Patent Grant
10213384
This invention relates to foamable pharmaceutical and cosmetic compositions and foams, containing aprotic polar solvents and uses.
External topical administration is an important route for the administration of drugs in disease treatment. Administration into body cavities is gaining in importance. Many groups of drugs, including, for example, antibiotic, anti-fungal, anti-inflammatory, anesthetic, analgesic, anti-allergic, corticosteroid, retinoid and anti-proliferative medications are preferably administered in creams and ointment.
There are many different types of foams and within each foam type there are many levels of qualities. For example, the froth on the head of beer, lather of shampoo, and lather of shaving cream have been loosely described as foam but all are different from one another. Such differences speak to usability applicability. At one end of the cosmetic or pharmaceutical foam spectrum, the foam can be long-lasting and not readily breakable upon mechanical stimulation like shaving foams. Such foams lack suitability for pharmaceutical use since they lather with mechanical stimulation and require washing off. At the other end of the spectrum, the foam can be quick breaking without mechanical stimulation and collapse upon release. Such foams can be inconvenient since they can disappear rapidly before they can be conveniently applied to the intended target. Yet another type of foam is delayed foaming gel which is expelled as a gel but is said to expand into a type of foam on exposure to body temperature. Such expansion can be slow or delayed and inconvenient. Foams are considered a more convenient vehicle for topical delivery of active agents. There are several types of topical foams, including aqueous foams, such as commonly available shaving foams; hydroalcoholic foams; emulsion-based foams, comprising oil and water components; and oleaginous foams, which consist of high oil content. In skin therapy, oil containing foams are preferred, since oil contributes to skin protection and moisturization, which improve the therapeutic effect of the formulation. Typically foams are made using liquefied hydrocarbon gas propellant, such as propane, butane and isobutene, or hydro-fluoro carbon propellants.
Formulations containing aprotic polar solvents, such as Dimethyl sulfoxide (“DMSO”), have been occasionally known. However, these formulations have only been known as creams, gels or liquid formulations. Yet, despite the many benefits of pharmaceutical and cosmetic foam formulations, until now DMSO-containing formulations have not been developed in a commercial foam form.
The present invention relates to foamable pharmaceutical and cosmetic compositions and foams, comprising aprotic polar solvents.
There is provided, easy to use, stable foamable formulations and foams containing aprotic polar solvents, with improved delivery properties, especially for treatment of dermal and mucosal tissues.
In one or more embodiments waterless formulations comprising at least one aprotic polar solvent are provided. In certain embodiments the waterless formulations are formulated with surfactant. In some embodiments they may also comprise a polymer and or a foam adjuvant. In certain other embodiments they are formulated without surfactant. Surfactant free formulations may in one or more embodiments comprise a polymer and or a foam adjuvant and preferably both. In one or more embodiments the aprotic waterless formulation comprises a short chain alcohol. In one or more embodiments the waterless formulation may form an emulsion, for example between a hydrophobic phase and an aprotic phase. In certain embodiments the formulation may be a single phase until addition of propellant. In one or more embodiments an emulsion is formed or reformed after addition of hydrophobic propellant.
In one or more other embodiments water comprising formulations comprising at least one aprotic polar solvent are provided. In certain embodiments the water comprising formulations are formulated with surfactant. In some embodiments they may also comprise a polymer and or a foam adjuvant. In certain other embodiments they are formulated without surfactant. Surfactant free formulations may in one or more embodiments comprise a polymer and or a foam adjuvant and preferably both. In one or more embodiments the aprotic-aqueous formulation comprises a short chain alcohol. In one or more embodiments the water comprising formulation may form an emulsion, for example between a hydrophobic phase and an aqueous aprotic phase. In certain embodiments the formulation may be a single phase until addition of propellant. In one or more embodiments an emulsion is formed or reformed after addition of hydrophobic propellant.
According to one or more embodiments the foamable carrier comprises:
According to one or more embodiments the foamable carrier comprises:
According to one or more embodiments the foamable composition is aqueous and comprises two or more of the foaming or stabilizing members. In one or more embodiments the composition further comprises one of a protic polar solvent or a hydrophobic carrier or mixtures thereof.
According to one or more embodiments the foamable carrier is water-containing (aqueous) and comprises:
According to one or more certain embodiments the aqueous foamable carrier is aqueous without a hydrophobic carrier and comprises one stabilizing member comprising a non ionic surfactant with a HLB between about 9 to about 16.
According to one or more embodiments, the foamable composition, comprises a therapeutically effective concentration of an aprotic polar solvent, which possesses inherent therapeutic properties.
In preferred embodiments, the therapeutic aprotic polar solvent comprises Dimethyl sulfoxide (DMSO).
The carrier or pharmaceutical or cosmetic composition is stored in a pressurized canister and when released a foam is formed that is thermally stable, yet breaks easily upon application of shear force. So in one or more embodiments the foam composition is breakable. The breakable foam is thermally stable, yet breaks easily upon application of shear force. By thermally stable is meant that the foam is stable for a sufficient period of time—both at room temperature and when applied to the skin or subjected to at temperature of about 36 C—to facilitate easy and relaxed use and allow for possible distractions or interruptions. In one or more embodiments the foam is stable for at least about 30 secs, at least about 40 secs, at least about 50 secs, at least about 60 secs, at least about 80 secs, at least about 100 secs, at least about 120 secs, at least about 140 secs, at least about 160 secs, at least about 180 secs, at least about 210 secs, at least about 240 secs, at least about 270 secs or at least about 300 secs.
In one or more alternative embodiments the foam composition is quick-break or thermolabile. The quick-breaking foam is thermally instable, and collapses easily upon exposure to body temperature without the need to apply shear force. In one or more embodiments the foam has low stability or is unstable and collapses in less than about 30 secs, in less than about 25 secs, in less than about 20 secs, in less than about 15 secs; in less than about 10 secs, or in less than about 5 secs. Foam can be quick-breaking, for example, wherein the foam formulation comprises high levels of a short chain alcohol, such as, ethanol.
According to one or more embodiments the concentration of the aprotic polar solvent, about 3% to about 97% by weight of the total composition.
According to one or more embodiments, the composition comprises a hydrophobic carrier; and the composition is an emulsion between the water/aprotic polar solvent mixture and the hydrophobic carrier.
According to one or more embodiments, the composition is waterless. In some embodiments the composition is waterless and comprises a protic polar solvent or a hydrophobic carrier or mixtures thereof. In certain embodiments, the composition is waterless, and the composition is a waterless emulsion between the aprotic polar solvent and the hydrophobic carrier.
According to one or more embodiments, the composition is substantially waterless.
According to one or more embodiments the foamable carrier is non-aqueous (waterless) and comprises:
According to one or more embodiments, the foamable carrier is substantially non-aqueous (substantially waterless), and comprises:
According to one or more embodiments, the foamable carrier is substantially waterless, and comprises:
According to one or more embodiments, the composition is alcohol-free, or substantially alcohol-free. According to one or more other certain embodiments the composition is alcoholic.
According to one or more embodiments, the composition is a waterless foamable carrier comprising:
According to one or more embodiments, the hydrophobic solvent comprises a petrolatum.
According to one or more embodiments, the protic polar solvent comprises ethanol.
According to one or more embodiments, the composition further comprises urea.
According to one or more embodiments, the composition is a water containing foamable carrier comprising:
According to one or more embodiments, the water is less than about 5% and the formulation is substantially waterless.
According to one or more embodiments the foamable carrier, further comprises an active agent; In one or more additional embodiments, the aprotic polar solvents possesses inherent therapeutic properties and therefore it can be considered as an “active agent”.
According to one or more embodiments the method of treating a disorder of a mammalian subject, includes:
administering a foamable therapeutic composition to a target site, the composition comprising:
According to one or more embodiments the method of treating a disorder of a mammalian subject, includes:
According to one or more embodiments, the method comprises a waterless foamable carrier or composition with at least one of a surfactant, a polymer and a foam adjuvant. According to one or more other embodiments, the method comprises a substantially waterless foamable carrier or composition with at least one of a surfactant, a polymer and a foam adjuvant and up to about 5% water. According to one or other embodiments, the method comprises an aqueous carrier or composition with at least two of a surfactant, a polymer and a foam adjuvant.
According to one or more embodiments, the method comprises foamable carrier or composition, further comprises an active agent.
According to one or more embodiments, the method comprises pre-treating the target area with a foamable carrier or composition comprising an agent that can ameliorate or prevent a taste or odor being experienced after a DMSO foam is applied to a target. According to one or more other embodiments, the method comprises treating the target area with a foamable carrier or composition further comprising an agent that can ameliorate or prevent a taste or odor being experienced after a DMSO foam is applied to a target.
According to one or more embodiments the foamable composition, comprises a therapeutically effective concentration of an aprotic polar solvent, which possesses inherent therapeutic properties.
All % values herein are provided on a weight (w/w) basis.
According to one or more embodiments the present invention includes the embodiments described above in the Summary of the invention as more particularly detailed, specified and exemplified below.
Aprotic Polar Solvent
Solvents can be broadly classified into polar (hydrophilic) and nonpolar (lipophilic). The polarity can be measured as the dielectric constant or the dipole moment of a compound.
An aprotic solvent is an organic solvent that does not contain an O—H or N—H bond; or does not exchange protons with a substance dissolved in it. In the context herein, the aprotic polar solvent is a solvent with a comparatively high relative permittivity (or dielectric constant), greater than about 15, and a sizable permanent dipole moment, that cannot donate suitably labile hydrogen atoms to form strong hydrogen bonds; and it is miscible in water. Examples of aprotic polar solvents, suitable according to the present invention include, but are not limited to dimethyl sulfoxide (DMSO), dimethylformamide (DMF), acetonitrile, acetone, methyl ethyl ketone, 1,4-Dioxane and tetrahydrofuran (THF). Additional non-limiting examples include N-methylpyrrolidone, pyridine, piperidine, dimethyl ether, hexamethylphosphorotriamide, dimethylformamide, methyl dodecyl sulfoxide, N-methyl-2-pyrrolidone and 1-methyl-2-pyrrolidinone) and azone (1-dodecylazacycloheptan-2-one).
An aprotic solvent can be a defoamer in certain embodiments. It can in certain embodiments act to accelerate the breakdown of the foam and reduce its stability. To an extent this may be countered by adding one or more agents that can stabilize the foam and boost its stability. For example, addition of a polymer and or a foam adjuvant can help to improve the collapse time and likewise slow liquid drainage driven by gravity, which otherwise can and will cause the walls of bubbles to thin and ultimately collapse into adjacent bubble walls that are likewise thinning to form larger bubbles. Examples 1 and 2 indicate, for example, that DMSO is not prone to foaming.
DMSO
Dimethyl sulfoxide (DMSO) is the chemical compound with the formula (CH3)2SO. This colorless liquid is an important aprotic polar solvent that dissolves both polar and nonpolar compounds and is miscible in a wide range of organic solvents as well as water. It has a distinctive property of penetrating the skin very readily, so that some people report that one can taste it soon after it comes into contact with the skin. In this connection, taking DMSO internally is reported to cause a fish- or oyster-like taste or odor in the mouth. With its high polarity combined with a high dielectric constant, DMSO is known to be an excellent solvent for polar or polarizable organic compounds, but also many acids, alkalis and mineral salts. DMSO is miscible with most co-solvents. The following table provides certain physical characteristics of DMSO and DMF.
DMSO can penetrate the skin and other membranes without damaging them and could carry other compounds into a biological system. DMSO has been used most widely as a topical analgesic, in a 70% DMSO, 30% water solution. Laboratory studies suggest that DMSO reduces pain by blocking peripheral nerve C fibers. DMSO also is said to reduce inflammation by several mechanisms. It is further an antioxidant—a scavenger of the free radicals that gather at the site of injury. DMSO also stabilizes membranes and slows or stops leakage from injured cells and is recommended for many inflammatory conditions not caused by infection or tumor. Because DMSO increases the rate of absorption of some compounds through organic tissues including skin and nails, it can be used as a drug delivery system.
In one or more embodiments a method is provided to ameliorate or prevent possible side effects of DMSO such as a taste, which has been described as “garlicy” and a breath odor. As an initial observation although a high proportion of DMSO can be present in the formulations because they are presented as a low density foam it is possible to apply a much thinner layer and cover the same area with a substantially or much smaller amount than a cream or ointment. That being said the position can be further improved by first applying to the target area a composition containing one or more of urea, ethanol, and or lipophilic compounds and then subsequently applying the DMSO foam to the target area. The time interval between the first application and the second application can be about almost immediately afterwards, about 30 Secs afterwards, about 1 minute afterwards, about 2 minutes afterwards, about 5 minutes afterwards, about 10 minutes afterwards, about 20 minutes afterwards, about 30 minutes afterwards, about 40 minutes afterwards, about 50 minutes afterwards, about 60 minutes afterwards, or sometimes longer. In one or more embodiments the DMSO presented to the target area simultaneously with another foam containing one or more ingredients known to ameliorate or prevent the taste and odor by using a dual chamber device to apply the two foams such as is described in US publication 2007/0069046 entitled “MEASURE OF CONTENT FROM A PLURALITY OF CONTAINERS” and incorporated herein by reference. In an alternative approach the formulation may itself include one or more ingredients known to ameliorate or prevent the taste and odor.
Concentration
In an embodiment the aprotic polar solvent can be incorporated in the foamable composition of the present invention in a concentration between about 3% and about 98% or between about 10% and about 97%, for example above about 15%, above about 20%, above about 25%, above about 30%, above about 35%; above about; 40%, above about 45%, above about 50%, above about 55%, above about, 60%; above about 70%, above about 80%, above about 90%, or any range between any of the aforesaid amounts; and more preferably from about 10% to about 60% of at least one aprotic polar solvent.
In certain embodiments, the aprotic polar solvent is DMSO and its concentration is in the range between about 30% and about 60%. In an embodiment it is between about 40% to about 50%. In an embodiment, aprotic polar solvent is DMSO and its concentration is about 45%.
In other embodiments, the composition contains more than 60% aprotic polar solvent, and in certain cases, up to about 98% of at least one aprotic polar solvent.
In one or more embodiments where ever a phrase is used to refer to a concentration of above X % or below X % it can also include X % or of above about X % or below about X % it can also include about X %.
General
In one or more embodiments, the aprotic polar solvent is a combination of two or more aprotic solvents. In certain embodiments the main aprotic solvent is DMSO.
In one or more embodiments, the aprotic polar solvent is used in combination with a solid aprotic compound. Non limiting examples of solid aprotic compounds are octyl methyl sulfoxide, nonyl methyl sulfoxide, decyl methyl sulfoxide, undecyl methyl sulfoxide, and dodecyl methyl sulfoxide.
In one or more embodiments, the aprotic polar solvent is used in combination with a sulfoxide derivative which is not aprotic. Non limiting examples of non aprotic sulfoxide compounds having hydroxyl groups are 2-hydroxydecyl methyl sulfoxide, 2-hydroxyundecyl methyl sulfoxide and hydroxydodecyl methyl sulfoxide.
In one or more embodiments, formulations comprising DMSO can produce a quality foam with one or more surfactants without the addition of a polymer and or without the addition of a foam adjuvant. Aprotic solvents are not oil so which surfactants are preferred is not obvious. In one or more embodiments preferred surfactants or surfactant combinations include polyoxyethylene fatty acid ethers, polyoxyethylene fatty acid esters, polysorbates, sucrose esters, glycerides esters, sorbitol esters.
In one or more embodiments, formulations comprising DMSO can unexpectedly produce a quality foam without one or more surfactants. In one or more embodiments good quality waterless foams comprising DMSO can be achieved with a combination of a polymeric agent and a fatty alcohol. In an embodiment the fatty alcohol may be replaced by the fatty acid. In an embodiment a combination of fatty alcohol and fatty acid may be applied together with the polymeric agent.
In one or more embodiments good quality aqueous foams comprising DMSO can be achieved with a combination of a polymeric agent and a fatty alcohol. In one or more embodiments good quality aqueous foams comprising DMSO can be achieved with the addition of a short chain alcohol, such as ethanol, even in high concentrations.
By the term “aqueous” in relation to formulations herein it is intended to indicate and describe a multiplicity of formulations containing some water including formulations comprising low amounts, medium amounts or high amounts of water so as to apply a wide meaning to the term.
Foamable Composition and Foam Properties
The ability to achieve quality foam with substantial concentration of at least one aprotic polar solvent, is surprising, because usually, such solvents are not prone to create a foam. The challenge is not just to achieve a quality foam but also to attain a formulation that will satisfy a plurality of two, three, four, five, six or more of property specifications simultaneously.
Based on extensive investigations and trial and error experiments, it has been found that such properties can be achieved for formulations comprising water by incorporating into the composition at least two stabilizing members, and also for formulations that are substantially waterless by incorporating into the composition at least one stabilizing member selected from the group consisting of:
The type, quality, properties and mechanism of foam formation for aprotic formulations cannot be predicted or deduced based on the literature or on existing product experience. The challenge to achieve such foam formulations may be even more pronounced when the aprotic polar solvent composition is waterless or substantially waterless.
As detailed and exemplified below, the aqueous or water containing compositions containing aprotic polar solvents, such as DMSO, conform with the desirable and favorable sensory properties of foam. They further deliver efficacious therapy, as exemplified herein.
As further detailed and exemplified below, even waterless or substantially waterless compositions, containing aprotic polar solvents, such as DMSO, provide favorable sensory properties of foam.
Surface Active Agent
The composition of the present invention contains a surface-active agent. Surface-active agents (also termed “emulsifiers” or “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. 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 foams 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. Surfactants also play a role in foam formation where the foamable formulation is a single phase composition.
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, especially in compositions with low water content, or non-aqueous compositions.
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 for oil in water emulsions.
According to one or more other embodiments the composition contains a single surface active agent having an HLB value between about 9 and 20, or more than one surface active agent and the weighted average of their HLB values is between about 9 and about 20.
In a waterless or substantially waterless environment a wide range of HLB values may be suitable; however, surfactants of the low range are sometimes preferred.
Preferably, the composition of the present invention contains a non-ionic surfactant. Nonlimiting examples of possible non-ionic surfactants include:
In one or more embodiments of the composition comprises water and a single stabilizing member, which is at least one surface active agent. In such embodiments the at least one surface active agent is non ionic and can comprise a solid (for example ceteth-20) or liquid surfactant (for example Tween 80) with a HLB between about 9 and about 16. As can be seen from the results in Example 8 in which a non ionic surfactant alone with a HLB between about 9-16 provides a better foam quality and stability than a non ionic surfactant alone with a HLB value lower than about 9 or higher than about 16. However, in order to improve stability and collapse time the aqueous formulations comprise a second stabilizing member, which can be an appropriate polymeric agent (such as hydroxypropyl methylcellulose) and or an appropriate foam adjuvant (such as cetostearyl alcohol, stearyl alcohol, stearic acid and isostearic acid) or a polymeric agent, which has surfactant properties such as a poloxamer. In certain embodiments a combination of at least two stabilizing members is a synergistic combination, such as observed in Example 9. Also by providing two or more stabilizing members it can allow a wider range of agents and or a broader range of HLB. In one or more other embodiments the formulation comprises a hydrophobic or lipophilic component and the formulation prior to addition of the propellant is an emulsion. In such embodiments the surface active agent has a role in stabilizing the emulsion and a role in generating a stable breakable foam. Furthermore a system has to be selected such that upon addition of the propellant the emulsion is not destabilized. The emulsion can be an oil in water emulsion or if an appropriate surfactant is used such as the following non limiting examples of glyceryl stearate, sorbitan stearate, polyglyceryl oleate or other surfactants with an HLB value lower than about 9, a water in oil emulsion may be formed.
In one or more embodiments the composition is a waterless composition and a single stabilizing member. The stabilizing member can be at least one polymeric agent, at least one foam adjuvant or at least one surface active agent. In such embodiments the at least one surface active agent is non ionic and can comprise a solid surface active agent, which is a solid ambient temperature. In one preferred embodiment the surfactant generally comprises a linear molecule with a more polar head, for example sorbitan monostearate and or glyceryl monostearate. It has been observed, for example, that when a surfactant with a non linear unsaturated fatty acid chain is used, such as sorbitan monoleate, only a bubbly liquid is achieved (See Example 3). This incidentally is in contrast to the position with an aqueous system where for example Tween 80 has been used successfully although it has an oleate moiety. In another preferred embodiment, in the context of a waterless composition, the surfactant has a low HLB value, being between about 2 and about 9. In certain embodiments, the HLB of the solid surface active agent is between about 2 and about 5. It has been surprisingly discovered that a solid surface active agent, having low HLB provides a foam with better quality and stability than a liquid and/or a high HLB surfactant. It has been further surprisingly discovered that a solid surface active agent, having low HLB evolves a breakable foam of quality, even without any additional foam stabilizing agents (such as a polymer or a foam adjuvant).
In one or more embodiments the surface active agent is a combination of two or more surface active agents. Such a combination may be in certain cases more effective than a single surfactant and provides a more stable emulsion or improved foam quality. For example and by way of non-limiting explanation it has been found that by choosing two surfactants, one hydrophobic and the other hydrophilic the combination can produce a more stable emulsion than a single surfactant. In certain embodiments the combination is a synergistic combination. In one or more embodiments the difference in the HLB of two surfactants is about at least 2, or is about at least 3, or is about at least 4.
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 s 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. We have surprisingly found that non-ionic surfactants alone can provide formulations and foams of good or excellent quality in the carriers and compositions disclosed herein.
