Patent Application
20140112959
This invention relates to topical preparations for the treatment of skin conditions. More particularly the invention relates to a storage stable, lotion based composition of a corticosteroid material such as halobetasol propionate and related species, and to methods for the use of such compositions in the treatment of dermatoses.
Halobetasol propionate is in widespread use for the treatment of various dermatological conditions. Typically, halobetasol materials are used in cream or ointment based preparations, and one such product in wide commercial use is sold under the trade name “Ultravate® Cream” and the product is generally regarded as a standard in the art. While, in many instances, physicians and/or patients prefer lotion-based preparations, it is generally believed that lotion-based preparations of corticosteroids are inferior in their therapeutic performance as compared to corresponding cream-based preparations.
As will be explained in detail hereinbelow, the present invention is directed to lotion-based preparations of halobetasol propionate and its salts, as well as other halobetasol esters and their salts, solvates, and the like (collectively “halobetasol materials”) which have high patient acceptability and which demonstrate a clinical efficacy which is equal to, and in many instances superior to, that of cream-based halobetasol material preparations. In addition, it has been found that the compositions of the present invention are stable and demonstrate very good long term storage stability. Skin conductance studies have also demonstrated that the compositions of the present invention very rapidly penetrate outer skin layers ensuring optimal bioavailability and therapeutic action. The compositions of the present invention comprise particular combinations of ingredients which interact synergistically to produce the enhanced results described above.
Storage stable, topical lotion compositions of the present invention for treating a skin disorder or condition are described herein, including a halobetasol material including halobetasol or its pharmaceutically acceptable salts, esters, and solvates, such as halobetasol propionate; and a pharmaceutically acceptable carrier which includes: (a) one or more fatty alcohols and/or one or more alkoxylated fatty alcohols, (b) one or more polyol humectants, and (c) diisopropyl adipate.
Storage stable, topical lotion compositions of the present invention for treating a skin disorder or condition are described herein including halobetasol propionate or its pharmaceutically acceptable salts, esters, and solvates; and a pharmaceutically acceptable carrier which includes: (a) one or more fatty alcohols and/or one or more alkoxylated fatty alcohols, (b) one or more polyol humectants, and (c) diisopropyl adipate.
Storage stable, topical lotion compositions of the present invention for treating a skin disorder or condition are described herein wherein the fatty alcohol is selected from the group consisting of lauryl alcohol, myristyl alcohol, cetyl alcohol, stearyl alcohol, octyldodecanol, and mixtures thereof.
Storage stable, topical lotion compositions of the present invention for treating a skin disorder or condition are described herein wherein the alkoxylated fatty alcohol is an ethoxylated alcohol selected from the group consisting of lauryl alcohol ethoxylate, myristyl alcohol ethoxylate, cetyl alcohol ethoxylate, stearyl alcohol ethoxylate, octyldodecanol ethoxylate, and mixtures thereof.
Storage stable, topical lotion compositions of the present invention for treating a skin disorder or condition are described herein wherein the polyol humectant is selected from the group consisting of glycerin, propylene glycol, butylene glycol, dipropylene glycol, pentylene glycol, and mixtures thereof.
Storage stable, topical lotion compositions of the present invention for treating a skin disorder or condition are described herein wherein the amount of degradation of the halobetasol material, such as halobetasol propionate, produced after storage at 1 month at a temperature of approximately 40° C. is less than 5% of the amount of the halobetasol material in the lotion.
Storage stable, topical lotion compositions of the present invention for treating a skin disorder or condition are described herein wherein the amount of degradation of the halobetasol material, such as halobetasol propionate, produced after storage at 1 month at a temperature of approximately 40° C. is less than 2% of the amount of the halobetasol material in the lotion.
Storage stable, topical lotion compositions of the present invention for treating a skin disorder or condition are described herein wherein the amount of degradation of the halobetasol material, such as halobetasol propionate, produced after storage of at least 3 months at a temperature of approximately 30° C. is less than 5% of the amount of the halobetasol material in the lotion.
Storage stable, topical lotion compositions of the present invention for treating a skin disorder or condition are described herein wherein the amount of degradation of the halobetasol material, such as halobetasol propionate, produced after storage of at least 3 months at a temperature of approximately 30° C. is less than 2% of the amount of the halobetasol material in the lotion.
Storage stable, topical lotion compositions of the present invention optionally further include one or more members selected from the group consisting of: coloring agents, preservatives, pH control agents, viscosity control agents, and fragrances.
Storage stable, topical lotion compositions of the present invention for treating a skin disorder or condition are described herein wherein the ratio of the fatty alcohols and alkoxylated fatty alcohols to the humectants, to the diisopropyl adipate is, on a weight basis, in the range of 30-60:30-60:5-15.
