock Emulsion
2b. Stock Emulsion+API's
2c. Stock Emulsion+API's
3a. Stock Emulsion with Zinc Oxide
Zinc oxide is uniformly dispersed in the formula, no aggregation or flocculation of zinc oxide was observed. The emulsion is non washable and enable tick occlusive persistent layer on the applied skin.
3b. Stock Emulsion with Zinc Oxide+API's
3c. Stock Emulsion with Zinc Oxide+API's
This application claims the benefit of priority under 35 U.S.C. §119(e) to co-pending U.S. Provisional Application No. 60/899,176 filed Feb. 2, 2007, entitled “Non-Alcoholic Foamable Petrolatum Based Pharmaceutical And Cosmetic Compositions And Their Uses”, which is incorporated in its entirety by reference This application claims the benefit of priority under 35 U.S.C. §119(e) to co-pending U.S. Provisional Application No. 60/915,859 filed May 3, 2007, entitled “Non-Aqueous Foamable Petrolatum And Miscible Solvent Based Pharmaceutical And Cosmetic Compositions And Their Uses”, which is incorporated in its entirety by reference. This application is a continuation of U.S. patent application Ser. No. 12/778,591, filed on May 12, 2010, which is a continuation of U.S. patent application Ser. No. 12/025,547, filed on Feb. 4, 2008, which is a continuation-in-part of co-pending U.S. patent application Ser. No. 11/940,290, filed on Nov. 14, 2007, which claims the benefit of priority under 35 U.S.C. §119(e) to U.S. Provisional Patent Application No. 60/858,747, filed on Nov. 14, 2006, both entitled “Stable Non-Alcoholic Foamable Pharmaceutical Emulsion Compositions With An Unctuous Emollient And Their Uses”, all of which are herein incorporated in their entirety by reference.
| Number | Name | Date | Kind |
|---|---|---|---|
| 1159250 | Moulton | Nov 1915 | A |
| 1666684 | Carstens | Apr 1928 | A |
| 1924972 | Beckert | Aug 1933 | A |
| 2085733 | Bird | Jul 1937 | A |
| 2390921 | Clark | Dec 1945 | A |
| 2524590 | Boe | Oct 1950 | A |
| 2586287 | Apperson | Feb 1952 | A |
| 2617754 | Neely | Nov 1952 | A |
| 2767712 | Waterman | Oct 1956 | A |
| 2968628 | Reed | Jan 1961 | A |
| 3004894 | Johnson et al. | Oct 1961 | A |
| 3062715 | Reese et al. | Nov 1962 | A |
| 3067784 | Gorman | Dec 1962 | A |
| 3092255 | Hohman | Jun 1963 | A |
| 3092555 | Horn | Jun 1963 | A |
| 3141821 | Compeau | Jul 1964 | A |
| 3142420 | Gawthrop | Jul 1964 | A |
| 3144386 | Brightenback | Aug 1964 | A |
| 3149543 | Naab | Sep 1964 | A |
| 3154075 | Weckesser | Oct 1964 | A |
| 3178352 | Erickson | Apr 1965 | A |
| 3236457 | Kennedy et al. | Feb 1966 | A |
| 3244589 | Sunnen | Apr 1966 | A |
| 3252859 | Silver | May 1966 | A |
| 3261695 | Sienkiewicz | Jul 1966 | A |
| 3263867 | Lehmann | Aug 1966 | A |
| 3263869 | Corsette | Aug 1966 | A |
| 3298919 | Bishop et al. | Jan 1967 | A |
| 3301444 | Wittke | Jan 1967 | A |
| 3303970 | Breslau et al. | Feb 1967 | A |
| 3330730 | Hernandez | Jul 1967 | A |
| 3333333 | Noack | Aug 1967 | A |
| 3334147 | Brunelle et al. | Aug 1967 | A |
| 3342845 | Sayigh et al. | Sep 1967 | A |
| 3346451 | Collins et al. | Oct 1967 | A |
| 3366494 | Bower et al. | Jan 1968 | A |
| 3369034 | Chalmers | Feb 1968 | A |
| 3377004 | Wittke | Apr 1968 | A |
| 3383280 | Kuehns | May 1968 | A |
| 3384541 | Clark et al. | May 1968 | A |
| 3395214 | Mummert | Jul 1968 | A |
| 3395215 | Schubert | Jul 1968 | A |
| 3401849 | Weber, III | Sep 1968 | A |
| 3419658 | Sanders | Dec 1968 | A |
| 3456052 | Gordon | Jul 1969 | A |
| 3527559 | Sliwinski | Sep 1970 | A |
| 3540448 | Sunnen | Nov 1970 | A |
| 3559890 | Brooks et al. | Feb 1971 | A |
| 3561262 | Borucki | Feb 1971 | A |
| 3563098 | Weber, III | Feb 1971 | A |
| 3574821 | Pfirrmann | Apr 1971 | A |
| 3577518 | Shepherd | May 1971 | A |
| 3667461 | Zamarra | Jun 1972 | A |
| 3751562 | Nichols | Aug 1973 | A |
| 3770648 | Mackles | Nov 1973 | A |
| 3787566 | Gauvreau | Jan 1974 | A |
| 3819524 | Schubert et al. | Jun 1974 | A |
| 3824303 | Lanzet et al. | Jul 1974 | A |
| 3841525 | Siegel | Oct 1974 | A |
| 3849569 | Mead | Nov 1974 | A |
| 3849580 | Weinstein et al. | Nov 1974 | A |
| 3865275 | De Nunzio | Feb 1975 | A |
| 3866800 | Schmitt | Feb 1975 | A |
| 3878118 | Watson | Apr 1975 | A |
| 3882228 | Boncey et al. | May 1975 | A |
| 3886084 | Vassiliades | May 1975 | A |
| 3890305 | Weber et al. | Jun 1975 | A |
| 3912665 | Spitzer et al. | Oct 1975 | A |
| 3912667 | Spitzer et al. | Oct 1975 | A |
| 3923970 | Breuer | Dec 1975 | A |
| 3929985 | Webb, Jr. | Dec 1975 | A |
| 3952916 | Phillips | Apr 1976 | A |
| 3953591 | Snyder | Apr 1976 | A |
| 3959160 | Horsler et al. | May 1976 | A |
| 3962150 | Viola | Jun 1976 | A |
| 3963833 | DeSalva et al. | Jun 1976 | A |
| 3966090 | Prussin et al. | Jun 1976 | A |
| 3966632 | Colliopoulos et al. | Jun 1976 | A |
| 3970219 | Spitzer et al. | Jul 1976 | A |
| 3970584 | Hart et al. | Jul 1976 | A |
| 3993224 | Harrison | Nov 1976 | A |
| 3997467 | Jederstrom | Dec 1976 | A |
| 4001391 | Feinstone et al. | Jan 1977 | A |
| 4001442 | Stahlberger et al. | Jan 1977 | A |
| 4018396 | Shoemaker et al. | Apr 1977 | A |
| 4019657 | Spitzer et al. | Apr 1977 | A |
| 4052513 | Kaplan | Oct 1977 | A |
| 4083974 | Turi | Apr 1978 | A |
| 4102995 | Hebborn | Jul 1978 | A |
| 4110426 | Barnhurst et al. | Aug 1978 | A |
| 4124149 | Spitzer et al. | Nov 1978 | A |
| 4145411 | Mende | Mar 1979 | A |
| 4151272 | Geary et al. | Apr 1979 | A |
| 4160827 | Cho et al. | Jul 1979 | A |
| 4178373 | Klein et al. | Dec 1979 | A |
| 4213979 | Levine | Jul 1980 | A |
| 4214000 | Papa | Jul 1980 | A |
| 4226344 | Booth et al. | Oct 1980 | A |
| 4229432 | Geria | Oct 1980 | A |
| 4230701 | Holick et al. | Oct 1980 | A |
| 4241048 | Durbak et al. | Dec 1980 | A |
| 4241149 | Labes et al. | Dec 1980 | A |
| 4252787 | Sherman et al. | Feb 1981 | A |
| 4254104 | Suzuki et al. | Mar 1981 | A |
| 4268499 | Keil | May 1981 | A |
| 4271149 | Winicov et al. | Jun 1981 | A |
| 4278206 | Prussin | Jul 1981 | A |
| 4292250 | DeLuca et al. | Sep 1981 | A |
| 4292326 | Nazzaro-Porro et al. | Sep 1981 | A |
| 4299826 | Luedders | Nov 1981 | A |
| 4305936 | Klein | Dec 1981 | A |
| 4309995 | Sacco | Jan 1982 | A |
| 4310510 | Sherman et al. | Jan 1982 | A |
| 4323582 | Siegel et al. | Apr 1982 | A |
| 4323694 | Scala, Jr. | Apr 1982 | A |
| 4325939 | Shah | Apr 1982 | A |
| 4329990 | Sneider | May 1982 | A |
| 4335120 | Holick et al. | Jun 1982 | A |
| 4338211 | Stiros | Jul 1982 | A |
| 4352808 | Rane et al. | Oct 1982 | A |
| 4363806 | Bergström et al. | Dec 1982 | A |
| 4385161 | Caunt et al. | May 1983 | A |
| 4386104 | Nazzaro-Porro | May 1983 | A |
| 4393066 | Garrett et al. | Jul 1983 | A |
| 4427670 | Ofuchi et al. | Jan 1984 | A |
| 4439416 | Cordon et al. | Mar 1984 | A |
| 4439441 | Hallesy et al. | Mar 1984 | A |
| 4440320 | Wernicke | Apr 1984 | A |
| 4447486 | Hoppe et al. | May 1984 | A |
| 4469674 | Shah et al. | Sep 1984 | A |
| 4508705 | Chaudhuri et al. | Apr 1985 | A |
| 4522948 | Walker | Jun 1985 | A |
| 4529601 | Broberg et al. | Jul 1985 | A |
| 4529605 | Lynch et al. | Jul 1985 | A |
| 4552872 | Cooper et al. | Nov 1985 | A |
| 4574052 | Gupte et al. | Mar 1986 | A |
| 4576961 | Lorck et al. | Mar 1986 | A |
| 4595526 | Lai | Jun 1986 | A |
| 4603812 | Stoesser et al. | Aug 1986 | A |
| 4607101 | Bernstein | Aug 1986 | A |
| 4627973 | Moran et al. | Dec 1986 | A |
| 4628063 | Haines et al. | Dec 1986 | A |
| 4661340 | Nagy née Kricsfalussy et al. | Apr 1987 | A |
| 4661524 | Thomson et al. | Apr 1987 | A |
| 4672078 | Sakai et al. | Jun 1987 | A |
| 4673569 | Shernov et al. | Jun 1987 | A |
| 4678463 | Millar | Jul 1987 | A |
| 4701320 | Hasegawa et al. | Oct 1987 | A |
| 4725609 | Kull, Jr. et al. | Feb 1988 | A |
| 4738396 | Doi et al. | Apr 1988 | A |
| 4741855 | Grote et al. | May 1988 | A |
| 4752465 | Mackles | Jun 1988 | A |
| 4770634 | Pellico | Sep 1988 | A |
| 4772427 | Dawson | Sep 1988 | A |
| 4780309 | Geria et al. | Oct 1988 | A |
| 4784842 | London et al. | Nov 1988 | A |
| 4792062 | Goncalves | Dec 1988 | A |
| 4798682 | Ansmann | Jan 1989 | A |
| 4804674 | Curtis-Prior et al. | Feb 1989 | A |
| 4806262 | Snyder | Feb 1989 | A |
| 4808388 | Beutler et al. | Feb 1989 | A |
| 4822613 | Rodero | Apr 1989 | A |
| 4822614 | Rodero | Apr 1989 | A |
| 4826048 | Skorka et al. | May 1989 | A |
| 4827378 | Gillan et al. | May 1989 | A |
| 4828837 | Uster et al. | May 1989 | A |
| 4836217 | Fischer et al. | Jun 1989 | A |
| 4837019 | Georgalas et al. | Jun 1989 | A |
| 4837378 | Borgman | Jun 1989 | A |
| 4844902 | Grohe | Jul 1989 | A |
| 4847068 | Dole et al. | Jul 1989 | A |
| 4849117 | Bronner et al. | Jul 1989 | A |
| 4851154 | Grollier et al. | Jul 1989 | A |
| 4855294 | Patel et al. | Aug 1989 | A |
| 4863900 | Pollock et al. | Sep 1989 | A |
| 4867967 | Crutcher | Sep 1989 | A |
| 4873078 | Edmundson et al. | Oct 1989 | A |
| 4874794 | Katz | Oct 1989 | A |
| 4876083 | Grollier et al. | Oct 1989 | A |
| 4877805 | Kligman | Oct 1989 | A |
| 4885282 | Thornfeldt | Dec 1989 | A |
| 4897262 | Nandagiri et al. | Jan 1990 | A |
| 4902281 | Avoy | Feb 1990 | A |
| 4906453 | Tsoucalas | Mar 1990 | A |
| 4913893 | Varco et al. | Apr 1990 | A |
| 4919934 | Deckner et al. | Apr 1990 | A |
| 4933330 | Jorgensen et al. | Jun 1990 | A |
| 4950420 | Svarz | Aug 1990 | A |
| 4954487 | Cooper et al. | Sep 1990 | A |
| 4956049 | Bernheim et al. | Sep 1990 | A |
| 4957732 | Grollier et al. | Sep 1990 | A |
| 4963351 | Weston | Oct 1990 | A |
| 4965063 | Casey et al. | Oct 1990 | A |
| 4966779 | Kirk | Oct 1990 | A |
| 4970067 | Panandiker et al. | Nov 1990 | A |
| 4975466 | Bottcher et al. | Dec 1990 | A |
| 4981367 | Brazelton | Jan 1991 | A |
| 4981677 | Thau | Jan 1991 | A |
| 4981679 | Briggs et al. | Jan 1991 | A |
| 4981845 | Pereira et al. | Jan 1991 | A |
| 4985459 | Sunshine et al. | Jan 1991 | A |
| 4992478 | Geria | Feb 1991 | A |
| 4993496 | Riedle et al. | Feb 1991 | A |
| 4996193 | Hewitt et al. | Feb 1991 | A |
| 5002540 | Brodman et al. | Mar 1991 | A |
| 5002680 | Schmidt et al. | Mar 1991 | A |
| 5007556 | Lover | Apr 1991 | A |
| 5013297 | Cattanach | May 1991 | A |
| 5015471 | Birtwistle et al. | May 1991 | A |
| 5019375 | Tanner et al. | May 1991 | A |
| 5034220 | Helioff et al. | Jul 1991 | A |
| 5035895 | Shibusawa et al. | Jul 1991 | A |
| 5053228 | Mori et al. | Oct 1991 | A |
| 5071648 | Rosenblatt | Dec 1991 | A |
| 5071881 | Parfondry et al. | Dec 1991 | A |
| 5073371 | Turner et al. | Dec 1991 | A |
| 5082651 | Healey et al. | Jan 1992 | A |
| 5087618 | Bodor | Feb 1992 | A |
| 5089252 | Grollier et al. | Feb 1992 | A |
| 5091111 | Neumiller | Feb 1992 | A |
| 5094853 | Hagarty | Mar 1992 | A |
| 5100917 | Flynn et al. | Mar 1992 | A |
| 5104645 | Cardin et al. | Apr 1992 | A |
| 5112359 | Murphy et al. | May 1992 | A |
| 5114718 | Damani | May 1992 | A |
| 5122519 | Ritter | Jun 1992 | A |
| 5130121 | Kopolow et al. | Jul 1992 | A |
| 5133972 | Ferrini et al. | Jul 1992 | A |
| 5135915 | Czarniecki et al. | Aug 1992 | A |
| 5137714 | Scott | Aug 1992 | A |
| 5143717 | Davis | Sep 1992 | A |
| 5156765 | Smrt | Oct 1992 | A |
| 5160665 | Owada et al. | Nov 1992 | A |
| 5164357 | Bartman et al. | Nov 1992 | A |
| 5164367 | Pickart | Nov 1992 | A |
| 5167950 | Lins | Dec 1992 | A |
| 5171577 | Griat et al. | Dec 1992 | A |
| 5196405 | Packman | Mar 1993 | A |
| 5204090 | Han | Apr 1993 | A |
| 5204093 | Victor | Apr 1993 | A |
| 5208031 | Kelly | May 1993 | A |
| 5217707 | Szabo et al. | Jun 1993 | A |
| 5219877 | Shah et al. | Jun 1993 | A |
| 5221534 | DesLauriers et al. | Jun 1993 | A |
| 5221696 | Ke et al. | Jun 1993 | A |
| 5230897 | Griffin et al. | Jul 1993 | A |
| 5236707 | Stewart, II | Aug 1993 | A |
| 5252246 | Ding et al. | Oct 1993 | A |
| 5254334 | Ramirez et al. | Oct 1993 | A |
| 5262407 | Leveque et al. | Nov 1993 | A |
| 5266592 | Grub et al. | Nov 1993 | A |
| 5279819 | Hayes | Jan 1994 | A |
| 5286475 | Louvet et al. | Feb 1994 | A |
| 5294365 | Welch et al. | Mar 1994 | A |
| 5300286 | Gee | Apr 1994 | A |
| 5301841 | Fuchs | Apr 1994 | A |
| 5308643 | Osipow et al. | May 1994 | A |
| 5314904 | Egidio et al. | May 1994 | A |
| 5318774 | Alban et al. | Jun 1994 | A |
| 5322683 | Mackles et al. | Jun 1994 | A |
| 5326557 | Glover et al. | Jul 1994 | A |
| 5344051 | Brown | Sep 1994 | A |
| 5346135 | Vincent | Sep 1994 | A |
| 5352437 | Nakagawa et al. | Oct 1994 | A |
| 5369131 | Poli et al. | Nov 1994 | A |
| 5378451 | Gorman et al. | Jan 1995 | A |
| 5378730 | Lee et al. | Jan 1995 | A |
| 5380761 | Szabo Anna Z. et al. | Jan 1995 | A |
| 5384308 | Henkin | Jan 1995 | A |
| 5385943 | Nazzaro-Porro | Jan 1995 | A |
| 5389305 | Repinec et al. | Feb 1995 | A |
| 5389676 | Michaels | Feb 1995 | A |
| 5397312 | Rademaker et al. | Mar 1995 | A |
| 5398846 | Corba et al. | Mar 1995 | A |
| 5399205 | Shinohara et al. | Mar 1995 | A |
| 5411992 | Eini et al. | May 1995 | A |
| 5422361 | Munayyer et al. | Jun 1995 | A |
| 5429815 | Faryniarz et al. | Jul 1995 | A |
| 5435996 | Glover et al. | Jul 1995 | A |
| 5439670 | Purewal et al. | Aug 1995 | A |
| 5439682 | Wivell et al. | Aug 1995 | A |
| 5447725 | Damani et al. | Sep 1995 | A |
| 5449520 | Frigerio et al. | Sep 1995 | A |
| 5451404 | Furman | Sep 1995 | A |
| 5482965 | Rajadhyaksha | Jan 1996 | A |
| 5491245 | Gruning et al. | Feb 1996 | A |
| 5500211 | George et al. | Mar 1996 | A |
| 5508033 | Briand | Apr 1996 | A |
| 5512555 | Waldstreicher | Apr 1996 | A |
| 5514367 | Lentini et al. | May 1996 | A |
| 5514369 | Salka et al. | May 1996 | A |
| 5520918 | Smith | May 1996 | A |
| 5523078 | Baylin | Jun 1996 | A |
| 5527534 | Myhling | Jun 1996 | A |
| 5527822 | Scheiner | Jun 1996 | A |
| 5529770 | McKinzie et al. | Jun 1996 | A |
| 5531703 | Skwarek et al. | Jul 1996 | A |
| 5534261 | Rodgers et al. | Jul 1996 | A |
| 5536743 | Borgman | Jul 1996 | A |
| 5540853 | Trinh et al. | Jul 1996 | A |