Yet, in certain embodiments, the foamable composition includes a mixture of at least one non-ionic surfactant and at least one ionic surfactant, selected from the group of anionic, cationic, zwitterionic, amphoteric and ampholytic surfactants, 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 selecting a suitable surfactant or combination thereof it should be borne in mind that the upper amount of surfactant that can 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%. In certain embodiments by comprising a second or a second and a third stabilizing member it is possible to minimize the amount of surfactant used in the formulation, for example such that the surface active agent is between about 0.5% and about 3%.
If the composition as formulated is a substantially non shakable composition it is nevertheless possible as an exception in the scope disclosed herein 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 formulation.
Foam Adjuvant
In one or more embodiments the foamable vehicle further includes a foam adjuvant. More particularly the foam adjuvant is preferably a fatty acid or a fatty alcohol. 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 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 arachidyl alcohol (C20), behenyl alcohol (C22), 1-triacontanol (C30), as well as alcohols with longer carbon chains (up to C50).
In one or more embodiments the foam adjuvant 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 alcohol is employed.
Optionally, the carbon atom chain of the fatty alcohol or the fatty acid may have at least one double bond. A further class of foam adjuvant 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.
An important property of the fatty alcohols and fatty acids used in context of the composition disclosed herein 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, a combination of a foam adjuvant and a polymeric agent is employed. In certain embodiments the combination is synergistic, for example as observed in Example 5 Part B, where stearyl alcohol and hydroxypropyl methylcellulose were noted to have a synergistic effect.
In one or more embodiments, a combination of a foam adjuvant and a surface active agent is employed.
In one or more embodiments, a combination of a foam adjuvant and a polymeric agent is employed.
In one or more embodiments, a combination of a foam adjuvant, a polymeric agent and a surface active agent is employed.
Polymeric Agent
In one or more embodiments, the composition disclosed herein contains a polymeric agent selected from the group consisting of a bioadhesive agent, a gelling agent, a film forming agent and a phase change agent. A polymeric agent enhances the creation of foam having fine bubble structure, which does not readily collapse upon release from the pressurized aerosol can. The polymeric agent serves to stabilize the foam composition and to control drug residence in the target organ. In certain embodiments the polymer can have surfactant like properties and contribute to the stabilization of emulsion formulations, such as poloxamer or pemulen.
Exemplary polymeric agents include, in a non-limiting manner, 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, cationic guars, hydroxypropyl guar gum, starch, amine-bearing polymers such as chitosan; acidic polymers obtainable from natural sources, such as alginic acid and hyaluronic acid; chemically modified starches and the like, carboxyvinyl polymers, polyvinylpyrrolidone, polyvinyl alcohol, polyacrylic acid polymers, polymethacrylic acid polymers, polyvinyl acetate polymers, polyvinyl chloride polymers, polyvinylidene chloride polymers and the like.
Additional exemplary polymeric agents include semi-synthetic polymeric materials such as cellulose ethers, such as methylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, hydroxy propylmethyl cellulose, methylhydroxyethylcellulose, methylhydroxypropylcellulose, hydroxyethylcarboxymethylcellulose, carboxymethyl cellulose, carboxymethylcellulose carboxymethylhydroxyethylcellulose, and cationic celluloses, carbomer (homopolymer of acrylic acid is crosslinked with an allyl ether pentaerythritol, an allyl ether of sucrose, or an allyl ether of propylene, such as Carbopol® 934, Carbopol® 940, Carbopol® 941, Carbopol® 980 and Carbopol® 981. Poloxamers (synthetic block copolymer of ethylene oxide and propylene) such as Poloxamer 124, Poloxamer 188, Poloxamer 237, Poloxamer 338 and Poloxamer 407. Other useful Poloxamers are: 181, 182, 183, 184, 185, 212, 215, 217, 231, 234, 235, 238, 331, 333, 334, 335; 401, 402, and 403. Polyethylene glycol, having molecular-weight of 1000 or more (e.g., PEG 1,000, PEG 4,000, PEG 6,000 and PEG 10,000) also have gelling capacity and they are also considered polymeric agents.
In one or more embodiments the polymer is hydroxypropyl methyl cellulose, for example where the formulation is waterless and a single stabilizing member is utilized, the polymeric agent comprises hydroxypropyl methyl cellulose.
Mixtures of the above polymeric agents are contemplated.
In one or more embodiments the polymer is used in combination with another stabilizing member, which can be a surfactant and or a foam adjuvant.
The concentration of the polymeric agent should be selected so that the composition, after filling into aerosol canisters and pressurized with propellant, is flowable, and can be shaken in the canister. In one or more embodiments, the concentration of the polymeric agent is selected such that the viscosity of the composition, prior to filling of the composition into aerosol canisters, is less than about 30,000 CP, and more preferably, less than about 15,000 CP. In one or more embodiments, the viscosity of the composition, prior to filling of the composition into aerosol canisters, is less than about 10,000 CP, or less than about 5,000 CP, or less than about 3,000 CP.
Combination of a Foam Adjuvant and a Polymeric Agent
Interestingly, when a foam adjuvant (e.g., stearyl alcohol) alone or a polymeric agent (e.g., hydroxypropyl methylcellulose) alone is used with DMSO, a foam of good quality is obtained, but it quickly collapses upon exposure to 36° C. (collapse time 10 and 30 sec respectively), as shown in formulations D21 and D07. However, surprisingly, when these two components are combined with DMSO, they act synergistically to produce a good quality foam with a collapse time of 120 seconds as shown in formulation D22 (See Example 5 Part B).
Optional Organic Carriers
Optionally, the foamable composition further includes at least one organic carrier selected from the group consisting of a hydrophobic organic carrier, a petrolatum, an organic protic polar solvent, and mixtures thereof, at a concentration of about 2% to about 50% by weight.
Hydrophobic Solvent/Emollient
One or more hydrophobic solvents are optionally included in the composition, in order to add to the sensory properties of the composition and/or in order to impart skin conditioning properties. In an embodiment, the hydrophobic solvent is an emollient, i.e., a substance that softens and soothes the skin. Emollients are used to correct dryness and scaling of the skin. The hydrophobic solvent and/or the emollient can be selected from the group consisting of mineral oil, alkyl esters of fatty acids such as isopropyl palmitate, isopropyl isostearate, diisopropyl adipate, diisopropyl dimerate, octyl palmitate, cetyl lactate, cetyl ricinoleate, tocopheryl acetate, acetylated lanolin alcohol, cetyl acetate, phenyl trimethicone, glyceryl oleate, tocopheryl linoleate, wheat germ glycerides, arachidyl propionate, myristyl lactate, decyl oleate, ricinoleate, isopropyl lanolate, pentaerythrityl tetrastearate, neopentylglycol dicaprylate/dicaprate, isononyl isononanoate, isotridecyl isononanoate, myristyl myristate, triisocetyl citrate, octyl dodecanol, maleated soybean oil, unsaturated or polyunsaturated oils, such as 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; essential oils; and silicone oils, such as dimethicone, cyclomethicone, polyalkyl siloxane, polyaryl siloxane, polyalkylaryl siloxane, a polyether siloxane copolymer and a poly(dimethylsiloxane)-(diphenyl-siloxane) copolymer. In certain embodiments the carrier is a petrolatum.
While the aprotic polar solvent and water are generally miscible, when a hydrophobic carrier is included to the composition, it is necessary to create an emulsion between the water/aprotic polar solvent mixture and the hydrophobic carrier. Even when the composition is waterless, the hydrophobic carrier is typically insoluble in the aprotic solvent, and therefore it is necessary to create an emulsion between the aprotic polar solvent and the hydrophobic carrier.
Protic Polar Solvent
A “protic polar solvent” is an organic solvent that has a hydrogen atom bound to an oxygen as in a hydroxyl group or a nitrogen as in an amine group. They are typically soluble in both water and oil.
In one or more embodiments, the formulation can comprise a protic polar solvent.
In one or more embodiments, the protic 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 protic 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), butanediol. (e.g., 1,4-butanediol), butanediol (e.g., 1,3-butanediol 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.
Additional examples of protic polar solvents include polyols, such as glycerol (glycerin), propylene glycol, hexylene glycol, diethylene glycol, propylene glycol n-alkanols, terpenes, di-terpenes, tri-terpenes, terpen-ols, limonene, terpene-ol, 1-menthol, dioxolane, ethylene glycol, other glycols, alkanols, such as dialkylamino acetates, and admixtures thereof. dimethyl isosorbide, 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.
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. So where a lower molecular weight alcohol is used in a formulation other ingredients are ideally selected to ameliorate or prevent such side effects.
Many 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.
Additional Components
In an embodiment, a composition disclosed herein includes one or more additional components. Such additional components include but are not limited to anti oxidants anti perspirants, anti-static agents, buffering agents, bulking agents, chelating agents, cleansers, colorants, conditioners, deodorants, diluents, dyes, emollients, fragrances, hair conditioners, herbal extracts, humectants, keratolytic agents, 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, flavonoids and vitamins. 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.
Propellants
The composition of the present invention requires the addition of a propellant in order to generate a foam. In one or more embodiments the propellant makes up between about 3% and about 45% or between about 3% and about 35% of the foamable composition, preferably between about 5% and about 25% of the composition. In preparing the formulations the ingredients other than propellant are combined to 100% and the propellant is added thereafter so that the ratio of formulation to propellant can range from 100:3 to 100:45 or from 100:3 to 100:35 or preferably 100:5 to 100:25. In the case of bag in can where the propellant is separate from the composition any amount can be used that is sufficient to drive the contents of the bag out of the canister. In certain embodiments the propellant in the bag can be the same as and in certain other embodiments be different from the propellant in the composition.
Suitable propellants include volatile hydrocarbons such as butane, propane, isobutene or mixtures thereof. In one or more embodiments a hydrocarbon mixture AP-70 is used. Hydrofluorocarbon (HFC) propellants are also suitable as propellants in the context disclosed herein. Exemplary HFC propellants include 1,1,1,2 tetrafluorethane (Dymel 134), and 1,1,1,2,3,3,3 heptafluoropropane (Dymel 227). Dimethyl ether is also useful. In one or more embodiments use of compressed gases (e.g., air, carbon dioxide, nitrous oxide, and nitrogen) is also possible. Chloro fluorocarbon propellants on the other hand are no longer considered suitable for use in cosmetic, pharmaceutical and other formulations due to inter alia the potential environmental damage that they can do.
In one or more embodiments a combination of at least two propellants, selected from HFC, hydrocarbon propellants, dimethyl ether and compressed gases is contemplated.
In one or more embodiments the propellant can also be used to expel formulation using a bag in can system or a can in can system as will be appreciated by someone skilled in the art. In certain embodiments the part of the propellant system is in the formulation and part separate from the formulation. In this way it is possible to reduce the amount of surfactant in the formulation but still provide good expulsion from the canister, where the foamable formulation is expelled quickly but without jetting or noise.
Alcohol Free
According to one or more embodiments, the foamable composition is substantially 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, butanol, iso-butanol, t-butanol and pentanol, are considered less desirable solvents or polar solvents due to their skin-irritating effect. Thus, the composition is substantially alcohol-free and includes less than about 5% final concentration of lower alcohols, preferably less than about 2%, more preferably less than about 1%.
Alcoholic
According to one or more certain other embodiments, the foamable composition includes a short chain alcohol. In a preferred embodiment the short chain alcohol is ethanol. In one embodiment the composition is waterless. In another embodiment it is aqueous or water containing and in a further embodiment it is substantially non-aqueous. In various embodiments the amount of short chain alcohol is about or above about 5%, about or above about 10%; about or above about 15% about or above about 20%. In one or more embodiments the range of short chain alcohol is between about 5% to about 25%. In certain embodiments when short chain alcohol is present the formulation is breakable and not thermolabile or substantially not thermolabile. By substantially not thermolabile is meant that the foam upon expulsion onto a warm body surface at about 35-37° C. does not collapse rapidly within about 30 seconds. In one or more alternative embodiments the formulation is thermolabile.
In one or more alternative embodiments the formulation comprises high amounts of short chain alcohol. In certain embodiments the amount of short chain alcohol is about or above about 25%, is about or above about 30%, is about or above about 35%, is about or above about 40%; is about or above about 45%, is about or above about 50%; is about or above about 55% or is about or above about 60%.
In one or more embodiments there is provided a composition comprising an aprotic polar solvent and a protic polar solvent, in which the protic polar solvent can be a short chain alcohol. Such a combination may conceivably contribute to directed skin delivery of active agents.
Aprotic-Aqueous Formulations
In certain cases, the active agent is soluble in the presence of water, and therefore, in such cases the presence of water in the composition can be desirable. In certain preferred embodiments, the composition comprises only a small amount of water. In other embodiments water is a substantial component. In one or more embodiments the range of water can be from about 0.1% to about 5%, or from about 5% to about 15%, or from about 15% to about 25%, or from about 25% to about 35%, or from about 35% to about 45%, or from about 45% to about 55%, or from about 56% to about 65%, or from about 55% to about 65%, or from about 65% to about 75%, or from about 75% to about 85% or from about 5% to about 85%, or from about 10% to about 75%. In one or more embodiments the formulation can be a protic-hydroalcoholic.
Waterless Formulations
In certain cases, the active agent degrades in the presence of water, and therefore, in such cases the presence of water in the composition is not desirable. Thus, in certain preferred embodiments, the composition is substantially non-aqueous. The term “substantially non-aqueous” or “substantially waterless” is intended to indicate that the composition has water content below about 5%, preferably below about 2%, such as below about 1.5%. In certain other preferred embodiments the composition is non aqueous or waterless.
By non aqueous or waterless is meant that the composition contains no or substantially no, free or unassociated or absorbed water. It will be understood by a person of the art that the waterless solvents and substances miscible with them disclosed herein can be hydrophilic and can contain water in an associated or entrapped or absorbed form and may absorb water from the atmosphere and the ability to do so is its hygroscopic water capacity. It is intended that essentially non-aqueous formulations are included within its scope such that the formulations may have present a small amount of water. In some embodiments the composition ingredients are pretreated to reduce, remove or eliminate any residual or associated or absorbed water.
Modulating Agent
In one or more embodiments the formulation includes a 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 substance or residue may for example be acidic, basic or a buffer system and potentially alter an artificial pH in a waterless or substantially non-aqueous environment or it may be one or more metal ions which may act as a potential catalyst in a waterless or substantially non aqueous environment. In various certain embodiments it may be an ionization agent or an anti oxidization agent or a flavinoid or mixtures thereof that are effective in a waterless or substantially non aqueous environment. The modulating agent may in one or more embodiments act to modulate the ionic or polar characteristics and any acid-base balance of a waterless or substantially non-aqueous carrier, composition, foamable carrier or foamable composition or resultant foam disclosed herein.
In one or more other 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 embodiments the substance or residue may be one or more metal ions which may act as a potential catalyst in a aqueous environment. In various certain embodiments it may be an ionization agent or an anti oxidization agent or a flavonoid or mixtures thereof that are effective in an aqueous environment. The modulating agent may in one or more embodiments act to modulate the ionic or polar characteristics and any acid-base balance of an aqueous carrier, composition, foamable carrier or foamable composition or resultant foam disclosed herein.
In certain embodiments the formulation is an emulsion. The emulsion may be formed prior to the addition of propellant or upon the introduction of propellant. The emulsion may be a waterless emulsion or it may be an aqueous emulsion (oil in water or oil in water). In various 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 various certain embodiments it may be an ionization agent or an anti oxidization agent or a flavonoid or mixtures thereof that are effective in an emulsion environment. The modulating agent may in one or more embodiments act to modulate the ionic or polar characteristics and any acid-base balance of an emulsion carrier, composition, foamable carrier or foamable composition or resultant foam disclosed herein.
In one or more further embodiments the modulating agent 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 one or more embodiments a preferred non limiting example is EDTA.
In other embodiments the modulating agent is a buffer, as defined by Van Slyke [Van Slyke, J. Biol. Chem. 52, 525 (1922)], as “a substance which by its presence in solution increases the amount of acid or alkali that must be added to cause unit change in pH.”
Modulating agents may be added to the compositions of the subject invention, preferably from about 0.1% to about 10%, more preferably from about 1% to about 5%, of the composition. Where the active agent itself is the modulating agent alone or in combination with another modulating agent it will be added at an effective dose which may be outside these ranges. For example azelaic acid may be at about 15% of the composition.
It is important to maintain skin surface pH in order to prevent susceptibility to bacterial skin infections or skin damage and disease. Thus, adding a modulating agent, which contributes to the stabilization of skin pH at the desirable level, is advantageous.
In the same fashion, adding an acidic modulating agent to a foamable composition, which is intended for vaginal application is advantageous, since better protection against vaginal infection is attained with pH lower than about 4.5.
Non-limiting examples of antioxidants/radical scavengers are ascorbic acid and derivatives, tocopherol or derivatives thereof (succinate, or sorbate or acetate or other esters), propyl galate, butylated hydroxy toluene and butyl hydroxy anisol. 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 sulfate, sodium lauryl lactylate and phospholipids.
A non-limiting list of flavonoid compounds is: benzquercin, diosmin, ethoxazorutoside, flavodate, sodium hesperidin, leucocianido, monoxerutin, oxerutin, quercetin, rutoside, rosmarinic acid.
In one or more embodiments the modulating agent is mixture or combination of two or more modulating agents.
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.
In one or more embodiments the foamable composition has an acceptable shelf-life of at least six months or at least one year, or preferably, at least two years at ambient temperature.
The foamable compositions according to the present invention are stable chemically and physically. For example as seen in Example 14 following accelerated stability studies, the foam met the specified stability and assay criteria. The high quality foams disclosed herein can demonstrate desirable texture; can form fine bubble structures that do not break immediately upon contact with a surface, and can spread easily on the treated area and can absorb quickly.
The composition should also preferably be free flowing, to allow it to flow through the aperture of the container, e.g., and aerosol container, and create an acceptable foam.
Foam Quality
Foam quality can be graded as follows:
Grade E (excellent): very rich and creamy in appearance, does not show any bubble structure or shows a very fine (small) bubble structure; does not rapidly become dull; upon spreading on the skin, the foam retains the creaminess property and does not appear watery.
Grade G (good): rich and creamy in appearance, very small bubble size, “dulls” more rapidly than an excellent foam, retains creaminess upon spreading on the skin, and does not become watery.
Grade FG (fairly good): a moderate amount of creaminess noticeable, bubble structure is noticeable; upon spreading on the skin the product dulls rapidly, and becomes somewhat lower in apparent viscosity.
Grade F (fair): very little creaminess noticeable, larger bubble structure than a “fairly good” foam, upon spreading on the skin it becomes thin in appearance and watery.
Grade P (poor): no creaminess noticeable, large bubble structure, and when spread on the skin it becomes very thin and watery in appearance.
Grade VP (very poor): dry foam, large very dull bubbles, difficult to spread on the skin.
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.
Breakability
A further aspect of the foam is breakability. The balance between stability and breakability of the foam coming out of the container is very delicate: on one hand the foam should not be “quick breaking”, i.e., it should be stable upon release from the pressurized container and not break as a result of exposure to skin temperature; and on the other hand, it should be “breakable”, i.e., it should spread easily, break down and absorb into the skin or membrane upon application of mild shear force. The foam is thermally stable, yet breaks under shear force. Shear-force breakability of the foam is dearly advantageous over thermally induced breakability. Thermally sensitive foams immediately or quickly collapse upon exposure to skin temperature and, therefore, cannot be usefully applied on the hand and afterwards delivered to the afflicted area since transfer would have to be effected immediately.
Breakable foam is a specialized low density type of foam that is stable on release at least in the short time span of about minutes, but can break readily upon the application of shear force such as gentle rubbing to spread easily over a target surface. Unlike other types of foams, breakable foam is not thermolabile, nor does it display late or long-delayed expansion over minutes.
Foam Density
Another property of the foam is density (specific gravity), as measured upon release from the aerosol can. Typically, foams have specific gravity of about 0.20 g/mL or less, such as less than about 0.20 g/mL; or less than about 0.12 g/mL; or less than about 0.10 g/mL; or less than about 0.08 g/mL, depending on their composition and on the propellant concentration.
Shakability
‘Shakability’ means that the composition contains some or sufficient flow to allow the composition to be mixed or remixed on shaking. That is, it has fluid or semi fluid properties. Shakability is described further in the section on Tests.
Collapse Time
The collapse time of foam represents its tendency to be temperature-sensitive and its ability to be at least short term stable so as to allow a user sufficient time to comfortably handle and apply the foam to a target area without being rushed and or concerned that it may rapidly collapse, liquefy and or disappear. Collapse time is examined by dispensing a given quantity of foam and photographing sequentially its appearance with time during incubation at 36° C. Thus, it is useful for selecting foam products, which are “breakable” but not “quick breaking”, which maintain structural stability at skin temperature for at least a reasonable period of time. In one or more embodiments it can be about more than a minute, about more than two minutes; about more than 3 minutes, about more than 4 minutes, about more than 5 minutes or longer. In one or more limited embodiments it can be shorter than one minute, for example about more than 50 seconds, about more than 40 seconds and occasionally about more than 30 seconds. In a preferred embodiment it can be more than about one minute and in a more preferred embodiment it can be more than about 3 minutes. Collapse time can also provide an indication of the rate of drainage in the foam formulation of the fluid around the bubbles under the influence of gravity. Short collapse times indicate fast or rapid drainage, whilst long collapse times indicate slow drainage.