Storage stable, topical lotion compositions of the present invention for treating a skin disorder or condition are described herein wherein the ratio of the fatty alcohols and alkoxylated fatty alcohols to the humectants, to the diisopropyl adipate is, on a weight basis, in the range of 44-46:40-43:11-13.
Storage stable, topical lotion compositions of the present invention for treating a skin disorder or condition are described herein wherein the ratio of the fatty alcohols and alkoxylated fatty alcohols to the humectants, to the diisopropyl adipate is, on a weight basis, 46:42:12.
Storage stable, topical lotion compositions of the present invention for treating a skin disorder or condition are described herein, including, on a weight basis: 0.02-0.10% of a halobetasol material; 1-5% of diisopropyl adipate; 5-15% octyl dodecanol; 0.50-2% of polyethylene glycol 1000 cetyl ether; 0.50-2% of a surfactant; 1-3% cetyl alcohol; 1-2% stearyl alcohol; 0.05-0.2% of a preservative; 5-15% propylene glycol; 1-5% glycerin; an alkali in an amount sufficient to adjust the pH of the composition to a range of approximately 5-6.5; and water q.s.
Storage stable, topical lotion compositions of the present invention for treating a skin disorder or condition are described herein, including, on a weight basis: 0.02-0.10% of halobetasol propionate; 1-5% of diisopropyl adipate; 5-15% octyl dodecanol; 0.50-2% of polyethylene glycol 1000 cetyl ether; 0.50-2% of a surfactant; 1-3% cetyl alcohol; 1-2% stearyl alcohol; 0.05-0.2% of a preservative; 5-15% propylene glycol; 1-5% glycerin; an alkali in an amount sufficient to adjust the pH of the composition to a range of approximately 5-6.5; and water q.s.
Storage stable, topical lotion compositions of the present invention for treating a skin disorder or condition are described herein, including, on a weight basis: 0.02-0.10% of a halobetasol material; 1-5% of diisopropyl adipate; 5-15% octyl dodecanol; 0.50-2% of polyethylene glycol 1000 cetyl ether; 0.50-2% of a surfactant; 1-3% cetyl alcohol; 1-2% stearyl alcohol; 0.05-0.2% of a preservative; 5-15% propylene glycol; 1-5% glycerin; an alkali in an amount sufficient to adjust the pH of the composition to a range of approximately 5.2-6.2; and water q.s.
Storage stable, topical lotion compositions of the present invention for treating a skin disorder or condition are described herein, including, on a weight basis: 0.02-0.10% of halobetasol propionate; 1-5% of diisopropyl adipate; 5-15% octyl dodecanol; 0.50-2% of polyethylene glycol 1000 cetyl ether; 0.50-2% of a surfactant; 1-3% cetyl alcohol; 1-2% stearyl alcohol; 0.05-0.2% of a preservative; 5-15% propylene glycol; 1-5% glycerin; an alkali in an amount sufficient to adjust the pH of the composition to a range of approximately 5.2-6.2; and water q.s.
Storage stable, topical lotion compositions of the present invention for treating a skin disorder or condition are described herein, including, on a weight basis: 0.05% of a halobetasol material; 3.5% of diisopropyl adipate; 10% octyl dodecanol; 1% of polyethylene glycol 1000 cetyl ether; 1% of a surfactant; 2% cetyl alcohol; 0.66% stearyl alcohol; 0.15% of a preservative; 10% propylene glycol; 2.5% glycerin; an alkali in an amount sufficient to adjust the pH of the composition to a range of approximately 5-6.5; and water q.s.
Storage stable, topical lotion compositions of the present invention for treating a skin disorder or condition are described herein, including, on a weight basis: 0.05% of halobetasol propionate; 3.5% of diisopropyl adipate; 10% octyl dodecanol; 1% of polyethylene glycol 1000 cetyl ether; 1% of a surfactant; 2% cetyl alcohol; 0.66% stearyl alcohol; 0.15% of a preservative; 10% propylene glycol; 2.5% glycerin; an alkali in an amount sufficient to adjust the pH of the composition to a range of approximately 5-6.5; and water q.s.
According to aspects of the invention, the alkali is selected from: sodium hydroxide and potassium hydroxide.
Storage stable, topical lotion compositions of the present invention optionally further include a viscosity control agent. According to aspects of the present invention, an included viscosity control agent is a cross-linked polyacrylate in an amount of 0.1-0.2%. According to further aspects of the present invention, an included viscosity control agent is a carbomer in an amount of 0.1-0.2%.
