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Home , Descinolone, Hydrocortamate, Hydrocortisone valerate, Meprednisone

USOO7220424B2

(12) United States Patent (10) Patent No.: US 7,220,424 B2 Gans et al. (45) Date of Patent: May 22, 2007

(54) COMPOSITIONS AND METHODS FOR (58) Field of Classification Search ...... 514/169, ENHANCING 514/170, 171, 172, 177-180, 424/400 401 DELIVERY See application file for complete search history. (56) References Cited (75) Inventors: Eugene H. Gans, Westport, CT (US); U.S. PATENT DOCUMENTS Mitchell S. Wortzman, Scottsdale, AZ 3,934,013 A 1/1976 Poulsen ...... 514,170 (US) FOREIGN PATENT DOCUMENTS EP O 020 794. A 1, 1981 (73) Assignee: Medicis Pharmaceutical Corporation, WO WO 91.08733. A 6, 1991 Scottsdale, AZ (US) OTHER PUBLICATIONS Physicians' Desk Reference, 51 Edition, pp. 2299-2300, for (*) Notice: Subject to any disclaimer, the term of this example.* patent is extended or adjusted under 35 Bennett et al., “Optimization of bioavailability of topical : U.S.C. 154(b) by 382 days. non-occluded penetration enhancers under thermodynamic con trol”, Journal of Pharmacy and Pharmacology, vol. 37, No. 5, 1985, (21) Appl. No.: 10/407,380 pp. 298-304. * cited by examiner (22) Filed: Apr. 4, 2003 Primary Examiner San-Ming Hui (65) Prior Publication Data (74) Attorney, Agent, or Firm William J. McNichol, Jr.; Maryellen Feehery Hank; Reed Smith LLP US 2003/O176408 A1 Sep. 18, 2003 (57) ABSTRACT Related U.S. Application Data The present invention comprises a composition, method of (62) Division of application No. 10/037,360, filed on Dec. enhancing potency and method of delivering 21, 2001, now Pat. No. 6,765,001. in a Vehicle comprising at least two penetration enhancers, and solvents and emulsifiers. The propylene glycol and (51) Int. Cl. penetration enhancers are present in ratio to the total of the A6 IK3I/56 (2006.01) propylene glycol, penetration enhancers, and solvents and A6 IK 47/44 (2006.01) emulsifiers of at least about 0.70. (52) U.S. Cl...... 424/400: 514/171; 514/180; 514/169 15 Claims, No Drawings US 7,220,424 B2 1. 2 COMPOSITIONS AND METHODS FOR disrupt the epidermal barrier and increase penetration. ENHANCING CORTICOSTEROID Hydrating the skin has also been shown to increase the DELIVERY penetration of the corticosteroids. Once absorbed through the skin, topical corticosteroids RELATED APPLICATIONS are handled through pharmacokinetic pathways similar to systemically administered corticosteroids. The potencies of This application is a divisional of U.S. Ser. No. 10/037, corticosteroids vary greatly and it is a challenge to increase 360, filed Dec. 21, 2001 now U.S. Pat. No. 6,765,001 the potency of any particular .