Pharmaceutical Composition
The foamable composition is an ideal vehicle for active pharmaceutical ingredients and active cosmetic ingredients. In the context active pharmaceutical ingredients and active cosmetic ingredients are collectively termed “active agent” or “active agents”. In one or more embodiments the composition comprises a therapeutically effective concentration of at least one active agent. In one or more embodiments the composition comprises at least two therapeutic agents. In certain embodiments the aprotic formulation facilitates the combination of active agents otherwise unstable in water, which for example are unstable at different pH's.
Suitable active agents include but are not limited to an active herbal extract, an acaricides, an age spot and keratose removing agent, an allergen, an alpha hydroxyl acid, an analgesic agent, an antiacne agent, an antiallergic agent, an antiaging agent, an antibacterial agent, an antibiotic, an antiburn agent, an anticancer agent, an antidandruff agent, an antidepressant, an antidermatitis agent, an antiedemic anent, an antifungal agent, an antihistamine, an antihelminth agent, an antihyperlkeratolyte agent, an anti-infective agent, an antiinflammatory agent, an antiirritant, an antilipemic agent, an antimicrobial agent, an antimycotic agent, an antioxidant, an antiparasitic agent, an antiproliferative agent, an antipruritic agent, an antipsoriatic agent, an antirosacea agent, an antiseborrheic agent, an antiseptic agent, an antiswelling agent, an antiviral agent, an anti-wart agent, an anti-wrinkle agent, an antiyeast agents, an astringent, a beta-hydroxy acid, benzoyl peroxide, a topical cardiovascular agent, a chemotherapeutic agent, a corticosteroid, an immunogenic substance, a dicarboxylic acid, a disinfectant, a fungicide, a hair growth regulator, a haptene, a hormone, a hydroxy acid, an immunosuppressant, an immunoregulating agent, an immunomodulator, an insecticide, an insect repellent, a keratolytic agent, a lactam, a local anesthetic agent, a lubricating agent, a masking agent, a metals, a metal oxide, a mitocide, a neuropeptide, a non-steroidal anti-inflammatory agent, an oxidizing agent, a pediculicide, a peptide, a protein, a photodynamic therapy agent, a radical scavenger, a refatting agent, a retinoid, a sanative, a scabicide, a self tanning agent, a skin protective agent, a skin whitening agent, a steroid, a steroid hormone, a vasoconstrictor, a vasodilator, a vitamin, a vitamin A, a vitamin A derivative, a vitamin B, a vitamin B derivative, a vitamin C, a vitamin C derivative, a vitamin D, a vitamin D derivative, a vitamin D analog, a vitamin F, a vitamin F derivative, a vitamin K, a vitamin K derivative, a wound healing agent and a wart remover. As is known to one skilled in the art, in some instances a specific active agent may have more than one activity, function or effect.
Encapsulation of an Active Agent
In one or more embodiments, the active agent is encapsulated in particles, microparticles, nanoparticles, microcapsules, microspheres, nanocapsules, nanospheres, liposomes, niosomes, polymer matrix, silica-gel, graphite, nanocrystals or microsponges. Such particles can have various functions, such as (1) protection of the drug from degradation; (2) modification of the drug release rate from the composition; (3) control of skin penetration profile; and (4) mitigation of adverse effects, due to the controlled release of the active agent from the encapsulation particles.
Solubility of an Active Agent
In an embodiment, the active agent is not fully soluble in water or, is not fully soluble in the presence of a hydrophobic solvent in the formulation, or is not fully soluble in the oil phase of the emulsion. In one or more embodiments the active agent is soluble in the composition or a phase thereof. In one or more embodiments the active agent is insoluble in water and wherein the active agent is solubilized the in the composition. In an embodiment, the aprotic polar solvent is present in the composition in an amount sufficient to solubilize the active agent in the composition. In one or more embodiments, aprotic polar solvent acts to improve the solubility of an active agent. In certain preferred embodiments, the active agent to be solubilized is selected from the group consisting of a non-steroidal anti-inflammatory agent, a local anesthetic agent, a steroid, an immunomodulators, a keratolytically active agent, an anti-acne agent, an anti-rosacea agent, an antiinfective agent and an anti-psoriasis agent. In a preferred embodiment the active agent to be solubilized is diclofenac. In one or more embodiments a protic solvent acts to improve solubility of an active agent. In one or more embodiments the delivery of the active agent is improved by the aprotic solvent and or protic solvent.
In one or more embodiments the active agent is intended for transdermal delivery. In certain embodiments the aprotic polar solvent in included in the composition in a concentration which is sufficient to increase the rate of absorption of such active agent through organic tissues including skin and nails.
Exemplary Groups of Active Agents
NSAID
In an embodiment, the active agent is a non-steroidal anti-inflammatory agent. In the context a nonsteroidal antiinflammatory agent (also termed herein “NSAID”) is a pharmaceutically active compound, other than a corticosteroid, which affects the immune system in a fashion that results in a reduction, inhibition, prevention, amelioration or prevention of an inflammatory process and/or the symptoms of inflammation and or the production pro-inflammatory cytokines and other pro-inflammatory mediators, thereby treating or preventing a disease that involves inflammation.
In one or more embodiments, the NSAID is an inhibitor of the cyclooxygenase (COX) enzyme. Two forms of cyclooxygenase are known today: the constitutive cyclooxygenase (COX-1); and the inducible cyclooxygenase (COX-2), which is pro-inflammatory. Thus, in one or more embodiments, the NSAID is selected from the group consisting of a COX-1 inhibitor, a COX-2 inhibitor or a non-selective NSAID, which simultaneously inhibits both COX-1 and COX-2.
In one or more embodiments, the NSAID is salicylic acid a salicylic acid derivatives. Exemplary salicylic acid derivative include, in a non limiting fashion, aspirin, sodium salicylate, choline magnesium trislicylate, salsalate, diflunisal, salicylsalicylic acid, sulfasalazine, olsalazine, esters of salicylic acid with a carboxylic acid, esters of salicylic acid with a dicarboxylic acid, esters of salicylic acid with a fatty acid, esters of salicylic acid with a hydroxyl fatty acid, esters of salicylic acid with an essential fatty acid, esters of salicylic acid with a polycarboxylic acid, and any compound wherein salicylic acid is linked to an organic moiety through a covalent bond.
In one or more embodiments, the NSAID is para-aminophenol (e.g., acetaminophen) and salts and derivatives thereof.
In one or more embodiments, the NSAID is an indole or an indole-acetic acid derivative (e.g., indomethacin, sulindac, etodolac) and salts and derivatives thereof.
In one or more embodiments, the NSAID is an aryl acetic acids (e.g., tolmetin, diclofenac, ketorolac) and salts and derivatives thereof.
In one or more embodiments, the NSAID is an arylpropionic acid and salts and derivatives thereof. Exemplary arylpropionic acid derivative include, in a non limiting fashion, are ibuprofen, naproxen, flubiprofen, ketoprofen, fenoprofen, oxaprozin.
In one or more embodiments, the NSAID is anthranilic acids or an anthranilic acid derivative, also termed “fenamates” (e.g., mefenamic acid, meclofenamic acid) and salts and derivatives thereof.
In one or more embodiments, the NSAID is selected from the group of enolic acids, enolic acid salts, enolic acid esters, amides, anhydrides and salts and derivatives thereof. Non-limiting examples of enolic acid derivatives include oxicams (piroxicam, tenoxicam) and pyrazolidinediones (phenylbutazone, oxyphenthratrazone)
Yet, in additional embodiments, the NSAID is an alkanone (e.g., nabumetone).
Selective COX-2 inhibitors include, in an exemplary manner diaryl-substituted furanones (e.g., Rofecoxib); diaryl-substituted pyrazoles (e.g., Celecoxib); indole acetic acids (e.g., Etodolac); and sulfonanilides (e.g., Nimesulide) and salts and derivatives thereof.
In an embodiment, the aprotic polar solvent is present in the composition in an amount sufficient to solubilize the NSAID, as exemplified herein by the solubilization of diclofenac.
Local Anesthetic Agents
In an embodiment, the active agent is a local anesthetic agent. Without limiting the scope of the invention, the anesthetic agent can be selected from the group consisting of benzocaine, lidocaine, bupivacaine, chloroprocaine, dibucaine, etidocaine, mepivacaine, tetracaine, dyclonine, hexylcaine, procaine, cocaine, ketamine, pramoxine, phenol, any pharmaceutically acceptable salts thereof and mixtures of such anesthetic agents. Any mixture of synergistically beneficial anesthetic agents is contemplated. In an embodiment, the aprotic polar solvent is present in the composition in an amount sufficient to solubilize the anesthetic agent.
Steroids
In an embodiment, the active agent is a steroid. In certain embodiments the steroid is a corticosteroid, including but not limited to, hydrocortisone, hydroxyltriamcinolone, alpha-methyl dexamethasone, dexamethasone-phosphate, beclomethasone dipropionate, clobetasol valemate, desonide, desoxymethasone, desoxycorticosterone acetate, dexamethasone, dichlorisone, diflorasone diacetate, diflucortolone valerate, fluadrenolone, fluclorolone acetonide, fludrocortisone, flumethasone pivalate, fluosinolone acetonide, fluocinonide, flucortine butylester, fluocortolone, fluprednidene (fluprednylidene) acetate, flurandrenolone, halcinonide, hydrocortisone acetate, hydrocortisone butyrate, methylprednisolone, triamcinolone acetonide, cortisone, cortodoxone, flucetonide, fludrocortisone, difluorosone diacetate, fluradrenolone acetonide, medrysone, amcinafel, amcinafide, betamethasone and the balance of its esters, chloroprednisone, chlorprednisone acetate, clocortelone, clescinolone, dichlorisone, difluprednate, flucloronide, flunisolide, fluoromethalone, fluperolone, fluprednisolone, hydrocortisone valerate, hydrocortisone cyclopentylpropionate, hydrocortmate, mepreddisone, paramethasone, prednisolone, prednisone, beclomethasone dipropionate, triamcinolone, as well as analogs, derivatives, salts, ions and complexes thereof.
In certain embodiments, the steroid is a hormone or a vitamin, as exemplified by pregnane, cholestane, ergostane, aldosterone, androsterone, calcidiol, calciol, calcitriol, calcipotriol, clomegestone, cholesterol, corticosterone, cortisol, cortisone, dihydrotestosterone, ergosterol, estradiol, estriol, estrone, ethinylestradiol, fusidic acid, lanosterol, prednisolone, prednisone, progesterone, spironolactone, timobesone and testosterone, as well as analogs, derivatives, salts, ions and complexes thereof.
In an embodiment, the aprotic polar solvent is present in the composition in an amount sufficient to solubilize the steroid.
Keratolytically Active Agents
A keratolytic agent may be included as an active agent of a foamable composition. The term “keratolytically active agent” as used herein includes a compound that loosens and removes the stratum corneum of the skin, or alters the structure of the keratin layers of skin. Keratolytically active agents are used in the treatment of dermatological disorders that involve dry skin, hyperkeratinization (such as psoriasis), skin itching (such as xerosis), acne and rosacea.
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. As such, they are used in the treatment of dermatological disorders. Dihydroxybenzene and derivatives thereof have been recognized as potent keratolytic agents. Resorcinol (m-dihydroxybenzene) and derivatives thereof are used in anti-acne preparations. In addition to hydroquinone (p-dihydroxybenzene) having anti-pigmentation properties, hydroquinone is also known to be keratolytic. These compounds also exhibit antiseptic properties. Cresols also possess bactericidal and keratolytic properties.
Vitamin A and vitamin A derivatives, also termed herein “retinoids”, such as retinoic acid, isoretinoic acid, retinol and retinal are another 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 salicylic acid salts and pharmaceutically acceptable derivatives.
Another class of keratolytically active agents includes urea and urea derivatives.
Immunomodulators
In an embodiment, the active agent is an immunomodulator. Immunomodulators are chemically or biologically-derived agents that modify the immune response or the functioning of the immune system. Immunomodulators suitable for use according to the present invention include, among other options, cyclic peptides, such as cyclosporine, tacrolimus, tresperimus, pimecrolimus, sirolimus, verolimus, laflunimus, laquinimod and imiquimod, as well as analogs, derivatives, salts, ions and complexes thereof. Such compounds, delivered in the foam, are especially advantageous in skin disorders such as psoriasis, eczema and atopic dermatitis, where the large skin areas are to be treated. In an embodiment, the aprotic polar solvent is present in the composition in an amount sufficient to solubilize the immunomodulator.
Retinoids
In an embodiment, the active agent is a retinoid. Retinoids suitable for use according to the present invention include, among other options, retinol, retinal, retinoic acid, isotretinoin, tazarotene, adapalene, 13-cis-retinoic acid, acitretin all-trans beta carotene, alpha carotene, lycopene, 9-cis-beta-carotene, lutein and zeaxanthin, as well as analogs, derivatives, salts, ions and complexes thereof.
Anti-Acne and Anti-Rosacea Active Agents
In an embodiment, the active agent is an anti-acne or an anti-rosacea agent. The anti-acne agent can be selected from the group consisting of 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, coal tar, zinc salts and complexes, and combinations thereof, in a therapeutically effective concentration.
Antipsorasis Agents
In an embodiment, the active agent is an anti-psoriasis agent. Such anti-psoriasis agent can be selected, among other options, from the group of keratolytically-active agents, salicylic acid, coal tar, anthralin, corticosteroids, vitamin D and derivatives and analogs thereof, including vitamin D3 analogs such as calcitriol, calcipotriol; retinoids, such as tazarotene and photodynamic therapy agents.
Antiinfective Agents
In an embodiment, the active agent is an anti-infective agent. Such anti-infective agent can be selected from the group of an antibiotic agent, an antibacterial agent, an antifungal agent, an agent that controls yeast, an antiviral agent and an antiparasitic agent. Exemplary antiinfective agents are exemplified by beta-lactam antibiotic, an aminoglycoside, an ansa-type antibiotic, an anthraquinone, an azole, metronidazole, an antibiotic glycopeptide, a macrolide, erythromycin, clindamycin, an antibiotic nucleoside, an antibiotic peptide, polymyxin B, an antibiotic polyene, an antibiotic polyether, an antibiotic quinolone, an antibiotic steroid, fucidic acid, mupirocin, chloramphenicol, a sulfonamide, tetracycline, an antibiotic metal, silver, copper, zinc, mercury, tin, lead, bismuth, cadmium, chromium, an oxidizing agent, iodine, iodate, a periodate, a hypochlorite, a permanganate, a substance that release free radicals and/or active oxygen, a cationic antimicrobial agent, a quaternary ammonium compound, a biguanide, chlorohexidine, a triguanide, a bisbiguanide, a polymeric biguanide and a naturally occurring antibiotic compound, as well as analogs, derivatives, salts, ions and complexes thereof.
Aprotic Polar Solvents with Therapeutic Properties
In certain embodiments, the aprotic polar solvent possesses therapeutic properties on its own and therefore, it can be regarded as “active agent”. For example, DMSO acts as a topical analgesic, it reduces pain and it also reduces inflammation by several mechanisms. It is an antioxidant—a scavenger of the free radicals that gather at the site of injury.
Because aprotic polar solvents, such as DMSO increases the rate of absorption of some compounds through organic tissues including skin and nails, formulations comprising such aprotic polar solvents can be used as a drug delivery system.
Fields of Applications
The foamable carrier is suitable for treating any inflicted surface. In one or more embodiments, foamable carrier is suitable for administration to the skin, a body surface, a mucosal surface and a body cavity, e.g., the cavity and/or the mucosa of the nose, mouth, eye, ear; respiratory system, vagina or rectum (severally and interchangeably termed herein “target site”).
By selecting a suitable active agent, or a combination of two or more active agents, the foamable composition is useful in treating an animal or a human patient having any one of a variety of dermatological disorders, including dermatological pain, dermatological inflammation, acne, acne vulgaris, inflammatory acne, non-inflammatory acne, acne fulminans, nodular papulopustular acne, acne conglobata, dermatitis, bacterial skin infections, fungal skin infections, viral skin infections, parasitic skin infections, skin neoplasia, skin neoplasms, pruritis, cellulitis, acute lymphangitis, lymphadenitis, erysipelas, cutaneous abscesses, necrotizing subcutaneous infections, scalded skin syndrome, folliculitis, furuncles, hidradenitis suppurativa, carbuncles, paronychial infections, rashes, erythrasma, impetigo, ecthyma, yeast skin infections, warts, molluscum contagiosum, trauma or injury to the skin, post-operative or post-surgical skin conditions, scabies, pediculosis, creeping eruption, eczemas, psoriasis, pityriasis rosea, lichen planus, pityriasis rubra pilaris, edematous, erythema multiforme, erythema nodosum, granuloma annulare, epidermal necrolysis, sunburn, photosensitivity, pemphigus, bullous pemphigoid, dermatitis herpetiformis, keratosis pilaris, callouses, corns, ichthyosis, skin ulcers, ischemic necrosis, miliaria, hyperhidrosis, moles, Kaposi's sarcoma, melanoma, malignant melanoma, basal cell carcinoma, squamous cell carcinoma, poison ivy, poison oak, contact dermatitis, atopic dermatitis, rosacea, purpura, moniliasis, candidiasis, baldness, alopecia, Behcets syndrome, cholesteatoma, Dercum disease, ectodermal dysplasia, gustatory sweating, nail patella syndrome, lupus, hives, hair loss, Halley-Halley disease, chemical or thermal skin burns, scleroderma, aging skin, wrinkles, sun spots, necrotizing fascitis, necrotizing moistens, gangrene, scarring, and vitiligo.
Likewise, the foamable composition is suitable for treating a disorder of a body cavity or mucosal surface, e.g., the mucosa of the nose, mouth, eye, ear, respiratory system, vagina or rectum. Non limiting examples of such conditions include chlamydia infection, gonorrhea infection, hepatitis B, herpes, HIV/AIDS, human papillomavirus (HPV), genital warts, bacterial vaginosis, candidiasis, chancroid, granuloma Inguinale, lymphogranuloma 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.
In an embodiment the composition is useful for the treatment of an infection. In one or more embodiments, the composition is suitable for the treatment of an infection, selected from the group of a bacterial infection, a fungal infection, a yeast infection, a viral infection and a parasitic infection.
In an embodiment the composition is useful for the treatment of wound, ulcer and burn.
In an embodiment the target site is selected from the group consisting of the skin, a body cavity, a mucosal surface, the nose, the mouth, the eye, the ear canal, the respiratory system, the vagina and the rectum.
The composition is also suitable for administering a hormone to the skin or to a mucosal membrane or to a body cavity, in order to deliver the hormone into the tissue of the target organ, in any disorder that responds to treatment with a hormone.
In an embodiment the target site is selected from the group consisting of the skin, a body cavity, a mucosal surface, the nose, the mouth, the eye, the ear canal, the respiratory system, the vagina and the rectum. In an embodiment the disorder is selected from the group consisting of dermatological pain, dermatological inflammation, acne, acne vulgaris, inflammatory acne, non-inflammatory acne, acne fulminans, nodular papulopustular acne, acne conglobata, dermatitis, bacterial skin infections, fungal skin infections, viral skin infections, parasitic skin infections, skin neoplasia, skin neoplasms, pruritis, cellulitis, acute lymphangitis, lymphadenitis, erysipelas, cutaneous abscesses, necrotizing subcutaneous infections, scalded skin syndrome, folliculitis, furuncles, hidradenitis suppurativa, carbuncles, paronychial infections, rashes, erythrasma, impetigo, ecthyma, yeast skin infections, warts, molluscum contagiosum, trauma or injury to the skin, post-operative or post-surgical skin conditions, scabies, pediculosis, creeping eruption, eczemas, psoriasis, pityriasis rosea, lichen planus, pityriasis rubra pilaris, edematous, erythema multiforme, erythema nodosum, granuloma annulare, epidermal necrolysis, sunburn, photosensitivity, pemphigus, bullous pemphigoid, dermatitis herpetiformis, keratosis pilaris, callouses, corns, ichthyosis, skin ulcers, ischemic necrosis, miliaria, hyperhidrosis, moles, Kaposi's sarcoma, melanoma, malignant melanoma, basal cell carcinoma, squamous cell carcinoma, poison ivy, poison oak, contact dermatitis, atopic dermatitis, rosacea, purpura, moniliasis, candidiasis, baldness, alopecia, Behcet's syndrome, cholesteatoma, Dercum disease, ectodermal dysplasia, gustatory sweating, nail patella syndrome, lupus, hives, hair loss, Hailey-Hailey disease, chemical or thermal skin burns, scleroderma, aging skin, wrinkles, sun spots, necrotizing fasciitis, necrotizing myositis, gangrene, scarring, and vitiligo, chlamydia infection, gonorrhea infection, hepatitis B, herpes, HIV/AIDS, human papillomavirus (HPV), genital warts, bacterial vaginosis, candidiasis, chancroid, granuloma inguinale, lymphogranuloma 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, fetal incontinence, constipation, polyps of the colon and rectum; and wherein the active agent is suitable for treating said disorder.
In one embodiment the disorder is an inflammation, skin inflammation, acne, rosacea, actinic keratosis, skin cancer, a local pain, joint pain and osteoarthritis; the active agent is a nonsteroidal anti-inflammatory drug, given at a therapeutically effective concentration.
In one embodiment the disorder is psoriasis; the active agent is a vitamin D, a vitamin D derivative, a vitamin D analog, a vitamin D3 analog (such as calcitriol and calcipotriol) given at a concentration between about 0.0001% and about 0.02% by weight.
In one embodiment the active agent is permethrin. In a Preferred embodiment it is at a concentration between about 1% and about 8% by weight.