An included surfactant is poloxamer 407 according to aspects of the present invention.
An included preservative is a paraben preservative according to aspects of the present invention.
An included preservative is selected from the group consisting of: propyl paraben, butyl paraben and a combination thereof, according to aspects of the present invention.
Methods for treating steroid responsive dermatoses are provided by the present invention which include topically administering to a patient in need thereof, a storage stable, topical lotion composition of the present invention, including a halobetasol material including halobetasol or its pharmaceutically acceptable salts, esters, and solvates, such as halobetasol propionate; and a pharmaceutically acceptable carrier which includes: (a) one or more fatty alcohols and/or one or more alkoxylated fatty alcohols, (b) one or more polyol humectants, and (c) diisopropyl adipate.
Methods for treating steroid responsive dermatoses are provided by the present invention which include topically administering to a patient in need thereof, a storage stable, topical lotion composition of the present invention, including halobetasol propionate or its pharmaceutically acceptable salts, esters, and solvates; and a pharmaceutically acceptable carrier which includes: (a) one or more fatty alcohols and/or one or more alkoxylated fatty alcohols, (b) one or more polyol humectants, and (c) diisopropyl adipate.
Methods for treating steroid responsive dermatoses are provided by the present invention which include topically administering to a patient in need thereof, a storage stable, topical lotion composition of the present invention, including, on a weight basis: 0.02-0.10% of a halobetasol material; 1-5% of diisopropyl adipate; 5-15% octyl dodecanol; 0.50-2% of polyethylene glycol 1000 cetyl ether; 0.50-2% of a surfactant; 1-3% cetyl alcohol; 1-2% stearyl alcohol; 0.05-0.2% of a preservative; 5-15% propylene glycol; 1-5% glycerin; an alkali in an amount sufficient to adjust the pH of the composition to a range of approximately 5-6.5; and water q.s.
Methods for treating steroid responsive dermatoses are provided by the present invention which include topically administering to a patient in need thereof, a storage stable, topical lotion composition of the present invention, including, on a weight basis: 0.02-0.10% of halobetasol propionate; 1-5% of diisopropyl adipate; 5-15% octyl dodecanol; 0.50-2% of polyethylene glycol 1000 cetyl ether; 0.50-2% of a surfactant; 1-3% cetyl alcohol; 1-2% stearyl alcohol; 0.05-0.2% of a preservative; 5-15% propylene glycol; 1-5% glycerin; an alkali in an amount sufficient to adjust the pH of the composition to a range of approximately 5-6.5; and water q.s.
Methods for treating steroid responsive dermatoses are provided by the present invention which include topically administering to a patient in need thereof, a storage stable, topical lotion composition of the present invention, including, on a weight basis: 0.02-0.10% of a halobetasol material; 1-5% of diisopropyl adipate; 5-15% octyl dodecanol; 0.50-2% of polyethylene glycol 1000 cetyl ether; 0.50-2% of a surfactant; 1-3% cetyl alcohol; 1-2% stearyl alcohol; 0.05-0.2% of a preservative; 5-15% propylene glycol; 1-5% glycerin; an alkali in an amount sufficient to adjust the pH of the composition to a range of approximately 5.2-6.2; and water q.s.
Methods for treating steroid responsive dermatoses are provided by the present invention which include topically administering to a patient in need thereof, a storage stable, topical lotion composition of the present invention, including, on a weight basis: 0.02-0.10% of halobetasol propionate; 1-5% of diisopropyl adipate; 5-15% octyl dodecanol; 0.50-2% of polyethylene glycol 1000 cetyl ether; 0.50-2% of a surfactant; 1-3% cetyl alcohol; 1-2% stearyl alcohol; 0.05-0.2% of a preservative; 5-15% propylene glycol; 1-5% glycerin; an alkali in an amount sufficient to adjust the pH of the composition to a range of approximately 5.2-6.2; and water q.s.
Methods for treating steroid responsive dermatoses are provided by the present invention which include topically administering to a patient in need thereof, a storage stable, topical lotion composition of the present invention, including, on a weight basis: 0.05% of a halobetasol material; 3.5% of diisopropyl adipate; 10% octyl dodecanol; 1% of polyethylene glycol 1000 cetyl ether; 1% of a surfactant; 2% cetyl alcohol; 0.66% stearyl alcohol; 0.15% of a preservative; 10% propylene glycol; 2.5% glycerin; an alkali in an amount sufficient to adjust the pH of the composition to a range of approximately 5-6.5; and water q.s.