FIELD OF THE INVENTION 10 BACKGROUND OF THE INVENTION

Topical corticosteroids are useful for their anti-inflamma The clinical effectiveness of corticoids is related to four tory, anti-pruritic and vasoconstrictive actions. Corticoster basic properties: vasoconstriction, antiproliferative effects, oids (or corticoids) are any steroids (lipids that contain a immunosuppression, and anti-inflammatory effects. Topical hydrogenated cyclopentoperhydrophenanthrene ring sys 15 steroids cause the capillaries in the Superficial dermis to tem) elaborated by the adrenal cortex (except sex hormones constrict, thus reducing erythema. The ability of a given of adrenal origin) in response to the release of adrenocorti agent to cause vasoconstriction usually cor cotrophin or adrenocorticotropic hormone by the pituitary relates with its anti-inflammatory potency. Vasoconstrictor gland, or to any synthetic equivalent, or to angiotensin II. assays are used in the art and by the U.S. Food and Drug Corticosteroids include but are not limited to Administration for determining the potency of topical cor dipropionate, , amcinafel, , bec ticosteroid preparations. Topical glucocorticoid preparations lamethasone, , betamethasone dipropionate, have been divided in the field into seven classes based on , propionate, chloro potency based on double-blind clinical Studies and vasocon , clocortelone, , , cortodoxone, strictor assays. Class 1 includes the most potent, while class difluorosone diacetate, , , deflupred 25 nate, dihydroxycortisone, , , 7 contains the least potent. , diacetate, , esters of The following glucocorticoid preparations were desig betamethasone, flucetonide, flucloronide, fluorocortisone, nated in Fitzpatrick, Dermatology in General Medicine, 5" flumethasone, , , edition, CD-ROM, 1999, Table 243-1, with the following classes. acetonide, flucortolone, , , 30 fluroandrenolone acetonide, , fluran drenolide, fluorametholone, propionate, hydro TABLE 1. cortisone, butyrate, , Corticosteroid , , , methylpred Preparation Corticosteroid Class Source nisone, , furoate, 35 , prednisone, , prednidone, tri Temovate (R) Clobetasone 1 GlaxoWellcome Cream O.05% propionate amcinolone acetonide, and . Temovate (R) Clobetasone 1 GlaxoWellcome Hydrocortisone was the first corticosteroid found to be ointment 0.05% propionate topically effective. Other more potent glueoeorticoids, Diprolene (R) Betamethasone 1 Schering Corp. cream O.O.5% ipropionate which are a subset of corticosteroids that affect carbohydrate 40 Diprolene (R) Betamethasone 1 Schering Corp. metabolism, inhibit corticotropin secretion, and possess pro ointment 0.05% ipropionate nounced anti-inflammatory activity, have since been devel Psorcon (R) Diflorasone 1 Dermik Laboratories, oped. Currently, topical steroids are among the most fre ointment iacetate Inc. quently prescribed of all dermatological drug products. Cyclocort (R) Amcinonide 2 Fujisawa ointment 0.1% It is believed that exert their potent anti 45 Diprolene (R) Betamethasone 2 Schering Corp. inflammatory effects by inhibiting the formation of prostag cream AF ipropionate landins and other derivatives of the arachidonic acid path O.05% Diprosone (R) Betamethasone 2 Schering Corp. way. It is known that glucocorticoids inhibit the release of ointment 0.05% ipropionate phospholipase A2, the enzyme responsible for liberating Elocon (R) MometaSone 2 Schering Corp. arachidonic acid from cell membranes, thus inhibiting the 50 ointment 0.1% O8c arachidonic acid pathway. Currently, it is believed that Florone (R) Diflorasone 2 Dermilk ointment 0.05% iacetate glucocorticoids inhibit phospholipase A2, in cells by directly Halog (R) cream 2 Westwood-Squibb inducing phosphorylation of the enzyme. O.1% Steroids are commonly divided into two classes, fluori Lidex (R) gel Fluocinonide 2 Medicis Pharmaceuticals nated and nonfluorinated. Fluorinated steroids have been 55 O.05% Corp. Lidex (R) cream Fluocinonide 2 Medicis Pharmaceuticals chemically