Cosmetic Use
In one or more embodiments, the aprotic polar solvent foamable carrier may be used for cosmetic use. For example it may be used as part of a cosmetic formulation to prevent a cosmetic disorder or to improve the skin. Alternatively it may be used with cosmetic effect for example as a cosmetic remover. Unexpectedly, it has been found that foam containing aprotic solvents displays advantages over the prior art removers. It can be dispensed in small quantities as a foam targeted to a surface and applied locally with mechanical force causing the foam to break. The aprotic solvent can then solubilize the cosmetic which can then be and removed for example using a cloth. The foam is short term stable and avoids the mess, spills and over use of liquid aprotic solvents.
The following examples further exemplify the aprotic polar solvent foamable pharmaceutical carriers, pharmaceutical compositions thereof, cosmetic carriers, cosmetic compositions thereof, methods for preparing the same, and uses of the compositions. The examples are for the purposes of illustration only and are not intended to be limiting of the invention. Many variations may be carried out by one of ordinary skill in the art and are contemplated within the full scope disclosed herein.
In one embodiment the foamable compositions and foams are suitable for use in treating, ameliorating, reducing or preventing a dermatological, cosmetic or mucosal disorder. More particularly, they are suitable for use where such disorders would otherwise be less responsive when treated with one agent alone.
General Manufacturing Procedures
The following procedures are used to produce the foam samples described in the examples below, in which only the steps relevant to each formulation are performed depending on the type and nature of ingredients used.
A) Waterless Formulations
Step 1: Gelling agents, if present, are added to the aprotic polar solvent at room temperature under mixing until formulation homogeneity is obtained.
Step 2: The mixture/solvent is warmed to about 50-60° C., surfactants and/or foam adjuvants, if present, are added under agitation until complete dissolution.
Step 3: Hydrophobic and/or hydrophilic solvents, if present are heated to 50-60° C. and added under mixing until formulation homogeneity is achieved.
Step 4: The mixture is cooled down to room temperature and temperature-sensitive agents (e.g., active agents), humectants, preservatives, pH-buffering agents or cosmetic agents, if present, are added under mixing until dissolution.
Step 5: The formulation is packaged in aerosol canisters which are crimped with a valve, pressurized with propellant and equipped with an actuator suitable for foam dispensing.
B) Aqueous or Water Containing Formulations
Step 1: Water is added to the aprotic polar solvent at room temperature. Gelling agents, if present, are added to the mixture at room temperature under mixing until formulation homogeneity is obtained.
Step 2: The mixture/aqueous solvent is warmed to about 50-60° C., surfactants and/or foam adjuvants, if present, are added under agitation until complete dissolution.
Step 3: Hydrophobic and/or hydrophilic solvents, if present, are heated to 50-60° C. and added under mixing until formulation homogeneity is achieved (to form an emulsion).
Step 4: The mixture is cooled down to room temperature and temperature-sensitive agents (e.g., active agents), humectants, preservatives, pH-buffering agents or cosmetic agents, if present, are added under mixing until dissolution.
Step 5: The formulation is packaged in aerosol canisters which are crimped with a valve, pressurized with propellant and equipped with an actuator suitable for foam dispensing.
Materials
Production Under Vacuum
Optionally, the foamable carrier 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 desiccator to remove oxygen prior to filing and crimping.
Canisters Filling and Crimping
Each aerosol canister is filled with the pre-foam formulation (“PFF”, i.e., foamable carrier) and crimped with valve using vacuum crimping machine. The process of applying a vacuum will cause most of the oxygen present to be eliminated. Addition of hydrocarbon propellant may without being bound by any theory further help to reduce the likelihood of any remaining oxygen reacting with the active ingredient. It may do so, without being bound by any theory, by one or more of dissolving in the oil or hydrophobic phase of the formulation, by dissolving to a very limited extent in the aqueous phase, by competing with some oxygen from the formulation, by diluting out any oxygen, by a tendency of oxygen to occupy the dead space, and by oxygen occupying part of the space created by the vacuum being the unfilled volume of the canister or that remaining oxygen is rendered substantially ineffective in the formulation.
Pressurizing
Pressurizing is carried out using a hydrocarbon gas or gas mixture. Canisters are filled and then warmed for 30 seconds in a warm bath at 50° C. and well shaken immediately thereafter.
Tests
By way of non-limiting example stability tests are briefly set out below as would be appreciated by a person of the art.
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. Foams which are structurally stable on the skin for at least one minute are termed “short term stable” carriers or foams.
Density
In this procedure, the foam product is dispensed into vessels (including dishes or tubes) of a known volume and weight. Replicate measurements of the mass of foam filling the vessels are made and the density is calculated. The canister and contents are allowed to reach room temperature. Shake the canister to mix the contents and dispense and discard 5-10 mL. Then dispense foam into a pre-weighed tube, filling it until excess is extruded. Immediately remove (level off) excess foam at both ends and weigh the filled tube on the weighing balance.
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.
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 one or more of 5 C, at 25 C, at, 40 C and at 50 C. At appropriate time intervals canisters are removed and the amount of active agent in the foam sample is measured.
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 10 MP) 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.
Microscopic Observation
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).
When foam is examined under a microscope for the presence of particles, crystals or agglomerates, for example, a cover slide is carefully placed over a small foam sample and pressure is applied to the cover causing most of the bubbles to break. Some of the foam bubbles can sometimes still be observed in the formulations, as can be seen in
Shakability
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:
The invention is described with reference to the following examples. This invention is not limited to these examples and experiments. Many variations will suggest themselves and are within the full intended scope.
Comments: Formulation D01 did not give a foam, but a bubbly liquid. DMSO alone does not have self-foaming or foam-boosting properties. The results may also suggest a defoaming effect or role of aprotic solvents.
Comments: Various different gelling agents were mixed with DMSO. With the exception of xanthan gum, all the other polymers dissolved in DMSO to form liquid gels prior to the addition of propellant. Xanthan did not dissolve and remained as a powder. Compositions D02 to D06, merely produced either bubbly liquids or very watery foams that rapidly collapse and not of quality. The results may also indicate a defoaming effect or role of aprotic solvents.
Comments: Surprisingly, the addition of hydroxypropyl methylcellulose to DMSO improves the foam quality and gave good quality foams. In contrast hydroxypropyl cellulose without the methyl group even with 4 times the concentration does not produce a foam of quality with DMSO. Moreover, and increase in the hydroxypropyl methylcellulose concentration from 0.5% to 1% improved the foam collapse time from 30 sec to 45 sec. There is however still is a need for a longer collapse time to improve ease of application on the skin. In one or more embodiments the polymeric or gelling agent is hydroxypropyl methylcellulose.
Comments: Whilst it was shown above in Part B that the addition of hydroxypropyl methylcellulose to DMSO can improve foam quality and generate good quality foam it can been seen here that in the presence of paraffin wax hydroxypropyl methylcellulose was ineffective and poor foam was produced.
Comments: Various different non-ionic surfactants (surface active agents) were dissolved into DMSO. As shown in formulations 009 to D12, the addition of several surfactants of various HLB values and physical states (solid vs. liquid) merely produced either bubbly liquids or very watery foams that rapidly collapse and not of quality. Formulations D13 and D16 gave good quality foams, but they quickly collapsed and turned into bubbly liquids. Combining linear surfactants one with a high HLB and one with a low HLB (see D16) did not appear to result in any improvement. Therefore, it is not obvious how to create good quality breakable foams with random addition of surfactants.
However, very surprisingly, the addition of sorbitan monostearate or glycerol monostearate to DMSO dramatically improved the foam quality and good to excellent quality breakable foams were produced, which did not collapse after 180 sec of incubation at 36° C. Upon application to a target site and a simple rub of the foams with the hand, these quality foams broke, spread evenly over the skin and were readily absorbed into the skin. For waterless formulations a solid surfactant with a low HLB is preferred.
It can be noted that sorbitan monostearate and glycerol monostearate share some common properties: both of them are solids at room temperature; have a linear fatty acid chain; a polar head (glycerol/sorbitan) and have an HLB value smaller that 5.0. Each one of these properties taken alone is not sufficient to create a good quality breakable foam, as described in formulations D09 to D12 and D16. But without being bound by any theory it is thought that when the properties of solid at room temperature, low HLB, linear hydrophobic chain with a polar head are combined, they act synergistically to create good to excellent quality breakable foams as shown in formulations D14 and D15. In one or more embodiments the surface active agent is a solid with a low HLB. In further embodiments the surface active agent may include a linear hydrophobic chain and a polar head.
Comments: Several active pharmaceutical agents (“API”) were dissolved into stock formulation D15 described above, containing DMSO and glycerol monostearate. As shown in formulations D17 to D19, the addition of various drugs gave good quality breakable foams which did not collapse after 180 sec of incubation at 36° C. Moreover, microscopic observation of foam samples revealed the API's were dissolved in these formulations. It follows that the API bioavailability should be improved if dissolved since the DMSO can then aid penetration
Part A—with Surface Active Agents
Comments: A foam adjuvant (stearyl alcohol) was dissolved into DMSO and used with a surfactant Tween. Although the formulation produced a good quality foam it collapsed almost immediately. As shown in Formulation D26, the random combination of a foam adjuvant and a surfactant does not achieve satisfactory results in terms of foam quality and stability, showing the need for an appropriate selection of the foam stabilizing components as taught in this disclosure. Replacing Tween with glycerol monostearate produced quality foam with a collapse time of more than three minutes. In the presence of glycerol monostearate the addition of a foam adjuvant or a gelling agent produced no significant change in the measured parameters. Thus, formulations D23, D24 and D25 describe combinations of two or more stabilizing components appropriately selected from the group consisting of a surfactant; a foam adjuvant and a gelling agent that gave good quality breakable foams that did not collapse after 180 sec at 36° C.
There are advantages to combine one or both of foam adjuvants and gelling agents with surfactants, as this can inter alia bring; a higher formulation viscosity and structure which is suitable for formulations which are to contain a suspension of non-dissolved active agents and thus provide a more homogeneous API suspension; an improved foaming; a more stable emulsion; greater stability when the propellant is added into the formulation, although adding an inappropriate combination or too high viscosity can lead to destabilization on addition of propellant such that successful combinations and the amounts are non obvious in order to achieve a foam of quality and a stable foamable formulation. Moreover, achieving a specific type of foam and foam properties is certainly non obvious. Nevertheless, in one or more embodiments the combination of foam adjuvants and gelling agents with surfactants may enable a decrease in the surfactant concentration without any degradation of the foam properties. Such a decrease in surfactant concentration can be desirable in topical applications, as lower levels can avoid or minimize potential irritation, particularly if the formulations are to be used on sensitive targets such as wounds or body cavities. Moreover, such combinations have been unexpectedly observed to produce surprising synergetic effects.
Formulation D55 containing Dimethylformamide in contrast to what was surprisingly observed with DMSO fails to give a foam of acceptable quality, showing that not all aprotic polar solvents are suitable to be used at high concentrations in combination with glyceryl monostearate.
Part B—without Surface Active Agents
A foam adjuvant was dissolved in DMSO instead of a surfactant. As seen from formulations D20 and D21, the addition of stearic acid to DMSO gave a bubbly liquid whereas the addition of stearyl alcohol gave a good quality foam but that collapsed almost immediately after 10 sec.
Interestingly, both stearyl alcohol and hydroxypropyl methylcellulose when used separately with DMSO give good quality foams that quickly collapse, after 10 and 30 sec respectively, as seen in formulations D21 and 007. But very surprisingly, when these two components are combined with DMSO, they act synergistically to produce a good quality foam with a substantially improved collapse time of 120 seconds as seen in formulation D22.
In one or more embodiments there is provided a surfactant-free foam formulation comprising DMSO, and fatty alcohols and polymeric agents. In one or more alternative embodiments there is provided a surfactant-free foam formulation comprising DMSO, and fatty alcohols essentially free of polymeric agents. In one or more other embodiments there is provided a surfactant-free foam formulation comprising DMSO and polymeric agents essentially free of fatty alcohols.
Part A—DMSO Formulations
Comments: Formulations D27 is an example of a waterless foam of good to excellent quality containing 45% DMSO, Ethanol, humectants, a foam adjuvant, a low HLB solid surfactant and a gelling agent. It can be noted that the addition of about 20% of ethanol did not appear to affect the foam stability or quality.
A preliminary study was run with formulations D50, D51 and D52 to determine whether any formulations can prevent the known side effect of or after taste and breath odor after use of DMSO. These DMSO side effects were observed to be suppressed when urea is added to the formulation (see D50), are unexpectedly greatly reduced in case of petrolatum (see D52), but are still present when water is added to the formulation (see D51). Thus, in one or more embodiments, there are provided DMSO formulations that are useful in reducing after taste and breath odor side effects.
Comments: All the formulations D50, D51, D52, produced good to excellent quality foam with low density and good collapse time. To determine which formulations would be compatible and suitable for use with human skin and their hydration effect, if any, double blind corneometer studies were carried out to determine the skin-hydration effect of the formulations.
Part B—Manufacturing Procedure
Formulation D50:
Comparison of Formulations D50, D51, D52 with DMSO and a Classic Emollient tested for skin hydration.
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 is capable of detecting even slight changes in the skin hydration level.
Study Flow Chart is Shown Below:
Skin hydration level is assessed at baseline with the Corneometer® CM 825. The formulations are applied in designated chambers under occlusion for 4 hours which are then removed and the skin cleaned. Hydration is then measured.
Study protocol: The study was performed in a temperature controlled room (20-24° C.). Subjects washed their arms with water (no soap) and dried their arms with dry paper towel. Formulations were applied using test chambers. The location of each chamber within the stripe was marked once applied (maximum of 6 stripes on each arm). Each stripe contained only one formulation. One stripe served as a control, non treated area. Formulations, control products and control non treated areas were randomly assigned to the treatment sites according to a randomization list, provided by the study statistician. The application array was unknown to the study operator and subjects. An amount of approximately 4 mg (40 ul) of each of the study formulations was applied on the treatment sites as described by the randomization list. Skin hydration level was assessed at baseline T=0 (minimum 15 minutes following rinse), using the Corneometer® CM 825, and tested based on study design.
Healthy subjects were applied with single dose of formulations D50, D51, and D52 as shown in Part A above and the emollient formulation herein. As shown in
Part D—Aprotic-Alcoholic Formulations with 0% 20% and 40% Ethanol and Foam Properties
Comments: Formulations D27, D50 and D101 were prepared according to the General Manufacturing Procedures described in the Method/Test section. As can be seen from the above Table Formulations D27 D50, which are waterless formulations containing up to 20% ethanol provide good to excellent quality breakable foams. However, when the ethanol content reaches 40% of the formulation, a clear defoaming effect is observed and no quality foam was produced, unlike as in formulation D101. The aprotic alcoholic defoaming effect was observed in the presence of surfactant so it follows that in the absence of surfactant the defoaming effect may be of the same order or more pronounced. So in one or more embodiments the level of short chain alcohols, such as, ethanol, is about or less than about 35%, is about or less than about 30%; is about or less than about 25%, is about or is less than about 20%, is about or is less than about 15%, is about or is less than about 10%, is about or is less than about 5%.
Comments: A hydrophobic solvent was added into a mixture of DMSO and glyceryl monostearate. As shown in formulation D28, the addition of mineral oil to DMSO gave a fairly good quality foam that collapsed after 90 sec. In comparison with example D15 (containing DMSO and glyceryl monostearate only), it can be seen that the addition of a hydrophobic solvent has a defoaming effect.
Formulations D29 and D30 show that, when sufficient amounts of a foam adjuvant and a gelling agent are further added to the components of formulation D28, good quality breakable foam that did not collapse after 180 sec can be produced. Thus, in the presence of a hydrophobic solvent the inclusion of additional foam stabilizers to the surfactant substantially improves collapse time.
Comments: Various different surfactants were dissolved into a mixture of DMSO and water. As shown in formulation D34 and D35, the addition of solid or liquid surfactants of HLB value smaller than 5 does not give satisfying foams, but either bubbly liquids or very watery foams that rapidly collapse. This is in contrast to what was observed with waterless formulations where low HLB solid surfactants with a linear fatty acid and a more polar head were preferred. Glycerol monostearate which produces excellent waterless quality foams with DMSO is rendered ineffective here by the addition of water. Further, as seen in formulation D36, the addition of PEG-100 Stearate, a solid surfactant with a high HLB value of 18.8 produced a very watery foam. Thus, making quality foams containing both water and dimethyl sulfoxide is not obvious considering was has been learned above in the production of waterless DMSO foams.
However, surprisingly, the addition of liquid or solid surfactants of HLB value close to 15 such as Tween 80 and Ceteth 20 to the water/DMSO mixture dramatically improves the foam quality. Moreover, this was achieved without the addition of polymer to stabilize the foam. As shown in formulations D32 and D33, excellent quality breakable foams were produced, that did not collapse after 75 to 90 seconds of incubation at 36° C. Upon application to a target site and a simple rub of the foams with the hand, the foams broke, spread evenly over the skin and were readily absorbed into the skin. Without being bound by any theory it may be that the range of surfactants which can be applied successfully in aqueous or water containing DMSO formulations is much wider than available for waterless formulations.
Part A—Formulation Containing Surfactants
Comments: Formulations D36 and D38 each of which contained only one foam stabilizing component (PEG-100 Stearate and Poloxamer respectively) provided only fairly good foam quality. However, formulations D37 and D39, which contain at least two foam stabilizing components (Cetostearyl alcohol+Poloxamer 407+Methocel K100M; or Poloxamer 188+PEG 100-Stearate) provided good to excellent foam quality. It is interesting to note that PEG-100 Stearate alone and Poloxamer alone fail to produce foams of good quality even at 5% by weight (see formulations D36 and D38). However, when these two components are combined, they surprisingly act synergistically to provide stable and breakable foams of good quality. Thus in one or more embodiments the aprotic foamable compositions comprise a synergistic combination of surface active agent and a polamer with surface active agent like properties, such as PEG 100 Stearate and Poloxamer.
Part B—Formulations without Surfactant
Comments: Formulation D103 was prepared according to the General Manufacturing Procedures described in the Method/Test section. This formulation is an example of an aqueous vehicle containing very high amounts of DMSO, some water, a fatty alcohol, a polymeric agent but no surfactant. Surprisingly, and despite the absence of surfactant and the high aprotic solvent level, a breakable foam of good quality was obtained which did not collapse for 90 seconds at 36° C.
In one or more embodiments, there is provided a surfactant-free foam formulation comprising DMSO, water, fatty alcohols and polymeric agents which provides a breakable foam of good quality. In one or more alternative embodiments there is provided a surfactant-free foam formulation comprising DMSO, water, and fatty alcohols essentially free of polymeric agents. In one or more other embodiments there is provided a surfactant-free foam formulation comprising DMSO, water, and polymeric agents essentially free of fatty alcohols.
Part A—with and without API
Comments: Formulations D40 to D43 are examples of foam vehicles with and without an active agent, containing 45% of DMSO, water, humectants, gelling agents, a foam adjuvant and/or surfactants. Formulations which contain at least two foam stabilizing components provided breakable foams of good to excellent quality that did not collapse after 180 sec at 36° C.
It can be noted that the addition of about 10% of ethanol did not appear to affect the foam stability or quality. It can also be noted that the addition of an active agent did not appear to affect foam quality and stability, and that all these compositions fully dissolve diclofenac sodium. Accordingly, the penetration of the dissolved API should be facilitated by the aprotic solvent DMSO to provide good bioavailability.
Part B—DMSO Carrier Formulation without Polymer
Comments: Formulation D100 was prepared according to the General Manufacturing Procedures described in the Method/Test section. This formulation is an example of a foam vehicle without polymer containing 45% of DMSO, water, humectant, a foam adjuvant and surfactants that can generate excellent quality foam that did not collapse after 180 sec at 36° C. The presence of about 10% of ethanol did not appear to affect the foam quality or the collapse time.
Part C
A sample of formulation D40 above was tested for additional physical parameters and the results are provided below:
Comments: Formulation D44 is an example of a foam vehicle containing 19% of DMSO, 50% of water, a hydrophobic solvent, a gelling agent, a foam adjuvant and a surfactant. It can be seen that formulations containing a protic polar solvent, an aprotic polar solvent, an apolar solvent and a suitable combination of foam stabilizing agents, can provide breakable foams of good to excellent quality that do not collapse after 180 sec.
Part D—Emulsion with Hydrophobic Solvent
Comments: All the formulations provide quality foams with satisfactory collapse times. Surprisingly, there is no apparent change in quality or collapse on removal of the foam adjuvant and polymer but the density is unexpectedly less when they are present. Without being bound to any theory, it may be that foam adjuvants and/or polymeric agents can enable a better propellant dissolution within the pressurized formulation, and so an improved expansion upon foam dispensing.
Part E—without Surfactant
See Example 9, Part B from which it was unexpectedly observed that a surfactant-free foam formulation comprising DMSO, water, fatty alcohols and polymeric agents provides a breakable foam of good quality.
Part F—Manufacture:
Formulation D53:
Part A—Various Other Examples of Aprotic Solvents
Comments: Formulations D45 to D47 are examples of foam vehicles containing 45% of a polar aprotic solvent, ethanol, water, humectants, gelling agents and a foam adjuvant. The polar aprotic solvents used comprise acetone, acetonitrile and dimethyl formamide. The three formulations provided breakable foams of good to excellent quality that did not collapse after 120 to 180 sec at 36° C., showing that the present invention includes a range of polar aprotic solvents. It can be noted that the addition of about 10% of ethanol did not appear to affect the foam stability or quality.
