CA2471041C - Compositions and methods for enhancing corticosteriod delivery - Google Patents

Compositions and methods for enhancing corticosteriod delivery Download PDF

Info

Publication number
CA2471041C
CA2471041C CA2471041A CA2471041A CA2471041C CA 2471041 C CA2471041 C CA 2471041C CA 2471041 A CA2471041 A CA 2471041A CA 2471041 A CA2471041 A CA 2471041A CA 2471041 C CA2471041 C CA 2471041C
Authority
CA
Canada
Prior art keywords
composition
present
corticosteroid
solvents
emulsifiers
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
CA2471041A
Other languages
French (fr)
Other versions
CA2471041A1 (en
Inventor
Eugene H. Gans
Mitchell S. Wortzman
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Medicis Pharmaceutical Corp
Original Assignee
Medicis Pharmaceutical Corp
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=21893928&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=CA2471041(C) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Application filed by Medicis Pharmaceutical Corp filed Critical Medicis Pharmaceutical Corp
Publication of CA2471041A1 publication Critical patent/CA2471041A1/en
Application granted granted Critical
Publication of CA2471041C publication Critical patent/CA2471041C/en
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/0012Galenical forms characterised by the site of application
    • A61K9/0014Skin, i.e. galenical aspects of topical compositions
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/56Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/56Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A61K31/573Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/56Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/58Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00Drugs for dermatological disorders
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00Drugs for dermatological disorders
    • A61P17/04Antipruritics
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00Drugs for disorders of the cardiovascular system
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/20Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/22Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • GPHYSICS
    • G11INFORMATION STORAGE
    • G11CSTATIC STORES
    • G11C16/00Erasable programmable read-only memories
    • G11C16/02Erasable programmable read-only memories electrically programmable
    • G11C16/04Erasable programmable read-only memories electrically programmable using variable threshold transistors, e.g. FAMOS
    • G11C16/0408Erasable programmable read-only memories electrically programmable using variable threshold transistors, e.g. FAMOS comprising cells containing floating gate transistors
    • G11C16/0433Erasable programmable read-only memories electrically programmable using variable threshold transistors, e.g. FAMOS comprising cells containing floating gate transistors comprising cells containing a single floating gate transistor and one or more separate select transistors
    • GPHYSICS
    • G11INFORMATION STORAGE
    • G11CSTATIC STORES
    • G11C2216/00Indexing scheme relating to G11C16/00 and subgroups, for features not directly covered by these groups
    • G11C2216/02Structural aspects of erasable programmable read-only memories
    • G11C2216/10Floating gate memory cells with a single polysilicon layer

Abstract

The present invention comprises a composition, method of enhancing potency and method of delivering corticosteroids in a vehicle comprising at least two penetration enhancers, and solvents and emulsifiers. The propylene glycol and penetration enhancers are present in ratio to the total of the propylene glycol, penetration enhancers, and solvents and emulsifiers of at least about 0.70.

Description

COMPOSITIONS AND METHODS FOR
ENHANCING CORTICOSTEROID DELIVERY
Field of the Invention [1] Topical corticosteroids are useful for their anti-inflammatory, anti-pruritic and vasoconstrictive actions. Corticosteroids (or corticoids) are any steroids (lipids that contain a hydrogenated cyclopentoperhydrophenanthrene ring system) elaborated by the adrenal cortex (except sex hormones of adrenal origin) in response to the release of adrenocorticotrophin or adrenocorticotropic hormone by the pituitary gland, or to any synthetic equivalent, or to angiotensin II. Corticosteroids include but are not limited to alclometasone dipropionate, amcinonide, amcinafel, amcinafide, beclamethasone, betamethasone, betamethasone dipropionate, betamethasone valerate, clobetasone propionate, chloroprednisone, clocortelone, cortisol, cortisone, cortodoxone, difluorosone diacetate, descinolone, desonide, defluprednate, dihydroxycortisone, desoximetasone, dexamethasone, deflazacort, diflorasone diacetate, dichlorisone, esters of betamethasone, flucetonide, flucloronide, fluorocortisone, flumethasone, flunisolide, fluocinonide, fluocinolone acetonide, flucortolone, fluperolone, fluprednisolone, fluroandrenolone acetonide, fluocinolone acetonide, flurandrenolide, fluorametholone, fluticasone propionate, hydrocortisone, hydrocortisone butyrate, hydrocortisone valerate, hydrocortamate, medrysone, meprednisone, methylprednisone, methylprednisolone, mometasone furoate, paramethasone, prednisone, prednisolone, prednidone, triamcinolone acetonide, and triamcinolone.