modified to increase potency. These modifica O.05% Corp. tions, such as halogenation and methylation, can result in Lidex (R) Fluocinonide 2 Medicis Pharmaceuticals improved activity within the target cell and in decreased ointment 0.05% Corp. breakdown to inactive metabolites. These modifications can Maxiflor (R) Diflorasone 2 Allergan Herbert ointment 0.05% diacetate also lead to more systemic side effects. However, modifi 60 Topicort (R) DeSoximetasome 2 Medicis Pharmaceuticals cation of the chemical structure of the steroid is not the only cream 0.25% Corp. way to increase potency. Topicort (R) gel DeSoximetasome 2 Medicis Pharmaceuticals The potency of preparations is strongly O.05% Corp. Topicort (R) DeSoximetasome 2 Medicis Pharmaceuticals correlated to their absorption through the skin. Treatment of ointment 0.25% Corp. the skin prior to application of the topical steroid may also 65 Aristocort A (R) Triamcinolone 3 Fujisawa affect the absorption of the compounds into the skin. Treat ointment 0.1% acetonide ments with keratolytics or with fat solvents (such as acetone) US 7,220,424 B2 3 4 loneR cream or ointment of Schering and Class 1 Psorcon R TABLE 1-continued ointment of Dermik Laboratories, Inc. Corticosteroid Several factors such as the vehicle, the integrity of the Preparation Corticosteroid Class Source epidermal barrier, and the use of occlusive dressings affect the percutaneous absorption and resulting potency of corti Cultivate (R) Fluticasone 3 GlaxoWellcome ointment propionate costeroids regardless of the intrinsic potency of the gluco O.005% corticosteroid (or glucocorticoid) molecule. Further, inflam Cyclocort (R) Amcinonide 3 Fujisawa mation and/or other disease processes in the skin increase cream 0.1% Cyclocort (R) Amcinonide 3 Fujisawa 10 percutaneous absorption. Lotion 0.1% The vehicle in which the corticoid is incorporated may be Diprosone (R) Betamethasone 3 Schering Corp. cream O.O.5% dipropionate as important as the corticoid molecule itself in determining Florone (R) cream Diflorasone 3 Dermilk the potency of a given formulation because the vehicle O.05% diacetate affects the amount of corticoid that is released in any given Halog (R) Halcinonide 3 Westwood-Squibb 15 ointment 0.1% period of time, and its absorption. In many corticosteroid Lidex (R) E Fluocinonide 3 Medicis Pharmaceutical compositions, the vehicle is as much as 99% of the total cream O.O.5% Corp. composition. Very occlusive vehicles, such as ointments Maxiflor (R) Diflorasone 3 Allergan Herbert cream O.O.5% diacetate (water-insoluble mixtures of oil and petrolatum), increase Vallisone (R) Betamethasone 3 Schering Corp. the corticosteroid effect because they provide increased ointment 0.1% valerate hydration of the stratum corneum and increase the skin's Cordran (R) Furandrenolide 4 Oclassen permeability. By covering the skin with an occlusive dress ointment 0.05% Elocon (R) cream MometaSone 4 Schering Corp. ing Such as plastic wrap, this effect can be heightened as O.1% urOate much as 100-fold. The solubility of the corticoid in the Kenalog (R) Triameinolone 4 Westwood-Squibb vehicle also affects penetration into the skin. cream 0.1% acetonide 25 Synalar (R) Fluocinolone 4 Medicis Pharmaceuticals Creams, which are suspensions of oil in water, have also ointment acetonide Corp. been used as vehicles for corticosteroids. The compositions O.025% Westcort (R) Hydrocortisone 4 Westwood-Squibb of creams vary and are far less greasy than ointments but do ointment 0.2% valerate not provide the same degree of hydration to the skin, and Cordran (R) Furandrenolide 5 Oclassen 30 therefore may not have as high penetration as ointments. cream O.O.5% Cultivate (R) FluticaSone 5 GlaxoWellcome Lotions, which are suspensions of oil in water and are cream O.O.5% propionate similar to creams, are vehicles which include agents to help Diprosone (R) Betamethasone 5 Schering Corp. solubilize the corticosteroids. Solutions have been used as