| 5545401 | Shanbrom | Aug 1996 | A |
| 5547989 | Chamness | Aug 1996 | A |
| 5558872 | Jones et al. | Sep 1996 | A |
| 5560859 | Hartmann et al. | Oct 1996 | A |
| 5567420 | McEleney et al. | Oct 1996 | A |
| 5576016 | Amselem et al. | Nov 1996 | A |
| 5578315 | Chien et al. | Nov 1996 | A |
| 5585104 | Ha et al. | Dec 1996 | A |
| 5589157 | Hatfield | Dec 1996 | A |
| 5589515 | Suzuki et al. | Dec 1996 | A |
| 5597560 | Bergamini et al. | Jan 1997 | A |
| 5603940 | Candau et al. | Feb 1997 | A |
| 5605679 | Hansenne et al. | Feb 1997 | A |
| 5608119 | Amano et al. | Mar 1997 | A |
| 5611463 | Favre | Mar 1997 | A |
| 5612056 | Jenner et al. | Mar 1997 | A |
| 5613583 | Kono et al. | Mar 1997 | A |
| 5613623 | Hildebrandt | Mar 1997 | A |
| 5614171 | Clavenna et al. | Mar 1997 | A |
| 5614178 | Bloom et al. | Mar 1997 | A |
| 5618516 | Clavenna et al. | Apr 1997 | A |
| 5635469 | Fowler et al. | Jun 1997 | A |
| 5641480 | Vermeer | Jun 1997 | A |
| 5643600 | Mathur | Jul 1997 | A |
| 5645842 | Gruning et al. | Jul 1997 | A |
| 5648380 | Martin | Jul 1997 | A |
| 5650554 | Moloney | Jul 1997 | A |
| 5658575 | Ribier et al. | Aug 1997 | A |
| 5658749 | Thornton | Aug 1997 | A |
| 5658956 | Martin et al. | Aug 1997 | A |
| 5663208 | Martin | Sep 1997 | A |
| 5672634 | Tseng et al. | Sep 1997 | A |
| 5679324 | Lisboa et al. | Oct 1997 | A |
| 5683710 | Akemi et al. | Nov 1997 | A |
| 5686088 | Mitra et al. | Nov 1997 | A |
| 5693258 | Tonomura et al. | Dec 1997 | A |
| 5695551 | Buckingham et al. | Dec 1997 | A |
| 5695747 | Forestier et al. | Dec 1997 | A |
| 5700396 | Suzuki et al. | Dec 1997 | A |
| 5705472 | Hayes et al. | Jan 1998 | A |
| 5716611 | Oshlack et al. | Feb 1998 | A |
| 5716621 | Bello | Feb 1998 | A |
| 5719122 | Chiodini et al. | Feb 1998 | A |
| 5719197 | Kanios et al. | Feb 1998 | A |
| 5725872 | Stamm et al. | Mar 1998 | A |
| 5725874 | Oda | Mar 1998 | A |
| 5730964 | Waldstreicher | Mar 1998 | A |
| 5733558 | Breton et al. | Mar 1998 | A |
| 5733572 | Unger et al. | Mar 1998 | A |
| 5747049 | Tominaga | May 1998 | A |
| 5753241 | Ribier et al. | May 1998 | A |
| 5753245 | Fowler et al. | May 1998 | A |
| 5753270 | Beauchamp et al. | May 1998 | A |
| 5759520 | Sachetto | Jun 1998 | A |
| 5759579 | Singh et al. | Jun 1998 | A |
| 5767104 | Bar-Shalom et al. | Jun 1998 | A |
| 5773410 | Yamamoto | Jun 1998 | A |
| 5783202 | Tomlinson et al. | Jul 1998 | A |
| 5788664 | Scalise | Aug 1998 | A |
| 5792448 | Dubief et al. | Aug 1998 | A |
| 5792922 | Moloney et al. | Aug 1998 | A |
| 5797955 | Walters | Aug 1998 | A |
| 5804546 | Hall et al. | Sep 1998 | A |
| 5807571 | List | Sep 1998 | A |
| 5817322 | Xu et al. | Oct 1998 | A |
| 5824650 | De Lacharriere et al. | Oct 1998 | A |
| 5833960 | Gers-Barlag et al. | Nov 1998 | A |
| 5833961 | Siegfried et al. | Nov 1998 | A |
| 5837270 | Burgess | Nov 1998 | A |
| 5840744 | Borgman | Nov 1998 | A |
| 5840771 | Oldham et al. | Nov 1998 | A |
| 5843411 | Hernandez et al. | Dec 1998 | A |
| 5846983 | Sandborn et al. | Dec 1998 | A |
| 5849042 | Lim et al. | Dec 1998 | A |
| 5856452 | Moloney et al. | Jan 1999 | A |
| 5858371 | Singh et al. | Jan 1999 | A |
| 5865347 | Welschoff | Feb 1999 | A |
| 5866040 | Nakama et al. | Feb 1999 | A |
| 5869529 | Sintov et al. | Feb 1999 | A |
| 5871720 | Gutierrez et al. | Feb 1999 | A |
| 5877216 | Place et al. | Mar 1999 | A |
| 5879469 | Avram et al. | Mar 1999 | A |
| 5881493 | Restive | Mar 1999 | A |
| 5885581 | Massand | Mar 1999 | A |
| 5889028 | Sandborn et al. | Mar 1999 | A |
| 5889054 | Yu et al. | Mar 1999 | A |
| 5891458 | Britton et al. | Apr 1999 | A |
| 5902574 | Stoner et al. | May 1999 | A |
| 5902789 | Stoltz | May 1999 | A |
| 5905092 | Osborne et al. | May 1999 | A |
| 5910382 | Goodenough et al. | Jun 1999 | A |
| 5911981 | Dahms et al. | Jun 1999 | A |
| 5912007 | Pan et al. | Jun 1999 | A |
| 5914122 | Otterbeck et al. | Jun 1999 | A |
| 5914310 | Li et al. | Jun 1999 | A |
| 5919830 | Gopalkrishnan et al. | Jul 1999 | A |
| 5922331 | Mausner | Jul 1999 | A |
| 5925669 | Katz et al. | Jul 1999 | A |
| 5939376 | Durbut et al. | Aug 1999 | A |
| 5948682 | Moloney | Sep 1999 | A |
| 5951544 | Konwitz | Sep 1999 | A |
| 5951989 | Heymann | Sep 1999 | A |
| 5951993 | Scholz et al. | Sep 1999 | A |
| 5952373 | Lanzendorfer et al. | Sep 1999 | A |
| 5952392 | Katz et al. | Sep 1999 | A |
| 5955414 | Brown et al. | Sep 1999 | A |
| 5959161 | Kenmochi et al. | Sep 1999 | A |
| 5961957 | McAnalley | Oct 1999 | A |
| 5961998 | Arnaud et al. | Oct 1999 | A |
| 5972310 | Sachetto | Oct 1999 | A |
| 5976555 | Liu et al. | Nov 1999 | A |
| 5980904 | Leverett et al. | Nov 1999 | A |
| 5990100 | Rosenberg et al. | Nov 1999 | A |
| 5993846 | Friedman et al. | Nov 1999 | A |
| 6001341 | Genova et al. | Dec 1999 | A |
| 6006948 | Auer | Dec 1999 | A |
| 6019967 | Breton et al. | Feb 2000 | A |
| 6024942 | Tanner et al. | Feb 2000 | A |
| 6030630 | Fleury et al. | Feb 2000 | A |
| 6033647 | Touzan et al. | Mar 2000 | A |
| 6039936 | Restle et al. | Mar 2000 | A |
| 6042848 | Lawyer et al. | Mar 2000 | A |
| 6045779 | Mueller et al. | Apr 2000 | A |
| 6060041 | Candau et al. | May 2000 | A |
| 6071536 | Suzuki et al. | Jun 2000 | A |
| 6071541 | Murad | Jun 2000 | A |
| 6075056 | Quigley, Jr. et al. | Jun 2000 | A |
| 6080394 | Lin et al. | Jun 2000 | A |
| 6087310 | Heinkel | Jul 2000 | A |
| 6087317 | Gee | Jul 2000 | A |
| 6090772 | Kaiser et al. | Jul 2000 | A |
| 6093408 | Hasenoehrl et al. | Jul 2000 | A |
| 6096756 | Crain et al. | Aug 2000 | A |
| 6110477 | Hernandez et al. | Aug 2000 | A |
| 6110966 | Pollock | Aug 2000 | A |
| 6113888 | Castro et al. | Sep 2000 | A |
| 6116466 | Gueret | Sep 2000 | A |
| 6121210 | Taylor | Sep 2000 | A |
| 6126920 | Jones et al. | Oct 2000 | A |
| 6133327 | Kimura et al. | Oct 2000 | A |
| 6140355 | Egidio et al. | Oct 2000 | A |
| 6146645 | Deckers et al. | Nov 2000 | A |
| 6146664 | Siddiqui | Nov 2000 | A |
| 6162834 | Sebillotte-Arnaud et al. | Dec 2000 | A |
| 6165455 | Torgerson et al. | Dec 2000 | A |
| 6168576 | Reynolds | Jan 2001 | B1 |
| 6171347 | Kunz et al. | Jan 2001 | B1 |
| 6180669 | Tamarkin | Jan 2001 | B1 |
| 6183762 | Deckers et al. | Feb 2001 | B1 |
| 6186367 | Harrold | Feb 2001 | B1 |
| 6187290 | Gilchrist et al. | Feb 2001 | B1 |
| 6189810 | Nerushai et al. | Feb 2001 | B1 |
| 6190365 | Abbott et al. | Feb 2001 | B1 |
| 6204285 | Fabiano et al. | Mar 2001 | B1 |
| 6210656 | Touzan et al. | Apr 2001 | B1 |
| 6210742 | Deckers et al. | Apr 2001 | B1 |
| 6214318 | Osipow et al. | Apr 2001 | B1 |
| 6214788 | Velazco et al. | Apr 2001 | B1 |
| 6217887 | Beerse et al. | Apr 2001 | B1 |
| 6221381 | Shelford et al. | Apr 2001 | B1 |
| 6221823 | Crisanti et al. | Apr 2001 | B1 |
| 6224888 | Vatter et al. | May 2001 | B1 |
| 6231837 | Stroud et al. | May 2001 | B1 |
| 6232315 | Shafer et al. | May 2001 | B1 |
| 6241971 | Fox et al. | Jun 2001 | B1 |
| 6251369 | Stoltz | Jun 2001 | B1 |
| 6258374 | Friess et al. | Jul 2001 | B1 |
| 6261544 | Coury et al. | Jul 2001 | B1 |
| 6270781 | Gehlsen | Aug 2001 | B1 |
| 6271295 | Powell et al. | Aug 2001 | B1 |
| 6274150 | Simonnet et al. | Aug 2001 | B1 |
| 6283336 | Dwyer et al. | Sep 2001 | B1 |
| 6284802 | Bissett et al. | Sep 2001 | B1 |
| 6287546 | Reich et al. | Sep 2001 | B1 |
| 6294550 | Place et al. | Sep 2001 | B1 |
| 6299023 | Arnone | Oct 2001 | B1 |
| 6299032 | Hamilton | Oct 2001 | B1 |
| 6299900 | Reed et al. | Oct 2001 | B1 |
| 6305578 | Hildebrandt et al. | Oct 2001 | B1 |
| 6306841 | Place et al. | Oct 2001 | B1 |
| 6308863 | Harman | Oct 2001 | B1 |
| 6319913 | Mak et al. | Nov 2001 | B1 |
| 6328950 | Franzke et al. | Dec 2001 | B1 |
| 6328982 | Shiroyama et al. | Dec 2001 | B1 |
| 6333362 | Lorant | Dec 2001 | B1 |
| 6335022 | Simonnet et al. | Jan 2002 | B1 |
| 6341717 | Auer | Jan 2002 | B2 |
| 6344218 | Dodd et al. | Feb 2002 | B1 |
| 6348229 | Eini et al. | Feb 2002 | B1 |
| 6355230 | Gers-Barlag et al. | Mar 2002 | B2 |
| 6358541 | Goodman | Mar 2002 | B1 |
| 6358924 | Hoffmann | Mar 2002 | B1 |
| 6364854 | Ferrer et al. | Apr 2002 | B1 |
| 6372234 | Deckers et al. | Apr 2002 | B1 |
| 6375936 | Allard et al. | Apr 2002 | B1 |
| 6375960 | Simonnet et al. | Apr 2002 | B1 |
| 6383471 | Chen et al. | May 2002 | B1 |
| 6395258 | Steer | May 2002 | B1 |
| 6395300 | Straub et al. | May 2002 | B1 |
| 6403061 | Candau et al. | Jun 2002 | B1 |
| 6403069 | Chopra et al. | Jun 2002 | B1 |
| 6410036 | De Rosa et al. | Jun 2002 | B1 |
| 6423323 | Neubourg | Jul 2002 | B2 |
| 6423329 | Sine et al. | Jul 2002 | B1 |
| 6428772 | Singh et al. | Aug 2002 | B1 |
| 6433003 | Bobrove et al. | Aug 2002 | B1 |
| 6433024 | Popp et al. | Aug 2002 | B1 |
| 6433033 | Isobe et al. | Aug 2002 | B1 |
| 6433068 | Morrison et al. | Aug 2002 | B1 |
| 6437006 | Yoon et al. | Aug 2002 | B1 |
| 6440429 | Torizuka et al. | Aug 2002 | B1 |
| 6447801 | Salafsky et al. | Sep 2002 | B1 |
| 6451777 | Bradbury et al. | Sep 2002 | B1 |
| 6455076 | Hahn et al. | Sep 2002 | B1 |
| 6468989 | Chang et al. | Oct 2002 | B1 |
| 6479058 | McCadden | Nov 2002 | B1 |
| 6479060 | Jones et al. | Nov 2002 | B1 |
| 6479532 | Kamimura et al. | Nov 2002 | B1 |
| 6482810 | Brem et al. | Nov 2002 | B1 |
| 6486168 | Skwierczynski et al. | Nov 2002 | B1 |
| 6488947 | Bekele | Dec 2002 | B1 |
| 6511655 | Muller et al. | Jan 2003 | B1 |
| 6514487 | Barr | Feb 2003 | B1 |
| 6524594 | Santora et al. | Feb 2003 | B1 |
| 6531118 | Gonzalez et al. | Mar 2003 | B1 |
| 6534455 | Maurin et al. | Mar 2003 | B1 |
| 6536629 | van der Heijden | Mar 2003 | B2 |
| 6544530 | Friedman | Apr 2003 | B1 |
| 6544562 | Singh et al. | Apr 2003 | B2 |
| 6547063 | Zaveri et al. | Apr 2003 | B1 |
| 6548074 | Mohammadi | Apr 2003 | B1 |
| 6551604 | Beck et al. | Apr 2003 | B1 |
| 6562355 | Renault | May 2003 | B1 |
| 6566350 | Ono et al. | May 2003 | B2 |
| 6582679 | Stein et al. | Jun 2003 | B2 |
| 6582710 | Deckers et al. | Jun 2003 | B2 |
| 6589509 | Keller et al. | Jul 2003 | B2 |
| 6596287 | Deckers et al. | Jul 2003 | B2 |
| 6599513 | Deckers et al. | Jul 2003 | B2 |
| 6607716 | Smith et al. | Aug 2003 | B1 |
| 6610315 | Scholz et al. | Aug 2003 | B2 |
| 6620773 | Stork et al. | Sep 2003 | B1 |
| 6638981 | Williams et al. | Oct 2003 | B2 |
| 6649571 | Morgan | Nov 2003 | B1 |
| 6649574 | Cardis et al. | Nov 2003 | B2 |
| 6672483 | Roy | Jan 2004 | B1 |
| 6682726 | Marchesi et al. | Jan 2004 | B2 |
| 6682750 | Loffler et al. | Jan 2004 | B2 |
| 6691898 | Hurray et al. | Feb 2004 | B2 |
| 6706290 | Kajander et al. | Mar 2004 | B1 |
| 6709663 | Espinoza | Mar 2004 | B2 |
| 6723309 | Deane | Apr 2004 | B1 |
| 6730288 | Abram | May 2004 | B1 |
| 6736860 | Patel et al. | May 2004 | B2 |
| 6753000 | Breton et al. | Jun 2004 | B2 |
| 6753013 | Didriksen et al. | Jun 2004 | B1 |
| 6753167 | Moloney et al. | Jun 2004 | B2 |
| 6762158 | Lukenbach et al. | Jul 2004 | B2 |
| 6765001 | Gans et al. | Jul 2004 | B2 |
| 6774114 | Castiel et al. | Aug 2004 | B2 |
| 6777591 | Chaudhary et al. | Aug 2004 | B1 |
| 6790435 | Ma et al. | Sep 2004 | B1 |
| 6796973 | Contente et al. | Sep 2004 | B1 |
| RE38623 | Hernandez et al. | Oct 2004 | E |
| 6811767 | Bosch et al. | Nov 2004 | B1 |
| 6834778 | Jinbo et al. | Dec 2004 | B2 |
| 6841547 | Brown et al. | Jan 2005 | B2 |
| 6843390 | Bristor | Jan 2005 | B1 |
| 6875438 | Kraemer et al. | Apr 2005 | B2 |
| 6881271 | Ochiai | Apr 2005 | B2 |
| 6890567 | Nakatsu et al. | May 2005 | B2 |
| 6897195 | Su et al. | May 2005 | B2 |
| 6902737 | Quemin et al. | Jun 2005 | B2 |
| 6911211 | Eini et al. | Jun 2005 | B2 |
| 6914057 | Ryan et al. | Jul 2005 | B1 |
| 6946120 | Wai-Chiu So et al. | Sep 2005 | B2 |
| 6946139 | Henning | Sep 2005 | B2 |
| 6951654 | Malcolm et al. | Oct 2005 | B2 |
| 6955816 | Klysz | Oct 2005 | B2 |
| 6956062 | Beilfuss et al. | Oct 2005 | B2 |
| 6958154 | Andolino Brandt et al. | Oct 2005 | B2 |
| 6967023 | Eini et al. | Nov 2005 | B1 |
| 6968982 | Burns | Nov 2005 | B1 |
| 6969521 | Gonzalez et al. | Nov 2005 | B1 |
| RE38964 | Shillington | Jan 2006 | E |
| 6986883 | Pellico | Jan 2006 | B2 |
| 6994863 | Eini et al. | Feb 2006 | B2 |
| 7002486 | Lawrence | Feb 2006 | B2 |
| 7014844 | Mahalingam et al. | Mar 2006 | B2 |
| 7021499 | Hansen et al. | Apr 2006 | B2 |
| 7029659 | Abram | Apr 2006 | B2 |
| 7060253 | Mundschenk | Jun 2006 | B1 |
| 7078058 | Jones et al. | Jul 2006 | B2 |
| 7083799 | Giacomoni | Aug 2006 | B1 |
| 7137536 | Walters et al. | Nov 2006 | B2 |
| 7195135 | Garcia | Mar 2007 | B1 |
| 7222802 | Sweeton | May 2007 | B2 |
| 7225518 | Eidenschink et al. | Jun 2007 | B2 |
| 7226230 | Liberatore | Jun 2007 | B2 |
| 7235251 | Hamer et al. | Jun 2007 | B2 |
| 7252816 | Angel et al. | Aug 2007 | B1 |
| 7270828 | Masuda et al. | Sep 2007 | B2 |
| 7455195 | Mekata | Nov 2008 | B2 |
| 7497354 | Decottignies et al. | Mar 2009 | B2 |
| 7575739 | Tamarkin et al. | Aug 2009 | B2 |
| 7645803 | Tamarkin et al. | Jan 2010 | B2 |
| 7654415 | van der Heijden | Feb 2010 | B2 |
| 7682623 | Eini et al. | Mar 2010 | B2 |
| 7700076 | Tamarkin et al. | Apr 2010 | B2 |
| 7704518 | Tamarkin et al. | Apr 2010 | B2 |
| 7758888 | Lapidot et al. | Jul 2010 | B2 |
| 7793807 | Goujon et al. | Sep 2010 | B2 |
| 7820145 | Tamarkin et al. | Oct 2010 | B2 |
| 7842791 | Britten et al. | Nov 2010 | B2 |
| 7960416 | Sato et al. | Jun 2011 | B2 |
| 8114385 | Tamarkin et al. | Feb 2012 | B2 |
| 8119106 | Tamarkin et al. | Feb 2012 | B2 |
| 8119109 | Tamarkin et al. | Feb 2012 | B2 |
| 8158109 | Abram et al. | Apr 2012 | B2 |
| 8192749 | Ashley | Jun 2012 | B2 |
| 8211874 | Theobald et al. | Jul 2012 | B2 |
| 8343945 | Tamarkin et al. | Jan 2013 | B2 |
| 8362091 | Tamarkin et al. | Jan 2013 | B2 |
| 8435498 | Tamarkin et al. | May 2013 | B2 |
| 8486374 | Tamarkin et al. | Jul 2013 | B2 |
| 8486375 | Tamarkin et al. | Jul 2013 | B2 |
| 8486376 | Friedman et al. | Jul 2013 | B2 |