Part B—Aprotic-Hydroalcoholic Formulations with 10%; 11.3% and 40% Alcohol
Comments: Formulations D40, D42 and D102 were prepared according to the General Manufacturing Procedures described in the Method/Test section. All these aprotic-aqueous formulations produced a foam of quality. Formulation D102 is ah example of aqueous foam containing 30% DMSO, a humectant, a fatty alcohol, a polymer and a surfactant, with a high ethanol content of 40% which surprisingly generated a foam of excellent quality. Due to the high ethanol content of D102, the collapse time is shorter than in formulations D40 and D42, but remains essentially satisfactory. In complete contrast, as can be seen in Example 6 Part D, a similar non-aqueous formulation with 40% alcohol did not produce a foam. Thus, it follows that Aprotic—hydroalcoholic formulations are more resilient than their non-aqueous counterparts and that the presence of a relatively small amount of water aids in the quality and or stabilization of the resultant foam.
A panel of three testers was asked to apply on their hand an aqueous DMSO foam preparation and a waterless DMSO foam preparation. The waterless formulation was D15 (see Example 3 above) and the aqueous formulation was D33 (see Example 8 above).
Each was asked to describe their feelings about the ease of application, skin feeling and penetrability of each of the products.
Both formulations were described as having a good appearance and an excellent ease of application and penetration speed into the skin upon slight rubbing. Testers added that the aqueous formulation has a very slight greasy feeling on skin, and the waterless formulation has a slight greasy feeling on skin. In both cases, the greasy feeling disappeared after 10 to 20 seconds. Testers did not report any after-taste or bad breath after application. It may be a further unexpected advantage of DMSO foams that such side effects are absent or ameliorated due to the low density of the foam—allowing small amounts to be spread over a target area—and or due to the composition of formulation.
Part A—Background
Aprotic solvents, such as, DMSO have outstanding solvent properties, being able to dissolve a wide range of organic and inorganic compounds, including plastics, resins and alloys used in fabrication of canisters and valve parts. Therefore, packaging components for holding and delivering such solvents can readily corrode and/or deteriorate especially when high concentrations are present in the compositions, as disclosed in the present foam formulations.
Aerosol packaging is primarily composed of a coated canister, a valve, an actuator and optionally a dip-tube. The components being in prolonged contact with the formulations are mainly the canister internal coating and valve parts (cup and housing). In the following study the compatibility of various packaging components with highly concentrated DMSO solution was assessed in the absence of propellant.
Part B—Procedure
The tested packaging components are incubated in contact with a solution of DMSO in water (50:50 w/w) during up to six months at 50° C. At the desired time-points, the packaging components are removed from the incubators, canisters are opened and a visual observation is performed to determine the presence deterioration, corrosion, peeling, scratches, etc that may result from the prolonged contact with the DMSO solution.
Part C—Compatibility Results
An aluminum canister with a polyimide amide (PAM) internal coating was filled with a solution of DMSO in water (50:50 w/w), crimped with an epoxy coated valve having a dip-tube and incubated at 50° C.
Surprisingly, no canister deterioration was observed, even after 6 months at 50° C. No corrosion or deterioration was observed in the valve cup and in the dip-tube. Only a minor change in color of the valve housing was observed, which is acceptable and not considered as deterioration.
However, a canister with an internal coating made of phenol epoxy and containing formulation D22 showed signs of corrosion after 6 months at room temperature. The valve cup and housing though was of epoxy type and did not show any sign of corrosion. There was no diptube in this canister. So over time during storage canisters, for example, with phenol epoxy coatings can display corrosion and deterioration.
In one or more embodiments, there is provided a kit comprising an aerosol canister, a valve, an actuator, optionally a dip-tube, and a DMSO foam formulation, wherein the packaging components are compatible with a formulation containing DMSO, and wherein essentially no corrosion or deterioration is observed. In one or more embodiments the canisters are essentially free of corrosion and or deterioration for 1 month, or 2 months or for 3 months or for 6 months or for 12 months or for 18 months or for 24 months at room temperature. In one or more further embodiments the canisters are essentially free of corrosion and or deterioration for t month, or for 2 months, or for 3 months, or for 6 months, or for 12 months, or for 18 months, or for 24 months at 40° C. In one or more further embodiments the canisters are essentially free of corrosion and or deterioration for 1 month, or 2 months or for 3 months, or for 6 months, or for 12 months, or for 18 months, or for 24 months at 50° C. In one or more other embodiments any corrosion and or deterioration observed was not of significance. In one or more embodiments any corrosion and or deterioration observed in the canisters was not of significance for 1 month, or for 2 months, or for 3 months, or for 6 months, or for 12 months, or for 18 months, or for 24 months at room temperature. In one or more further embodiments any corrosion and or deterioration observed in the canisters was not of significance for 1 month, or for 2 months, or for 3 months, or for 6 months, or for 12 months, or for 18 months, or for 24 months at 40° C. In one or more further embodiments any corrosion and or deterioration observed in the canisters was not of significance for 1 month, or for 2 months, or for 3 months, or for 6 months, or for 12 months, or for 18 months, or for 24 months at 50° C.
Part D—Can in Can
Background: A bag in can be used in three basic ways with propellant, namely, a) with the propellant not in the bag and being separate from the formulation in the bag; b) with propellant present in the formulation in the bag only; c) with propellant both in the bag and outside of the bag. In case a) without surfactant the formulation is likely to exit as a gel or fluid. In cases b) and c) the formulation can foam. The propellant outside the bag is to expel the contents of the bag. The propellant within the formulation in the bag is to generate foam. When the formulation is primarily expelled by propellant outside the bag then the amount of propellant in the formulation can influence foam properties, such as, density.
An aluminum can-in-can canister with a phenol epoxy internal coating was filled with a solution of DMSO in water (50:50 w/w), crimped with an epoxy coated valve without dip-tube and incubated for one month at 50° C.
After opening of the canister, no corrosion or deterioration was observed neither on the canister internal coating, nor on the different valve parts.
In one or more embodiments, there is provided a kit comprising a can-in-can aerosol canister, a valve, an actuator, optionally a dip-tube, and a DMSO foam formulation, wherein the packaging components are compatible with a formulation containing DMSO, and wherein no corrosion or deterioration is observed. In one or more embodiments the canisters are essentially free of corrosion and or deterioration for 1 month, or 2 months or for 3 months or for 6 months or for 12 months or for 18 months or for 24 months at room temperature. In one or more further embodiments the canisters are essentially free of corrosion and or deterioration for 1 month, or for 2 months, or for 3 months, or for 6 months, or for 12 months, or for 18 months, or for 24 months at 40° C. In one or more further embodiments the canisters are essentially free of corrosion and or deterioration for 1 month, or 2 months or for 3 months, or for 6 months, or for 12 months, or for 18 months, or for 24 months at 50° C. In one or more other embodiments any corrosion and or deterioration observed was not of significance. In one or more embodiments any corrosion and or deterioration observed in the canisters was not of significance for 1 month, or for 2 months, or for 3 months; or for 6 months, or for 12 months, or for 18 months, or for 24 months at room temperature. In one or more further embodiments any corrosion and or deterioration observed in the canisters was not of significance for 1 month, or for 2 months, or for 3 months, or for 6 months, or for 12 months, or for 18 months, or for 24 months at 40° C. In one or more further embodiments any corrosion and or deterioration observed in the canisters was not of significance for 1 month, or for 2 months, or for 3 months, or for 6 months, or for 12 months, or for 18 months, or for 24 months at 50° C.
This application is a Continuation of U.S. patent application Ser. No. 15/639,114, filed on Jun. 30, 2017, which is a Division of U.S. patent application Ser. No. 13/263,201, filed on Dec. 28, 2011, which is a § 371 National Stage entry of PCT/IB2010/001126, filed on Apr. 28, 2010, which claims priority to U.S. Provisional Patent Application No. 61/173,378, filed on Apr. 28, 2009, all of which are incorporated herein 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 | Showmaker 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 |
| 4612193 | Gordon et al. | Sep 1986 | A |
| 4627973 | Moran et al. | Dec 1986 | A |
| 4628063 | Haines et al. | Dec 1986 | A |
| 4661340 | Nagy 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 |
| 4849211 | Schrauzer | 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 | Gnat 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 |
| 5221530 | Janchitraponvej 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 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 et al. | 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 |
| 5854246 | Francois 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 |
| 6017912 | Bussell | Jan 2000 | 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 |
| 6180662 | Lanzendörfer 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 |
| 6264964 | Mohammadi | 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 |
| 6352727 | Takahashi | Mar 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 | Loeffler 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 | Meketa | 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 |
| 8119150 | 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 |
| 8778365 | Hardas et al. | Jul 2014 | B1 |
| 8784780 | Gurge et al. | Jul 2014 | B2 |
| 8795635 | Tamarkin et al. | Aug 2014 | B2 |
| 8795693 | Tamarkin et al. | Aug 2014 | B2 |
| 8840869 | Friedman et al. | Sep 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 |
| 8900553 | Tamarkin et al. | Dec 2014 | B2 |
| 8900554 | Tamarkin et al. | Dec 2014 | B2 |
| 8945516 | Tamarkin et al. | Feb 2015 | B2 |
| 8992896 | Tamarkin et al. | Mar 2015 | B2 |
| 9050253 | Tamarkin et al. | Jun 2015 | B2 |
| 9072667 | Tamarkin et al. | Jul 2015 | B2 |
| 9101662 | Tamarkin et al. | Aug 2015 | B2 |
| 9161916 | Tamarkin et al. | Oct 2015 | B2 |
| 9167813 | Tamarkin et al. | Oct 2015 | B2 |
| 9192558 | Chen et al. | Nov 2015 | B2 |
| 9211259 | Friedman et al. | Dec 2015 | B2 |
| 9265725 | Tamarkin et al. | Feb 2016 | B2 |
| 9265740 | Johnston et al. | Feb 2016 | B2 |
| 9271930 | At | Mar 2016 | B2 |
| 9320705 | Tamarkin et al. | Apr 2016 | B2 |
| 9439857 | Tamarkin et al. | Sep 2016 | B2 |
| 9474720 | Yamamoto | Oct 2016 | B2 |
| 9492412 | Tamarkin et al. | Nov 2016 | B2 |
| 9539208 | Tamarkin et al. | Jan 2017 | B2 |
| 9539266 | Mansouri | Jan 2017 | B2 |
| 9549898 | Tamarkin et al. | Jan 2017 | B2 |
| 9572775 | Tamarkin et al. | Feb 2017 | B2 |
| 9592246 | Salman et al. | Mar 2017 | B2 |
| 9622947 | Tamarkin et al. | Apr 2017 | B2 |
| 9636405 | Tamarkin et al. | May 2017 | B2 |
| 9662298 | Tamarkin et al. | May 2017 | B2 |
| 9668972 | Tamarkin et al. | Jun 2017 | B2 |
| 9675700 | Tamarkin et al. | Jun 2017 | B2 |
| 9682021 | Tamarkin et al. | Jun 2017 | B2 |
| 9713643 | Friedman et al. | Jul 2017 | B2 |
| 9795564 | Tamarkin et al. | Oct 2017 | B2 |
| 9849142 | Tamarkin et al. | Dec 2017 | B2 |
| 9884017 | Tamarkin et al. | Feb 2018 | B2 |
| 9931328 | Kandavilli et al. | Apr 2018 | B2 |
| 10029013 | Tamarkin et al. | Jul 2018 | B2 |
| 20010006654 | Cannell et al. | Jul 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 |
| 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 |
| 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 |
| 20030148949 | Podolsky | Aug 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 | Hon 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 | Mecurio | 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 |
| 20040106688 | Koike et al. | 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 |
| 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 |
| 20040258627 | Riedel et al. | Dec 2004 | A1 |
| 20040258628 | Riedel et al. | Dec 2004 | A1 |
| 20040258643 | Yaqub et al. | Dec 2004 | A1 |
| 20050002976 | Wu | Jan 2005 | A1 |
| 20050013853 | Gil-Ad et al. | Jan 2005 | A1 |
| 20050042182 | Arkin et al. | Feb 2005 | A1 |
| 20050054991 | Tobyn et al. | Mar 2005 | A1 |
| 20050069566 | Tamarkin et al. | Mar 2005 | A1 |
| 20050075407 | Tamarkin et al. | Apr 2005 | A1 |
| 20050079139 | Jacques et al. | Apr 2005 | A1 |
| 20050079228 | Jaiswal 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 et al. | Oct 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 |
| 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 et al. | 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 | Meketa | Mar 2006 | A1 |
| 20060057168 | Larm et al. | Mar 2006 | A1 |
| 20060099151 | Neubourg | May 2006 | A1 |
| 20060108377 | Glynn et al. | May 2006 | A1 |
| 20060110415 | Gupta | 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 |
| 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 |
| 20070264317 | Yosha et al. | Nov 2007 | A1 |
| 20070271235 | Frank et al. | Nov 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 |
| 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 |
| 20080311167 | Oronsky et al. | Dec 2008 | A1 |
| 20080317679 | Tamarkin et al. | Dec 2008 | A1 |
| 20090017147 | Lintner et al. | Jan 2009 | A1 |
| 20090053290 | Sand et al. | Feb 2009 | A1 |
| 20090061001 | Hougaz | 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 |
| 20090214628 | De Rijk | Aug 2009 | A1 |
| 20090291917 | Akama et al. | Nov 2009 | A1 |
| 20100111879 | Tamarkin et al. | May 2010 | A1 |
| 20100221194 | Loupenok | Sep 2010 | A1 |
| 20100247449 | Graupe et al. | Sep 2010 | A1 |
| 20100286417 | Mendes et al. | Nov 2010 | A1 |
| 20110002969 | Serraima et al. | Jan 2011 | A1 |
| 20110097279 | Tamarkin et al. | Apr 2011 | A1 |
| 20110207765 | Van Den Bussche et al. | Aug 2011 | A1 |
| 20110262542 | Ashley | Oct 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 |
| 20120237453 | Tamarkin et al. | Sep 2012 | A1 |
| 20130011342 | Tamarkin et al. | Jan 2013 | A1 |
| 20130053353 | Tamarkin et al. | Feb 2013 | A1 |
| 20130115173 | Trumbore et al. | May 2013 | A1 |
| 20130161351 | Eini et al. | Jun 2013 | A1 |
| 20130164225 | Tamarkin et al. | Jun 2013 | A1 |
| 20130189195 | Tamarkin et al. | Jul 2013 | A1 |
| 20130189196 | Tamarkin et al. | Jul 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 |
| 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 |
| 20140182585 | Tamarkin et al. | Jul 2014 | A1 |
| 20140186269 | Tamarkin et al. | Jul 2014 | A1 |
| 20140221320 | Joks et al. | Aug 2014 | A1 |
| 20140228355 | Kortagere et al. | Aug 2014 | A1 |
| 20140242016 | Binks et al. | Aug 2014 | A1 |
| 20150025060 | Tamarkin et al. | Jan 2015 | A1 |
| 20150098907 | Tamarkin et al. | Apr 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 |
| 20150196570 | Tamarkin et al. | Jul 2015 | A1 |
| 20150209296 | Yamamoto | Jul 2015 | A1 |
| 20150374625 | Tamarkin et al. | Dec 2015 | A1 |
| 20160101184 | Tamarkin et al. | Apr 2016 | A1 |
| 20160128944 | Chawrai et al. | May 2016 | A1 |
| 20160158261 | Friedman et al. | Jun 2016 | A1 |
| 20160213757 | Edelson et al. | Jul 2016 | A1 |
| 20160279152 | Chen et al. | Sep 2016 | A1 |
| 20160287615 | Chan et al. | Oct 2016 | A1 |
| 20160354473 | Tamarkin et al. | Dec 2016 | A1 |
| 20160361252 | Franke | Dec 2016 | A1 |
| 20160361320 | Zhao et al. | Dec 2016 | A1 |
| 20170014517 | Tamarkin | Jan 2017 | A1 |
| 20170049712 | Bhalani et al. | Feb 2017 | A1 |
| 20170119665 | Tamarkin et al. | May 2017 | A1 |
| 20170157175 | Tamarkin et al. | Jun 2017 | A1 |
| 20170172857 | Tamarkin et al. | Jun 2017 | A1 |
| 20170181970 | Tamarkin et al. | Jun 2017 | A1 |
| 20170216334 | Tamarkin et al. | Aug 2017 | A1 |
| 20170231909 | Tamarkin et al. | Aug 2017 | A1 |
| 20170274084 | Friedman et al. | Sep 2017 | A1 |
| 20170340743 | Tamarkin et al. | Nov 2017 | A1 |
| 20170348418 | Tamarkin et al. | Dec 2017 | A1 |
| 20170354597 | Tamarkin et al. | Dec 2017 | A1 |
| 20170360705 | Tamarkin et al. | Dec 2017 | A1 |
| 20180000734 | Tamarkin et al. | Jan 2018 | A1 |
| 20180064638 | Tamarkin et al. | Mar 2018 | A1 |
| 20180147218 | Tamarkin et al. | May 2018 | A1 |
| 20180153804 | Tamarkin et al. | Jun 2018 | A1 |
| 20180193468 | Tamarkin et al. | Jul 2018 | A1 |
| 20180193469 | Tamarkin et al. | Jul 2018 | A1 |
| 20180214558 | Tamarkin et al. | Aug 2018 | A1 |
| 20180235984 | Eini et al. | Aug 2018 | A1 |
| Number | Date | Country |
|---|---|---|
| 198780257 | Sep 1986 | AU |
| 782515 | Dec 2005 | AU |
| 2114537 | Feb 1993 | CA |
| 2154438 | Jan 1996 | CA |
| 2422244 | Sep 2003 | CA |
| 2502986 | May 2004 | CA |
| 2534372 | Oct 2005 | CA |
| 639913 | Dec 1983 | CH |
| 1 882 100 | Nov 1963 | DE |
| 1926796 | Mar 1970 | DE |
| 2 608 226 | Sep 1977 | DE |
| 4140474 | Jun 1993 | DE |
| 10009233 | Aug 2000 | DE |
| 10138495 | Feb 2003 | DE |
| 102004016710 | Oct 2005 | DE |
| 0 052 404 | May 1982 | EP |
| 0 156 507 | Oct 1985 | EP |
| 0 186 453 | Jul 1986 | EP |
| 0 213 827 | Mar 1987 | EP |
| 0 214 865 | Mar 1987 | EP |
| 0 270 316 | Jun 1988 | EP |
| 0 297 436 | Jan 1989 | EP |
| 0 336 812 | Oct 1989 | EP |
| 0 414 920 | Mar 1991 | EP |
| 0 211 550 | Apr 1991 | EP |
| 0 216 856 | Jul 1991 | EP |
| 0 454 102 | Oct 1991 | EP |
| 0 326 196 | Mar 1992 | EP |
| 0 484 530 | May 1992 | EP |
| 0 485 299 | May 1992 | EP |
| 0 488 089 | Jun 1992 | EP |
| 0 528 190 | Feb 1993 | EP |
| 0 552 612 | Jul 1993 | EP |