lotion 0.05% dipropionate vehicles and are water based with propylene glycol. Gels are Kenalog (R) Triamcinolone 5 Westwood-Squibb 35 lotion 0.1% acetonide Solid components at room temperature but melt on the skin. Locoid (R) cream Hydrocortisone 5 Ferndale Lotions, gels and solutions have less penetration than oint O.1% butyrate mentS. Synalar (R) cream Flucinolone 5 Medicis Pharmaceuticals O.025% acetonide Corp. Many vehicles for corticosteroids include propylene gly Vallisone (R) Betamethasone 5 Schering Corp. 40 col for dissolving the corticosteroid in the vehicle. In gen cream 0.1% valerate Westcort (R) Hydrocortisone 5 Westwood-Squibb eral, compositions that contain higher amounts of propylene cream 0.2% valerate glycol tend to be more potent. Aclovate (R) AlclometaSone 6 GlaxoWellcome Vehicles are so important in the potency of corticosteroids cream O.O.5% dipropionate Aclovate (R) AlclometaSone 6 GlaxoWellcome that different formulations containing the same amount of ointment 0.05% dipropionate 45 the same corticosteroid often are in different potency classes. Aristocort (R) Triamcinolone 6 Fujisawa For example, commercially available preparations of 0.05% cream 0.1% acetonide Desowen (R) Desonide 6 Galderma betamethasone dipropionate are classified as having Class 1. cream O.O.5% Class 2 or Class 3 potency, depending on their vehicles (as Synalar (R) Fluocinolone 6 Medicis Pharmaceuticals seen in Table 1). solution 0.01% acetonide Corp. 50 Synalar (R) cream Fluocinolone 6 Medicis Pharmaceuticals O.01% acetonide Corp. SUMMARY OF THE INVENTION Tridesilon (R) Desonide 6 Miles cream O.O.5% Vallisone (R) Betamethasone 6 Schering Corp. The present invention comprises a novel vehicle which is lotion 0.1% valerate 55 safe for topical application, stable, and provides increased Topicals with 7 potency for corticosteroid preparations, especially fluori hydrocortisone nated corticosteroids. dexamethasone, flumethasone, An embodiment of the present invention delivers the prednisolone, and corticosteroid in a vehicle that comprises a corticosteroid, 60 and (a) at least two penetration enhancers, including propy methylprednisolone lene glycol, dimethyl isosorbide or diuSopropyl adipate, (b) solvents and/or emulsifiers for the corticosteroid and option All percentages given are weight percentages unless oth ally the penetration enhancers and (c) optionally, non erwise noted. solvent/emulsifier ingredients. The vehicle has a ratio of Although there is no significant difference between poten 65 a:(a+b) that is greater than or equal to 0.70, preferably cies within Class 2, within Class 1 Temovate R cream or greater than or equal to 0.80 and most preferably greater ointment is significantly more potent than Class 1 Dipro than or equal to 0.90 or 0.95. US 7,220,424 B2 5 6 DETAILED DESCRIPTION OF THE Soap and water. Skin vasoconstrictor evaluations were per PREFERRED EMBODIMENTS formed on a four point scale (0–3) at approximately 18 hours after application. The present invention enhances the potency of corticos Scores for skin vasoconstriction were Summed for each teroid preparations with a vehicle comprising at least two composition (each composition was applied to thirty-six penetration enhancers, including diuSopropyl adipate, dim volunteers and those thirty-six scores were summed). For ethyl isosorbide, propylene glycol, 1.2.6-hexanetriol, and each composition tested, the ratio of penetration enhancers benzyl alcohol. The corticosteroids with which this inven (a) to the Sum of penetration enhancers, and solvents and tion may be used include, but are not limited to, fluorinated emulsifiers (a+b) was calculated (a:(a+b)). All of the com corticosteroids. 