Methods for treating steroid responsive dermatoses are provided by the present invention which include topically administering to a patient in need thereof, a storage stable, topical lotion composition of the present invention, including, on a weight basis: 0.05% of halobetasol propionate; 3.5% of diisopropyl adipate; 10% octyl dodecanol; 1% of polyethylene glycol 1000 cetyl ether; 1% of a surfactant; 2% cetyl alcohol; 0.66% stearyl alcohol; 0.15% of a preservative; 10% propylene glycol; 2.5% glycerin; an alkali in an amount sufficient to adjust the pH of the composition to a range of approximately 5-6.5; and water q.s.
Storage stable, topical lotion compositions of the present invention for treating a skin disorder or condition are packaged in a container suitable for storage and delivery of the composition according to aspects of the present invention. The container is optionally comprised of a ferrous alloy, aluminum, glass, plastic, or combinations thereof. In a further option, the container further includes one or more protective coatings.
A container for a storage stable, topical lotion composition of the present invention optionally includes at least two separate compartments and the composition is disposed in one of the compartments.
According to aspects of methods for treating steroid responsive dermatoses of the present invention, the patient is instructed to prepare the area to be treated by cleansing with a suitable surfactant-containing composition.
According to aspects of methods for treating steroid responsive dermatoses of the present invention, the storage stable, topical lotion composition is an oil in water emulsion of droplets having a mean particle size in the range of 0.1-50 microns, such as a range of between 1 and 10 microns, such as a range of between 1.5 and 7 microns.
According to aspects of methods for treating steroid responsive dermatoses of the present invention, the treatment is effective to improve skin surface hydration levels as measured with a Skicon-200 conductance apparatus.
According to aspects of methods for treating steroid responsive dermatoses of the present invention, the treatment is effective to improve skin surface hydration levels as measured with a Skicon-200 conductance apparatus, wherein said improvement is observed at 2 hours post treatment.
According to aspects of methods for treating steroid responsive dermatoses of the present invention, the treatment is effective to improve skin surface hydration levels as measured with a Skicon-200 conductance apparatus, wherein said improvement is observed at 4 hours post treatment.
Methods for the preparation of storage stable, topical lotion compositions of the present invention are also provided by the present invention, including the steps of: preparing an aqueous phase that includes a first portion of the components of said composition; maintaining said aqueous phase at a temperature in the range of 40-50° C.; preparing an oil phase that includes a second portion of the components of said composition; adding said oil phase to said aqueous phase while stirring at a temperature of about 40-50° C. so as to obtain an emulsion; cooling said emulsion to a temperature of about 25-35° C.; and adjusting the pH of said emulsion to a pH in the range of 5.0-6.5.
Methods for the preparation of storage stable, topical lotion compositions of the present invention are also provided by the present invention, including the steps of: preparing an aqueous phase that includes a first portion of the components of said composition; maintaining said aqueous phase at a temperature in the range of 40-50° C.; preparing an oil phase that includes a second portion of the components of said composition; adding said oil phase to said aqueous phase while stirring at a temperature of about 40-50° C. so as to obtain an emulsion; cooling said emulsion to a temperature of about 25-35° C.; and adjusting the pH of said emulsion to a pH in the range of 5.2-6.2.
Storage stable, topical lotion compositions of the present invention for treating a skin disorder or condition are described herein which include: a therapeutically active material; and a pharmaceutically acceptable carrier which includes: (a) one or more fatty alcohols and/or one or more alkoxylated fatty alcohols, (b) one or more polyol humectants, and (c) diisopropyl adipate.
Storage stable, topical lotion compositions of the present invention for treating a skin disorder or condition are described herein which include: a corticosteroid or its pharmaceutically acceptable salts, esters, and solvates; and a pharmaceutically acceptable carrier which includes: (a) one or more fatty alcohols and/or one or more alkoxylated fatty alcohols, (b) one or more polyol humectants, and (c) diisopropyl adipate.
Methods for treating a skin condition according to aspects of the present invention include topically administering to a patient in need thereof a storage stable, topical lotion composition of the present invention for treating a skin disorder or condition which includes: a therapeutically active material; and a pharmaceutically acceptable carrier which includes: (a) one or more fatty alcohols and/or one or more alkoxylated fatty alcohols, (b) one or more polyol humectants, and (c) diisopropyl adipate.
Methods for treating a skin condition according to aspects of the present invention include topically administering to a patient in need thereof a storage stable, topical lotion composition of the present invention for treating a skin disorder or condition which includes: a corticosteroid or its pharmaceutically acceptable salts, esters, and solvates; and a pharmaceutically acceptable carrier which includes: (a) one or more fatty alcohols and/or one or more alkoxylated fatty alcohols, (b) one or more polyol humectants, and (c) diisopropyl adipate.