[21 Hydrocortisone was the first corticosteroid found to be topically effective. Other more potent glucocorticoids, which are a subset of corticosteroids that affect carbohydrate metabolism, inhibit corticotropin secretion, and possess pronounced anti-inflammatory activity, have since been developed. Currently, topical steroids are among the most frequently prescribed of all dermatological drug products.

[3] It is believed that glucocorticoids exert their potent anti-inflammatory effects by inhibiting the formation of prostaglandins and other derivatives of the arachidonic acid pathway. It is known that glucocorticoids inhibit the release of phospholipase A2, the enzyme responsible for liberating arachidonic acid from cell membranes, thus inhibiting the arachidonic acid pathway. Currently, it is believed that glucocorticoids -inhibit phospholipase A2, in cells by directly inducing phosphorylation of the enzyme.
[41 Steroids are commonly divided into two classes, fluorinated and nonfluorinated.
Fluorinated steroids have been chemically modified to increase potency. These modifications, such as halogenation and methylation, can result in improved activity within the target cell and in decreased breakdown to inactive metabolites.
These modifications can also lead to more systemic side effects. However, modification of the chemical structure of the steroid is not the only way to increase potency.

151 The potency of topical steroid preparations is strongly correlated to their absorption through the skin. Treatment of the skin prior to application of the topical steroid may also affect the absorption of the compounds into the skin. Treatments with keratolytics or with fat solvents (such as acetone) disrupt the epidermal barrier and increase penetration. Hydrating the skin has also been shown to increase the penetration of the corticosteroids.

[6] Once absorbed through the skin, topical corticosteroids are handled through pharmacokinetic pathways similar to systemically administered corticosteroids.
The potencies of corticosteroids vary greatly and it is a challenge to increase the potency of any particular steroid.

Background of the Invention [7] The clinical effectiveness of corticoids is related to four basic properties:
vasoconstriction, antiproliferative effects, immunosuppression, and anti-inflammatory effects. Topical steroids cause the capillaries in the superficial dermis to constrict, thus reducing erythema. The ability of a given glucocorticoid agent to cause vasoconstriction usually correlates with its anti-inflammatory potency.
Vasoconstrictor assays are used in the art and by the U.S. Food and Drug Administration for determining the potency of topical corticosteroid preparations. Topical glucocorticoid preparations have been divided in the field into seven classes based on potency based on double-blind clinical studies and vasoconstrictor assays. Class 1 includes the most potent, while class 7 contains the least potent.

[81 The following glucocorticoid preparations were designated in Fitzpatrick, Dermatology in General Medicine, 5th edition, CD-ROM, 1999, Table 243-1, with the following classes.

[91 Table 1 Corticosteroid Corticosteroid Class Source Preparation Temovate Cream Clobetasone propionate 1 Glaxo Wellcome 0.05%

Temovate ointment Clobetasone propionate 1 Glaxo Wellcome 0.05%

Diprolene cream Betamethasone 1 Schering Corp.
0.05% dipropionate Diprolene ointment Betamethasone 1 Schering Corp.
0.05% dipropionate Psorcon ointment Diflorasone diacetate 1 Dermik Laboratories, Inc.
Cyclocort ointment Amcinonide 2 Fujisawa 0.1%
Diprolene cream AF Betamethasone 2 Schering Corp.
0.05% dipropionate Diprolone ointment Betamethasone 2 Schering Corp.
0.05% dipropionate ' Elocon ointment 0.1% Mometasone furoate 2 Schering Corp.
Florone ointment Diflorasone diacetate 2 Dermik 0.05%
Halog cream 0.1% Halcinonide 2 Westwood-Squibb Lidex gel 0.05% Fluocinonide 2 Medicis Pharmaceuticals Corp.
Lidex cream 0.05% Fluocinonide 2 Medicis Pharmaceuticals Corp.
Lidex ointment 0.05% Fluocinonide 2 Medicis Pharmaceuticals Corp.
Maxiflor ointment Diflorasone diacetate 2 Allergan Herbert 0.05%
Topicort cream 0.25% Desoximetasone 2 Medicis Pharmaceuticals Corp.
Topicort gel 0.05% Desoximetasone 2 Medicis Phannaceuticals Corp.
Topicort ointment Desoximetasone 2 Medicis Pharmaceuticals Corp.
0.25%