10 positions comprise 0.10% fluocinonide. Another embodiment of the present invention is a method for enhancing the potency of corticosteroids, preferably TABLE 2 fluorinated corticosteroids. The corticosteroid is combined Range of 1- O.94 O.89- O.79- O.69– O.S9 with two or more penetration enhancers (preferably propy a:(a + b) O.95 O.90 O.8O O.70 O.6O O.SO lene glycol and at least one other penetration enhancer), and 15 one or more solvents and emulsifiers for the corticosteroid Average of 93 85 71 72 62 58 Summed and optionally penetration enhancers, wherein the penetra Vasoconstrictor tion enhancers are present in ratio to the total of the Scores penetration enhancers, and solvents and emulsifiers of at least about 0.70, preferably at least 0.80 and most preferably *means there were no samples with the range of 0.59 to 0.55. 0.90 or 0.95. Optionally, one or more inactive ingredients As seen in the above table, the average vasoconstrictor may also be combined with the corticosteroid. scores are significantly lower for ranges of a:(a+b)-0.70. Another embodiment of the present invention is a method The corticosteroid preparations with average vasoconstrictor of delivering corticosteroids to skin, nails or hair, preferably scores of 58 and 62 are significantly less potent than those mammalian skin, most preferably human, dog or cat skin. 25 preparations with average vasoconstrictor scores of 72 and The corticosteroids are preferably fluorinated corticoster higher. Scores of 62 and 58 are not significantly different. oids. The corticosteroid is combined with two or more This magnitude of increase in vasoconstrictor scores is penetration enhancers, and one or more solvents and emul typical of an increase in class. sifiers for the corticosteroid, wherein the penetration 30 Several control compositions (with 0.10% fluocinonide enhancers are present in ratio to the total of the penetration and no penetration enhancers, as defined below, were enhancers, and solvents and emulsifiers of at least about 0.70, preferably at least 0.85 and most preferably 0.90 or included) were also tested for their vasoconstrictor scores in 0.95. Optionally, one or more inactive ingredients may also the same manner. Therefore, the ratios of a:(a+b) are Zero. be combined with the corticosteroid. The vasoconstrictor scores are 60.00 and 59.00, which are 35 significantly lower than the present invention’s embodi As indicated above, this invention is broadly applicable to ments’ vasoconstrictor scores. corticosteroids in general, and fluorinated corticosteroids in Additionally, several other control compositions were particular, most preferably fluocinonide or fluocinolone tested for their vasoconstrictor scores (“vasoscores'). These acetonide. The following examples show its application to compositions comprised 0.10% fluocinonide, and no diiso preparations of fluocinonide, a commonly used fluorinated 40 proyl adipate, propylene glycol or dimethyl isosorbide. corticosteroid. Fluocinonide is a corticosteroid which is the Their vasoscores were 49.00, 47.00 and 44.00. 21-acetate ester of fluocinolone acetonide with the chemical The experiments also included several Class 1 composi name pregna-1,4-diene-320-dione.21-(acetyloxy)-6.9-dif tions as comparison points. luoro-11-hydroxy-16, 17-(1-methylethylidene)bis(oxy)- Psorcon R ointment by Dermik Laboratories, Inc. of Col (6C, 11B, 16C.)-. 45 legeville, Pa. with 0.05% had a vasos Compositions containing 0.05% (all percentages are core of 101. UltravateR ointment by Westwood-Squibb of weight percentages) fluocinonide are commonly classified Evansville, Ind. with 0.05% halobetasol propionate had a as Class 2. vasoscore of 97, while UltravateR) cream by Westwood Squibb with 0.05% halobetasol propionate had a vasoscore EXAMPLE 1. 