The topical lotion compositions of the present invention are storage stable and comprise a mixture of a corticosteroid such as a halobetasol material together with a carrier which includes one or more of: fatty alcohols, ethoxylated fatty alcohols, polyol humectants, and diisopropyl adipate. The fatty alcohol may, in some instances, comprise a long chain alcohol such as lauryl alcohol, myristyl alcohol, cetyl alcohol, stearyl alcohol, and octyldodecanol, used either singly or in combination. Yet other fatty alcohols will be apparent to those of skill in the art. In the preparations of the present invention, the compositions may further include alkoxylated forms of the fatty alcohols; and in specific instances, these will comprise ethoxylated fatty alcohols.
The polyol component of the composition functions as a humectant for the skin and may comprise materials such as glycerin, propylene glycol, butylene glycol, dipropylene glycol, pentylene glycol, and the like; and these polyol materials may be used either singly or in combination in the preparations of the present invention.
In specific embodiments of the present invention, the foregoing ingredients are present in particular ratios. In this regard, the fatty alcohols and alkoxylated fatty alcohols are collectively considered to be fatty alcohol excipients, and the polyols are collectively referred to as humectants. In specific compositions of the present invention the ratio of fatty acid excipients to humectants to the diisopropyl adipate (DIA) generally comprises, on a weight basis, 30-60 fatty alcohol excipients:20-60 humectants:5-15 DIA. In some specific instances, the ratios are 44-46 fatty alcohol excipients:40-43 humectants:11-13 DIA. An exemplary composition of the present invention comprises fatty alcohol excipients 46:humectants 42: DIA 12. Preparations based upon these ratios will further include the halobetasol material and may also include ancillary ingredients such as preservatives, fragrances, coloring agents, viscosity control agents and the like. Other excipients commonly known as useful in the preparation of topical compositions are further contemplated as within the scope of the present invention. These other materials include, for example, those listed in the current edition of the Ingredients Buyers Guide published by the Personal Care Products Council, 1101 17th Street, NW, Suite 300, Washington D.C. 20036-4702 the entire contents of which are hereby incorporated by reference.
Typically, preparations of the present invention will include a pH adjustment agent as necessary to maintain the product at a pH in the general range of 5.0-6.5 at the time of manufacture, and in particular at a pH of about 5.2-6.2. Such pH adjustment is accomplished by the use of basic materials such as ammonium salts; alkali metal salts, including sodium and potassium salts; alkaline earth metal salts such as calcium and magnesium salts; salts with organic bases such as dicyclohexylamine salts; methyl-D-glucamine; amines, amino acids such as arginine, lysine, and the like, and salts of amino acids. pH adjustment may also be accomplished by the use of nitrogen-containing materials such as quaternized compounds as well as inorganic materials such as sodium, potassium, and ammonium hydroxides.
The compositions of the present invention are found to exhibit very good stability under storage conditions. As is known in the art, halobetasol can degrade under storage conditions, and some of the degradates or impurities produced thereby include:
In some specific instances, the lotion of the present invention is an emulsified preparation comprising droplets of an oil phase dispersed in an aqueous phase, and the droplets have a mean particle size in the range of 0.1-50 microns, and in more particular instances a mean particle size in the range of about 1 to 10 microns. In some particular instances, the mean particle size of the droplets ranges from about 1.5 to 7 microns. There are a number of formulations which may be prepared in accord with the present invention. Table 1 hereinbelow lists compositional ranges for one such formulation.
In this composition, ceteth-20 is a polyethylene glycol-1000 cetyl alcohol ether, and other similar materials may be substituted therefor. Poloxamer 407 is a particular hydrophilic nonionic surfactant comprising a triblock copolymer consisting of a central hydrophobic block of polypropylene glycol flanked by two hydrophilic blocks of polyethylene glycol. Other such surfactants may be substituted therefor. The present preparation further includes parabens, specifically propylparaben and butylparaben; and as is known in the art, these materials are antimicrobial agents which function as preservatives. The composition further includes carbomer 980 which is a cross-linked polyacrylate gelling agent, and other such viscosity control agents may be substituted therefor. The composition is preferably adjusted to a pH in the range of 5-6.5, and in particular instances 5.2-6.2 and this may be accomplished by the use of an alkali such as sodium hydroxide, potassium hydroxide, or the like.