| 0 569 773 | Nov 1993 | EP |
| 0 404 376 | Mar 1994 | EP |
| 0 598 412 | May 1994 | EP |
| 0 391 124 | Jun 1995 | EP |
| 0 662 431 | Jul 1995 | EP |
| 0 535 327 | Oct 1996 | 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 |
| 0 676 198 | Oct 1998 | 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 |
| 0 504 301 | Mar 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 |
| 1 500 385 | Jan 2005 | EP |
| 1 537 916 | Jun 2005 | EP |
| 1 600 185 | Nov 2005 | EP |
| 0 928 608 | Mar 2006 | EP |
| 1 734 927 | Dec 2006 | EP |
| 1 758 547 | Mar 2007 | EP |
| 1 483 001 | Nov 2007 | EP |
| 1 584 324 | Nov 2007 | EP |
| 1 889 609 | Feb 2008 | EP |
| 1 902 706 | Mar 2008 | EP |
| 2 422 768 | Feb 2012 | EP |
| 2 494 959 | 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 |
| 2 166 651 | May 1986 | GB |
| 2 153 686 | Jul 1987 | GB |
| 2 172 298 | Nov 1988 | GB |
| 2 206 099 | Dec 1988 | GB |
| 2 337 461 | Nov 1999 | GB |
| 2 367 809 | Apr 2002 | GB |
| 2 406 330 | Mar 2005 | GB |
| 2 406 791 | Feb 2008 | GB |
| 2 474 930 | May 2011 | GB |
| 49491 | Sep 1979 | IL |
| 152 486 | May 2003 | IL |
| 55-069682 | May 1980 | JP |
| 56-039815 | Apr 1981 | JP |
| 57-044429 | Mar 1982 | JP |
| 60-001113 | Jan 1985 | JP |
| 61-275395 | Dec 1986 | JP |
| 62-241701 | Oct 1987 | JP |
| 63-119420 | May 1988 | JP |
| 01-100111 | Apr 1989 | JP |
| 01-156906 | Jun 1989 | JP |
| 02-184614 | Jul 1990 | JP |
| 02-255890 | Oct 1990 | JP |
| 03-050289 | Mar 1991 | JP |
| 04-51958 | Feb 1992 | JP |
| 04-282311 | Oct 1992 | JP |
| 04-312521 | Nov 1992 | JP |
| 05-070340 | Mar 1993 | JP |
| 05-213734 | Aug 1993 | JP |
| 06-100414 | Apr 1994 | JP |
| 06-263630 | Sep 1994 | JP |
| 06-329532 | Nov 1994 | JP |
| 07-215835 | Aug 1995 | JP |
| 08-040899 | Feb 1996 | JP |
| 08-501529 | Feb 1996 | JP |
| 08-119831 | May 1996 | JP |
| 08-165218 | Jun 1996 | JP |
| 08-277209 | Oct 1996 | JP |
| 09-84855 | Mar 1997 | JP |
| 09-099553 | Apr 1997 | JP |
| 09-110636 | Apr 1997 | JP |
| 10-114619 | May 1998 | JP |
| 10-332456 | Dec 1998 | JP |
| 11-501045 | Jan 1999 | JP |
| 11-250543 | Sep 1999 | JP |
| 2000-017174 | Jan 2000 | JP |
| 2000-080017 | Mar 2000 | JP |
| 2000-128734 | May 2000 | JP |
| 2000-191429 | Jul 2000 | JP |
| 2000-239140 | Sep 2000 | JP |
| 2000-351726 | Dec 2000 | JP |
| 2000-354623 | Dec 2000 | JP |
| 2001-002526 | Jan 2001 | JP |
| 2001-019606 | Jan 2001 | JP |
| 2001-072963 | Mar 2001 | JP |
| 2002-012513 | Jan 2002 | JP |
| 2002-047136 | Feb 2002 | JP |
| 2002-524490 | Aug 2002 | JP |
| 2002-302419 | Oct 2002 | JP |
| 2003-012511 | Jan 2003 | JP |
| 2003-055146 | Feb 2003 | JP |
| 2004-047136 | Feb 2004 | JP |
| 2004-250435 | Sep 2004 | JP |
| 2004-348277 | Dec 2004 | JP |
| 2005-314323 | Nov 2005 | JP |
| 2005-350378 | Dec 2005 | JP |
| 2006-008574 | Jan 2006 | JP |
| 2006-036317 | Feb 2006 | JP |
| 2006-103799 | Apr 2006 | JP |
| 2006-525145 | Nov 2006 | JP |
| 2007-131539 | May 2007 | JP |
| 2007-155667 | Jun 2007 | JP |
| 2007-326996 | Dec 2007 | JP |
| 0143232 | Jul 1998 | KR |
| 2001-003063 | Jan 2001 | KR |
| 520014 | May 2005 | NZ |
| 540166 | Jun 2007 | NZ |
| 2277501 | Jun 2006 | RU |
| 66796 | Jul 2001 | UA |
| WO 82001821 | 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 92005142 | Apr 1992 | WO |
| WO 9205763 | Apr 1992 | WO |
| WO 9211839 | Jul 1992 | WO |
| WO 9213602 | Aug 1992 | WO |
| WO 93025189 | Dec 1993 | WO |
| WO 94006440 | 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 200009082 | Feb 2000 | WO |
| WO 200015193 | Mar 2000 | WO |
| WO 200023051 | Apr 2000 | WO |
| WO 200033825 | Jun 2000 | WO |
| WO 200038731 | Jul 2000 | WO |
| WO 200061076 | Oct 2000 | WO |
| WO 200062776 | Oct 2000 | WO |
| WO 200072805 | Dec 2000 | WO |
| WO 200076461 | Dec 2000 | WO |
| WO 200101949 | Jan 2001 | WO |
| WO 200105366 | Jan 2001 | WO |
| WO 200108681 | Feb 2001 | WO |
| WO 200110961 | Feb 2001 | WO |
| WO 200153198 | Jul 2001 | WO |
| WO 200154212 | Jul 2001 | WO |
| WO 200154679 | Aug 2001 | WO |
| WO 200162209 | Aug 2001 | WO |
| WO 200170242 | Sep 2001 | WO |
| WO 200176579 | Oct 2001 | WO |
| WO 200182880 | Nov 2001 | WO |
| WO 200182890 | Nov 2001 | WO |
| WO 200185102 | Nov 2001 | WO |
| WO 200185128 | Nov 2001 | WO |
| WO 200195728 | Dec 2001 | WO |
| WO 200200820 | Jan 2002 | WO |
| WO 200207685 | Jan 2002 | WO |
| WO 200215860 | Feb 2002 | WO |
| WO 200215873 | Feb 2002 | WO |
| WO 200224161 | Mar 2002 | WO |
| WO 200228435 | Apr 2002 | WO |
| WO 200241847 | May 2002 | WO |
| WO 200243490 | Jun 2002 | WO |
| WO 2002062324 | Aug 2002 | WO |
| WO 2002078667 | Oct 2002 | WO |
| WO 2002087519 | Nov 2002 | WO |
| WO 2003000223 | Jan 2003 | WO |
| WO 2003002082 | Jan 2003 | WO |
| WO 2003005985 | Jan 2003 | WO |
| WO 2003013984 | Feb 2003 | WO |
| WO 2003015699 | Feb 2003 | WO |
| WO 2003051294 | Jun 2003 | WO |
| WO 2003053292 | Jul 2003 | WO |
| WO 2003055445 | Jul 2003 | WO |
| WO 2003055454 | Jul 2003 | WO |
| WO 2003070301 | Aug 2003 | WO |
| WO 2003071995 | Sep 2003 | WO |
| WO 2003075851 | Sep 2003 | WO |
| WO 2003092641 | Nov 2003 | WO |
| WO 2003094873 | Nov 2003 | WO |
| WO 2003097002 | 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 2005009416 | Feb 2005 | 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 2007054818 | May 2007 | WO |
| WO 2007072216 | Jun 2007 | WO |
| WO 2007082698 | Jul 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 2011013008 | Feb 2011 | WO |
| WO 2011013009 | Feb 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 2015075640 | May 2015 | WO |
| WO 2015114320 | Aug 2015 | WO |
| WO 2015153864 | Oct 2015 | WO |
| WO 2017029647 | Feb 2017 | WO |
| WO 2017030555 | Feb 2017 | WO |
| Entry |
|---|
| “Everything but the Olive.” The Olive Oil Source 1998-2016 [online]. Retrieved from the Internet: http://www.oliveoilsource.com/pageA chemical-characteristics. |
| “Suppositories?” CareCure Community, SCI Forum [online]. http://sci.rutgers.edu/forum/showthread.php?4176-Suppositories. Published: Apr. 16, 2002, 3 pages. |
| 1058. Benzalkonium Chloride; 2350. Citric Acid; 6143. Methyl Salicylate. The Merck Index: An Encyclopedia of Chemicals, Drugs, and Biologicals. 13th Edition, 2001, pp. 181, 405-406, 1090-1091, 1556. |
| 242. Allantoin, The Merck Index: An Encyclopedia of Chemicals, Drugs, and Biologicals. 10th edition, Merck & Co., Inc., 1983, p. 39. |
| Abdullah, G.Z. et al. (Jan. 2013) “Carbopol 934, 940 and Ultrez 10 as viscosity modifiers of palm olein esters based nano-scaled emulsion containing ibuprofen” Pak J Pharm Sci, 26(1):75-83. |
| Abrams et al., “Ciclopirox gel treatment of scalp seborrheic dermatitis,” in: Shuster, S. (ed.) Hydroxy-Piridones as Antifungal Agents with Special Emphasis on Onychomycosis. Springer, Berlin, Heidelberg; 1999, Chapter 8, pp. 45-50. |
| Adachi, “Storage and Oxidative Stability of O/W/ Nano-emulsions,” Foods Food Ingredients J. Jpn., 2004, 209(11), 1 page (Abstract). |
| Adisen et al., “Topical tetracycline in the treatment of acne vulgaris,” J Drugs Dermatol., Oct. 2008, 7(10):953-955. |
| Alcohol SDA 40B, 200 Proof. Material Safety Data Sheets [online]. Retrieved from the Internet: http://www.pharmco-prod.com/pages/MSDS/SDA.sub.--40B.sub.--200.pdf, on Dec. 9, 2008. MSDS 044, Revision 2.1, Revision Date Dec. 2005, 2 pages. |
| Alcohol, Wikipedia, the free encyclopedia [online]. Last modified on Apr. 23, 2014. Retrieved on May 17, 2014, http://en.wikipedia.org/wiki/Alcohol, 17 pages. |
| Aldara™ (imiquimod) Cream. Highlights of Prescribing Information, Graceway Pharmaceuticals, LLC, Mar. 2007, 29 pages. |
| Allantoin, Römpp Online, retrieved on Sep. 23, 2015, https://roempp.thieme.de/roempp4.0/do/data/RD-O 1-01552, 5 pages. |
| 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. |
| Ambrose 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, Sep. 1991, 35(9):1799-1803. |
| Aminobenzoic Acid, Knovel, 2006, retrieved on Apr. 18, 2012, http://www.knovel.com/web/portal/knovel_content?p_p_id=EXT_KNOVEL_CONTENT . . . , 2 pages. |
| Anton 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, Dec. 2002, 24(6):357-366 (Abstract Only). |
| Arisan, Kozmetic ve Kisisel Bakim Urunleri Grubu, retrieved on Dec. 10, 2008, http://www.arisankimya.com/kozmetik.htm, 8 pages. |
| 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. |
| Aslam et al. (2015) “Emerging drugs for the treatment of acne” Expert Opin Emerging Drugs, 20:91-101. |
| Atopic Dermatitis/Eczema, ibabydoc.com, Copyright 2000, retrieved on Jan. 30, 2010, http://www.ibabydoc.com/online/diseaseeczema.asp 6 pages. |
| Ausburger and Shangraw, “Bubble size analysis of high consistency aerosol foams and its relationship to foam rheology; Effects fo Container Emptying, Propellent Type, and Time,” J. Pharma Sci, Apr. 1968, 57(4):624-631. |
| Austria, et al., “Stability of vitamin C derivatives in solution and topical formulations”, Journal of Pharmaceutical and Biomedical Analysis, 1997, 15:795-801. |
| Barry and Badal, “Stability of minocycline, doxycycline, and tetracycline stored in agar plates and microdilution trays,” Current Microbiology, 1978, 1:33-36. |
| Barry and Woodford, “Comparative bio-availability and activity of proprietary topical corticosteroid preparations: vasoconstrictor assays on thirty-one ointments,” British J. Dermatology, 1975, 93:563-571. |
| 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. |
| Beauty Banter, “Interesting list of comedogenic ingredients!!!!!!!!!!!” QVC blog, Interesting list of comedogenic ingredients, 2014, 1-14. |
| Bell-Syer et al., “A systematic review of oral treatments for fungal infections of the skin of the feet,” J. Dermatology. Treat., 2001, 12:69-74. |
| Ben-Et and Tatarsky “Application of NMR for the Determination of HLB Values of Nonionic Surfactants,” Journal of the American Oil Chemists Society,Mar. 20, 1972, 49:499-500. |
| Bernstein and Harrison, “Effects of the Immunomodulating Agent R837 on Acute and Latent Herpes Simplex Virus Type 2 Infections,” Antimicrobial Agents and Chemotherapy, Sep. 1989, 33(9):1511-1515. |
| Blaney and Cook, “Topical use of tetracycline in the treatment of acne,” Arch Dermatol, Jul. 1976, 112:971-973. |
| Blute et al., “Phase behaviour of alkyl glycerol ether surfactants”, Physikalische Chemie/Physical Chemistry Tenside Surf. Det., 1998, 35(3):207-212. |
| Boehm et al., “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., 1994, 37:408-414. |
| Brenes, et al., “Stability of Copigmented Anthocyanins and Ascorbic Acid in a Grape Juice Model System”, J. Agric Food Chem, 2005, 53(1):49-56 (Abstract Only). |
| Brisaert, M. et al. (1996) “Investigation on the chemical stability of erythromycin in solutions using an optimization system” Pharm World Sci, 18(5):182-186. |
| Bronopol, 2-Bromo-2-Nuro-1,3-Propanediol, Chemical land, Jul. 17, 2006, retrieved on Jun. 4, 2011, http://chemicalland21.com/specialtychem/perchem/BRONOPOL.html, 4 pages. |
| Brown et al., “Structural dependence of flavonoid interactions with Cu2+ ions: implications for their antioxidant properties,” Biochem. J., 1998, 330:1173-1178. |
| Buck and Guth, “Treatment of Vaginal Intraepithelial Neoplasia (Primarily Low Grade) with Imiquimod 5% Cream”, Journal of Lower Genital Tract Disease, 2003, 7(3):290-293. |
| Bucks et al., “Bioavailability of Topically Administered Steroids: A “Mass Balance” Technique,” J. Investigative Dermatology, 1988, 91(1):29-33. |
| Bunker and Dowd, “Alterations in Scalp Blood Flow after the Epicutaneous Application of 3% Minoxidil and 0.1% Hexyl Nicotinate in Alopecia,” British Society for Investigative Dermatology, Sep. 1986, 117(5):668-669. |
| Burn Patients Need Vitamin D Supplements, NUTRAingredients.com, Jan. 23, 2004, retrieved on May 5, 2010, http://www.nutraingredients.com/Research/Burn-patients-need-vitamin-D-supplements, 1page. |
| Burton and Marshall, “Hypertrichosis due to minoxidil,” British J. Dermatology, 1979, 101:593-595. |
| C12-15 Alkyl Benzoate, Paula's Choice Skincare, retrieved on Oct. 24, 2010, http://ww.cosmeticscop.com/cosmetic-ingredient-dictionary/definition/259/c12-15-alkyl-benzoate.aspx, 1 page. |
| Campos and Silva, “Ascorbic Acid and Its Derivatives in Cosmetic Formulations”, Cosmetics and Toiletries, 2000, 115(6):59-62 (Abstract Only. |
| 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. |
| Canavan et al. (2016) “Optimizing Non-Antibiotic Treatments for Patients with Acne: A Review” Dermatol Ther, 6:555-578. |
| Carapeti et al., “Topical diltiazem and bethanechol decrease anal sphincter pressure and heal anal fissures without side effects,” Dis Colon Rectum, 2000, 43(10):1359-1362. |
| Carbowax 1000MSDS, Material Safety Data Sheet for Polyethylene glycol 1000 MSDS, last updated Nov. 6, 2008, retrieved on Dec. 13, 2008, http://www.sciencelab.com/xMSDS-Polyethylene.sub.-glycol.sub.-1000-9926-622, 6 pages. |
| Carelli et al., “Effect of Vehicles on Yohimbine Permeation Across Excised Hairless Mouse Skin”, Pharm Acta Hely, Aug. 1978, 73(3):127-134 (Abstract Only). |
| Causes of Psoriasis, retrieved on Sep. 9, 2010, http://www.quickcare.org/skin/causes-of0psoriasis.html, 3 pages. |
| Cetearyl Alcohol, Natural Wellbeing, Copyright 2001-2012, retrieved on Apr. 10, 2014, http://www.naturalwellbeing.com/learning-center/Cetearyl_Alcohol, 3 pages. |
| Chebil et al., “Solubility of Flavonoids in Organic Solvents,” J. Chem. Eng. Data, 2007, 52(5):1552-1556 (Abstract Only). |
| Chemical Characteristics, The Olive Oil Source, ©1998-2015, retrieved on Jun. 12, 2015, http://www.oliveoilsource.com/page/chemical-characteristics, 10 pages. |
| Cheshire and Freeman, “Disorders of Sweating,” Semin Neurol, 2003, 23(4):399-406. |
| Chevrant-Breton et al., “Etude du Traitement Capillaire <<Bioscalin>> dans les Alopecies Diffuses de la Femme”, Gazette Medicale, 1986, 93(17):75-79 (English Abstract). |
| Chiang et al., “Bioavailability Assessment of Topical Delivery Systems: In Vitro Delivery of Minoxidil from Prototypical Semi-Solid Formulations”, Int. J. Pharm, 1989, 49(2):109-114 (Abstract Only). |
| Chinnian et al., “Photostability Profiles of Minoxidil Solutions”, PDA J. Pharm Sci Technol., Mar.-Apr. 1996, 50(2):94-98 (English Abstract). |
| Chollet et al., “Development of a Topically Active Imiquimod Formulation”, Pharmaceutical Development and Technology, 1999, 4(1):35-43. |
| Chollet et al., “The Effect of Temperatures on the Solubility of Imiquimod in Isostearic Acid”, Abstract 3031, Pharmaceutical Research, Nov. 1997, 14(11 Supplemental):S475. |
| Chrysos et al., “Effect of nifedipine on rectoanal motility,” Dis Colon Rectum, Feb. 1996, 39(2):212-216. |
| Clobetasol Propionate Cream and Ointment, Apr. 2006, retrieved Jul. 3, 2014, http://dailymed.nlm.nih.gov/dailymed/archives/fdaDrugInfo.cfm?archiveid=994, 7 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, 15:233-240. |
| Coal Tars and Coal-Tar Pitches, Report on Carcinogens, Twelfth Edition, 2011, 3 pages. |
| Coatzee et al., “Acceptability and feasibility of Micralax® applicators and of methyl cellulose gel placebo for large-scale clinical trials of vaginal microbicides,” AIDS, 2001, 15:1837-1842. |
| Coconut Oil, Wikipedia, the free encyclopedia, retrieved on Jul. 3, 2015, https://en.wikipedia.org/wiki/Coconut_oil, 8 pages. |
| Codex Standard for Olive Oils and Olive Pomace Oils Codex Stan 33-1981, Adopted in 1981, recently amended 2013, 8 pages. |
| Cole and Gazewood, “Diagnosis and Treatment of Impetigo,” American Family Physical Website, 2007, http://www.aafp.org/afp, 6 pages. |
| Colloidal Silica, W.R. Grace & Co. Enriching Lives, Everywhere™, 2011, retrieved on Jun. 4, 2011, http://www.grace.com/engineeredmaterials/materialsciences/colloidalsilica/default.aspx, 4 pages. |
| Communication of a Notice of Opposition in European Application No. 03772600.7, dated Jan. 13, 2015, 36 pages. |
| Cook and Mortenson, “Nifedipine for treatment of anal fissures,” Dis Colon Rectum, 2000, 43(3):430-431. |
| Craig, D.Q.M. et al. (Jul. 1994) “An investigation into the structure and properties of Carbopol 934 gels using dielectric spectroscopy and oscillatory rheometry” J Controlled Rel, 30(3):213-223 (Abstract). |
| Cremophor A Grades, BASF The Chemical Company, Jan. 2008, 6 pages. |
| Croda Crop Care, Arlacel 165, 2011, retrieved on Aug. 3, 2015, http://www.crodapersonalcare.com/home.aspx?view=dtl&d=content&s=157&r=401&p=2578&productName=&inciname=&application=&subapplication=&productfunction=&consumerbenefit=&prodID=1926, 2 pages. |
| Croda Product Care Europe, Cetomacrogol 1000, 2011, retrieved on Aug. 3, 2015, http://www.crodapersonalcare.com/home.aspx?view=dtl&d=content&s=157&r=273&p=1859&productName=&in ciname=&chemicaltype=&application=&subapplication=&productfunction=&consumerbenefit=&prodID=27, 1 page. |
| Crohn'S Disease, Merck Manual Home Edition, retrieved on Jan. 16, 2013, <http://www.merckmanuals.com/home/digestive_disorders/infiammatory_bowel_diseases_ibd/crohn_disease.html?qt=crohn's disease&alt=sh>, 3 pages. |
| Cunha, “Minocycline versus Doxycycline in the treatment of Lyme Neuroborreliosis,” Clin. Infect. Diseases. 2000, 30: 237-238. |
| Dacarbazine, Chemical Book, 2010, retrieved on Oct. 18, 2013, <URL: http://www.chemicalbook.com/ChemicalProductProperty_EN_CB7710656.htm>, 2 pages. |
| Dalby et al., “Determination of Drug Solubility in Aerosol Propellants,” Pharmaceutical Research, 1991, 8(9):1206-1209. |
| Dawber and Rundegren, “Hypertrichosis in Females Applying Minoxidil Topical Solution and in Normal Controls”, JEADV, 2003, 17:271-275. |
| Denatonium Benzoate, retrieved Dec. 9, 2008, http://www.newdruginfo.com/pharmaceopeia/usp28/v28230/usp28nf23s0_m-22790.htm, 2 pages. |
| Dentinger, et al., “Stability of Nifedipine in an Extemporaneously Compounded Oral Solution”, American Journal of Health-System Pharmacy, 2003, 60(10):1019-1022 (English Abstract). |
| Derivative, Merriam Webster Online Dictionary, retrieved on Jul. 5, 2008, http://www.merriam-webster.com/cgi-bin/dictionary?book=dictionary&va=derivative, 1 page. |
| Devos and Miller, “Antisense Oligonucleotides: Treating neurodegeneration at the Level of RNA,” Neurotherapeutics, 2013, 10:486-497. |
| Diethyltoluamide, 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. |
| Disorder, American Heritage Dictionary of the English Language, 2007, retrieved on Oct. 9, 2010, http://www.credoreference.com/entry/hmdictenglang/disorder, 1 page. |
| Draelos, “Antiperspirants and the Hyperhidrosis Patients,” Dermatologic Therapy, 2001, 14:220-224. |
| Drug Index—Dacarbazine, BC Cancer Agency, Jun. 2004, retrieved on Oct. 18, 2013, <URL:http://www.bccancer.bc.ca/HPI/DrugDatabase/DrugIndexPro/Dacarbazine.htm>, 6 pages. |
| Drugfuture, Chemical Index Database, “Sorbitan Esters” Monograph [online]. Retrieved from: http://www.drugfuture.com/chemdata/sorbitan-esters.html on Jul. 1, 2016, 2 pages. |