50 of 92. In the ratio of (a): (a+b), penetration enhancers include at Experiments were conducted with embodiments of the least two of propylene glycol, diisopropyl adipate, dimethyl present invention and several control compositions. Com isosorbide, 1.2.6 hexanetriol, and benzyl alcohol (collec positions were prepared and the investigator was blinded tively referred to as “a”). The solvents and emulsifiers for the with respect to the compositions. Thirty-six healthy volun 55 corticosteroid include one or more of dehydrated alcohol, teers were enrolled for two-day trials. On day 1, a single alcohol (95% V/v) USP 3-Cyclohexene-1-Methanol, application of approximately 10 milligrams of at least eight OC4-Dimethyl-a-(4-Methyl-3-Pentenyl)-, Steareth-2, Ste compositions was made to 1 cm sites on the lower aspect of areth-21, citric acid, CPE-215, diisopropanolamine (1:9), each volunteers forearms in accordance with a computer DIPA/PG (1:9), ethoxydiglycol, Potassium hydroxide generated randomization code. After applying the composi 60 (10%), PEG-40 Stearate, PEG-7000, Polysorbate 60, potas tions, the sites were protected using a raised perforated sium hydroxide (1%), propylene carbonate USP propyleth guard. The guard was secured to the arm with a non ylene glycol 4, oleyl alcohol, Sodium lauryl Sulfate, Sorbitan occlusive tape and the subjects were scheduled to return the monostearate, Sorbitan Stearate, and 1.2.3-Propanetriol Ester following day after being instructed to keep the sites dry. (collectively referred to as “b'). After approximately 16 hours of contact with the skin, the 65 The compositions optionally comprise non-solvent/emul protective guards were removed and the compositions were sifier ingredients, such as Glyceryl Stearate (and) PEG-100 removed from the test sites by gently washing with mild Stearate, carbopol 980, cyclomethicone NF, glyceryl US 7,220,424 B2 7 8 monostearate, hydroxyethyl cellulose, hydroxypropyl cellu defined by the scope of the appended claims. Other aspects, lose, isopropyl myristate, methyl paraben NF, mineral oil, advantages, and modifications are evident from a review of oleic acid NF, PEG-100 Stearate, petrolatum, propyl paraben the following claims. NF, purified water, stearyl alcohol, white petrolatum, and white wax. What is claimed is: The combination of penetration enhancers used in the invention have a remarkable and unexpected result. Com 1. A method of delivering corticosteroids to skin com pounds using similar concentrations of a single penetration prising: enhancer (e.g. propylene glycol as the sole penetration Topically applying a composition comprising one or more enhancer with 0.10% fluocinonide yielded vasoscores of 10 corticosteroids with two or more penetration enhancers, 72.00, and 50.00, depending on the solvents, emulsifiers and and one or more of the group consisting of solvents and non-solvent/emulsifier ingredients used) do not have simi emulsifiers, wherein the penetration enhancers are larly high Vaso scores. Compositions with the combination present in ratio to a total of the penetration enhancers, of penetration enhancers and formula scores of less than and solvents and emulsifiers of at least about 0.90, and 0.65 also have low vaso scores. Therefore the invention 15 wherein the penetration enhancers comprise two or results in an unexpected increase in potency of the fluoci more of the group consisting of propylene glycol, nonide. diisopropyl adipate, dimethyl isosorbide, 1.2.6 hexan etriol, and benzyl alcohol. EXAMPLE 2 2. A method of delivering corticosteroids to skin, com prising: One embodiment of the present invention is detailed in Topically applying a composition comprising one or more the chart below. corticosteroids with two or more penetration enhancers, and one or more of the group consisting of solvents and emulsifiers, wherein the penetration enhancers are TABLE 3 25 present in ratio to a total of the penetration enhancers, Component % Wiw % Wiw and solvents and emulsifiers of at least about 0.90, and Fluocinonide Micronized, O.1 O.1 wherein the penetration enhancers comprise two or USP more of the group consisting of propylene glycol, Propylene Glycol, USP 7O.O 74.9 diisopropyl adipate and dimethyl isosorbide. Dimethyl isosorbide 1S.O 30 Diisopropyl Adipate 3.0 3. A method of delivering corticosteroids to skin, com Isopropyl Myristate, NF 5.0 prising: 1.2.6 Trihydroxyhexane 2.5 Topically applying a composition compXisina one or more Carbopol. 