As discussed above, the compositions of the present invention may be fabricated as emulsified materials; and in a general procedure for doing so, one portion of the components is dissolved in water to prepare an aqueous phase. This phase is typically maintained at an elevated temperature in the range of 40-70° C. A second portion of the components is used to prepare a nonaqueous oil phase, and this oil phase is then mixed into the aqueous phase under conditions which will favor formation of a suspension/emulsion structure. This mixing is carried out at an elevated temperature, again typically in the range of 40-70° C. Following mixing, the composition is cooled to form a thickened emulsified lotion.
In one specific procedure, a lotion is prepared in accord with the present invention utilizing the formulation of Table 2. Listed in Table 2 is a specific composition based upon the ranges set forth hereinabove.
In this procedure, an aqueous phase is prepared by mixing water with the carbomer material, sodium hydroxide, glycerin, and propylene glycol. These materials are then mixed at a temperature of approximately 65° C. A second mixture comprising a DIA, octyldodecanol, ceteth-20, poloxamer 407, cetyl alcohol, stearyl alcohol, parabens, and halobetasol. This mixture is stirred at approximately 65° C. for a period of time sufficient to dissolve the halobetasol material. The resulting aqueous and oil phases are disposed in a Mokon emulsifier and mixed at a speed of approximately 6000 rpm to produce a homogenized mixture. The resultant mixture is cooled with mixing to a temperature of approximately 30° C. under vacuum, after which the preparation is complete. Clearly, modifications and variations of this procedure will be readily apparent to those of skill in the art.
A series of studies was carried out to evaluate the properties and advantages of the compositions of the present invention. These studies were carried out utilizing an emulsified lotion preparation having a formulation in accord with Table 2 as prepared by the procedure set forth above. In a first study, the efficacy of the composition with regard to skin hydration was determined utilizing a Skicon-200 apparatus which determined the net change in skin conductance as a function of time, following application of a material. Compositions of the present invention were compared with the industry standard Ultravate® Cream and with a shaved skin control sample. The resultant data are summarized in
Statistical Summary for Net Change in Skicon Conductance at 2, 4 and 6 Hrs Post Treatment
aTukey-Kramer Multiple Comparisons Test
bDunn's Multiple Comparisons Test
A study was carried out measuring transepidermal water loss (TEWL) of skin treated with the lotion of the present invention and skin treated with Ultravate® Cream, as compared to a dry shaved control. Computerized evaporimetry was carried out utilizing a state of the art Derm RG-1 Evaporometer; a research grade and open-chamber device based on the time proven vapor pressure gradient estimation method pioneered by Gert Nilsson. Data from this evaluation are summarized in
A further experimental study evaluated the efficacy of the lotion of the present invention having the formulation described above, in the treatment of subjects with plaque psoriasis. The study involved a double-blind, randomized, multicenter, vehicle-controlled parallel group study involving a 2 week course of treatment. The efficacy and safety of a topical lotion composition composition of the present invention including halobetasol propionate (HBP) 0.05%, applied twice daily for 14 consecutive days in subjects with moderate to severe plaque psoriasis was determined and compared with Vehicle Lotion applied twice daily for 14 consecutive days in subjects with moderate to severe plaque psoriasis. The study involved 72 subjects, with approximately 36 per treatment group, and was carried out at three separate sites with approximately 24 subjects at each site. Subjects were selected so that their plaque psoriasis involved a minimum of 2% and no more than approximately 10% of their BSA (excluding the face, scalp, groin, axillae, and other intertriginous areas).
Definitions: In this study “treatment success” is indicated by a score of 0 or 1 for overall disease severity (ODS) and the clinical signs and symptoms of psoriasis. Further, the term “improved” refers to at least a two (2) grade decrease in severity score relative to Baseline for overall disease severity (ODS) and the clinical signs and symptoms of psoriasis. Note: Dichotomization of scores for clinical signs and symptoms of psoriasis will exclude subjects with Baseline scores of 0 or 1 unless the corresponding sign score at Day 8 or Day 15 is >1.
Efficacy Endpoints included a primary efficacy endpoint and secondary efficacy endpoints. The primary efficacy endpoint is the proportion of subjects with Overall Disease Severity (ODS) “treatment success” at End of Treatment (EOT) where EOT is the last visit (Day 8 if early termination or Day 15) with Last Observation Carried Forward (LOCF) imputation for early terminations. Secondary efficacy endpoints are: 1) the proportion of subjects with ODS “treatment success” at Day 8 and Day 15 (no LOCF imputation); and 2) the proportion of subjects rated “improved” with respect to ODS at Days 8 and 15, respectively.
Additional details of the study design and results of this study are shown in TABLES 4-8.