| 8512718 | Eini et al. | Aug 2013 | B2 |
| 8518376 | Tamarkin et al. | Aug 2013 | B2 |
| 8518378 | Tamarkin et al. | Aug 2013 | B2 |
| 8592380 | Trumbore et al. | Nov 2013 | B2 |
| 8617100 | Eini et al. | Dec 2013 | B2 |
| 8618081 | Tamarkin et al. | Dec 2013 | B2 |
| 8623330 | Gurge et al. | Jan 2014 | B2 |
| 8636982 | Tamarkin et al. | Jan 2014 | B2 |
| 8652443 | Varanasi et al. | Feb 2014 | B2 |
| 8709385 | Tamarkin et al. | Apr 2014 | B2 |
| 8722021 | Friedman et al. | May 2014 | B2 |
| 8735377 | Sipos | May 2014 | B1 |
| 8741265 | Tamarkin et al. | Jun 2014 | B2 |
| 8784780 | Gurge et al. | Jul 2014 | B2 |
| 8795693 | Tamarkin et al. | Aug 2014 | B2 |
| 8846039 | Chung et al. | Sep 2014 | B2 |
| 8865139 | Tamarkin et al. | Oct 2014 | B1 |
| 8871184 | Tamarkin et al. | Oct 2014 | B2 |
| 8895536 | Bannister et al. | Nov 2014 | B2 |
| 8992896 | Tamarkin et al. | Mar 2015 | B2 |
| 9050253 | Tamarkin et al. | Jun 2015 | B2 |
| 9101662 | Tamarkin et al. | Aug 2015 | B2 |
| 9192558 | Chen et al. | Nov 2015 | B2 |
| 20010006654 | Cannell et al. | Jul 2001 | A1 |
| 20010026790 | Gers-Barlag et al. | Oct 2001 | A1 |
| 20010027218 | Stern et al. | Oct 2001 | A1 |
| 20010027981 | Yquel | Oct 2001 | A1 |
| 20010033838 | Farmer | Oct 2001 | A1 |
| 20010036450 | Verite et al. | Nov 2001 | A1 |
| 20010054574 | Navarro | Dec 2001 | A1 |
| 20020002151 | Ono et al. | Jan 2002 | A1 |
| 20020004063 | Zhang | Jan 2002 | A1 |
| 20020013481 | Schonrock et al. | Jan 2002 | A1 |
| 20020015721 | Simonnet et al. | Feb 2002 | A1 |
| 20020031478 | Keller et al. | Mar 2002 | A1 |
| 20020032171 | Chen et al. | Mar 2002 | A1 |
| 20020035046 | Lukenbach et al. | Mar 2002 | A1 |
| 20020035070 | Gardlik et al. | Mar 2002 | A1 |
| 20020035087 | Barclay | Mar 2002 | A1 |
| 20020035182 | L'Alloret et al. | Mar 2002 | A1 |
| 20020039591 | Dahle | Apr 2002 | A1 |
| 20020044659 | Ohta | Apr 2002 | A1 |
| 20020045659 | Michelet et al. | Apr 2002 | A1 |
| 20020048798 | Avery et al. | Apr 2002 | A1 |
| 20020058010 | Picard-Lesboueyries et al. | May 2002 | A1 |
| 20020072544 | Miller et al. | Jun 2002 | A1 |
| 20020090386 | Halswanter et al. | Jul 2002 | A1 |
| 20020098215 | Douin et al. | Jul 2002 | A1 |
| 20020111281 | Vishnupad | Aug 2002 | A1 |
| 20020117516 | Lasserre et al. | Aug 2002 | A1 |
| 20020122811 | Stein et al. | Sep 2002 | A1 |
| 20020134376 | Castro et al. | Sep 2002 | A1 |
| 20020136755 | Tyrrell et al. | Sep 2002 | A1 |
| 20020143188 | Garvey et al. | Oct 2002 | A1 |
| 20020153390 | Vlodek | Oct 2002 | A1 |
| 20020165170 | Wilson et al. | Nov 2002 | A1 |
| 20020182162 | Shahinpoor et al. | Dec 2002 | A1 |
| 20020182234 | Riedel et al. | Dec 2002 | A1 |
| 20020187181 | Godbey et al. | Dec 2002 | A1 |
| 20020198136 | Mak et al. | Dec 2002 | A1 |
| 20030006193 | Ikeda et al. | Jan 2003 | A1 |
| 20030013692 | Gullans et al. | Jan 2003 | A1 |
| 20030017181 | Rood et al. | Jan 2003 | A1 |
| 20030031693 | Breton et al. | Feb 2003 | A1 |
| 20030053961 | Eccard | Mar 2003 | A1 |
| 20030077297 | Chen et al. | Apr 2003 | A1 |
| 20030077301 | Maibach et al. | Apr 2003 | A1 |
| 20030078172 | Guiramand et al. | Apr 2003 | A1 |
| 20030082120 | Milstein | May 2003 | A1 |
| 20030108502 | Uchida et al. | Jun 2003 | A1 |
| 20030114520 | Pereira et al. | Jun 2003 | A1 |
| 20030118515 | Jew et al. | Jun 2003 | A1 |
| 20030118527 | Jager et al. | Jun 2003 | A1 |
| 20030129259 | Mahalingam et al. | Jul 2003 | A1 |
| 20030130247 | Gans et al. | Jul 2003 | A1 |
| 20030175232 | Elliott et al. | Sep 2003 | A1 |
| 20030175315 | Yoo et al. | Sep 2003 | A1 |
| 20030180347 | Young et al. | Sep 2003 | A1 |
| 20030185839 | Podolsky | Oct 2003 | A1 |
| 20030185861 | Hori et al. | Oct 2003 | A1 |
| 20030194379 | Brugger et al. | Oct 2003 | A1 |
| 20030195128 | Deckman et al. | Oct 2003 | A1 |
| 20030206955 | Sonneville-Aubrun et al. | Nov 2003 | A1 |
| 20030215418 | Asmus et al. | Nov 2003 | A1 |
| 20030215472 | Bonda et al. | Nov 2003 | A1 |
| 20030235597 | Withiam et al. | Dec 2003 | A1 |
| 20040002550 | Mercurio | Jan 2004 | A1 |
| 20040018228 | Fischell et al. | Jan 2004 | A1 |
| 20040028752 | Kamm et al. | Feb 2004 | A1 |
| 20040038912 | Michelet et al. | Feb 2004 | A1 |
| 20040053797 | Chen et al. | Mar 2004 | A1 |
| 20040058878 | Walker | Mar 2004 | A1 |
| 20040063787 | Villanueva | Apr 2004 | A1 |
| 20040067970 | Foster et al. | Apr 2004 | A1 |
| 20040072638 | Enos et al. | Apr 2004 | A1 |
| 20040076651 | Brocks et al. | Apr 2004 | A1 |
| 20040078896 | Hellyer et al. | Apr 2004 | A1 |
| 20040079361 | Clayton et al. | Apr 2004 | A1 |
| 20040105825 | Henning | Jun 2004 | A1 |
| 20040120917 | Perrier et al. | Jun 2004 | A1 |
| 20040127554 | Ghisalberti | Jul 2004 | A1 |
| 20040138179 | Goldstein et al. | Jul 2004 | A1 |
| 20040151671 | Abram et al. | Aug 2004 | A1 |
| 20040151756 | Richards et al. | Aug 2004 | A1 |
| 20040161447 | Paul | Aug 2004 | A1 |
| 20040184992 | Abram | Sep 2004 | A1 |
| 20040185123 | Mazzio et al. | Sep 2004 | A1 |
| 20040191196 | Tamarkin | Sep 2004 | A1 |
| 20040192754 | Shapira et al. | Sep 2004 | A1 |
| 20040195276 | Fuchs | Oct 2004 | A1 |
| 20040197276 | Takase et al. | Oct 2004 | A1 |
| 20040197295 | Riedel et al. | Oct 2004 | A1 |
| 20040198706 | Carrara | Oct 2004 | A1 |
| 20040219122 | Masuda et al. | Nov 2004 | A1 |
| 20040219176 | Dominguez | Nov 2004 | A1 |
| 20040220187 | Stephenson et al. | Nov 2004 | A1 |
| 20040229813 | DiPiano et al. | Nov 2004 | A1 |
| 20040234475 | Lannibois-Drean et al. | Nov 2004 | A1 |
| 20040241099 | Popp et al. | Dec 2004 | A1 |
| 20040247531 | Riedel et al. | Dec 2004 | A1 |
| 20040253275 | Eini et al. | Dec 2004 | A1 |
| 20040258627 | Riedel et al. | Dec 2004 | A1 |
| 20040258628 | Riedel et al. | Dec 2004 | A1 |
| 20040258643 | Yaqub et al. | Dec 2004 | A1 |
| 20040265240 | Tamarkin et al. | Dec 2004 | A1 |
| 20050002976 | Wu | Jan 2005 | A1 |
| 20050013853 | Gil-Ad et al. | Jan 2005 | A1 |
| 20050031547 | Tamarkin | Feb 2005 | A1 |
| 20050042182 | Arkin et al. | Feb 2005 | A1 |
| 20050054991 | Tobyn et al. | Mar 2005 | A1 |
| 20050069566 | Tamarkin et al. | Mar 2005 | A1 |
| 20050074414 | Tamarkin et al. | Apr 2005 | A1 |
| 20050075407 | Tamarkin et al. | Apr 2005 | A1 |
| 20050079139 | Jacques et al. | Apr 2005 | A1 |
| 20050084551 | Jensen et al. | Apr 2005 | A1 |
| 20050085843 | Opolski et al. | Apr 2005 | A1 |
| 20050100517 | Sanzgiri et al. | May 2005 | A1 |
| 20050101936 | Gonzales et al. | May 2005 | A1 |
| 20050106197 | Blin et al. | May 2005 | A1 |
| 20050123494 | Swaile et al. | Jun 2005 | A1 |
| 20050123496 | Shah et al. | Jun 2005 | A1 |
| 20050148552 | Ryan et al. | Jul 2005 | A1 |
| 20050153943 | Ashley | Jul 2005 | A1 |
| 20050164993 | Ashley | Jul 2005 | A1 |
| 20050186142 | Tamarkin et al. | Aug 2005 | A1 |
| 20050186147 | Tamarkin et al. | Aug 2005 | A1 |
| 20050189377 | Lanzendorfer et al. | Sep 2005 | A1 |
| 20050196414 | Dake et al. | Sep 2005 | A1 |
| 20050205086 | Tamarkin et al. | Sep 2005 | A1 |
| 20050207837 | Kosh et al. | Sep 2005 | A1 |
| 20050222090 | Cheng et al. | Oct 2005 | A1 |
| 20050232869 | Tamarkin | Oct 2005 | A1 |
| 20050244342 | Friedman et al. | Nov 2005 | A1 |
| 20050244354 | Speron | Nov 2005 | A1 |
| 20050245902 | Cornish et al. | Nov 2005 | A1 |
| 20050252995 | Westphal et al. | Nov 2005 | A1 |
| 20050255048 | Hirsh et al. | Nov 2005 | A1 |
| 20050258189 | Peterson et al. | Nov 2005 | A1 |
| 20050266035 | Healy et al. | Dec 2005 | A1 |
| 20050268416 | Sommers | Dec 2005 | A1 |
| 20050271596 | Friedman et al. | Dec 2005 | A1 |
| 20050271598 | Friedman et al. | Dec 2005 | A1 |
| 20050276836 | Wilson et al. | Dec 2005 | A1 |
| 20050281749 | Willcox et al. | Dec 2005 | A1 |
| 20050281755 | Zarif et al. | Dec 2005 | A1 |
| 20050281766 | Martin et al. | Dec 2005 | A1 |
| 20050285912 | Delametter et al. | Dec 2005 | A1 |
| 20050287081 | Aust | Dec 2005 | A1 |
| 20060008432 | Scarampi et al. | Jan 2006 | A1 |
| 20060018937 | Friedman et al. | Jan 2006 | A1 |
| 20060018938 | Neubourg | Jan 2006 | A1 |
| 20060029565 | Xu et al. | Feb 2006 | A1 |
| 20060051301 | Galopin et al. | Mar 2006 | A1 |
| 20060054634 | Mekata | Mar 2006 | A1 |
| 20060057168 | Larm et al. | Mar 2006 | A1 |
| 20060088561 | Eini et al. | Apr 2006 | A1 |
| 20060099151 | Neubourg | May 2006 | A1 |
| 20060108377 | Glynn et al. | May 2006 | A1 |
| 20060110418 | Johnson | May 2006 | A1 |
| 20060114745 | Ollmann et al. | Jun 2006 | A1 |
| 20060121073 | Goyal et al. | Jun 2006 | A1 |
| 20060140984 | Tamarkin et al. | Jun 2006 | A1 |
| 20060140990 | Bortz et al. | Jun 2006 | A1 |
| 20060160713 | Sekine et al. | Jul 2006 | A1 |
| 20060165616 | Brock et al. | Jul 2006 | A1 |
| 20060177392 | Walden | Aug 2006 | A1 |
| 20060193789 | Tamarkin et al. | Aug 2006 | A1 |
| 20060193813 | Simonnet | Aug 2006 | A1 |
| 20060204446 | Lulla et al. | Sep 2006 | A1 |
| 20060222675 | Sabnis et al. | Oct 2006 | A1 |
| 20060233721 | Tamarkin et al. | Oct 2006 | A1 |
| 20060239937 | Neubourg | Oct 2006 | A2 |
| 20060251684 | Annis et al. | Nov 2006 | A1 |
| 20060254597 | Thompson | Nov 2006 | A1 |
| 20060263323 | Hoang et al. | Nov 2006 | A1 |
| 20060269485 | Friedman et al. | Nov 2006 | A1 |
| 20060272199 | Licciardello et al. | Dec 2006 | A1 |
| 20060275218 | Tamarkin et al. | Dec 2006 | A1 |
| 20060275221 | Tamarkin et al. | Dec 2006 | A1 |
| 20060285912 | Eini et al. | Dec 2006 | A1 |
| 20060292080 | Abram et al. | Dec 2006 | A1 |
| 20070009607 | Jones | Jan 2007 | A1 |
| 20070010580 | De Paoli Ambrosi | Jan 2007 | A1 |
| 20070015739 | Walker et al. | Jan 2007 | A1 |
| 20070017696 | Lin et al. | Jan 2007 | A1 |
| 20070020213 | Tamarkin et al. | Jan 2007 | A1 |
| 20070020304 | Tamarkin et al. | Jan 2007 | A1 |
| 20070027055 | Koivisto et al. | Feb 2007 | A1 |
| 20070036831 | Baker | Feb 2007 | A1 |
| 20070053943 | Wang et al. | Mar 2007 | A1 |
| 20070059253 | Popp et al. | Mar 2007 | A1 |
| 20070069046 | Eini et al. | Mar 2007 | A1 |
| 20070071688 | Illel et al. | Mar 2007 | A1 |
| 20070098647 | Neubourg | May 2007 | A1 |
| 20070111956 | Matsushima et al. | May 2007 | A1 |
| 20070134174 | Irwin et al. | Jun 2007 | A1 |
| 20070140998 | Kato et al. | Jun 2007 | A1 |
| 20070140999 | Puglia et al. | Jun 2007 | A1 |
| 20070141086 | Ohara et al. | Jun 2007 | A1 |
| 20070142263 | Stahl et al. | Jun 2007 | A1 |
| 20070148112 | Dingley et al. | Jun 2007 | A1 |
| 20070148194 | Amiji et al. | Jun 2007 | A1 |
| 20070154402 | Trumbore et al. | Jul 2007 | A1 |
| 20070160548 | Riccardi et al. | Jul 2007 | A1 |
| 20070166274 | Mazur et al. | Jul 2007 | A1 |
| 20070224143 | Konis | Sep 2007 | A1 |
| 20070237724 | Abram et al. | Oct 2007 | A1 |
| 20070253911 | Tamarkin et al. | Nov 2007 | A1 |
| 20070264317 | Yosha et al. | Nov 2007 | A1 |
| 20070271235 | Frank et al. | Nov 2007 | A1 |
| 20070280891 | Tamarkin et al. | Dec 2007 | A1 |
| 20070281999 | Fox et al. | Dec 2007 | A1 |
| 20070292355 | Tamarkin et al. | Dec 2007 | A1 |
| 20070292359 | Friedman et al. | Dec 2007 | A1 |
| 20070292461 | Tamarkin et al. | Dec 2007 | A1 |
| 20080008397 | Kisilev | Jan 2008 | A1 |
| 20080015263 | Bolotin et al. | Jan 2008 | A1 |
| 20080015271 | Abram et al. | Jan 2008 | A1 |
| 20080031907 | Tamarkin et al. | Feb 2008 | A1 |
| 20080031908 | Aubrun-Sonneville et al. | Feb 2008 | A1 |
| 20080035155 | Dahl | Feb 2008 | A1 |
| 20080044444 | Tamarkin et al. | Feb 2008 | A1 |
| 20080050317 | Tamarkin et al. | Feb 2008 | A1 |
| 20080058055 | LeMay et al. | Mar 2008 | A1 |
| 20080063682 | Cashman et al. | Mar 2008 | A1 |
| 20080069779 | Tamarkin et al. | Mar 2008 | A1 |
| 20080131378 | Keller et al. | Jun 2008 | A1 |
| 20080138293 | Tamarkin et al. | Jun 2008 | A1 |
| 20080138296 | Tamarkin et al. | Jun 2008 | A1 |
| 20080152596 | Friedman et al. | Jun 2008 | A1 |
| 20080153789 | Dmowski et al. | Jun 2008 | A1 |
| 20080166303 | Tamarkin et al. | Jul 2008 | A1 |
| 20080167376 | Bar-Or et al. | Jul 2008 | A1 |
| 20080181854 | Eini et al. | Jul 2008 | A1 |
| 20080188445 | Muldoon et al. | Aug 2008 | A1 |
| 20080188446 | Muldoon et al. | Aug 2008 | A1 |
| 20080193762 | Dubertret et al. | Aug 2008 | A1 |
| 20080206155 | Tamarkin et al. | Aug 2008 | A1 |
| 20080206159 | Tamarkin et al. | Aug 2008 | A1 |
| 20080206161 | Tamarkin et al. | Aug 2008 | A1 |
| 20080241079 | Neubourg | Oct 2008 | A1 |
| 20080253973 | Tamarkin et al. | Oct 2008 | A1 |
| 20080255498 | Houle | Oct 2008 | A1 |
| 20080260655 | Tamarkin et al. | Oct 2008 | A1 |
| 20080292560 | Tamarkin et al. | Nov 2008 | A1 |
| 20080299220 | Tamarkin et al. | Dec 2008 | A1 |
| 20080311167 | Oronsky et al. | Dec 2008 | A1 |
| 20080317679 | Tamarkin et al. | Dec 2008 | A1 |
| 20090017147 | Lintner et al. | Jan 2009 | A1 |
| 20090041680 | Tamarkin et al. | Feb 2009 | A1 |
| 20090053290 | Sand et al. | Feb 2009 | A1 |
| 20090061001 | Hougaz | Mar 2009 | A1 |
| 20090068118 | Eini et al. | Mar 2009 | A1 |
| 20090093514 | Statham et al. | Apr 2009 | A1 |
| 20090130029 | Tamarkin et al. | May 2009 | A1 |
| 20090131488 | Harel et al. | May 2009 | A1 |
| 20090175799 | Tamarkin et al. | Jul 2009 | A1 |
| 20090180970 | Tamarkin et al. | Jul 2009 | A1 |
| 20090214628 | De Rijk | Aug 2009 | A1 |
| 20090291917 | Akama et al. | Nov 2009 | A1 |
| 20090317338 | Tamarkin et al. | Dec 2009 | A1 |
| 20100111879 | Tamarkin et al. | May 2010 | A1 |
| 20100137198 | Eini et al. | Jun 2010 | A1 |
| 20100221194 | Loupenok | Sep 2010 | A1 |
| 20100221195 | Tamarkin et al. | Sep 2010 | A1 |
| 20100247449 | Graupe et al. | Sep 2010 | A1 |
| 20100266510 | Tamarkin et al. | Oct 2010 | A1 |
| 20100286417 | Mendes et al. | Nov 2010 | A1 |
| 20110002857 | Tamarkin et al. | Jan 2011 | A1 |
| 20110002969 | Serraima et al. | Jan 2011 | A1 |
| 20110008266 | Tamarkin et al. | Jan 2011 | A1 |
| 20110045037 | Tamarkin et al. | Feb 2011 | A1 |
| 20110097279 | Tamarkin et al. | Apr 2011 | A1 |
| 20110212033 | Tamarkin et al. | Sep 2011 | A1 |