| Durian et al., “Scaling behavior in shaving cream,” The American Physical Society, Dec. 1991, 44(12):R7902-7905. |
| Durmortier et al., “A review of poloxamer 407 pharmaceutical and pharmacological characteristics,” Pharmaceutical Res., Dec. 2006, 23(12):2709-2728. |
| E7023 Ethanol 200 Proof (Absolute), Sigma-Aldrich Co., © 2008, retrieved on Dec. 9, 2008, http://www.sigmaaldrich.com/catalog/ProductDetail.do?N4=E7023SIAL&N5=SEAR- CH.sub.--CONCAT.sub.--PNOBRAND.sub.--KEY&F=SPEC, 2 pages. |
| 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 Safety of Active Vitamin C in a New Dual-Chamber Dispenser”, Journal of Applied Cosmetology, 1999, 17(4):136-143 (English Abstract). |
| Edirisinghe et al., “Effect of fatty acids on endothelium-dependent relaxation in the rabbit aorta”, Clin Sci, Aug. 2006, 111(2): 145-51. |
| Edwards, “Imiquimod in Clinical Practice,” J. Am Acad Dermatol., Jul. 2000 43(1, Pt 2):S12-S17 (English Abstract). |
| 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, 103-120. |
| Ellis et al., “The Treatment of Psoriasis with Liquor Carbonis Detergens,” J. Invest Dermatology, 1948, 10:455-459. |
| Emulsifiers With HLB Values, The Herbarie, retrieved on Aug. 5, 2009, http://www.theherbarie.com/files/resources-center/formulating/Emulsifiers- .sub.--HLB.sub.--Values.pdf, 3 pages. |
| Esposito et al., “Nanosystems for Skin Hydration: A Comparative Study,” International Journal of Cosmetic Science, 2007, 29: 39-47. |
| Established (“Approved”) Excipients, Encyclopedia of Pharmaceutical Technology, Second Edition, © 2002, vol. 3, 2146-2147. |
| Ethylene Oxide Derivatives: An Essence of Every Industry, retrieved on Jul. 12, 2011, http://www.emulsifiers.in/ethylene_oxide_derivatives2.htm, 3 pages. |
| European Patent Application No. 03772600.7 (Patent No. 1556009): Communication of a Notice of Opposition, dated Sep. 23, 2015, 42 pages. |
| European Patent Application No. 03772600.7 (Patent No. 1556009): Communication of a Notice of Opposition. dated Sep. 24, 2015, 30 pages. |
| European Patent Application No. 03772600.7 (Patent No. 1556009): Reply of the Patent Proprietor to the Notices of Opposition, dated May 9, 2016, 134 pages. |
| European Patent Application No. 03772600.7 (Patent No. 1556009): Summons to Attend Oral Proceedings, dated Jun. 30, 2016, 19 pages. |
| European Patent Application No. 03772600.7 (U.S. Pat. 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. |
| Excessive Sweating, Merck Manual Home Edition, Oct. 2007, retrieved on Apr. 14, 2011, www.merckmanuals.com/home/print/sec18/ch206/ch206c.html, 2 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, Feb. 1995, 39:400-405. |
| Farahmand et al., “Formulation and Evaluation of a Vitamin C Multiple Emulsion”, Pharmaceutical Development and Technology, May 2006, 11(2):255-261 (English Abstract). |
| Flick, Cosmetic and Toiletry Formulations, 2nd Edition, Copyright 1996, vol. 5, 251-309. |
| Floyd, “Silicone Surfactants: Applicants in the Personal Care Industry,” Silicone Surfactants, 1999, Chapter 7, 181-207. |
| Fluhr et al., “Glycerol accelerates recovery of barrier function in vivo,” Acta Derm. Venereol, 1999, 79:418-421. |
| Foamix Pharmaceuticals Ltd. (May 1, 2017) “Foamix Pharmaceuticals Announces Plans for Additional Phase 3 Trial for FMX101 in Moderate to Severe Acne,” Press Release [online]. Retrieved from: http://www.foamix.co.il/news.asp?nodeID=564&itemID=204, on Jun. 12, 2017, 5 pages. |
| Foamix Pharmaceuticals, Statement: Use of LUVIQUAT FC 370, Approved by Yohan Hazot, May 3, 2016, 3 pages. |
| Fontana, “Water Activity: Why It is Important for Food Safety,” International Conference on Food Safety, Nov. 16-18, 1998, 177-185. |
| Frankel, A.J. et al. (2010) “Coal Tar 2% Foam in Combination with a Superpotent Corticosteroid Foam for Plaque Psoriasis. Case Report and Clinical Implications” J Clin Aesthet Dermatol, 3(10):42-45. |
| Fully-Refined Paraffin Wax (FRP Wax), Industrial Raw Materials LLC, Feb. 21, 2008, retrieved on Aug. 22, 2013, <http://irmwax.com/Wax/Paraffin/fully_refined.asp> 1 page. |
| Gallarate et al., “On the Stability of Ascorbic Acid in Emulsified Systems for Topical and Cosmetic Use”, International Journal of Pharmaceutics, 1999, 188:233-241. |
| Galligan et al., “Adhesive Polyurethane Liners for Anterior Restorations,” J. Dent. Res., Jul.-Aug. 1968, 629-632. |
| Garti et al. “Sucrose Esters microemulsions,” J. Molec. Liquids, 1999, 80:253-296. |
| Gas Gangrene, Merck 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. |
| Gelbard et al. “Primary Pediatric Hyperhidrosis: A Review of Current Treatment Options,” Pediatric Dermatology, 2008, 25(6):591-598. |
| Gels, Unc: The Pharmaceutics and Compounding Laboratory, retrieved on Aug. 25, 2014, http://pharmlabs.unc.edu/labs/gels/agents/htm, 4 pages. |
| Ghica, M.V. et al. (2011) “Design and optimization of some collagen-minocycline based hydrogels potentially applicable for the treatment of cutaneous wound infections” Pharmazie, 66:853-861. |
| Gill et al., “Adverse Drug Reactions in a Paediatric Intensive Care Unit,” Acta Paediatric, 1995, 84:438-441. |
| Gladkikh, “Ascorbic Acid and Methods of Increasing its Stability in Drugs”, Translated from Khimiko-Farmatsevticheskii Zhurnal, 1970, 4(12):37-42. |
| Glaser and Ballard, “Hyperhidrosis: A Comprehensive and Practical Approach to Patient Management,” Expert Rev. Dermatol., Oct. 2006, 1(6):773-775. |
| 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 et al., “Structure of Concentrated Nanoemulsions,” The Journal of Chemical Physics, Apr. 1, 2005, 122:134703, 6 pages. |
| Griffin, “Calculation of HLB Values of Non-Ionic Surfactants,” Journal of the Society of Cosmetic Chemists, May 14, 1954, 249-256. |
| Groveman et al., “Lack of Efficacy of Polysorbate 60 in the Treatment of Male Pattern Baldness”, Arch Intern Med, 1985, 145:1454-1458. |
| Gschnait et al., “Topical Indomethacin Protects from UVB and UVA Irradiation,” Arch. Dermatol. Res., 1984, 276:131-132. |
| Hakan et al., “The protective effect of fish oil enema in acetic acid and ethanol induced colitis,” The Turkish Journal of Gastroenterology, 2000, 11(2):155-161. |
| Hall, “Diaper Area Hemangiomas: A Unique Set of Concerns,” retrieved on Dec. 1, 2008, http://members.tripod.com/.about.Michelle.sub.--G/diaper.html, 8 pages. |
| Hallstar® GMS SE/AS, retrieved on Jun. 4, 2011, 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, 2003, 114-115. |
| Harrison et al., “Effects of cytokines and R-837, a cytokine inducer, on UV-irradiation augmented recurrent genital herpes in guinea pigs”, Antiviral Res., 1991, 15(4):315-322. |
| Harrison et al., “Modification of Immunological Responses and Clinical Disease During Topical R-837 Treatment of Genital HSV-2 Infection,” Antiviral Research, 1988, 10:209-224. |
| Harrison et al., “Pharmacokinetics and Safety of Imiquimod 5% Cream in the Treatment of Actinic Keratoses of the Face, Scalp, or Hands and Arms”, Arch. Dermatol. Res., Jun. 2004, 296(1):6-11 (English Abstract). |
| 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, Sep. 1994, 38(9):2059-2064. |
| Harry, “Skin Penetration,” The British Journal of Dermatology and Syphilis, 1941, 53:65-82. |
| Hashim et al., “Tinea versicolor and visceral leishmaniasis,” Int J Dermatol., Apr. 1994; 33(4):258-259 (Abstract). |
| Haute.De, “Substance (INCI-Designation): Triethanolamine” [online]. Retrieved on Sep. 14, 2015, http://www.haut.de/service/inci/anzeige&id=I6384&query=Triethanolamine&funktio . . . ; German with English translation, 3 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. |
| Healy, “Gelled Emollient Systems for Controlled Fragrance Release and Enhanced Product Performance,” Cosmetics and toiletries, 2002, 117(2): 47-54. |
| Heart Failure, The Merck Manual, 2008, retrieved Oct. 9, 2010, http://www.merck.com/mmhe/sec03/ch025/ch025a.html, 12 pages. |
| Helmenstine, “Surfactant Definition—Chemistry Glossary Definition of Surfactant,” About.com Chemistry, retrieved on Mar. 5, 2012, http://chemistry.about.com/od/chemistryglossary/g/surfactant.htm, 1 page. |
| Hepburn, “Cutaneous leishmaniasis,” Clin Exp Dermatol, Jul. 2000, 25(5):363-370 (Abstract). |
| HLB Systems, Pharmcal.tripod.com, retrieved on Sep. 17, 2010, http://pharmcal.tripod.com/ch17.htm, 3 pages. |
| HLB-Numbers, Sigma Aldrich, 2009, retrieved on Feb. 2, 2009, http://www.sigmaaldrich.com/materials-science/micro-and-nanoelectronics/l-ithography-nanopatterning/hlb-numbers.html, 3 pages. |
| How to Have a Healthy Libido in Mid-Life and Beyond, GreenWillowTree.com, Jan. 2001, retrieved on Jul. 28, 2012, http://www.greenwillowtree.com/Page.bok?file=libido.html, 5 pages. |
| Hubbe, Colloidal Silica, Mini-Encyclopedia of Papermaking Wet-End Chemistry: Additives and Ingredients, their Composition, Functions, Strategies for Use, Feb. 1, 2001, retrieved on Jun. 4, 2011, http://www4.ncsu.edu/˜hubbe/CSIL.htm, 2 pages. |
| Human Immunodeficiency Virus Infection, Merck 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. |
| Hwang et al., “Isolation and identification of mosquito repellents in Artemisia vulgaris,”J. Chem. Ecol., 1985, 11: 1297-1306. |
| ICI Americas Inc., “Meaning of HLB Advantages and Limitations” Chapter 1 in The HLB System. A Time-Saving Guide to Emulsifier Selection. Wilmington, Delaware: 1980; pp. 1-4. |
| Ikuta et al., “Scanning Electron Microscopic Observation of Oil/Wax/Water/Surfactant System”, Journal of SCCJ, 2004, 34(4):280-291 (English Abstract). |
| Indomethacin, Aug. 15, 2009, retrived on Jun. 3, 2011, http://it03.net/com/oxymatrine/down/1249534834.pdf, 3 pages. |
| Innocenzi et al., “An Open-Label Tolerability and Effacy Study of an Aluminum Sesquichlorhydrate Topical Foam in Axillary and Palmar Primary Hyperhidrosis,” Dermatologic Therapy, 2008, 21:S27-S30. |
| Izquierdo et al. “Formation and Stability of Nano-Emulsions Prepared Using the Phase Inversion Temperature Method,” Langmuir, 2002, 18(1):26-30 (Abstract). |
| Jan, “Troubled Times: Detergent Foam,” retrieved on Feb. 9, 2012, http://zetatalk.com/health/theal17c.htm, 2 pages. |
| Joseph, “Understanding foams & foaming,” University of Minnesota, May 1997, http://www.aem.umn.edu/people/faculty/joseph/archive/docs/understandingfoams.pdf, 8 pages. |
| Kalkan et al., “The Measurement of Sweat Intensity Using a New Technique,” Tr. J. of Medical Sciences, 1998, 28:515-517. |
| Kanamoto et al., “Pharmacokinetics of two rectal dosage forms of ketoprofen in patients after anal surgery,” J Pharmacobiodyn., Mar. 1988, 11(3):141-145. |
| Kang et al., “Enhancement of the Stability and Skin Penetration of Vitamin C by Polyphenol”, Immune Netw., Dec. 2004, 4(4):250-254 (English Abstract). |
| Kanicky, J.R. and D.O. Shah (2002) “Effect of Degree, Type, and Position of Unsaturation on the pKa of Long-Chain Fatty Acids” J Colloid and Interface Science, 256:201-207. |
| Karasu et al., “Practice Guideline for the Treatment of Patients with Major Depressive Disorder,” Second Edition, Apr. 2000, 78 pages. |
| Kathon™ CG, Rohm and Haas Personal Care, Jun. 2006, 9 pages. |
| 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. |
| Kim, “Stability of Minoxidil in Aqueous Solution”, Yakhak Hoechi, 1986, 30(5):228-231 (English Abstract). |
| Kinnunen and Hannuksela, “Skin reactions to hexylene glycol,” Contact Dermatitis, Sep. 1989, 21(3):154-158. |
| Kircik, L.H. and S. Kumar (Aug. 2010) “Scalp Psoriasis” J Drugs Dermatol, 9(8 Suppl):s101-s137. |
| Kleber et al., “Practice Guideline for the Treatment of Patients with Substance Use Disorders,” Aug. 2006, 276 pages. |
| 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. |
| Knight et al., “Topical diltiazem ointment in the treatment of chronic anal fissure,” Br. J. Surg., 2001, 88(4):553-556. |
| Koerber, “Humectants and Water Activity,” Water Activity News, 2000, 8 pages. |
| Kreuter, “Nanoparticles and microparticles for drug and vaccine delivery,” J. Anat., 1996, 189:503-505. |
| Kucharekova et al., “Effect of a lipid-rich emollient containing ceramide 3 in experimentally induced skin barrier dysfunction,” Contact Dermatitis, Jun. 2002, 46:331-338. |
| Kumar et al., “Application of Broad Spectrum Antiseptic Povidone Iodine as Powerful Action: A Review,” Journal of Pharmaceutical Science and Technology, 2009, 1(2):48-58. |
| Kwak et al. “Study of Complete Transparent Nano-Emulsions which Contain Oils.” IFSCC Conference, Seoul Korea, Sep. 2003, 3 pages. |
| Laboratory 6—Characteristics of Surfactants and Emulsions, retrieved on Jan. 29, 2010, http://web.archive.org/web/20000106225413/http://pharmacy.wilkes.edu/kibbeweb/lab7.html, 5 pages. |
| Lautenschlager, “A Closer Look on Natural Agents: Facts and Future Aspects,” Kosmetic Konzept Kosmetische Praxis, 2006, 5:8-10. |
| Le Vine et al., “Components of the Goeckerman Regimen,” Journal of Investigative Dermatology, 1979, 73:170-173. |
| Lebwohl and Ali, “Treatment of psoriasis. Part 1. Topical therapy and phototherapy,” J. Am Acad Dermatol, Oct. 2001, 487-498. |
| 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., Jan./Feb. 2004, 55:1-12. |
| 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. |
| 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. |
| Leung and Robinson, “Bioadhesive Drug Delivery,” American Chemical Society, 1991, Chapter 23, 350-366. |
| Li et al., “Solubility Behavior of Imiquimod in Alkanoic Acids”, Pharmaceutical Research, Abstract 3029, Nov. 1997,14(11):5475, 2 pages. |
| Licking Vaginal Dryness Without a Prescription, retrieved on Dec. 14, 2008, http://www.estronaut.com/a/vag.sub.--dryness.htm, 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, 125:826-832. |
| Lippacher et al., “Liquid and Semisolid SLN Dispersions for Topical Application: Rheological Characterization,” European Journal of Pharmaceutics and Biopharmaceutics, 2004, 58:561-567. |
| Livingstone and Hubel, “Segregation of form, color, movement, and depth: Anatomy, physiology, and perception,” Science, May 1988, 240:740-749. |
| Lupke 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, 2001, 19:467-473. |
| Luviquat Polymer Grades, BASF The Chemical Company, May 2012, 32 pages. |
| Mailer, “Chemistry and quality of olive oil,” NSW Dept. of Primary Industries, Aug. 2006, Primefact 227, 1-4. |
| Martindale: The Complete Drug Reference, 33rd Edition, Jun. 2002, Pharmaceutical Press, pp. 1073 and 1473. |
| Martindale: The Complete Drug Reference, Thirty-third edition, Bath Press, London, 2002, 1073 and 1473. |
| Martindale: The Extra Pharmacopoeia, Twenty-eighth edition, The Pharmaceutical Press, London, 1982, 862-864. |
| Material Safety Data Sheet, Luvitol EHO, Caelo, Nov. 28, 2013, 4 pages. |
| 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, Hydroxyethyl Cellulose, Sigma-Aldrich, Jan. 14, 2004, http://terpconnect.umd.edu/-choi/MSDS/Sigma-Aldrich/HYDROXYETHYL%20CELLULOSE, 5 pages. |
| Material Safety Data Sheet, Hydroxyethyl Cellulose, Sigma-Aldrich, Jan. 2004, 5 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. |
| 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. |
| Material Safety Data Sheet, Science Lab.com, Polyethylene Glycol 200, MSDS, Nov. 6, 2008, 6 pages. |
| Material Safety Data Sheet, USP, Progesterone, Apr. 26, 2006, 5 pages. |
| Mead, “Electrostatic Mechanisms Underlie Neomycin Block of the Cardiac Ryanodine Receptor Channel (RyR2),” Biophysical Journal, 2004, (87): 3814-3825. |
| Messenger et al., “Minoxidil: Mechanisms of Action on Hair Growth”, British Journal of Dermatology, 2004, 150:186-194. |
| Metronidazole (Veterinary—Systemic), The United States Pharmacopeial Convention, 2007, retrieved on Sep. 10, 2009, www.usp.org/pdf/EN/veterinary/metronidazole.pdf, 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, Oct. 2004, 10:6411-6417. |
| Meucci et al., “Ascorbic Acid Stability in Aqueous Solutions”, Acta Vitaminol Enzymol, 1985, 7(3-4):147-153 (English Abstact). |
| Milton, D.T. et al. (2006) “A Phase I/II Study of Weekly High-Dose Erlotinib in Previously Treated Patients With Nonsmall Cell Lung Cancer” Cancer, 107:1034-1041. |
| Mineral Oil USP, U.S. Department of Health & Human Services, Chemical Abstracts Service Registry No. 8012-95-1, 2011, 7 pages. |
| Minocycline (DB01017), Drug Bank, Feb 8, 2013, retrieved on Aug. 15, 2013, <http://www.drugbank.ca/drugs/DB01017>, 10 pages. |
| Minocycline, Wikipedia, the free encyclopedia, retrieved on Oct. 21, 2011, http://en.wikipedia.org/wiki/Minocycline, 7 page. |
| MMP Inc., International Development and Manufacturing, “Formulating specialties,” retrieved on Feb. 2, 2010, http://mmpinc.com, 3 pages. |
| Molan, “World Wide Wounds: Honey as a topical antibacterial agent for treatment of infected wounds,” Dec. 2001, retrieved May 7, 2008, http://www.worldwidewounds.com/2001/november/Molan/honey-as-topical-agent.html, 13 pages. |
| Molins PLC v. Textron Inc., 48 F.3d 1172, 33 USPQ2d 1823 (Fed. Cir. 1995), 19 pages. |
| Morgan et al., “Enhanced Skin Permeation of Sex Hormones with Novel Topical Spray Vehicles,” Journal of Pharmaceutical Sciences, Oct. 1998, 87(10):1213-1218. |
| Mousse, Merriam-Webster Online Dictionary, retrieved on Dec. 8, 2008, http://www.merriam-webster.com/dictionary/mousse, 2 pages. |
| Musial, W. and A. Kubis (2004) “Carbopols as factors buffering triethanolamine interacting with artificial skin sebum” Polim Med, 34(4):17-30 (Abstract). |
| 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 Clinical SPF 30 Facial Lifting Wrinkle Treatment, Apr. 28, 2010, retrieved on Sep. 11, 2010, http://www.cosmetoscope.com/2010/04/neutrogea-clinical-with-johnson-johnsons-cytomimic-techology/, 5 pages. |
| Neves et al., “Rheological Properties of Vaginal Hydrophilic Polymer Gels,” Current Drug Delivery, 2009, 6:83-92. |
| 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. |
| Nietz, “Molecular orientation at surfaces of solids,” J. Phys. Chem., 1928, 32(2): 255-269. |
| Niram Chemicals, Chemical products—Cetostearyl Alcohol, Cetyl Alcohol, Stearyl Alcohol and Polyethylene Glycol Importer & Supplier, retrieved on Jul. 17, 2012, http://www.indiamart.com/niramchemicals/chemicals.html, 7 pages. |
| Novartis “LAMISIL®” Product Information, T2001-29 [online]. Retrieved from: http://www.fda.gov/downloads/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm052213.pdf; Published: Apr. 2001, 8 pages. |
| Oh et al., “Antimicrobial activity of ethanol, glycerol monolaurate or lactic acid against Listeria moncylogenes,” Int. J. Food Microbiology, 1993, 20:239-246. |
| 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, Nov. 2007, 57:767-774. |
| OM-Cinnamate, MakingCosmetics.com, retrieved on Sep. 26, 2009, http://www.makingcosmetics.com/sunscreens/OM-Cinnamate-p102.html, 1 page. |