The topical lotion composition of the present invention exhibited very good results in the treatment of plaque psoriasis, showing treatment being a complete success with regard to 30.6% of the patients studied, and producing significant improvement with regard to 44.4% of the patients in the study. These results are very strong and significant particularly as compared to those achieved through the use of Ultravate® Cream and other comparable prior art compositions.
TABLE 9 compares the results for the halobetasol propionate lotion as achieved in the present study, with regard to those previously obtained utilizing FDA approved compositions of the prior art.
As noted above, “Treatment Success” is defined at the End of Treatment as a score of 0 or 1 for overall disease severity (ODS) and clinical signs and symptoms of psoriasis. “Improved” means subjects had at least a two (2) grade decrease in severity score relative to Baseline for overall disease severity (ODS) and the clinical signs and symptoms of psoriasis.
It should be noted that over the years the FDA has changed the parameters defining clinical “success” and has each time raised the bar. The results obtained with the present halobetasol propionate lotion were unexpectedly strong. The Ultravate® Cream results as shown in the first two rows of the TABLE 9 were filed with the FDA as a basis of an NDA approval, and it will be seen that the results achieved with the halobetasol propionate lotion of the present invention are superior to those achieved through the use of the Ultravate® Cream and are as good or better than any of the other Class 1 topical corticosteroids. It will be noted that the clobetasol propionate lotion results are similar to those achieved utilizing the present halobetasol propionate lotion; however, clobetasol propionate is generally believed to be a more potent steroid molecule than halobetasol propionate, and furthermore the clobetasol propionate studies ran for 4 weeks as compared to 2 weeks for the study involving the halobetasol propionate composition of the present invention. These results are unexpected given the relative potencies of halobetasol propionate and clobetasol propionate, and given the longer duration of the clobetasol propionate treatment. These results show unexpected therapeutic effects achieved through the composition of the present invention.
Items
1. A storage stable, topical lotion composition for treating a skin disorder or condition, said composition comprising: a halobetasol material comprising halobetasol or its pharmaceutically acceptable salts, esters, and solvates; and a pharmaceutically acceptable carrier which includes: (a) one or more fatty alcohols and/or one or more alkoxylated fatty alcohols, (b) one or more polyol humectants, and (c) diisopropyl adipate.
2. The topical lotion of item 1, wherein the fatty alcohol is selected from the group consisting of lauryl alcohol, myristyl alcohol, cetyl alcohol, stearyl alcohol, octyldodecanol, and mixtures thereof.
3. The topical lotion of item 1 or item 2, wherein the alkoxylated fatty alcohol is an ethoxylated alcohol selected from the group consisting of lauryl alcohol ethoxylate, myristyl alcohol ethoxylate, cetyl alcohol ethoxylate, stearyl alcohol ethoxylate, octyldodecanol ethoxylate, and mixtures thereof.
4. The topical lotion of any one of items 1-3, wherein the polyol humectant is selected from the group consisting of glycerin, propylene glycol, butylene glycol, dipropylene glycol, pentylene glycol, and mixtures thereof.
5. The topical lotion of any one of items 1-4, wherein the amount of degradation of said halobetasol material produced after storage at 1 month at a temperature of approximately 40° C. is less than 5% of the amount of said halobetasol material in said lotion, such as less than 2% of the amount of said halobetasol material in said lotion.
6. The topical lotion of any one of items 1-5, wherein the amount of degradation of said halobetasol material produced after storage of at least 3 months at a temperature of approximately 30° C. is less than 5% of the amount of said halobetasol material in said lotion, such as less than 2% of the amount of said halobetasol material in said lotion.
7. The topical lotion of any one of items 1-6, wherein said halobetasol material is a halobetasol ester such as halobetasol propionate.
8. The composition of any one of items 1-7, further including one or more members selected from the group consisting of: coloring agents, preservatives, pH control agents, viscosity control agents, and fragrances.
9. The composition of any one of items 1-8, wherein the ratio of said fatty alcohols and alkoxylated fatty alcohols to said humectants, to said diisopropyl adipate is, on a weight basis, in the range of 30-60:30-60:5-15.
10. The composition of item 9, wherein the weight ratio of said fatty alcohols and ethoxylated fatty alcohols to said polyol humectants to said diisopropyl adipate is in the range of 44-46:40-43:11-13, such as a ratio of 46:42:12.