| 20110262542 | Ashley | Oct 2011 | A1 |
| 20110268665 | Tamarkin et al. | Nov 2011 | A1 |
| 20120064136 | Baker, Jr. et al. | Mar 2012 | A1 |
| 20120082632 | Phillips et al. | Apr 2012 | A1 |
| 20120087872 | Tamarkin et al. | Apr 2012 | A1 |
| 20120128598 | Trumbore et al. | May 2012 | A1 |
| 20120141384 | Tamarkin | Jun 2012 | A1 |
| 20120148503 | Tamarkin et al. | Jun 2012 | A1 |
| 20120156144 | Tamarkin et al. | Jun 2012 | A1 |
| 20120164087 | Carter | Jun 2012 | A1 |
| 20120181201 | Heggie | Jul 2012 | A1 |
| 20120195836 | Tamarkin et al. | Aug 2012 | A1 |
| 20120213709 | Tamarkin et al. | Aug 2012 | A1 |
| 20120213710 | Tamarkin et al. | Aug 2012 | A1 |
| 20120237453 | Tamarkin et al. | Sep 2012 | A1 |
| 20130011342 | Tamarkin et al. | Jan 2013 | A1 |
| 20130028850 | Tamarkin et al. | Jan 2013 | A1 |
| 20130053353 | Tamarkin et al. | Feb 2013 | A1 |
| 20130064777 | Tamarkin et al. | Mar 2013 | A1 |
| 20130115173 | Trumbore et al. | May 2013 | A1 |
| 20130161351 | Eini et al. | Jun 2013 | A1 |
| 20130164225 | Tamarkin et al. | Jun 2013 | A1 |
| 20130183250 | Friedman et al. | Jul 2013 | A1 |
| 20130183251 | Tamarkin et al. | Jul 2013 | A1 |
| 20130189191 | Tamarkin et al. | Jul 2013 | A1 |
| 20130189193 | Tamarkin et al. | Jul 2013 | A1 |
| 20130189195 | Tamarkin et al. | Jul 2013 | A1 |
| 20130189196 | Tamarkin et al. | Jul 2013 | A1 |
| 20130195769 | Tamarkin et al. | Aug 2013 | A1 |
| 20130225536 | Tamarkin et al. | Aug 2013 | A1 |
| 20130251644 | Majhi et al. | Sep 2013 | A1 |
| 20130261565 | Wong et al. | Oct 2013 | A1 |
| 20130295022 | Friedman et al. | Nov 2013 | A1 |
| 20130296387 | Saad | Nov 2013 | A1 |
| 20140050673 | Tamarkin et al. | Feb 2014 | A1 |
| 20140066524 | Tamarkin et al. | Mar 2014 | A1 |
| 20140086848 | Tamarkin et al. | Mar 2014 | A1 |
| 20140121188 | Tamarkin et al. | May 2014 | A1 |
| 20140140937 | Gurge et al. | May 2014 | A1 |
| 20140147504 | Salman et al. | May 2014 | A1 |
| 20140182585 | Tamarkin et al. | Jul 2014 | A1 |
| 20140186269 | Tamarkin et al. | Jul 2014 | A1 |
| 20140186442 | Mansouri | Jul 2014 | A1 |
| 20140193502 | Tamarkin et al. | Jul 2014 | A1 |
| 20140221320 | Joks et al. | Aug 2014 | A1 |
| 20140227199 | Tamarkin et al. | Aug 2014 | A1 |
| 20140228355 | Kortagere et al. | Aug 2014 | A1 |
| 20140271494 | Tamarkin et al. | Sep 2014 | A1 |
| 20150025060 | Tamarkin et al. | Jan 2015 | A1 |
| 20150098907 | Tamarkin et al. | Apr 2015 | A1 |
| 20150118164 | Tamarkin et al. | Apr 2015 | A1 |
| 20150125496 | Yamamoto | May 2015 | A1 |
| 20150141381 | Levy et al. | May 2015 | A1 |
| 20150157586 | Tamarkin et al. | Jun 2015 | A1 |
| 20150164922 | Tamarkin et al. | Jun 2015 | A1 |
| 20150174144 | Bowser et al. | Jun 2015 | A1 |
| 20150190409 | Tamarkin et al. | Jul 2015 | A1 |
| 20150196570 | Tamarkin et al. | Jul 2015 | A1 |
| 20150209296 | Yamamoto | Jul 2015 | A1 |
| 20150374625 | Tamarkin et al. | Dec 2015 | A1 |
| 20160101051 | Tamarkin et al. | Apr 2016 | A1 |
| 20160101184 | Tamarkin et al. | Apr 2016 | A1 |
| 20160158261 | Friedman et al. | Jun 2016 | A1 |
| Number | Date | Country |
|---|---|---|
| 198780257 | Sep 1986 | AU |
| 782515 | Dec 2005 | AU |
| 2010219295 | Sep 2012 | AU |
| 2114537 | Feb 1993 | CA |
| 2154438 | Jan 1996 | CA |
| 2422244 | Sep 2003 | CA |
| 2502986 | Aug 2011 | CA |
| 2534372 | Jan 2012 | CA |
| 2536482 | Jul 2012 | CA |
| 639913 | Dec 1983 | CH |
| 1 882 100 | Nov 1963 | DE |
| 1926796 | Nov 1965 | DE |
| 4140474 | Jun 1993 | DE |
| 10009233 | Aug 2000 | DE |
| 10138495 | Feb 2003 | DE |
| 102004016710 | Oct 2005 | DE |
| 2 608 226 | Sep 2007 | DE |
| 52404 | May 1982 | EP |
| 0 156 507 | Oct 1985 | EP |
| 0 186 453 | Jul 1986 | EP |
| 0 211 550 | Feb 1987 | EP |
| 0 213 827 | Mar 1987 | EP |
| 0 214 865 | Mar 1987 | EP |
| 0 216 856 | Apr 1987 | EP |
| 0 270 316 | Jun 1988 | EP |
| 0 297 436 | Jan 1989 | EP |
| 0 326 196 | Aug 1989 | EP |
| 0 336 812 | Oct 1989 | EP |
| 0 391 124 | Oct 1990 | EP |
| 0 404 376 | Dec 1990 | EP |
| 0 414 920 | Mar 1991 | EP |
| 0 484 530 | May 1992 | EP |
| 0 485 299 | May 1992 | EP |
| 0 488 089 | Jun 1992 | EP |
| 0 504 301 | Sep 1992 | EP |
| 0 528 190 | Feb 1993 | EP |
| 0 535 327 | Apr 1993 | EP |
| 0 552 612 | Jul 1993 | EP |
| 0 569 773 | Nov 1993 | EP |
| 0 598 412 | May 1994 | EP |
| 0 662 431 | Jul 1995 | EP |
| 0 676 198 | Oct 1995 | EP |
| 0 738 516 | Oct 1996 | EP |
| 0 757 959 | Feb 1997 | EP |
| 0 824 911 | Feb 1998 | EP |
| 0 829 259 | Mar 1998 | EP |
| 0 928 608 | Jul 1999 | EP |
| 0 979 654 | Feb 2000 | EP |
| 0 993 827 | Apr 2000 | EP |
| 1 025 836 | Aug 2000 | EP |
| 1 055 425 | Nov 2000 | EP |
| 0 506 197 | Jul 2001 | EP |
| 1 215 258 | Jun 2002 | EP |
| 1 287 813 | Mar 2003 | EP |
| 1 308 169 | May 2003 | EP |
| 1 375 386 | Jan 2004 | EP |
| 1 428 521 | Jun 2004 | EP |
| 1 438 946 | Jul 2004 | EP |
| 1 189 579 | Sep 2004 | EP |
| 1 475 381 | Nov 2004 | EP |
| 1 483 001 | Dec 2004 | EP |
| 1 500 385 | Jan 2005 | EP |
| 1 537 916 | Jun 2005 | EP |
| 1 600 185 | Nov 2005 | EP |
| 1 653 932 | May 2006 | EP |
| 1 734 927 | Dec 2006 | EP |
| 1 758 547 | Mar 2007 | EP |
| 1 584 324 | Nov 2007 | EP |
| 1 889 609 | Feb 2008 | EP |
| 1 902 706 | Mar 2008 | EP |
| 2 129 383 | Dec 2009 | EP |
| 2422768 | Feb 2012 | EP |
| 2494959 | Sep 2012 | EP |
| 2 456 522 | Dec 1980 | FR |
| 2 591 331 | Jun 1987 | FR |
| 2 640 942 | Jun 1990 | FR |
| 2 736 824 | Jan 1997 | FR |
| 2 774 595 | Aug 1999 | FR |
| 2 789 371 | Aug 2000 | FR |
| 2 793 479 | Nov 2000 | FR |
| 2 814 959 | Apr 2002 | FR |
| 2 833 246 | Jun 2003 | FR |
| 2 840 903 | Dec 2003 | FR |
| 2 843 373 | Feb 2004 | FR |
| 2 845 672 | Apr 2004 | FR |
| 2 848 998 | Jun 2004 | FR |
| 2 860 976 | Apr 2005 | FR |
| 2 915 891 | Nov 2008 | FR |
| 808 104 | Jan 1959 | GB |
| 808 105 | Jan 1959 | GB |
| 922 930 | Apr 1963 | GB |
| 933 486 | Aug 1963 | GB |
| 998 490 | Jul 1965 | GB |
| 1 026 831 | Apr 1966 | GB |
| 1 033 299 | Jun 1966 | GB |
| 1 081 949 | Sep 1967 | GB |
| 1 121 358 | Jul 1968 | GB |
| 1 162 684 | Aug 1969 | GB |
| 1 170 152 | Nov 1969 | GB |
| 1 201 918 | Aug 1970 | GB |
| 1 347 950 | Feb 1974 | GB |
| 1 351 761 | May 1974 | GB |
| 1 351 762 | May 1974 | GB |
| 1 353 381 | May 1974 | GB |
| 1 376 649 | Dec 1974 | GB |
| 1 397 285 | Jun 1975 | GB |
| 1 408 036 | Oct 1975 | GB |
| 1 457 671 | Dec 1976 | GB |
| 1 489 672 | Oct 1977 | GB |
| 2 004 746 | Apr 1979 | GB |
| 1 561 423 | Feb 1980 | GB |
| 2 114 580 | Aug 1983 | GB |
| 2 153 686 | Aug 1985 | GB |
| 2 172 298 | Sep 1986 | GB |
| 2 206 099 | Dec 1988 | GB |
| 2 166 651 | May 1996 | GB |
| 2 337 461 | Nov 1999 | GB |
| 2 367 809 | Apr 2002 | GB |
| 2 406 330 | Mar 2005 | GB |
| 2 406 791 | Apr 2005 | GB |
| 2 474 930 | Jul 2012 | GB |
| 49491 | Sep 1979 | IL |
| 152 486 | May 2003 | IL |
| 60001113 | Apr 1978 | JP |
| 55069682 | May 1980 | JP |
| 57044429 | Mar 1982 | JP |
| 56039815 | Apr 1984 | JP |
| 61275395 | Dec 1986 | JP |
| 62241701 | Oct 1987 | JP |
| 63119420 | May 1988 | JP |
| 1100111 | Apr 1989 | JP |
| 1156906 | Jun 1989 | JP |
| 2184614 | Jul 1990 | JP |
| 2255890 | Oct 1990 | JP |
| 4-51958 | Feb 1992 | JP |
| 4282311 | Oct 1992 | JP |
| 4312521 | Nov 1992 | JP |
| 5070340 | Mar 1993 | JP |
| 5213734 | Aug 1993 | JP |
| 6100414 | Apr 1994 | JP |
| H06-263630 | Jun 1994 | JP |
| 6329532 | Nov 1994 | JP |
| 2007155667 | Jun 1995 | JP |
| 7215835 | Aug 1995 | JP |
| 2008040899 | Feb 1996 | JP |
| 8501529 | Feb 1996 | JP |
| 8119831 | May 1996 | JP |
| 8165218 | Jun 1996 | JP |
| 8277209 | Oct 1996 | JP |
| 09 084855 | Mar 1997 | JP |
| 9099553 | Apr 1997 | JP |
| 9110636 | Apr 1997 | JP |
| 10114619 | May 1998 | JP |
| 3050289 | Sep 1998 | JP |
| 2010332456 | Dec 1998 | JP |
| 11501045 | Jan 1999 | JP |
| 11250543 | Sep 1999 | JP |
| 2000017174 | Jan 2000 | JP |
| 2000080017 | Mar 2000 | JP |
| 2000128734 | May 2000 | JP |
| 2000191429 | Jul 2000 | JP |
| 2000239140 | Sep 2000 | JP |
| 2000351726 | Dec 2000 | JP |
| 2000354623 | Dec 2000 | JP |
| 2001002526 | Jan 2001 | JP |
| 2001019606 | Jan 2001 | JP |
| 2001072963 | Mar 2001 | JP |
| 2002012513 | Jan 2002 | JP |
| 2002047136 | Feb 2002 | JP |
| 2002524490 | Aug 2002 | JP |
| 2002302419 | Oct 2002 | JP |
| 2003012511 | Jan 2003 | JP |
| 2003055146 | Feb 2003 | JP |
| 2004047136 | Feb 2004 | JP |
| 2004250435 | Sep 2004 | JP |
| 2004348277 | Dec 2004 | JP |
| 2005314323 | Nov 2005 | JP |
| 2005350378 | Dec 2005 | JP |
| 2006008574 | Jan 2006 | JP |
| 2006036317 | Feb 2006 | JP |
| 2006103799 | Apr 2006 | JP |
| 2006525145 | Nov 2006 | JP |
| 2007131539 | May 2007 | JP |
| 2007326996 | Dec 2007 | JP |
| 143232 | Jul 1998 | KR |
| 2001003063 | Jan 2001 | KR |
| 520014 | May 2005 | NZ |
| 540166 | Jun 2007 | NZ |
| 2277501 | Jun 2006 | RU |
| 66796 | Jun 2004 | UA |
| WO 8201821 | Jun 1982 | WO |
| WO 8605389 | Sep 1986 | WO |
| WO 8801502 | Mar 1988 | WO |
| WO 8801863 | Mar 1988 | WO |
| WO 8808316 | Nov 1988 | WO |
| WO 8906537 | Jul 1989 | WO |
| WO 9005774 | May 1990 | WO |
| WO 9111991 | Aug 1991 | WO |
| WO 9200077 | Jan 1992 | WO |
| WO 9205142 | Apr 1992 | WO |
| WO 9205763 | Apr 1992 | WO |
| WO 9211839 | Jul 1992 | WO |
| WO 9213602 | Aug 1992 | WO |
| WO 9325189 | Dec 1993 | WO |
| WO 9406440 | Mar 1994 | WO |
| WO 9603115 | Feb 1996 | WO |
| WO 9619921 | Jul 1996 | WO |
| WO 9624325 | Aug 1996 | WO |
| WO 9626711 | Sep 1996 | WO |
| WO 9627376 | Sep 1996 | WO |
| WO 9639119 | Dec 1996 | WO |
| WO 9703638 | Feb 1997 | WO |
| WO 9739745 | Oct 1997 | WO |
| WO 9817282 | Apr 1998 | WO |
| WO 9818472 | May 1998 | WO |
| WO 9819654 | May 1998 | WO |
| WO 9821955 | May 1998 | WO |
| WO 9823291 | Jun 1998 | WO |
| WO 9831339 | Jul 1998 | WO |
| WO 9836733 | Aug 1998 | WO |
| WO 9852536 | Nov 1998 | WO |
| WO 9908649 | Feb 1999 | WO |
| WO 9920250 | Apr 1999 | WO |
| WO 9937282 | Jul 1999 | WO |
| WO 9953923 | Oct 1999 | WO |
| WO 0009082 | Feb 2000 | WO |
| WO 0015193 | Mar 2000 | WO |
| WO 0023051 | Apr 2000 | WO |
| WO 0062776 | Apr 2000 | WO |
| WO 0033825 | Jun 2000 | WO |
| WO 0038731 | Jul 2000 | WO |
| WO 0061076 | Oct 2000 | WO |
| WO 0072805 | Dec 2000 | WO |
| WO 0076461 | Dec 2000 | WO |
| WO 0101949 | Jan 2001 | WO |
| WO 0105366 | Jan 2001 | WO |
| WO 0108681 | Feb 2001 | WO |
| WO 0110961 | Feb 2001 | WO |
| WO 0153198 | Jul 2001 | WO |
| WO 0154212 | Jul 2001 | WO |
| WO 0154679 | Aug 2001 | WO |
| WO 0162209 | Aug 2001 | WO |
| WO 0170242 | Sep 2001 | WO |
| WO 0182880 | Nov 2001 | WO |
| WO 0182890 | Nov 2001 | WO |
| WO 0185102 | Nov 2001 | WO |
| WO 0185128 | Nov 2001 | WO |
| WO 0195728 | Dec 2001 | WO |
| WO 0200820 | Jan 2002 | WO |
| WO 0207685 | Jan 2002 | WO |
| WO 0215860 | Feb 2002 | WO |
| WO 0215873 | Feb 2002 | WO |
| WO 0224161 | Mar 2002 | WO |
| WO 0228435 | Apr 2002 | WO |
| WO 0241847 | May 2002 | WO |
| WO 0243490 | Jun 2002 | WO |
| WO 02062324 | Aug 2002 | WO |
| WO 02078667 | Oct 2002 | WO |
| WO 02087519 | Nov 2002 | WO |
| WO 03000223 | Jan 2003 | WO |
| WO 03002082 | Jan 2003 | WO |
| WO 03005985 | Jan 2003 | WO |
| WO 03013984 | Feb 2003 | WO |
| WO 03015699 | Feb 2003 | WO |
| WO 03051294 | Jun 2003 | WO |
| WO 03053292 | Jul 2003 | WO |
| WO 03055445 | Jul 2003 | WO |
| WO 03055454 | Jul 2003 | WO |
| WO 03070301 | Aug 2003 | WO |
| WO 03071995 | Sep 2003 | WO |
| WO 03075851 | Sep 2003 | WO |
| WO 03092641 | Nov 2003 | WO |
| WO 03094873 | Nov 2003 | WO |
| WO 03097002 | Nov 2003 | WO |
| WO 2004017962 | Mar 2004 | WO |
| WO 2004037197 | May 2004 | WO |
| WO 2004037225 | May 2004 | WO |
| WO 2004003284 | Aug 2004 | WO |
| WO 2004064769 | Aug 2004 | WO |
| WO 2004064833 | Aug 2004 | WO |
| WO 2004071479 | Aug 2004 | WO |
| WO 2004078158 | Sep 2004 | WO |
| WO 2004078896 | Sep 2004 | WO |
| WO 2004093895 | Nov 2004 | WO |
| WO 2004112780 | Dec 2004 | WO |
| WO 2005011567 | Feb 2005 | WO |
| WO 2005018530 | Mar 2005 | WO |
| WO 2005032522 | Apr 2005 | WO |
| WO 2005044219 | May 2005 | WO |
| WO 2005063224 | Jul 2005 | WO |
| WO 2005065652 | Jul 2005 | WO |
| WO 2005076697 | Aug 2005 | WO |
| WO 2005097068 | Oct 2005 | WO |
| WO 2005102282 | Nov 2005 | WO |
| WO 2005102539 | Nov 2005 | WO |
| WO 2005117813 | Dec 2005 | WO |
| WO 2006003481 | Jan 2006 | WO |
| WO 2006010589 | Feb 2006 | WO |
| WO 2006011046 | Feb 2006 | WO |
| WO 2006020682 | Feb 2006 | WO |
| WO 2006028339 | Mar 2006 | WO |
| WO 2006031271 | Mar 2006 | WO |
| WO 2006045170 | May 2006 | WO |
| WO 2006079632 | Aug 2006 | WO |
| WO 2006081327 | Aug 2006 | WO |
| WO 2006091229 | Aug 2006 | WO |
| WO 2006100485 | Sep 2006 | WO |
| WO 2006120682 | Nov 2006 | WO |
| WO 2006121610 | Nov 2006 | WO |
| WO 2006122158 | Nov 2006 | WO |
| WO 2006129161 | Dec 2006 | WO |
| WO 2006131784 | Dec 2006 | WO |
| WO 2007007208 | Jan 2007 | WO |
| WO 2007010494 | Jan 2007 | WO |
| WO 2007012977 | Feb 2007 | WO |
| WO 2007023396 | Mar 2007 | WO |
| WO 2007031621 | Mar 2007 | WO |
| WO 2007039825 | Apr 2007 | WO |
| WO 2007050543 | May 2007 | WO |
| WO 2007054818 | May 2007 | WO |
| WO 2007072216 | Jun 2007 | WO |
| WO 2007082698 | Jul 2007 | WO |
| WO 2007085899 | Aug 2007 | WO |
| WO 2007085902 | Aug 2007 | WO |
| WO 2007099396 | Sep 2007 | WO |
| WO 2007111962 | Oct 2007 | WO |
| WO 2008008397 | Jan 2008 | WO |
| WO 2008010963 | Jan 2008 | WO |
| WO 2008038147 | Apr 2008 | WO |
| WO 2008041045 | Apr 2008 | WO |
| WO 2008075207 | Jun 2008 | WO |
| WO 2008087148 | Jul 2008 | WO |
| WO 2008104734 | Sep 2008 | WO |
| WO 2008110872 | Sep 2008 | WO |
| WO 2008152444 | Dec 2008 | WO |
| WO 2009007785 | Jan 2009 | WO |
| WO 2009069006 | Jun 2009 | WO |
| WO 2009072007 | Jun 2009 | WO |
| WO 2009087578 | Jul 2009 | WO |
| WO 2009090495 | Jul 2009 | WO |
| WO 2009090558 | Jul 2009 | WO |
| WO 2009098595 | Aug 2009 | WO |
| WO 2011006026 | Jan 2011 | WO |
| WO 2011026094 | Mar 2011 | WO |
| WO 2011039637 | Apr 2011 | WO |
| WO 2011039638 | Apr 2011 | WO |
| WO 2011064631 | Jun 2011 | WO |
| WO 2011106026 | Sep 2011 | WO |