980 1.2 1.O Diisopropanolamine 85%: 1.2 1.O corticosteroids with two or more penetration enhancers, propylene glycol (1:9) 35 and one or more of the group consisting of solvents and Citric Acid, USP O.O1 O.O1 emulsifiers, wherein the penetration enhancers are Purified Water, USP 2.49 2.49 present in ratio to a total of the penetration enhancers, Glyceryl monostearate 2.5 2.5 and solvents and emulsifiers of at least about 0.90, and Glyceryl monostearate & 7.5 7.5 PEG Stearate wherein one penetration enhancer comprises propylene 40 glycol. 4. The method of claim 1, wherein the corticosteroid comprises a fluorinated corticosteroid. EXAMPLE 3 5. The method of claim 1, wherein the corticosteroid comprises fluocinonide. Another embodiment of the present invention is detailed 45 6. The method of claim 1, wherein the corticosteroid in the chart below. comprises fluocinolone acetonide. 7. The method of claim 4, 5, 6, or 1, wherein the TABLE 4 corticosteroid is present at about 0.10%. Component % Wiw % Wiw 50 8. The method of claim 4, 5, 6 or 1, wherein the corti Fluocinonide Micronized, O.1 O.1 costeroid is present at at least about 0.50%. USP 9. The method of claim 4, 5, 6, or 1, wherein the Propylene Glycol, USP 66.8 69.9 corticosteroid is present at at least about 0.25%. Dimethyl isosorbide S.O Diisopropyl Adipate 2.0 10. The method of claim 1, 2, or 3, wherein the solvents Isopropyl Myristate, NF S.O S.O 55 and emulsifiers comprise one or more of the group consist Carbopol. 980 O.S O.S ing of dehydrated alcohol, alcohol (95% V/v)USP, 3-Cyclo Diisopropanolamine 85%: O.S O.S hexene-1-Methanol, 4-Dimethyl-a-(4-Methyl-3-Pentenyl)- propylene glycol (1:9) White Petrolatum, USP S.O S.O Steareth-2, Steareth-21, citric acid, CPE-215, diisopropano Glyceryl monostearate 6.O 6.O lamine (1:9), DIPA/PG (1:9), ethoxydiglycol, Potassium PEG 100 Stearate 6.O 6.O 60 hydroxide (10%), PEG-40 Stearate, PEG-7000, Polysorbate Stearyl alcohol, NF S.O S.O 60, potassium hydroxide (1%), propylene carbonate USP Sodium Lauryl Sulfate, NF O.1 propylethylene glycol 4, oleyl alcohol, Sodium lauryl Sul fate, Sorbitan monostearate, Sorbitan Stearate, and 1.2.3- It is to be understood that while the invention has been Propanetriyl Ester. described in conjunction with the detailed description 65 11. The method of claim 1, 2, or 3, wherein the compo thereof, that the foregoing description is intended to illus sition further comprises one or more non-solvent/emulsifier trate and not limit the scope of the invention, which is ingredients. US 7,220,424 B2 9 10 12. The method of claim 11 wherein the non-solvent/ 14. The method of claim 12 wherein the non-solvent/ emulsifier ingredients comprise one or more of the group emulsifier ingredients are present at about 11% to about consisting of Glyceryl Stearate (and) PEG-100 Stearate, 53%. carbopol 980, cyclomethicone NP glyceryl monostearate, 15. The method of claim 12 wherein the non-solvent/ hydroxyethyl cellulose, hydroxypropyl cellulose, isopropyl 5 emulsifier ingredients are present at about 11% to about myristate, methyl paraben NF, mineral oil, oleic acid NF, 27%. PEG-100 Stearate, petrolatum, propyl paraben NF, purified water, Stearyl alcohol, white petrolatum, and white wax. 13. The method of claim 1, 2, or 3, wherein the solvents and emulsifiers are present at about 4-5%. k . . . . UNITED STATES PATENT AND TRADEMARK OFFICE CERTIFICATE OF CORRECTION

PATENT NO. : 7.220,424 B2 Page 1 of 1 APPLICATIONNO. : 10/407380 DATED : May 22, 2007 INVENTOR(S) : Eugene H. Gans and Mitchell S. Wortzman It is certified that error appears in the above-identified patent and that said Letters Patent is hereby corrected as shown below:

Col. 8, Claim 3, line 32, “compxisina should read --comprising--. Col. 9, Claim 12, line 4, “cyclomethicone NP should read -cyclomethicone NF--.

Signed and Sealed this Tenth Day of July, 2007 WDJ

JON. W. DUDAS Director of the United States Patent and Trademark Office