11. A storage stable, topical lotion composition comprising, on a weight basis: 0.02-0.10% of a halobetasol material;
1-5% of diisopropyl adipate; 5-15% octyl dodecanol; 0.50-2% of polyethylene glycol 1000 cetyl ether; 0.50-2% of a surfactant such as poloxamer 407; 1-3% cetyl alcohol; 1-2% stearyl alcohol; 0.05-0.2% of a preservative such as a paraben preservative, for example propyl paraben and/or butyl paraben; 5-15% propylene glycol; 1-5% glycerin; an alkali such as sodium hydroxide, potassium hydroxide, or the like in an amount sufficient to adjust the pH of the composition to a range of approximately 5-6.5, and in particular 5.2-6.2; optionally a viscosity control agent which may be a cross-linked polyacrylate such as a carbomer in an amount of 0.1-0.2%; and water q.s.
12. A storage stable, topical lotion composition comprising, on a weight basis: 0.05% of a halobetasol material; 3.5% of diisopropyl adipate; 10% octyl dodecanol; 1% of polyethylene glycol 1000 cetyl ether; 1% of a surfactant such as poloxamer 407; 2% cetyl alcohol; 0.66% stearyl alcohol; 0.15% of a preservative such as a paraben preservative, for example propyl paraben and/or butyl paraben; 10% propylene glycol; 2.5% glycerin; an alkali such as sodium hydroxide, potassium hydroxide, or the like in an amount sufficient to adjust the pH of the composition to a range of approximately 5-6.5; optionally a viscosity control agent which may be a cross-linked polyacrylate such as a carbomer in an amount of 0.15%; and water q.s.
13. A method for treating steroid responsive dermatoses comprising: topically administering to a patient in need thereof, the composition of any one of items 1-12.
14. The method of item 13, wherein said composition is packaged in a container suitable for storage and delivery of said composition.
15. The method of item 14, wherein said container is comprised of a ferrous alloy, aluminum, glass, plastic, or combinations thereof.
16. The method of item 14 or item 15, wherein said container further includes one or more protective coatings.
17. The method of any one of items 14-16, wherein said container includes at least two separate compartments wherein said composition of any one of items 1-12 is disposed in one of said compartments.
18. The method of item 13, wherein the patient is further instructed to prepare the area to be treated by cleansing with a suitable surfactant-containing composition.
19. The method of item 13, wherein said composition is an oil in water emulsion of droplets having a mean particle size in the range of 0.1-50 microns, such as a range of between 1 and 10 microns, such as a range of between 1.5 and 7 microns.
21. The method of item 13, wherein said treatment is effective to improve skin surface hydration levels as measured with a Skicon-200 conductance apparatus.
22. The method of item 21, wherein said improvement is observed at 2 hours post treatment.
23. The method of item 21, wherein said improvement is observed at 4 hours post treatment.
24. A method for the preparation of the composition of any one of items 1-12, said method comprising the steps of:
preparing an aqueous phase that includes a first portion of the components of said composition; maintaining said aqueous phase at a temperature in the range of 40-50° C.;
preparing an oil phase that includes a second portion of the components of said composition; adding said oil phase to said aqueous phase while stirring at a temperature of about 40-50° C. so as to obtain an emulsion;
cooling said emulsion to a temperature of about 25-35° C.; and
adjusting the pH of said emulsion to a pH in the range of 5.0-6.5, preferably 5.2-6.2.
25. A storage stable, topical lotion composition for treating a skin disorder or condition, said composition comprising: a therapeutically active material; and a pharmaceutically acceptable carrier which includes: (a) one or more fatty alcohols and/or one or more alkoxylated fatty alcohols, (b) one or more polyol humectants, and (c) diisopropyl adipate.
26. The composition of item 25, wherein said therapeutically active material comprises comprising a corticosteroid or its pharmaceutically acceptable salts, esters, and solvates.
27. A method for treating a skin condition comprising: topically administering to a patient in need thereof, the composition of items 25 or 26.
The present invention provides therapeutic compositions which have unexpected therapeutic efficacy in the treatment of dermatoses. The lotion compositions of the present invention readily penetrate the skin to provide a rapid therapeutic effect and operate to promote hydration and limit water loss of the skin. While the foregoing describes some particular compositions based on therapeutically active halobetasol materials, it will be readily apparent to those of skill in the art that the principles of the present invention may be readily extended to other hydrocortisones as well as other therapeutically active ingredients. All of such modifications and variations thereof may be implemented by those of skill in the art, without undue experimentation. The foregoing drawings, discussion, and description are illustrative of specific embodiments of the invention but are not meant to be limitations upon the practice thereof. It is the following claims, including all equivalents, which define the scope of the invention.
This application claims priority to U.S. Provisional Patent Application Ser. No. 61/715,467, filed Oct. 18, 2012, the entire content of which is incorporated herein by reference.
| Number | Date | Country | |
|---|---|---|---|
| 61715467 | Oct 2012 | US |