| WO 2011138678 | Nov 2011 | WO |
| WO 2013136192 | Sep 2013 | WO |
| WO 2014134394 | Sep 2014 | WO |
| WO 2014134427 | Sep 2014 | WO |
| WO 2014151347 | Sep 2014 | WO |
| WO 2014201541 | Dec 2014 | WO |
| WO 2005009416 | Feb 2015 | WO |
| WO 2015075640 | May 2015 | WO |
| WO 2015114320 | Aug 2015 | WO |
| WO 2015153864 | Oct 2015 | WO |
| Entry |
|---|
| DeVos et al.“Antisense Oligonucleotides: Treating Neurodegeneration at the level of RNA.” Neurotherapeutics (2013): 1-12. |
| Al-Mughrabi et al. “Effectiveness of Essential Oils and Their Combinations with Aluminum starch octenyl succinate on Potato Storage Pathogens.” TEOP 16 (1) 2013 23-31. |
| U.S. Appl. No. 60/789,186, Apr. 4, 2006, Tamarkin. |
| U.S. Appl. No. 60/815,948, Jun. 23, 2006, Tamarkin. |
| U.S. Appl. No. 60/818,634, Jul. 5, 2006 Friedman. |
| U.S. Appl. No. 60/843,140, Sep. 8, 2006, Tamarkin. |
| U.S. Appl. No. 61/248,144, Oct. 2, 2009, Tamarkin. |
| U.S. Appl. No. 61/322,148, Apr. 8, 2010, Tamarkin. |
| U.S. Appl. No. 61/363,577, Jul. 12, 2010, Eini. |
| “Arquad HTL8-MS,”AkzoNobel Functional Applications, retrieved on Mar. 18, 2013, Retrieved from the Internet: <URL: http://sc.akzonobel.com/en/fa/Pages/product-detail.aspx?prodID=8764>, 1 page. |
| “Burn patients need vitamin D supplements.” Decision News Media, Jan. 23, 2004, http://www.nutraingredients.com/Research/Burn-patients-need-vitamin-D-supplements, Accessed: May 5, 2010. |
| “Can tuberous sclerosis be prevented?,” Sharecare, 2002, retrieved on Aug. 29, 2013, <URL: http://www.sharecare.com/health/autosomal-dominant-genetic-disorders/can-tuberous-sclerosis-be-prevented;jsessionid=850579B60520A907DE75930E061E60E6>, 2 pages. |
| “Coal tars and coal-tar pitches,” Report on Carcinogens, Twelfth Edition, 2011, 3 pages. |
| “Crohn's Disease,” Merch Manual Home Edition, retrieved on Jan. 16, 2013, <http://www.merckmanuals.com/home/digestive—disorders/inflammatory—bowel—diseases—ibd/crohn—disease.html?qt=crohn's disease&alt=sh>, 3 pages. |
| “Dacarbazine,” Chemical Book, 2010, retrieved on Oct. 18, 2013, <URL: http://www.chemicalbook.com/ChemicalProductProperty—EN—CB7710656.htm>, 2 pages. |
| “Drug Index (Professional)—Dacarbazine,” BC Cancer Agency, Jun. 2004, retrieved on Oct. 18, 2013, <URL:http://www.bccancer.bc.ca/HPI/DrugDatabase/DrugIndexPro/Dacarbazine.htm>, 6 pages. |
| “Fully refined paraffin waxes (FRP Wax),” Industrial Raw Materials LLC, Feb. 21, 2008, retrieved on Aug. 22, 2013, <http://irmwax.com/Wax/Paraffin/fully—refined.asp> 1 page. |
| “Gas Gangrene,” Merch Manual Home Edition, 2008, retrieved on Jan. 16, 2013, <http://www.merckmanuals.com/home/infections/bacterial—infections/gas—gangrene.html?qt=gasgangrene&alt=sh>1 page. |
| “HLB Systems”, http://pharmcal.tripod.com/ch17.htm, Accessed Sep. 17, 2010, pp. 1-3. |
| “Human Immunodeficiency Virus Infection,” Merch Manual Home Edition, 2008, retrieved on Jan. 16, 2013, <http://www.merckmanuals.com/home/infections/human—immunodeficiency—virus—hiv—infection/human—immunodeficiency—virus—infection.html?qt=human immunodeficiency virus infection&alt=sh>, 11 pages. |
| “Mineral oil USP,” Chemical Abstracts Service Registry No. 8012-95-1, 2011, 7 pages. |
| “Minocycline (DB01017),” DrugBank, Feb. 8, 2013, retrieved on Aug. 15, 2013, <http://www.drugbank.ca/drugs/DB01017>, 10 pages. |
| “Minocycline” accessed on Oct. 21, 2011 at en.wikipedia.org/wiki/Minocycline, 7 pages. |
| “New Nanomaterials to deliver anticancer drugs to cells developed,” Science Daily, Jun. 2007, retrieved on Oct. 14, 2013, <URL: http://www.sciencedaily.com/releases/2007/06/070607112931.htm>, 3 pages. |
| “Product Data Sheet for Meclocycline,” bioaustralis fine chemicals, Jun. 28, 2013, 1 page. |
| “Reaction Rate” Accessed at en.wikipedia.org/wild/Reaction—rate on Dec. 18, 2011, 6 pages. |
| “Shear,” Vocabulary.com, retrieved on Aug. 23, 2013, <URL: https://www.vocabulary.com/dictionary/shear>, 3 pages. |
| “Sheer,” Vocabulary.com, retrieved on Aug. 23, 2013, <URL: https://www.vocabulary.com/dictionary/sheer>, 3 pages. |
| “Tea tree oil,” Chemical Abstract No. 68647-73-4, 2012, 2 pages. |
| “View of NCT01171326 on Dec. 7, 2010,” ClinicalTrials.gov archive, Dec. 7, 2010, retrieved on Sep. 9, 2013, <http://clinicaltrials.gov/archive/NCT01171326/2010—12—07>, 4 pages. |
| “View of NCT01362010 on Jun. 9, 2011,” ClinicalTrials.gov archive, Jun. 9, 2011, retrieved on Sep. 9, 2013, <http://clinicaltrials.gov/archive/NCT01362010/2011—06—09>, 3 pages. |
| “What is TSC?,” Tuberous Sclerosis Alliance, Jan. 1, 2005, retrieved on Feb. 6, 2014, <URL: http://www.tsalliance.org.pages.aspx?content=2>, 3 pages. |
| ‘Niram Chemicals’ [online]. Niram Chemicals, [retrieved on Jul. 17, 2012]. Retrieved from the Internet: <URL: http://www.indiamart.com/niramchemicals/chemicals.html>, 7 pages. |
| ‘Surfactant’ [online]. Wikipedia, 2010, [retrieved on Oct. 24, 2010]. Retrieved from the Internet: <URL: http://en.wikipedia.org/wiki/Surfactant>, 7 pages. |
| Abrams et al., “Ciclopirox gel treatment of scalp seborrheic dermatitis,” Hydroxy-Piridones as Antifungal Agents with Special Emphasis on Onychomycosis, 1999, Chapter 8, 45-50. |
| Adachi, Shuji. “Storage and Oxidative Stability of O/W/ Nano-emulsions.” Foods Food Ingredients. J. Jpn. vol. 209, No. 11. 2004. 1 page. |
| Adisen et al. “Topical tetracycline in the treatment of acne vulgaris,” J Drugs Dermatol., 2008, 7:953-5. |
| Alcohol SDA 40B.http://www.pharmco-prod.com/pages/MSDS/SDA.sub.—40B.sub.--200.pdf Accessed Dec. 9, 2008, 2 pages. |
| Ambrose, Ursula et al., “In Vitro Studies of Water Activity and Bacterial Growth Inhibition of Sucrose-Polyethylene Glycol 400-Hydrogen Peroxide and Xylose-Polyethylene Glycol 400-Hydrogen Peroxide Pastes Used to Treat Infected Wounds,” Antimicrobial Agents and Chemotherapy, vol. 35, No. 9, pp. 1799-1803, 1991. |
| Anton, N. et al. “Water-in-Oil Nano-Emulsion Formation by the phase inversion Temperature Method: A Novel and General Concept, a New Template for Nanoencapsulation,” Proceedings of the 33rd Annual Meeting and Exposition of the Controlled Release Society, Jul. 2006, Vienna, Austria, 2 pages. |
| Arct et al., “Common Cosmetic Hydrophilic Ingredients as Penetration Modifiers of Flavonoids”, International Journal of Cosmetic Science, 24(6):357-366 (2002)—Abstract, 1 page. |
| Arisan, http://www.arisankimya.com/kozmetik.htm Accessed Dec. 10, 2008, 8 pages. |
| Augsburger, Larry L. et al. “Bubble Size Analysis of High Consistency Aerosol Foams and Its Relationship to Foam Rheology. Effects of Container Emptying, Propellent Type, and Time.” Journal of Pharmaceutical Sciences. vol. 57, No. 4. Apr. 1968. pp. 624-631. |
| Austria, et al., “Stability of Vitamin C Derivatives in Solution and Topical Formulations”, Journal of Pharmaceutical and Biomedical Analysis, 15:795-801 (1997). |
| Barry and Badal, “Stability of minocycline, doxycycline, and tetracycline stored in agar plates and microdilution trays,” Current Microbiology, 1978, 1:33-36. |
| Barry, B.W. et al, Comparative bio-availability and activity of proprietary topical corticosteroid preparations: vasoconstrictor assays on thirty-one ointments, British Journal of Dermatology, 93, 563-571, 1975. |
| Baskaran et al., “Poloxamer-188 improves capillary blood flow and tissue viability in a cutaneous burn wound,” J. Surg. Res., 2001, 101(1):56-61. |
| Bell-Syer et al. “A systematic review of oral treatments for fungal infections of the skin of the feet,” J. Dermatolog. Treat., 2001, 12:69-74. |
| Benet, et al., Application of NMR for the Determination of HLB Values of Nonionic Surfactants, Journal of the American Oil Chemists Society, vol. 49, 1972, 499-500. |
| Bernstein, et al., Effects of the Immunomodulating Agent R837 on Acute and Latent Herpes Simplex Virus Type 2 Invections, Antimicrobial Agents and Chemotherapy, 33(9):1511-1515 (1989). |
| Blaney and Cook, “Topical use of tetracycline in the treatment of acne,” Arch Dermatol, Jul. 1976, 112:971-973. |
| Blute, “Phase behavior of alkyl glycerol ether surfacants”, Physical Chemistry Tenside Sur. Det., 35(3):207-212 (1998). |
| Boehm et al. 1994, “Synthesis of high specific activity [.sup.3 H]-9-cis-retinoic acid and its application for identifying retinoids with unusual binding properties,” J. Med. Chem., 37:408-414;. |
| Brenes, et al., “Stability of Copigmented Anthocyanins and Asorbics Acid in a Grape Juice Model System”, J. Agric Food Chem, 53(1):49-56 (2005)—Abstrace, 1 page. |
| Bronopol. Revtrieved online on Jun. 4, 2011. <URL:http://chemicalland21.com/specialtychem/perchem/BRONOPOL.html>. Jul. 17, 2006. 4 pages. |
| Brown et al. “Structural dependence of flavonoid interactions with Cu2+ inos: implications for their antioxidant properties,” Biochem. J., 1998, 330:1173-1178. |
| Buck, et al., “Treatment of Vaginal Intraephithelial Neoplasia (Primarily Low Grade) with Imiquimod 5% Cream”, Journal of Lower Genetial Tract Disease, 7(3):290-293 (2003). |
| Bucks, Daniel A.W., et al., “Bioavailability of Topically Administered Steroids: A ‘Mass Balance’ Technique,” Journal of Investigative Dermatology, vol. 91, No. 1, Jul. 1988, pp. 29-33. |
| Bunker,et al., “Alterations in Scalp Blood Flow after the Epicutaneous Application of 3% Minoxidil and 0.1% Hexyl Nicotinate in Alopecia”, Presented as a poster at the meeting of the British Society for Investigavie Dermatology, York, Sep. 1986 (2 pages). |
| Burton, et al., “Hypertrichosis Due to Minoxidil”, British Journal of Dermatology, 101:593-595 (1979). |
| Campos, et al., “Ascorbic Acid and Its Derivatives in Cosmetic Formulations”, Cosmetics and Toiletries, 115(6):59-62 (2000)—Abstract, 1 page. |
| Carapeti et al., “Topical diltiazem and bethanechol decrease anal sphincter pressure and heal anal fissures without side effects,” Dis Colon Rectum, 2000, 43(10):1359-62. |
| Carbowax 1000MSDS; http://www.sciencelab.com/xMSDS-Polyethylene.sub.--glycol.sub.--1000-9926- 622. Accessed Dec. 13, 2008, 6 pages. |
| Carelli, et al., “Effect of Vehicles on Yohimbine Permeation Across Excised Hairless Mouse Skin”, Pharm Acta Helv, 73(3):127-134 (1998)—Abstract, 1 page. |
| Cetearyl Alcohol, Natural Wellbeing, Copyrigh 2001-2012, retrieved on Apr. 10, 2014, http://www.naturalwellbeing.com/learning-center/Cetearyl—Alcohol, 3 pages. |
| Chebil, et al., “Soulbility of Flavonoids in Organic Solvents”, J. Chem. Eng. Data, 52(5):1552-1556 (2007)—Abstract, 1 page. |
| Cheshire, et al., Disorders of Sweating, www.medscape.com, Semin Neurol 23(4):399-406, 2003. |
| Chevrant-Breton, et al., “Etude du Traitement Capillaire <<Bioscalin>> dans les Alopecies Diffuses de la Femme”, Gazette Medicale, 93(17):75-79 (1986) [English abstract]. |
| Chiang, et al., “Bioavailability Assessment of Topical Delivery Systems: In Vitro Delivery of Minoxidil from Prototypical Semi-Solid Formulations”, Int. J. Pharm, 49(2):109-114 (1989)—Abstract, 1 page. |
| Chinnian, et al., “Photostability Profiles of Minoxidil Solutions”, PDA J. Pharm Sci Technol., 50(2):94-98 (1996)—Abstract, 1 page. |
| Chollet, et al., “Development of a Topically Active Imiquimod Formulation”, Pharmaceutical Development and Technology, 4(1):35-43 (1999). |
| Chollet, et al., “The Effect of Temperatures on the Solubility of Immiquimod in Isostearic Acid”, Abstract 3031, Pharmaceutical Research, vol. 14, No. 11 Supplemental (Nov.), p. S475 (1997), 2 pages. |
| Cloez-Tayarani. et al., “Differential effect of serotonin on cytokine production in lipopolysaccharide-stimulated human peripheral blood mononuclear cells: involvement of 5-hydroxytryptamine2A receptors,” Int. Immunol., 2003, 15:233-40. |
| Coetzee, “Acceptability and Feasibility of Micralax applicators and of methyl cellulose gel placebo for large-scale clinical trials of vaginal microbicides,” Nicol.AIDS 2001, vol. 15, No. 14, pp. 1837-1842. |
| Colloidal Silica. Retrieved online on Jun. 4, 2011. <URL:http://www.grace.com/engineeredmaterials/materialsciences/colloidalsilica/default.aspx>. Copyright 2011. 4 pages. |
| Cook and Mortensen, “Nifedipine for treatment of anal fissures,” Dis Colon Rectum, 2000, 43(3):430-1. |
| Croda 2. Croda Cetomacrogol 1000 Product Information Sheet. 2011 (no month given). 1 page. |
| Croda. Aracel 165 Product Summary. 2011 (no month given). 1 page. |
| Cunha, “Minocycline versus Doxycycline in the treatment of Lyme Neuroborreliosis,” Clin. Infect. Diseases, 2000, 30: 237-238. |
| D.W.A. Sharp Dictionary of Chemistry, Penguin Books, 1983, 3 pages. |
| Dalby, “Determination of Drug Solubility in Aerosol Propellants,” Pharmaceutical Research, vol. 8, No. 9, 1991, pp. 1206-1209. |
| Dawber, et al., “Hypertrichosis in Females Applying Minoxidil Topical Solution and in Normal Controls”, JEADV, 17:271-275 (2003). |
| Denatonium Benzoate http://www.newdruginfo.com/pharmaceopeia/usp28/v28230/usp28nf23s0.sub.--m- 22790.htm Accessed Dec. 9, 2008, 2 pages. |
| Dentinger, et al., “Stability of Nifedipine in an Extemporaneously Compounded Oral Solution”, American Journal of Health-System Pharmacy, 60(10):1019-1022 (2003)—Abstract, 1 page. |
| Disorder. (2007). In the American Heritage Dictionary of the English Language. Retrieved from http://www.credoreference.com/entry/hmdictenglang/disorder. 1 page. |
| Draelos, Z. D. “Antiperspirants and the Hyperhidrosis Patients.” Dermatologic Therapy. 2001. vol. 14. pp. 220-224. |
| Dumortier et al., “A review of poloxamer 407 pharmaceutical and pharmacological characteristics,” Pharmaceutical Res., 2006, 23(12):2709-2728. |
| Durian et al., “Scaling behavior in shaving cream,” The Americal Physical Society, Dec. 1991, 44(12):R7902-7905. |
| Ebadi et al., “Healing effect of topical nifedipine on skin wounds of diabetic rats,” DARU, 2003, 11(1):19-22. |
| Edens, et al., “Storage Stability and Safey of Active Vitamin C in a New Dual-Chamber Dispenser”, Journal of Applied Cosmetology, 17(4):136-143 (1999)—Abstract, 1 page. |