| Omega-9 Fatty Acids (Oleic Acid), Orthomolecular.org, Dec. 2004, retrieved on Aug. 15, 2014, http://orthomolecular.org/nutrients/omega9.html, 1 page. |
| Optimization of Nano-Emulsions Production by Microfluidization, European Food Research and Technology. Sep. 2007, 22:5-6 (English Abstract). |
| 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. |
| Osborne and Henke, “Skin Penetration Enhancers Cited in the Technical Literature,” Pharm. Technology, Nov. 1997, 21(11):58-86. |
| Padhi et al., “Phospho-olivines as positive-electrode materials for rechargeable lithium batteries,” J. Electrochemical Soc., Apr. 1997, 144(4): 1188-1194. |
| Padi and Kulkarni, “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 Microemulsions with Alkyl Polyglycosides”, European Journal of Pharmaceutics and Biopharmaceutics, 2009, 72:444-452. |
| Palamaras and Kyriakis, “Calcium antagonists in dermatology: a review of the evidence and research-based studies,” Derm. Online Journal, 2005, 11(2):8. |
| Passi et al., “Lipophilic antioxidants in human sebum and aging,” Free Radical Research, 2002,36(4):471-477. |
| Pharmaceutical Benefits Advisory Committee (PBAC) of Australia. PBAC Public Summary Document—Nov. 2014 Meeting (5 pages). |
| Pendergrass et al., “The shape and dimension of the human vagina as seen in three-dimensional vinyl polysiloxane casts,” Gynecol Obstet. Invest., 1996, 42(3):178-82 (Abstract). |
| Penreco, “Intelligent Gel Technology Product Specifications,” Rev. Jun. 2016 (2 pages). |
| Permethrin (Insecticide), Wildpro, retrieved on Jun. 4, 2015, http://wildpro.twycrosszoo.org/S/00Chem/ChComplex/perm.htm, 5 pages. |
| Perotti et al., “Topical Nifedipine With Lidocaine Ointment vs. Active Control for Treatment of Chronic Anal Fissure,” Dis Colon Rectum, 2002, 45(11):1468-1475. |
| Polystyrene, Wikipedia the free encyclopedia, retrieved Apr. 21, 2014, http://web.archive.org/web/20060312210423/http://en.wikipedia.org/wiki/Polystyrene, 4 pages. |
| PPG-40-PEG-60 Lanolin Oil, Environmental Working Group, 2010, retrieved on May 19, 2010, http://www.cosmeticsdatabase.com/ingredient/722972/PPG-40-PEG-60_Lanolin_Oil/?ingred06=722972., 3 pages. |
| Prevent, The American Heritage Dictionary of the English Language, 2007, retrieved on Oct. 9, 2010, http://www.credoreference.com/entry/hmdictenglang/prevent, 1 page. |
| Product Data Sheet for Meclocycline, bioaustralis fine chemicals, Jun. 28, 2013, 1 page. |
| Promius™ Pharma LLC (2012) Scytera™ (coal tar) Foam, 2%. Product Information Sheet, 1 page. |
| Prud'Homme et al., Foams: theory, measurements and applications, Marcel Dekker, Inc., 1996, 327-328. |
| Purcell, “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, Jul./Aug. 2004, 17(4):200-206 (Abstract). |
| Ravet et al., “Electroactivity of natural and sythetic triphylite,” J. Power Sources, 2001, 97-98: 503-507. |
| Raymond, “Iodine as an Aerial Disinfectant,” J. Hygiene, May 1946, 44(5):359-361. |
| Reaction Rate, Wikipedia, the free encyclopedia, retrieved on Dec. 18, 2011, en.wikipedia.org/wiki/Reaction_rate, 6 pages. |
| Receptacle, Merriam Webster, retrieved on Jul. 12, 2011, http://www.merriam-webster.com/dictionary/receptacle, 1 page. |
| 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. |
| Regulation (EC) No. 2003/2003 of the European Parliament and of the Council, Official Journal of the European Union, Oct. 13, 2003, 2 pages. |
| Repa et al. “All-trans-retinol is a ligand for the retinoic acid receptors,” Proc. Natl. Acad Sci, USA, Aug. 1993, 90: 7293-7297. |
| Reregistration Eligibility Decision for Pyrethrins, EPA, Jun. 7, 2006, 108 pages. |
| Richwald, “Imiquimod”, Drugs Today, 1999, 35(7):497 (Abstract). |
| Rieger and Rhien, “Emulsifier Selection/HLB,” Surfactants in Cosmetics, 129, 1997. |
| Rohstoffinformationen, Hoffmann Mineral, 2008, 8 pages (with English translation). |
| Rosacea, Clinuvel Pharmaceuticals, 2010, retrieved on Sep. 9, 2010, http://clinuvel.com/skin-conditions/common-skin-conditions/rosacea#h0-6-prevention, 5 pages. |
| Rowe et al., “Glyceryl Monooleate,” Handbook of Pharmaceutical Excipients, 2011, 10 pages, retrieved on Dec. 19, 2011, http://www.medicinescomplete.com/mc/excipients/current/1001938996.htm?q=glyceryl%20monooleate&t=search&ss=text&p=I# hit. |
| Rowe et al., “Octyldodecanol,” Handbook of Pharmaceutical Excipients, 2011, 9 pages, retrieved on Dec. 19, 2011, URL:http://www.medicinescomplete.com/mc/excipients/current/1001942450.htm?q=octyldodecanol&t=search&ss=text&p=I# hit. |
| Rowe et al., “Sucrose Palmitate,” Handbook of Pharmaceutical Excipients, 2011, 11 pages, 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=I# hit. |
| Rowe et al., “Sucrose Stearate,” Handbook of Pharmaceutical Excipients, 2011, 11 pages, retrieved on Dec. 19, 2011, URL:http://www. medicinescomplete.com/mc/excipients/current/EXP-TD-cII-mnOOOI-mnOOOI.htm?q=sucrose%20stearate&t=search&ss=text&p=3# hit. |
| RSES (Oil in Refrigerator Systems, Service Application Manual, 2009). |
| Rutledge, “Some corrections to the record on insect repellents and attractants,” J. Am. Mosquito Control Assoc, Dec. 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, 6:128-134. |
| Sanders et al., “Stabilization of Aerosol Emulsions and Foams,” J. Soc. Cosmet. Chem., 1970, 21:377-391. |
| Savin et al., “Tinea versicolor treated with terbinafine 1% solution,” Int J. Dermatol, Nov. 1999; 38(11): 863-865. |
| Schaefer, “Silicone Surfactants,” Tenside Surf. Det., 1990, 27(3): 154-158. |
| Schmidt, “Malassezia furfur: a fungus belonging to the physiological skin flora and its relevance in skin disorders,” Cutis, Jan. 1997, 59(1):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. |
| Schutze, “Iodine and Sodium Hypochlorite as Wound Disinfectants,” The British Medical Journal, 1915, 921-922. |
| 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, “A Practical Guide to Equipment Selection and Operating Techniques,” Pharmaceutical Dosage Forms: Disperse Systems, vol. 3, Copyright 1998, 291-362. |
| 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, retrieved on Sep. 9, 2010, http://www.cumc.columbia.edu/student/health/pdf/R-S/Seborrhea%20Dermatitis.pdf, 2 pages. |
| Security Datasheet, Luvitol EHO, Cetearyloctanoat, Nov. 27, 2013, 10 pages. |
| Sehgal, “Ciclopirox: a new topical pyrodonium antimycotic agent: A double-blind study in superficial dermatomycoses,” British Journal of Dermatology, 1976, 95:83-88. |
| Sharp, “Oil,” Dictionary of Chemistry, Copyright 1990, 286. |
| Shear et al., “Pharmacoeconomic analysis of topical treatments for tinea infections,” Pharmacoeconomics, Mar. 1995, 7(3):251-267. |
| 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, https://www.vocabulary.com/dictionary/sheer, 3 pages. |
| Shemer, A. et al. (2016) “Topical minocycline foam for moderate to severe acne vulgaris: Phase 2 randomized double-blind, vehicle-controlled study results” J Am Acad Dermatol, 74(6):1251-1252. |
| 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., Jun. 2006, 32(5):595-607 (Abstract). |
| Shim et al., “Transdermal Delivery of Mixnoxidil with Block Copolymer Nanoparticles,” J. Control Release, Jul. 2004, 97(3):477-484 (Abstract). |
| Shrestha et al., “Forming properties of monoglycerol fatty acid esters in nonpolar oil systems,” Langmuir, 2006, 22: 8337-8345. |
| Sigma-Aldrich. http://www.sigmaaldrich.com/catalog/product/sial/p1754?lang=en® ion=. Published:Mar. 5, 2014. |
| Sigma Aldrich, “Surfactants Classified by HLB Numbers” 2017 [online]. Retrieved from the Internet: www.sigmaaldrich.com/materials-science/material-science-products.html?TablePage=22686648, on Jul. 8, 2017 (3 pages). |
| Silicone, Oxford Dictionaries Online, retrieved on Apr. 19, 2011, http://www.oxforddictionaries.com/definitions/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 et al., “The influence of Processing Variables on Performance of O/W Emulsion Gels Based on Polymeric Emulsifier (Pemulen ® TR-2NF),” International Journal of Cosmetic Science, Dec. 2001, 21(2)119-125 (Abstract). |
| Smith, “Hydroxy acids and skin again,” Soap Cosmetics Chemical Specialties, Sep. 1993, 69(9):54-59. |
| Smith, “Sore Nipples,” Breastfeeding Mom's Sore Nipples / Breastfeeding Basics, retrieved on Feb. 8, 2012, http://breastfeedingbasics.com/articles/sore-nipples, 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, New York, 1997, 1-17. |
| Solodyn® (Minocycline HCI, USP) Prescribing Information; revised Jun. 2016, 2 pages. |
| Sonneville-Aubrun et al., “Nanoemulsions: A New Vehicle for Skincare Products,” Advances in Colloid and Interface Science, 2004, 108-109:145-149. |
| Spa Collections, Ag & Co. Essential oil workshop, retrieved on Jan. 31, 2010, http://www.agworkshop.com/p3.asp, 1 page. |
| Squillante et al., “Codiffusion of propylene glycol and dimethyl isosorbide in hairless mouse skin,” European J. Pharm. Biopharm., 1998, 46:265-271. |
| Squire and Goode, “A randomized, 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 of dandruff/seborrhoeic dermatitis,” Dermatolog Treat., Jun. 2002, 13(2):51-60 (Abstract). |
| Sreenivasa et al., “Preparation and Evaluation of Minoxidil Gels for Topical Application in Alopecia,” Indian Journal of Pharmaceutical Sciences, 2006, 68(4):432-436. |
| Sreenivasan, B. et al. (1956)“Studies on Castor Oil. I. Fatty Acid Composition of Castor Oil” J Am Oil Chem Soc, 33:61-66. |
| 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 (Abstract). |
| Sugisaka et al., “The Physicochemical Properties of Imiquimod, The First Imidazoquinoline Immune Response Modifier”, Pharmaceutical Research, Nov. 1997, 14(11):5475, Abstract 3030. |
| Sun Pharmaceutical Industries LTD. v. Eli Lilly and Co., 611 F.3d 1381, 95 USPQ2d 1797 (Fed. Cir. 2010),7 pages. |
| Sung, J.H. et al. (2010) “Gel characterisation and in vivo evaluation of minocycline-loaded wound dressing with enhanced wound healing using polyvinyl alcohol and chitosan” Intl J Pharmaceut, 392:232-240. |
| Surfactant, Wikipedia, the free encyclopedia, retrieved on Oct. 24, 2010, http://en.wikipedia.org/wiki/Surfactant, 7 pages. |
| Tadros, “Surfactants in Nano-Emulsions.” Applied Surfactants: Principles and Applications, 2005, 285-308. |
| Tamarkin, D. (2013) “Foam: A Unique Delivery Vehicle for Topically Applied Formulations” in: Formulating Topical Applications—a Practical Guide. Dayan N, Ed., Carol Stream, IL: CT Books, Chapter 9, pp. 233-260. |
| Tan et al., “Effect of Carbopol and PolyvinYlpyrrolidone on the Mechanical, Rheological, and Release Properties of Bioadhesive Polyethylene Glycol Gels,” AAPS PharmSciTech, 2000; 1(3) Article 24, 10 pages. |
| Tanhehco, “Potassium Channel Modulators as Anti-Inflammatory Agents”, Expert Opinion on Therapeutic Patents, Jul. 2001, 11(7):1137-1145 (Abstract). |
| Tarumoto et al., “Studies on toxicity of hydrocortisone 17-butyrate 21-propionate -1. Acute toxicity of hydrocortisone 17-butyrate 21-propionate and its analogues in mice, rats and dogs (author's transl),” J Toxicol Sci., Jul. 1981, 6:1-16 (Abstract). |
| Tata et al., “Penetration of Minoxidil from Ethanol Propylene Glycol Solutions: Effect of Application Volume on Occlusion,” Journal of Pharmaceutical Sciences, Jun. 1995, 84(6):688-691. |
| Tata et al., “Relative Influence of Ethanol and Propylene Glycol Cosolvents on Deposition of Minoxidil into the Skin,” Journal of Pharmaceutical Sciences, Jul. 1994, 83(10):1508-1510. |
| Tavss 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. |
| TCI America, Safety Data Sheet; Product Name: Squalane. Product Code: H0096 [online]. Retrieved from: https://www.spectrumchemical.com/MSDS/TCI-H0096.pdf. Revised: Oct. 6, 2014, 5 pages. |
| Tea Tree Oil, LookChem, Chemical Abstract No. 68647-73-4, 2012, 2 pages. |
| The HLB System—A Time-Saving Guide to Emulsifier Selection, ICI Americas Inc., Mar. 1980, 1-22. |
| The United States Pharmacopeia: The National Formulary, USP23/NF18, US Pharmacopoeia, Jan. 1995, p. 10-14. |
| Third Party Submission in Published Patent Application, U.S. Appl. No. 12/014,088, Feb. 4, 2009, 4 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). |
| Tirumala 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. |
| Tjulandin, S. et al. (2013) “Phase I, dose-finding study of AZD8931, an inhibitor of EGFR (erbB1), HER2 (erbB2) and HER3 (erbB3) signaling, in patients with advanced solid tumors” Invest New Drugs, 32(1):145-153. |
| Todd et al., “Volatile Silicone Fluids for Cosmetic Formulations,” Cosmetics and Toiletries, Jan. 1976, 91:27-32. |
| Torma et al., “Biologic activities of retinoic acid and 3, 4-Didehydroretinoic acid in human keratinocytes are similar and correlate with receptor affinities and transactivation properties,” J. Invest. Dermatology, 1994, 102: 49-54. |
| Torres-Rodriguez, “New topical antifungal drugs,” Arch Med Res., Winter 1993, 24(4): 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), May 1995, retrieved on Dec. 9, 2008, http://ntp.niehs.nih.gob/?objectid-=0709F73D-A849-80CA-5FB784E86613576D1, 4 pages. |
| Trofatter, “Imiqimod in clinical practice”, European Journal of Dermatology, Oct./Nov. 1998, 8(7 Supp.):17-19 (Abstract). |
| Tsai et al., “Drug and Vehicle Deposition from Topical Applications: Use of In Vitro Mass Balance Technique with Minoxidil Solutions”, J. Pharm. Sci., Aug. 1992, 81(8):736-743 (Abstract). |
| Tsai et al., “Effect of Minoxidil Concentration on the Deposition of Drug and Vehicle into the Skin,” International Journal of Pharmaceutics, 1993, 96(1-3):111-117 (Abstract). |
| 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., 1994, 7:270-277. |
| Tyring, “Immune-Response Modifiers: A New Paradigm in the Treatment of Human Papillomavirus,” Current Therapeutic Research, Sep. 2000, 61(9):584-596 (Abstract). |
| Tzen 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. |
| Tzen et al., “Lipids, proteins and structure of seed oil bodies from diverse species,” Plant Physiol., 1993, 101:267-276. |
| U.S. Final Office Action for U.S. Appl. No. 11/430,437, Tamarkin et al., dated Dec. 16, 2008, 24 pages. |
| U.S. Office Action for U.S. Appl. No. 11/430,437, Tamarkin et al., dated May 9, 2008, 27 pages. |
| U.S. Office Action from U.S. Appl. No. 11/430,599, dated Jul. 28, 2008, 59 pages. |
| Uner 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, 2005, 60:751-755. |
| United States Standards for Grades of Olive Oil and Olive-Pomace Oil, United States Dept. of Agriculture, Oct. 25, 2010, 21 pages. |
| Valenta, “Effects of Penetration Enhancers on the In-vitro Percutaneous Absorption of Progesterone,” J. Pharm. Pharmacol., 1997, 49: 955-959. |
| Van Cutsem et al., “The anti-inflammatory effects of ketoconazole,” J. Am. Acad. Dermatol., Aug. 1991, 25(2):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 the buffer solution,” J. Biol. Chem., 1922, 52:525-570. |
| Vera et al., “Scattering optics of Foam,” Applied Optics, Aug. 20, 2001, 40(24):4210-4214. |
| Veron et al., “Stability of Minoxidil Topical Formulations”, Ciencia Pharmaceutica, 1992, 2(6):411-414 (Abstract). |
| 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. |
| 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. |
| Water Jel Technologies, “Material Safety Data Sheet for Neomycin Antibiotic Ointment,” Dec. 1, 2004, 7 pages. |
| WebMD (2014) “Psoriasis Health Center” [online]. Retrieved Apr. 13, 2015; retrieved from the Internet: http://www.webmd.com/skin-problems-and-treatments/psoriasis/psoriasis-symptoms, 3 pages. |
| WebMD (2014) “Understanding Rosacea—the Basics” [online]. Retrieved Apr. 13, 2015; retrieved from the Internet: http://www.webmd.com/skin-problems-and-treatments/understanding-rosacea-basics (5 pages). |
| WebMD (2017) “User Reviews & Ratings—Scytera topical” [online]. Retrieved Mar. 1, 2017; retrieved from the Internet: http://www.webmd.com/drugs/drugreview-151502-Scytera+topical.aspx?drugid=151502&drugname=Scytera+topical&sortby=3 (2 pages). |
| 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. |
| Wenninger et al., “International Cosmetic Ingredient Dictionary and Handbook,” The Cosmetic, Toiletry, and Fragrance Association, Washington, DC., 1997, vol. 1, 4 pages. |
| Wermuth, “Similarity in drugs: reflections on analogue design,” Drug Discovery Today, Apr. 2006, 11(7/8):348-354. |
| What is CP Serum, Skin Biology, retrieved on Dec. 1, 2008, http://web.archive.org/web/20030810230608/http://www.skinbio.com/cpserum.- html, 21 pages. |
| What is TSC?, Tuberous Sclerosis Alliance, Jan. 1, 2005, retrieved on Feb. 6, 2014, http://www.tsalliance.org.pages.aspx?content=2, 3 pages. |
| Williams et al., “Acne vulgaris,” Lancet, 2012, 379:361-372. |
| Williams et al., “Scale up of an olive/water cream containing 40% diethylene glycol monoethyl ether,” Dev. Ind. Pharm., 2000, 26(1):71-77. |
| Williams et al., “Urea analogues in propylene glycol as penetration enhancers in human skin,” International Journal of Pharmaceutics, 1989, 36, 43-50. |
| 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, 1998, 24:383. |
| Wrightson, W.R. et al. (1998) “Analysis of minocycline by high-performance liquid chromatography in tissue and serum” J Chromatography B, 706:358-361. |
| Wu et al., “Interaction of Fatty Acid Monolayers with Cobalt Nanoparticles,” NANO Letters, 2004, 4(2): 383-386. |
| 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. |
| Zeichner, J.A. (2010) “Use of Topical Coal Tar Foam for the Treatment of Psoriasis in Difficult-to-treat Areas” J Clin Aesthet Dermatol, 3(9):37-40. |
| Zinc Oxide, Knovel, 2006, retrieved on Apr. 18, 2012, http://www.knovel.com/web/portal/knovel_content?p_p_id=EXT_KNOVEL_CONTENT . . . , 2 pages. |
| 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). |
| Beuchat (Feb. 1983) “Influence of Water Activity on Growth, Metabolic Activities and Survival of Yeasts and Molds” J Food Prot, 46(2):135-141. |
| Fontana (Apr. 1999) “Pharmaceutical Applications for Water Activity” Pharmaceutical Online [online]. Retrieved from https://www.pharmaceuticalonline.com/doc/pharmaceutical-applications-for-water-activit- . . . , on Jan. 17, 2018 (4 pages). |
| Kolb, “Emulsifiers, emollients and solubilizers for personal care”, pp. 1-9, accessed Jun. 20, 2018. |
| Sarpotdar, P.P. et al. (Jan. 1986) “Effect of Polyethylene Glycol 400 on the Penetration of Drugs Through Human Cadaver Skin In Vitro” J Pharma Sci, 75(1):26-28. |
| Number | Date | Country | |
|---|---|---|---|
| 20180153804 A1 | Jun 2018 | US |
| Number | Date | Country | |
|---|---|---|---|
| 61173378 | Apr 2009 | US |
| Number | Date | Country | |
|---|---|---|---|
| Parent | 13263201 | US | |
| Child | 15639114 | US |
| Number | Date | Country | |
|---|---|---|---|
| Parent | 15639114 | Jun 2017 | US |
| Child | 15883134 | US |