| Edirisinghe, et al., “Effect of fatty acids on endothelium-dependent relaxation in the rabbit aorta”, Clin Sci (Lond). Aug. 2006; 111(2): 145-51. |
| Edwards, “Imiquimod in Clinical Practice”, J. Am Acad Dermatol., 43(1, Pt 2):S12-S17 (2000)—Abstract, 1 page. |
| Effendy and Maibach. “Surfactants and Experimental Irritant Contact Dermatitis.” Contact Dermatol., 1995, 33:217-225. |
| Elias and Ghadially, “The aged epidermal permeability barrier,” Clinical Geriatric Medicine, Feb. 2002, pp. 103-120. |
| Emulsifiers with HLB values. http://www.theherbarie.com/files/resources-center/formulating/Emulsifiers- .sub.--HLB.sub.--Values.pdf accessed Aug. 5, 2009 (3 pps). |
| Encyclopedia of Pharmaceutical Technology, Second Edition, vol. 3, Copyright 2002, 4 pages. |
| Esposito, E. et al. “Nanosystems for Skin Hydration: A Comparative Study.” International Journal of Cosmetic Science. 29. 2007. pp. 39-47. |
| Ethanol, Accessed http://www.sigmaaldrich.com/catalog/ProductDetail.do?N4=E7023SIAL&N5=SEAR- CH.sub.--CONCAT.sub.--PNOBRAND.sub.--KEY&F=SPEC Dec. 9, 2008, 2 pages. |
| Ethylene Oxide Derivatives: An Essence of Every Industry. A definition of Emulsifier. Http://www.emulsifiers.in/ethylene—oxide—derivatives2.htm. Accessed Jul. 12, 2011. 3 pages. |
| Fantin et al., “Critical influence of resistance to streptogramin B-type antibiotics on activity of RP 59500 (Quinupristin-dalfopristin) in experimental endocarditis due to Staphylococcus aureus,” Antimicrob Agents and Chemothery, 1999, 39:400-405. |
| Farahmand, et al., “Formulation and Evaluation of a Vitamin C Multiple Emulsion”, Pharmaceutical Development and Technology, 11(2):255-261 (2006)—Abstract, 1 page. |
| Final Office Action for U.S. Appl. No. 11/430,437, Tamarkin et al., Dec. 16, 2008, 24 pages. |
| Flick, Cosmetic and Toiletry Formulations, vol. 5, 2nd Edition, Copyright 1996, 63 pages. Relevant pp. 251-309. |
| Fluhr et al., “Glycerol accelerates recovery of barrier function in vivo,” Acta Derm. Venereol,. 1999, 79:418-21. |
| Fontana, Anthony J., “Water Activity: Why It is Important for Food Safety,” International Conference on Food Safety, Nov. 16-18, 1998, pp. 177-185. |
| Gallarate, et al., “On the Stability of Ascorbic Acid in Emulsified Systems for Topical and Cosmetic Use”, International Journal of Pharmaceutics, 188:233-241 (1999). |
| Galligan, John et al., “Adhesive Polyurethane Liners for Anterior Restorations,” J. Dent. Res., Jul.-Aug. 1968, pp. 629-632. |
| Garti et al. “Sucrose Esters microemulsions,” J. Molec. Liquids, 1999, 80:253-296. |
| Gelbard et al. “Primary Pediatric Hyperhidrosis: A Review of Current Treatment Options.” Pediatric Dermatology. 2008. 25 (6). pp. 591-598. |
| Gill, A.M, et al., “Adverse Drug Reactions in a Paediatric Intensive Care Unit,” Acta Paediatr 84:438-441, 1995. |
| Gladkikh, “Ascorbic Acid and Methods of Increasing its Stability in Drugs”, Translated from Khimiko-Farmatsevticheskii Zhurnal, 4(12):37-42 (1970)—1 page. |
| Glaser, et al., Hyperhidrosis: A Comprehensive and Practical Approach to Patient Management, Expert Rev. Dermatol. 1(6), 773-775 (2006). |
| Google search strategy for minocycline solubility, retrieved on Aug. 15, 2013, <http://www.googl.com/search?rls=com.microsoft%3Aen-us%3AIE-SearchBox&q-melocyc1ine+solubility>, 1 page. |
| Graves, S. et al. “Structure of Concentrated Nanoemulsions.” The Journal of Chemical Physics.. 122 America Institute of Physics. Published Apr. 1, 2005. 6 pages. |
| Groveman, et al., “Lack of Efficacy of Polysorbate 60 in the Treatment of Male Pattern Baldness”, Arch Intern Med, 145:1454-1458 (1985). |
| Gschnait, F., et al., “Topical Indomethacin Protects from UVB and UVA Irriadiation,” Arch. Dermatol. Res. 276:131-132, 1984. |
| Hakan, et al., “The protective effect of fish oil enema in acetic acid and ethanol induced colitis,” The Turkish Journal of Gasroenterology, 2000, vol. 11, No. 2, pp. 155-161. |
| Hall, Karla, “Diaper Area Hemangiomas: A Unique Set of Concerns,” http://members.tripod.com/.about.Michelle.sub.—G/diaper.html, Dec. 1, 2008, 8 pages. |
| Hallstar. Retrieved online on Jun. 4, 2011. <URL:http://www.hallstar.com/pis.php?product=1H022>. 1 page. |
| Hammer et al. “Anti-Microbial Activity of Essential Oils and other Plant extracts,” J. Applied Microbiology, 1999, 86:985-990. |
| Hargreaves, “Chemical Formulation, An Overview of Surfactant-Based Preparations Used in Everyday Life”, The Royal Society of Chemistry, pp. 114-115 (2003). |
| Harrison, et al., “Effects of cytokines and R-837, a cytokine inducer, on UV-irradiation augmented recurrent genital herpes in guinea pigs”, Antivial Res., 15(4):315-322 (1991). |
| Harrison, et al., “Modification of Immunological Responses and Clinical Disease During Topical R-837 Treatment of Genital HSV-2 Infection”, Antiviral Research, 10:209-224 (1988). |
| Harrison, et al., “Pharmacokinetics and Safety of Iminquimod 5% Cream in the Treatment of Actinic Keratoses of the Face, Scalp, or Hands and Arms”, Arch. Dermatol. Res., 296(1):6-11 (2004)—Abstract, 1 page. |
| Harrison, et al., “Posttherapy Suppression of Genital Herpes Simplex Virus (HSV) Recurrences and Enhancement of HSV-Specific T-Cell Memory by Imiquimod in Guinea Pigs”, Antimicrobial Agents and Chemotherapy, 38(9):2059-2064 (1994). |
| Harry, “Skin Penetration,” The British Journal of Dermatology and Syphillis, 1941, 53:65-82. |
| Hashim, et al. “Tinea versicolor and visceral leishmaniasis,” Int J Dermatol., Apr. 1994; 33(4), pp. 258-259 (abstract only). |
| Heart Failure, The Merck Manual, 2008 <<http://www.merck.com/mmhe/sec03/ch025/ch025a.html>> 12 pages. |
| Hepburn, NC., “Cutaneous leishmaniasis,” Clin Exp Dermatol, Jul. 2000; 25(5), pp. 363-370 (abstract only). |
| Hill, Randall M. (Ed.) Silicone Surfactants, Table of Contents and Chapter 7, “Silicone Surfactants: Applicants in the Personal Care Industry,” by David T. Floyd, 1999 (30 Pages). |
| Hormones. Http://www.greenwillowtree.com/Page.bok?file=libido.html. Jan. 2001. |
| http://ibabydoc.com/online/diseaseeczema.asp., Atopic Dermatitis, Copyright 2000, 6 pages. |
| http://web.archive.org/web/20000106225413/http://pharmacy.wilkes.edu/kibbeweb/lab7.html, Characteristics of Surfactants and Emulsions, Jan. 29, 2010, 5 pages. |
| http://www.agworkshop.com/p3.asp, AG&Co. Essential oil workshop. 1 page. Accessed Jan. 31, 2010. |
| Hubbe, Martin. Mini-Encyclopedia of Papermaking Wet-End Chemistry: Additives and Ingredients, their Composition, Functions, Strategies for Use. Retrieved online on Jun. 4, 2011. <URL://http://www4.ncsu.edu/˜hubbe/CSIL.htm>. Feb. 1, 2001. 2 pages. |
| Hwang et al. “Isolation and identification of mosquito repellents in Artemisia vulgaris,” J. Chem. Ecol., 11: 1297-1306, 1985. |
| Hydroxyethylcellulose. Http: //terpconnect.umd.edu/-choi/MSDS/Sigma-Aldrich/HYDROXYETHYL%20CELLULOSE, 5 pages, Jan. 14, 2004. |
| ICI Americas Inc. “The HLB System: A Time-Saving Guide to Emulsifier Selection.” Mar. 1980. pp. 1-22. |
| Ikuta, et al., “Scanning Electron Microscopic Observation of Oil/Wax/Water/Surfacant System”, Journal of SCCJ, 34(4):280-291 (2004)—Abstract, 1 page. |
| Indomethacin. Retrieved online on Jun. 3, 2011. <URL:http://it03.net/com/oxymatrine/down/1249534834.pdf>. Aug. 15, 2009. 3 pages. |
| Innocenzi, Daniele et al., “An Open-Label Tolerability and Effacy Study of an Aluminum Sesquichlorhydrate Topical Foam in Axillary and Palmar Primary Hyperhidrosis,” Dermatologic Therapy, vol. 21, S27-S30, 2008. |
| Izquierdo, P. et al. “Formation and Stability of Nano-Emulsions Prepared Using the Phase Inversion Temperature Method.” University of Barcelona. Sep. 17, 2001. 1 page. |
| Jan. “Troubled Times: Detergent Foam.” http://zetatalk.com/health/theall7c.htm. Accessed Feb. 9, 2012. 2 pages. |
| Joseph, “Understanding foams & foaming,” University of Minnesota (1997), at http://www.aem.umn.edu/people/faculty/joseph/archive/docs/understandingfoams.pdf, pp. 1-8. |
| Kalkan, et al., The Measurement of Sweat Intensity Using a New Technique, Tr. J. of Medical Sciences 28, 515-517 (1998). |
| Kanamoto, et al., “Pharmacokinetics of two rectal dosage forms of ketoprofen in patients after anal surgery,” J Pharmacobiodyn., Mar. 1988; 11(3):141-5. |
| Kang,et al., “Enhancement of the Stability and Skin Penetration of Vitamin C by Polyphenol”, Immune Netw., 4(4):250-254 (2004)—Abstract, 1 page. |
| Karasu, T.B. et al., “Treatment of Patients with Major Depressive Disorder, Second Edition,” pp. 1-78, 2000. |
| Kathon.TM. CG (product information sheet by Rohm and Haas, Jun. 2006). |
| Kim, “Stability of Minoxidil in Aqueous Solution”, Yakhak Hoechi, 30(5):228-231 (1986)—Abstract, 1 page. |
| Kinnunen, “Skin reactions to hexylene glycol,” Contact Dermatitis Sep. 1989; 21(3): 154-8. |
| Kleber, M.D., H.D. et al., “Treatment of Patients with Substance Use Disorders, Second Edition,” pp. 1-276, 2006. |
| Knight et al., “Topical diltiazem ointment in the treatment of chronic anal fissure,” Br. J. Surg., 2001, 88(4):553-6. |
| Koerber, S., “Humectants and Water Activity,” Water Activity News, 2000, ISSN No. 1083-3943. |
| Kreuter, J. “Nanoparticles and microparticles for drug and vaccine delivery,” J. Anat. (1996) 189, pp. 503-505. |
| Kucharekova et al., “Effect of a lipid-rich emollient containing ceramide 3 in experimentally induced skin barrier dysfunction,” Contact Dermatitis, Jun. 2002, pp. 331-338. |
| Kumar, J. et ak., “Application of Broad Spectrum Antiseptic Povidone Iodine as Powerful Action: A Review,” Journal of Pharmaceutical Science and Technology vol. 1(2), 2009, 48-58. |
| Kwak et al. “Study of Complete Transparent Nano-Emulsions which Contain Oils.” IFSCC Conference 2003, Seoul, Korea, Sep. 22-24, 2003. 3 pages. |
| Lautenschlager, Dr. Hans. “A Closer Look on Natural Agents: Facts and Future Aspects.” Kosmetic Konzept. Kosmetische Praxis. 2006 (no month given). (5), 8-10. 3 pages. |
| Lebwohl et al. “Treatment of Psoriasis. Part 1. Topical Therapy and Phototherapy.” J. Am. Acad. Dermatol. 45:487-498. Oct. 2001. |
| Lebwohl et al., “A randomized, double-blind, placebo-controlled study of clobestasol propionate 0.05% foam in the treatment of nonscalp psoriasis,” International Journal of Dermatology, 2002, 41(5): 269-274. |
| Lee et al., “Historical review of melanoma treatment and outcomes,” Clinics in Dermatology, 2013, 31: 141-147. |
| Lee, et al., “The Stabilization of L-Ascorbic Acid in Aqueous Solution and Water-in-Oil-in-Water Double Emulsion by Controlling pH and Electrolyte Concentration”, J. Cosmet. Sci., 55:1-12 (Jan./Feb. 2004). |
| Leive et al, “Tetracyclines of various hydrophobicities as a probe for permeability of Escherichia coli outer membrane,” Antimicrobial Agents and Chemotherapy, 1984, 25:539-544. |
| Leung, et al., “Bioadhesive Drug Delivery in Water-Soluble Polymers,” American Chemical Society, Chapter 23, 1991, pp. 350-366. |
| Li, et al., “Solubility Behavior of Imiquimod in Alkanoic Acids”, Abstract 3029, Pharmaceutical Research, vol. 14, No. 11 Supplemental (Nov.), p. S475 (1997), 2 pages. |
| Licking Vaginal Dryness without a Prescription. Accessed http://www.estronaut.com/a/vag.sub.—dryness.htm on Dec. 14, 2008, 3 pages. |
| Lin et al., “Ferulic acid stabilizes a solution of vitamins c and e and doubles its photoprotection of skin,” J Invest Dermatol, 2005, 125:826-32. |
| Lippacher, A. et al. “Liquid and Semisolid SLN Dispersions for Topical Application Rheological Characterization.” European Journal of Pharmaceutics and Biopharmaceutics. 58. 2004. pp. 561-567. |
| Livingstone and Hubel, “Segregation of form, color, movement, and depth: Anatomy, physiology, and perception,” Science, May 1988, 240:740-749. |
| Luepke and Kemper, “The HET-CAM Test: An Alternative to the Draize Eye Test,” FD Chem. Toxic., 1986, 24:495-196. |
| LUPO, “Antioxidants and Vitamins in Cosmetics”, Clinics in Dermatology, 19:467-473 (2001). |
| Martindale, The extra pharmacopoeia [28th] edition, Eds.: Reynolds, J.E.F. and Prasad, A.B., The Pharmaceutical Press, London, pp. 862-864, 1982. |
| Martindale. 33 ed. London, Bath Press, 2002. pp. 1073 and 1473. |
| Material Safety Data Sheet, Progesterone, Apr. 26, 2006, 5 pages. |
| Material Safety Data Sheet, Science Lab.com, Polyethylene Glycol 1000, MSDS, Nov. 6, 2008, 6 pages. |
| Merck index, 10th edition, Merck & Co., Inc.: Rahway, NJ, 1983, pp. 39 (entry 242 for allantoin). |
| Merck index, 14th edition, O'Neill, ed., 2006, entry for p-amino benzoic acid. |
| Merck index, 14th edition, O'Neill, ed., 2006, entry for zinc oxide. |
| Merck Index, An Encyclopedia of Chemicals, Drugs, and Biologicals. 13th Edition. O'Neil et al eds. Entries 1058, 2350, 6143, and 8803. 2001. 7 pages. |
| Merck Manual Home Edition. “Excessive Sweating: Sweating Disorders.” Accessed Apr. 14, 2011 at www.merckmanuals.com/home/print/sec18/ch206/ch206c.html. 2 pages. |
| Merriam Webster Online Dictionary [online] retrieved from http://www.merriam-webster.com/cgi-bin/dictionary?book=dictionary&va=derivative on Jul. 5, 2008; 1 page. |
| Merriam-Webster Online Dictionaary, 2008, “Mousse,” Merriam-Webster Online, Dec. 8, 2008 http://www.merriam-webster.com/dictionary/mousse, 2 pages. |
| Messenger, et al., “Minoxidil: Mechanisms of Action on Hair Growth”, British Journal of Dermatology, 150:186-194 (2004). |
| Metronidazole. www.usp.org/pdf/EN/veterinary/metronidazole.pdf. accessed Sep. 10, 2009, 4 pages. |
| Metz, et al., “A Phase I Study of Topical Tempol for the Prevention of Alopecia Induced by Whole Brain Radiotherapy”, Clinical Cancer Research, 10:6411-6417 (2004). |
| Meucci, et al., “Ascorbic Acid Stability in Aqueous Solutions”, Acta Vitaminol Enzymol, 7(3-4):147-153 (1985)—Abstract, 1 page. |
| MMP Inc. International Development and Manufacturing, “Formulating specialities,” http://mmpinc.com, 3 pages. Feb. 2, 2010. |
| Molan, Peter Clark, “World Wide Wounds,” Dec. 2001, 13 pages. |
| Molins PLC v. Textron Inc., 48 F.3d 1172, 33 USPQ2d 1823 (Fed. Cir. 1995), 19 pages. |
| Morgan, Timothy M., et al., “Enhanced Skin Permeation of Sex Hormones with Novel Topical Spray Vehicles,” Journal of Pharmaceutical Sciences, vol. 87, No. 10, Oct. 1998, pp. 1213-1218. |
| Natural Skincare Authority, “Disodium EDTA: Cosmetic Toxin Data,” 2011, retrieved on Nov. 17, 2013, http://www.natural-skincare-authority.com/DISODIUM-EDTA.html, 4 pages. |
| Neutrogena. Http://www.cosmetoscope.com/2010/04/neutrogea-clinical-with-johnson-johnsons-cytomimic-techology/. Published Apr. 28, 2010. Accessed Sep. 11, 2010, 5 pages. |
| Neves et al., “Rheological Properties of Vaginal Hydrophilic Polymer Gels,” Current Drug Delivery, 2009, 6:83-92. |
| Nietz, “Molecular orientation at surfaces of solids,” J. Phys. Chem., 1928, 32(2): 255-269. |
| No Author Listed. “Opitmization of Nano-Emulsions Production by Microfluidization.” European Food Research and Technology. Volume 225, No. 5-6. Sep. 2007. Abstract. 1 page. |
| Office Action for U.S. Appl. No. 11/430,437, Tamarkin et al., May 9, 2008, 27 pages. |
| Office Action received from the U.S. Patent Office, U.S. Appl. No. 11/430,599, Jul. 28, 2008 (59 pages). |
| Oil. Dictionary of Chemistry. Editor: DWA Sharp. Copyright 1990. |
| Olsen, et al., “A Multicenter, Randomized, Placebo-Controlled, Double-Blind Clinical Trial of a Novel Formulation of 5% Minoxidil Topical Foam Versus Placebo in the Treatment of Androgenetic Alopecia in Men”, J. Am. Acad Dermatol, 57:767-774 (2007). |
| OM Cinnamate. http://www.makingcosmetics.com/sunscreens/OM-Cinnamate-p102.html accessed Sep. 26, 2009, 1 page. |
| Osborne and Henke, “Skin Penetration Enhancers Cited in the Technical Literature,” Pharm. Technology, Nov. 1997, pp. 58-86. |
| Padhi et al., “Phospho-olicines as positive-electrode materials for rechargeable lithium batteries,” J. Electrochemical Soc., 1997, 144(4): 1188-1194. |
| Padi. “Minocycline prevents the development of neuropathic pain, but not acute pain: possible anti-inflammatory and antioxidant mechanisms,” Eur J. Pharmacol, 2008, 601:79-87. |
| Pakpayat, et al., “Formulation of Ascorbic Acid Microemulstions with Alkyl Polyglycosides”, European Journal of Pharmaceutics and Biopharmaceutics, 72:444-452 (2009). |
| Palamaras and Kyriakis, “Calcium antagonists in dermatology: a review of the evidence and research-based studies,” Derm. Online Journal, 2005, 11(2):8. |
| Paragraph E.3.1 of regulation (EC) No. 2003 (See Directive 67/548/EEC OJ 196, 16.8, 1967, p. 1. |
| Passi et al., Lipophilic antioxidants in human sebum and aging, Free Radical Research, 2002, pp. 471-477. |
| Paula. http://ww.cosmeticscop.com/cosmetic-ingredient-dictionary/definition/259/c12-15-alkyl-benzoate.aspx. Printed Oct. 24, 2010. 1 page. |
| Pendergrass, “The shape and dimension of the human vagina as seen in three-dimensional vinyl polysiloxane casts,” Gynecol Obstet. Invest. 1996:42(3):178-82. |
| Perrotti et al., “Topical Nifedipine With Lidocaine Ointment vs. Active Control for Treatment of Chronic Anal Fissure,” Dis Colon Rectum, 2002, 45(11):1468-1475. |
| Prescription Information for Aldara, Mar. 2007 (29 pages). |
| Prevent. (2007). In the American Heritage Dictionary of the English Language. Retrieved from http://www.credoreference.com/entry/hmdictenglang/prevent. 1 page. |
| Prud'homme et al., Foams: theory, measurements and applications, Marcel Dekker, Inc., 1996, 327-328. |
| Psoriasis, http://www.quickcare.org/skin/causes-of0psoriasis.html. Accessed Sep. 9, 2010—3 pages. |
| Purcell, Hal C. “Natural Jojoba Oil Versus Dryness and Free Radicals.” Cosmetics and Toiletries Manufacture Worldwide. 1988. 4 pages. |
| Purdy et al., “Transfusion-transmitted malaria: unpreventable by current donor exclusion guidelines?” Transfusion, Mar. 2004, 44:464. |
| Raschke, et al., “Topical Activity of Ascorbic Acid: From In Vitro Optimization to In Vivo Efficacy”, Skin Pharmacology and Physiology, 17(4):200-206 (2004)—Abstract, 1 page. |
| Ravet et al., “Electroactivity of natural and synthetic triphylite,” J. of Power Sources, 2001, 97-98: 503-507. |
| Raymond, Iodine as an Aerial Disinfectant, Journal of Hygiene, vol. 44, No. 5 (May 1946), pp. 359-361. |
| Receptacle. Merriam Webster. Http://www.merriam-webster.com/dictionary/receptacle. Accessed Jul. 12, 2011. 1 page. |
| Repa et al. “All-trans-retinol is a ligand for the retinoic acid receptors,” Proc. Natl. Acad Sci, USA, 90: 7293-7297, 1993. |
| Reregistration Eligibility Decision for Pyrethrins, EPA, Jun. 7, 2006, 108 pages. |
| Richwald, “Imiquimod”, Drugs Today, 35(7):497 (1999)—Abstract, 1 page. |
| Rieger and Rhein. “Emulsifier Selection/HLB.” Surfactants in Cosmetics. 1997 (no month given). 1 page. |
| Rosacea, http://clinuvel.com/skin-conditions/common-skin-conditions/rosacea#h0-6-prevention. Accessed Sep. 9, 2010, 5 pages. |
| Ruledge, “Some corrections to the record on insect repellents and attractants,” J. Am. Mosquito Control Assoc, 1988, 4(4): 414-425. |
| Sakai et al., “Characterization of the physical properties of the stratum corneum by a new tactile sensor,” Skin Research and Technology, Aug. 2000, pp. 128-134. |
| Savin, et al., “Tinea versicolor treated with terbinafine 1% solution,” Int J. Dermatol, Nov. 1999; 38(11), pp. 863-865. |
| Schaefer, “Silicone Surfactants,” Tenside, Surfactants, Deterg., 1990, 27(3): 154-158. |
| Schmidt A., “Malassezia furfur: a fungus belonging to the physiological skin flora and its relevance in skin disorders,” Curtis., Jan. 1997; 59(1), pp. 21-24 (abstract). |
| Schmolka, “A review of block polymer surfactants,” Journal of the American Oil Chemists Society, Mar. 1977, 54: 110-116. |
| Schott, “Rheology,” Remington's Pharmaceutical Sciences, 17th Edition, 1985, 330-345. |
| Schulze, M.D., Harry “Iodine and Sodium Hypochlorite as Wound Disinfectants,” The British Medical Journal, pp. 921-922, 1915. |
| Sciarra, “Aerosol Technology,” Kirk-Othmer Encyclopedia of Chemical Technology, Jul. 2012, 20 pages. |
| Scientific Discussion for the approval of Aldara, EMEA 2005 (10 pages). |
| Scott as Published in Pharmaceutical Dosage Forms; Disperse Systems, vol. 3, Copyright 1998, 120 pages. |
| Scully et al., “Cancers of the oral mucosa treatment and management,” Medscape Drugs, Diseases and Procedures, Apr. 20, 2012, retrieved on Oct. 12, 2013, <http://emedicine.medscape.com/article/1075729-treatment>, 10 pages. |
| Seborrheic Dermatitis, http://www.cumc.columbia.edu/student/health/pdf/R-S/Seborrhea%20Dermatitis.pdf. Access Sep. 9, 2010, 2 pages. |
| Sehgal, “Ciclopirox: a new topical pyrodonium antimycotic agent: A double-blind study in superficial dermatomycoses,” British Journal of Dermatology, 1976, 95:83-88. |
| Shear, et al., “Pharmacoeconomic analysis of topical treatments for tinea infections,” Pharmacoeconomics. Mar. 1995; 7(3); pp. 251-267 (abstract only). |
| Sheu, et al., “Effect of Tocopheryl Polyethylene Glycol Succinate on the Percutaneous Penetration of Minoxidil from Water/Ethanol/Polyethylene Glycol 400 Solutions”, Drug Dev. Ind. Pharm., 32(5):595-607 (2006)—Abstract, 1 page. |
| Shim, et al., “Transdermal Delivery of Mixnoxidil with Block Copolymer Nanoparticles”, J. Control Release, 97(3):477-484 (2004)—Abstract, 1 page. |
| Shrestha et al., Forming properties of monoglycerol fatty acid esters in nonpolar oil systems, Langmuir, 2006, 22: 8337-8345. |
| Sigma Aldrich, “HLB—Numbers in Lithography Nanopatterning,” http://www.sigmaaldrich.com/materials-science/micro-and-nanoelectronics/l-ithography-nanopatterning/hlb-numbers.html, accessed: Feb. 2, 2009, pp. 1-3. |
| Sigma-Aldrich, Material Safety Data Sheet, Hydroxyethyl Cellulose, Mar. 3, 2004, 5 pages. |
| Silicone. Definition. Retrieved Apr. 19, 2011 from http://www.oxforddictionaries.com/definition/silicone?view=uk. 1 page. |
| Simoni et al., “Retinoic acid and analogs as potent inducers of differentiation and apoptosis. New promising chemopreventive and chemotherapeutic agents in oncology,” Pure Appl Chem., 2001, 73(9):1437-1444. |
| Simovic, S. et al., “The influence of Processing Variables on Performance of O/W Emulsion Gels Based on Polymeric Emulsifier (Pemulen ÒTR-2NF),” International Journal of Cosmetic Science, vol. 2(2): abstract only. Dec. 24, 2001, 1 page. |
| Skin Biology, CP Serum—Copper-Peptide Serum for Skin Regeneration and Reducing Wrinkles, Skin Biology, http;//web.archive.org/web/20030810230608/http://www.skinbio.com/cpserum.- html, Dec. 1, 2008, 21 pages. |
| Skin Deep Cosmetics. PPG-40-PEG-60 Lanolin Oil http://www.cosmeticsdatabase.com/ingredient/722972/PPG-40-PEG-60—Lanolin—Oil/?ingred06=722972. 2010, 3 pages. |
| Smith, “Hydroxy acids and skin again,” Soap Cosmetics Chemical Specialties, 1993, pp. 54-59. |
| Smith, Anne. “Sore Nipples.” Breastfeeding Mom's Sore Nipples: Breastfeeding Basics. http://breastfeedingbasics.com/articles/sore-nipples. Accessed Feb. 8, 2012. 9 pages. |
| Softemul-165: Product Data Sheet, Mohini Organics PVT LTD, retrieved Apr. 10, 2014, http://www.mohiniorganics.com/Softemul165.html#, 1 page. |
| Solans et al. “Overview of basic aspects of microemulsions,” Industrial Applications of Microemulsions, Solans et al Eds, New York, 1997, 66:1-17. |
| Sonneville-Aubrun, O. et al. “Nanoemulsions: A New Vehicle for Skincare Products.” Advances in Colloid and Interface Science. 108-109.. 2004. pp. 145-149. |
| Squillante et al., “Codiffusion of propylene glycol and dimethyl isosorbide in hairless mouse skin,” European J. Pharm. Biopharm., 1998, 46(3):265-71. |
| Squire. J, “A randomised, single-blind, single-centre clinical trial to evaluate comparative clinical efficacy of shampoos containing ciclopirox olamine (1.5%) and salicylic acid (3%), or ketoconazole (2%, Nizoral) for the treatment ofdandruff/seborrhoeic dermatitis,” Dermatolog Treat. Jun. 2002;13(2):51-60 (abstract only). |
| Sreenivasa, et al., “Preparation and Evaluation of Minoxidil Gels for Topical Application in Alopecia”, Indian Journal of Pharmaceutical Sciences, 68(4):432-436 (2006), 11 pages. |
| Stehle et al., Uptake of minoxidil from a new foam formulation devoid of propylene glycol to hamster ear hair follicles, J. Invest. Dermatol., 2005, 124(4), A101. |
| Sugisaka, et al., “The Physiochemical Properties of Imiquimod, The First Imidazoquinoline Immune Response Modifier”, Abstract 3030, Pharmaceutical Research, vol. 14, No. 11 Supplemental (Nov.), p. S475 (1997), 2 pages. |
| Sun Pharmaceutical Industried Ltd. v. Eli Lilly and Co., 611 F.3d 1381, 95 USPQ2d 1797 (Fed. Cir. 2010),7 pages. |
| Surfactant. Chemistry Glossary. Http://chemistry.about.com/od/chemistryglossary/g/surfactant.htm, 2012, 1 page. |
| Sweetman, Sean C. Martindale: The Complete Drug Reference. 33rd Edition. London. Pharmaceutical Press. Jun. 21, 2002. pags. 1073 and 1473. 5 pages. |
| Tadros, Tharwat F. “Surfactants in Nano-Emulsions.” Applied Surfactants: Principles and Applications. Wiley-VCH Verlag GmbH & Co. Weinheim. ISBN: 3-527-30629-3. 2005. pp. 285-308. |
| Tan et al., “Effect of Carbopol and Polyvinlpyrrolidone on the Mechanical Rheological and Release Properties of Bioadhesive Polyethylene Glycol Gels,” AAPS PharmSciTech, 2000; 1(3) Article 24, 2000, 10 pages. |
| Tanhehco, “Potassium Channel Modulators as Anti-Inflammatory Agents”, Expert Opinion on Therapeutic Patents, 11(7):1137-1145 (2001)—Abstract, 3 pages. |
| Tarumoto, et al., Studies on toxicity of hydrocortisone 17-butyrate 21-propionate -1. Accute toxicity of hydrocortisone 17-butyrate 21-propionate and its analogues in mice, rats and dogs (author's trans), J Toxicol Sci., Jul. 1981; 6 Suppl: 1-16 (Abstract only). |
| Tata, et al., “Penetration of Minoxidil from Ethanol Propylene Glycol Solutions: Effect of Application Volume on Occlusion”, Journal of Pharmaceutical Sciences, 84(6):688-691 (1995). |
| Tata, et al., “Relative Influence of Ethanol and Propylene Glycol Cosolvents on Deposition of Minoxidil into the Skin”, Journal of Pharmaceutical Sciences, 83(10):1508-1510 (1994). |
| Tayss et al., “Anionic detergent-induced skin irritation and anionic detergent-induced pH rise of bovine serum albumin,” J. Soc. Cosmet. Chem., Jul./Aug. 1988, 39:267-272. |
| Third Party Submission for U.S. Appl. No. 12/014,088, Feb. 4, 2009, 4 pages, cited by other. |
| Tirmula et al., “Abstract: D28.00011: Enhanced order in thinfilms of Pluronic (A-B-A) and Brij (A-B) Block copolymers blended with poly (acrylic acid),” Session D28: Block Copolymer Thin Films, Mar. 13, 2006, 1 page, Abstract. |
| Todd et al. “Volatile Silicone Fluids for Cosmetics,” 91 Cosmetics and Toiletries, 1976, 27-32. |
| Torma et al., “Biologic activities of retinoic acid and 3, 4-dehydroretinoic acid in human keratinoacytes are similar and correlate with receptor affinities and transactivation properties,” J. Invest. Dermatology, 1994, 102: 49-54. |
| Torres-Rodriguez, JM., “New topical antifungal drugs,” Arch Med Res. 1993 Winter; 24(4), pp. 371-375 (abstract). |
| Toxicology and Carcinogenesis Studies of t-Butyl Alcohol (CAS No. 75-65-0) in F344/N Rats and B6C3F1 Mice (Drinking Water Studies), http://ntp.niehs.nih.gob/?objectid-=0709F73D-A849-80CA-5FB784E866B576D1. Accessed Dec. 9, 2008, 4 pages. |
| Trofatter, “imiquimod in clinical Practice”, European Journal of Dermatology, 8(7 Supp.):17-19 (1998)—Abstract, 1 page. |
| Tsai, et al., “Drug and Vehicle Deposition from Topical Applications: Use of In Vitro Mass Balance Technique with Minosidil Solutions”, J. Pharm. Sci., 81(8):736-743 (1992)—Abstract, 1 page. |
| Tsai, et al., “Effect of Minoxidil Concentration on the Deposition of Drug and Vehicle into the Skin”, International Journal of Pharmaceutics, 96(1-3):111-117 (1993)—Abstract, 1 page. |
| Tsai, et al., “Influence of Application Time and Formulation Reapplication on the Delivery of Minoxidil through Hairless Mouse Skin as Measured in Franz Diffusion Cells”, Skin Pharmacol., 7:270-277 (1994). |
| Tyring, “Immune-Response Modifiers: A New Paradigm in the Treatment of Human Papillomavirus”, Current Therapeutic Research, 61(9):584-596 (2000)—Abstract, 1 page. |
| Tzen et al., Lipids, proteins and structure of seed oil bodies from diverse species; Plant Physiol., 1993, 101:267-276. |
| Tzen, Jason T.C. et al. “Surface Structure and Properties of Plant Seed Oil Bodies.” Department of Botany and Plant Sciences, University of California, Riverside, California 92521. Apr. 15, 1992. 9 pages. |
| Uner, M. et al. “Skin Moisturizing Effect and Skin Penetration of Ascorbyl Palmitate Entrapped in Solid Lipid Nanoparticles (SLN) and Nanostructured Lipid Carriers (NLC) Incorporated into Hydrogel.” Pharmazie. 60. 2005. 5 pages. |
| USP23/NF 18 The United States Pharmacopeia: The National Formulary, US Pharmacopoeia, 1995, p. 10-14. |
| Van Cutsem et al., “The antiinflammatory efects of ketoconazole,” J. Am. Acad. Dermatol.,1991, 25(2 pt 1):257-261. |
| Van Slyke, “On the measurement of buffer values and on the relationship of buffer value to the dissociation constant of the buffer and the concentration and reaction of buffer solution,” J. Biol. Chem., 1922, 52:525-570. |
| Veron, et al., “Stability of Minoxidil Topical Formulations”, Ciencia Pharmaceutica, 2(6):411-414 (1992), Abstract, 1 page. |
| Wang and Chen, “Preparation and surface active properties of biodegradable dextrin derivative surfactants,” Colloids and Surfaces A: Physicochemical and Engineering Aspects, 2006, 281(1-3):190-193. |
| Weindl et al., “Hyaluronic acid in the treatment and prevention of skin diseases: molecular biological, pharmaceutical and clinical aspects,” Skin Pharmacology and Physiology, 2004, 17: 207-213. |
| Wermuth, C.G. “Similarity in drugs: reflections on analogue design,” Drug Discovery Today, vol. 11, Nos. 7/8, Apr. 2006, pp. 348-354. |
| Williams, “Scale up of an olive/water cream containing 40% diethylene glycol momoethyl ether”, Dev. Ind. Pharm., 26(1):71-77 (2000). |
| Wormser et al., Protective effect of povidone-iodine ointment against skin lesions induced by sulphur and nitrogen mustards and by non-mustard vesicants, Arch. Toxicol., 1997, 71, 165-170. |
| Wormser, Early topical treatment with providone-iodine ointment reduces, and sometimes prevents, skin damage following heat stimulus, Letter to the Editor, Burns 24, pp. 383, 1998. |
| Xynos et al., “Effect of nifedipine on rectoanal motility,” Dis Colon Rectum, 1996, 39(2):212-216. |
| Yamada and Chung, “Crystal Chemistry of the Olivine-Type Li(MnyFel-y)PO4 and (MnyFel-y)PO4 as Possible 4 V Cathode Materials for Lithium Batteries,” J. Electrochemical Soc., 2001, 148(8): A960-967. |
| Yamada et al., “Candesartan, an angiotensin II receptor antagonist, suppresses pancreatic inflammation and fibrosis in rats,” J. Pharmacol. Exp. Ther., 2003, 307(1)17-23. |
| Alcohol, Wikipedia, the free encyclopedia, retrieved on May 17, 2014, http://en.wikipedia.org/wiki/Alcohol, 17 pages. |
| Clobetasol Propionate Cream and Ointment, Apr. 2006, retrieved Jul. 3, 2014, http://dailymed.nlm.nih.gov/dailymed/archives/fdaDrugInfo.cfm?archiveid=994, 7 pages. |
| Cole and Gazewood, “Diagnosis and Treatment of Impetigo,” American Family Physical Website, 2007, http://www.aafp.org/afp, 6 pages. |
| Communication of a Notice of Opposition in European Application No. 03772600.7, dated Jan. 13, 2015, 36 pages. |
| Cremophor A Grades, BASF The Chemical Company, Jan. 2008, 6 pages. |
| Ellis et al., “The Treatment of Psoriasis with Liquor Carbonis Detergens,” J. Invest Dermatology, 1948, 10:455-459. |
| Gels, UNC, The Pharmaceutics and Compounding Laboratory, retrieved on Aug. 25, 2014, http://pharmlabs.unc.edu/labs/gels/agents/htm, 4 pages. |
| Griffin, “Calculation of HLB Values of Non-Ionic Surfactants,” Journal of the Society of Cosmetic Chemists, May 14, 1954, 249-256. |
| Klucel Hydroxypropylcellulose; Chemical and Physical Properties, Hercules Limited, copyright 1986, retrieved on Aug. 25, 2014, http://legacy.library.ucsf.edu/tid/cnf81a99/pdf, 35 pages. |
| Le Vine et al., “Components of the Goeckerman Regimen,” Journal of Investigative Dermatology, 1979, 73:170-173. |
| Luviquat Polymer Grades, BASF The Chemical Company, May 2012, 32 pages. |
| Material Safety Data Sheet, Luvitol EHO, Caelo, Nov. 28, 2013, 4 pages. |
| Material Safety Data Sheet, Liquor carbonis detergens, Caelo, Nov. 28, 2013, 5 pages. |
| Material Safety Data Sheet, Mineral Oil, Macron Fine Chemicals, Oct. 24, 2011, 6 pages. |
| Omega-9 Fatty Acids (Oleic Acid), Orthomolecular.org, Dec. 2004, retrieved on Aug. 15, 2014, http://orthomolecular.org/nutrients/omega9.html. 1 page. |
| Oranje et al., “Topical retapamulin ointment, 1%, versus sodium fusidate ointment, 2%, for impetigo: a randomized, observer-blinded, noninferiority study,” Dermatology, 2007, 215(4):331-340. |
| Polystyrene, Wikipedia the free encyclopedia, retrieved Apr. 21, 2014, http://web.archive.org/web/20060312210423/http://en.wikipedia.org/wiki/Polystyrene, 4 pages. |
| Rohstoffinformationen, Hoffmann Mineral, 2008, 8 pages (with English translation). |
| Vera et al., “Scattering optics of Foam,” Applied Optics, Aug. 20, 2001, 40(24):4210-4214. |
| Ziolkowsky, “Moderne Aerosolschaume in der Kosmetik (Modern Aerosol Foams in Chemical and Marketing Aspects),”, Seifen-Ole-Fette-Wachse, Aug. 1986, 112(13): 427-429 (with English translation). |
| Al-Mughrabi et al., “Effectiveness of Essential Oils and Their Combinations with Aluminum Starch Octenylsuccinate on Potato Storage Pathogens,” TEOP, 2013, 16(1):23-31. |
| Beauty Banter, “Interesting list of comedogenic ingredients!!!!!!!!!!!” QVC blog, Interesting list of comedogenic ingredients, 2014, 1-14. |
| Chemical Characteristics, The Olive Oil Source, © 1998-2015, retrieved on Jun. 12, 2015, http://www.oliveoilsource.com/page/chemical-characteristics, 10 pages. |
| Codex Standard for Olive Oils and Olive Pomace Oils Codex Stan 33-1981, Adopted in 1981, recently amended 2013, 8 pages. |
| Haw, “The HLB System: A Time Saving Guide to Surfactant Selection,” Presentation to the Midwest Chapter of the Society of Cosmetic Chemists, Mar. 9, 2004, 39 pages. |
| Mailer, “Chemistry and quality of olive oil,” NSW Dept. of Primary Industries, Aug. 2006, Primefact 227, 1-4. |
| Oh et al., “Antimicrobial activity of ethanol, glycerol monolaurate or lactic acid against Listeria moncylogenes,”Int. J. Food Microbiology, 1993, 20:239-246. |
| Permethrin (Insecticide), Wildpro, retrieved on Jun. 4, 2015, http://wildpro.twycrosszoo.org/S/00Chem/ChComplex/perm.htm, 5 pages. |
| Refina, “Viscosity Guide for Paints, Petroleum & Food Products,” accessed Mar. 4, 2015, http://www.refina.co.uk/webpdfs/info—docs/Viscosity—guide—chart.pdf, 2 pages. |
| Thorgeirsdottir et al., “Antimicrobial activity of monocaprin: a monoglyceride with potential use as a denture disinfectant,” Acta Odontologica Scandinavica, Feb. 2006, 64:21-26 (Abstract only). |
| United States Standards for Grades of Olive Oil and Olive-Pomace Oil, United States Dept. of Agriculture, Oct. 25, 2010, 21 pages. |
| WebMD, “Psoriasis Health Center,” 2014, retrieved Apr. 13, 2015, http://www.webmd.com/skin-problems-and-treatments/psoriasis/psoriasis-symptoms, 3 pages. |
| WebMD, “Understanding Rosacea—the Basics,” 2014, retrieved Apr. 13, 2015, http://www.webmd.com/skin-problems-and-treatments/understanding -rosacea-basics, 5 pages. |
| Williams et al., “Acne vulgaris,” Lancet, 2012, 379:361-372. |
| Allantoin, Römpp Online, retrieved on Sep. 23, 2015, https://roempp.thieme.de/roempp4.0/do/data/RD-O 1-01552, 5 pages. |
| Coconut Oil, Wikipedia, the free encyclopedia, retrieved on Jul. 3, 2015, https://en.wikipedia.org/wiki/Coconut—oil, 8 pages. |
| Communication of a Notice of Opposition in European Application No. 03772600.7, dated Sep. 23, 2015, 42 pages. |
| Communication of a Notice of Opposition in European Application No. 03772600.7, dated Sep. 24, 2015, 30 pages. |
| Diethyltoluamid, Wikipedia, the free encyclopedia, retrieved on Sep. 11, 2015, https://de.wikipedia.org/wiki/Diethyltoluamid, 12 pages. |
| Dimethylphthalate, Wikipedia, the free encyclopedia, retrieved on Sep. 11, 2015, http://de.wikipedia.org/wiki/Dimethylphthalat, 8 pages. |
| Everything but the Olive, (the Olive Oil Source 1998-2016). http://www.oliveoilsource.com/pageAchemical-characteristics). |
| Healy, “Gelled Emollient Systems for Controlled Fragrance Release and Enhanced Product Performance,” Cosmetics and toiletries, 2002, 117(2): 47-54. |
| Lamisil, Lamisil.http://www.fda.gov/downloads/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm052213.pdf, Published: Apr. 2001. |
| Leunapon-F, Leuna-Tenside, Screenshot, retrieved on Sep. 18, 2015, http://www.leuna-tenside.de/2006—7—14—3143/2006—8—7 5750/2006—8—7 241/cas-68439-49-6, 1 page. |
| Mead, “Electrostatic Mechanisms Underlie Neomycin Block of the Cardiac Ryanodine Receptor Channel (RyR2),” Biophysical Journal, 2004, (87): 3814-3825. |
| Rowe et al., “Glyceryl Monooleate,” Handbook of Pharmaceutical Excipients, 2011, pp. 1-5, retrieved on Dec. 19, 2011, http://www.medicinescomplete.com/mc/excipients/current/1001938996.htm?q=glyceryl%20monooleate&t=search&ss=text&p=1# hit. |
| Rowe et al., “Octyldodecanol,” Handbook of Pharmaceutical Excipients, 2011, pp. 1-4, retrieved on Dec. 19, 2011, URL:http://www.medicinescomplete.com/mc/excipients/current/1001942450.htm?q=octyldodecanol&t=search&ss=text&p=1# hit. |
| Rowe et al., “Sucrose Palmitate,” Handbook of Pharmaceutical Excipients, 2011, pp. 1-5, retrieved on Dec. 19, 2011, URL:http://www.medicinescomplete.com/mc/excipients/current/EXP-TD-c46-mn0001.htm?q=sucrose%20stearate&t=search&ss=text&p=1# hit. |
| Rowe et al., “Sucrose Stearate,” Handbook of Pharmaceutical Excipients, 2011, pp. 1-4, retrieved on Dec. 19, 2011, URL:http://www.medicinescomplete.com/mc/excipients/current/EXP-TD-cll-mnOOO1-mnOOO1.htm?q=sucrose%20stearate&t=search&ss=text&p=3# hit. |
| RSES (Oil in Refrigerator Systems, Service Application Manual, 2009). |
| Security Datasheet, Luvitol EHO, Cetearyloctanoat, Nov. 27, 2013, 10 pages. |
| Sigma-Aldrich. http://www.sigmaaldrich.com/catalog/product/sial/p1754?lang=en® ion=. Published:Mar. 5, 2014. |
| Suppositories?, CareCure, http://sci.rutgers.edu/forum/showthread.php?4176-Suppositories. Published: Apr. 16, 2002. |
| Triethanolamine, haute.de, retrieved on Sep. 14, 2015, http://www.haut.de/service/inci/anzeige&id=16384&query=Triethanolamine&funktio . . . , 3 pages. |
| Valenta, “Effects of Penetration Enhancers on the In-vitro Percutaneous Absorption of Progesterone,” J. Phann Pharrnacol., 1997, 49: 955-959. |
| Wenninger et al., “International Cosmetic Ingredient Dictionary and Handbook,” The Cosmetic, Toiletry, and Fragrance Association, Washington, DC., 1997, vol. 1, 4 pages. |
| Williams et al., “Urea analogues in propylene glycol as penetration enhancers in human skin,” International Journal of Pharmaceutics, 1989, 36, 43-50. |
| Wu et al., “Interaction of Fatty Acid Monolayers with Cobalt Nanoparticles,” Nano Letters, 2004, 4(2): 383-386. |
| Kaur et al., “Formulation Development of Self Nanoemulsifying Drug Delivery System (SNEDDS) of Celecoxib for Improvement of Oral Bioavailability,” Pharmacophore, 2013, 4(4):120-133. |
| Material Safety Data Sheet, Butane, Gas Innovations, Sep. 7, 2007, 3 pages. |
| Material Safety Data Sheet, Carbon Dioxide, Airgas, Feb. 11, 2016, 11 pages. |
| Material Safety Data Sheet, Dimethyl Ether, Airgas, May 14, 2015, 12 pages. |
| Material Safety Data Sheet, N-Butane, Airgas, May 7, 2015, 13 pages. |
| Material Safety Data Sheet, Nitrous Oxide, Airgas, Feb. 11, 2016, 11 pages. |
| Material Safety Data Sheet, Propane, Airgas, Oct. 20, 2015, 12 pages. |
| Sanders et al., “Stabilization of Aerosol Emulsions and Foams,” J. Soc. Cosmet. Chem., 1970, 21:377-391. |
| Albrecht et al., “Topical minocycline foam for moderate to severe acne vulgaris: Phase 2 randomized double-blind, vehicle-controlled study results,” J. Am. Acad. Dermatol., 2016, 74(6):1251-1252. |
| Chapter 1 Meaning of HLB Advantages and Limitations 1980; 4 pages. |
| Foamix Pharmaceuticals Statement: Use of Luviquat FC 370, Approved by Yohan Hazot, May 3, 2016, 3 pages. |
| Material Safety Data Sheet, Squalane, TCI America, 5 pages, https://www.spectrumchemical.com/MSDS/TC1-H0096.pdf. Published: Oct. 6, 2014. |
| Reply of the Patent Proprietor to the Notices of Opposition in European Application No. 03772600.7, dated May 9, 2016, 134 pages. |
| Sorbitan Esters, [online] retrieved on Jul. 1, 2016 from: http://www.drugfuture.com/chemdata/sorbitan-esters.html 2 pages. |
| Sreenivasan et al., “Studies on Castor Oil. I. Fatty Acid Composition of Castor Oil,” Journal of the American Oil Chemists Society. 1956, 33:61-66. |
| Summons to Attend Oral Proceedings in European Application No. 03772600.7, dated Jun. 30, 2016, 19 pages. |
| Penreco, “Intelligent Gel Technology Product Specifications,” Rev. Jun. 2016 (2 pages). |
| European Patent Application No. 03772600.7 (Patent No. 1556009): Interlocutory Decision in Opposition Proceedings, dated Feb. 3, 2017, 54 pages. |
| European Patent Application No. 03772600.7 (Patent No. 1556009): Minutes of Oral Proceedings, dated Feb. 3, 2017, 6 pages. |
| Number | Date | Country | |
|---|---|---|---|
| 20140248219 A1 | Sep 2014 | US |
| Number | Date | Country | |
|---|---|---|---|
| 60858747 | Nov 2006 | US | |
| 60899176 | Feb 2007 | US | |
| 60915859 | May 2007 | US |
| Number | Date | Country | |
|---|---|---|---|
| Parent | 12778591 | May 2010 | US |
| Child | 14189559 | US | |
| Parent | 12025547 | Feb 2008 | US |
| Child | 12778591 | US |
| Number | Date | Country | |
|---|---|---|---|
| Parent | 11940290 | Nov 2007 | US |
| Child | 12025547 | US |