Aristocort A ointment Triamcinolone 3 Fujisawa 0.1% acetonide Cutivate ointment Fluticasone propionate 3 Glaxo Wellcome 0.005%

Cyclocort cream 0.1% Amcinonide 3 Fujisawa Cyclocort Lotion 0.1% Amcinonide 3 Fujisawa Diprosone cream Betamethasone 3 Schering Corp.
0.05% dipropionate Florone cream 0.05% Diflorasone diacetate 3 Dennik Halog ointment 0.1% Halcinonide 3 Westwood-Squibb Lidex E cream 0.05% Fluocinonide 3 Medicis Pharmaceutical Corp.
Maxiflor cream 0.05% Diflorasone diacetate 3 Allergan Herbert Valisone ointment Betamethasone valerate 3 Schering Corp.
0.1%

Cordran ointment Flurandrenolide 4 Oclassen 0.05%

Elocon cream 0.1% Mometasone furoate 4 Schering Corp.
Kenalog cream 0.1% Triamcinolone 4 Westwood-Squibb acetonide Synalar ointment Fluocinolone acetonide 4 Medicis Pharmaceuticals Corp.
0.025%
Westcort ointment Hydrocortisone 4 Westwood-Squibb 0.2% valerate Cordran cream 0.05% Flurandrenolide 5 Oclassen Cutivate cream 0.05% Fluticasone propionate 5 Glaxo Wellcome Diprosone lotion Betamethasone 5 Schering Corp.
0.05% dipropionate Kenalog lotion 0.1% Triamcinolone 5 Westwood-Squibb acetonide Locoid cream 0.1% Hydrocortisone 5 Ferndale butyrate Synalar cream 0.025% Flucinolone acetonide 5 Medicis Pharmaceuticals Corp.
Valisone cream 0.1% Betamethasone valerate 5 Schering Corp.

Westcort cream 0.2% Hydrocortisone 5 Westwood-Squibb valerate Aclovate cream 0.05% Alclometasone 6 Glaxo Wellcome dipropionate Aclovate ointment Alclometasone 6 Glaxo Wellcome 0.05% dipropionate Aristocort cream 0.1% Triamcinolone 6 Fujisawa acetonide Desowen cream 0.05% Desonide 6 Galderma Synalar solution Fluocinolone acetonide 6 Medicis Pharmaceuticals Corp.
0.01%

Synalar cream 0.01% Fluocinolone acetonide 6 Medicis Pharmaceuticals Corp.
Tridesilon cream Desonide 6 Miles 0.05%
Valisone lotion 0.1% Betamethasone valerate 6 Schering Corp.
Topicals with 7 hydrocortisone dexamethasone, flumethasone, prednisolone, and methylprednisolone [101 All percentages given are weight percentages unless otherwise noted.

[III Although there is no significant difference between potencies within Class 2, within Class 1 Temovate cream or ointment is significantly more potent than Class 1 Diprolone cream or ointment of Schering and Class I Psorcon ointment of Dermik Laboratories, Inc.

[121 Several factors such as the vehicle, the integrity of the epidermal barrier, and the use of occlusive dressings affect the percutaneous absorption and resulting potency of corticosteroids regardless of the intrinsic potency of the glucocorticosteroid (or glucocorticoid) molecule. Further, inflammation and/or other disease processes in the skin increase percutaneous absorption.

[131 The vehicle in which the corticoid is incorporated may be as important as the corticoid molecule itself in determining the potency of a given formulation because the vehicle affects the amount of corticoid that is released in any given period of time, and its absorption. In many corticosteroid compositions, the vehicle is as much as 99%
of the total composition. Very occlusive vehicles, such as ointments (water-insoluble mixtures of oil and petrolatum), increase the corticosteroid effect because they provide increased hydration of the stratum corneum and increase the skin's permeability. By covering the skin with an occlusive dressing such as plastic wrap, this effect can be heightened as much as 100-fold. The solubility of the corticoid in the vehicle also affects penetration into the skin.

[141 Creams, which are suspensions of oil in water, have also been used as vehicles for corticosteroids. The compositions of creams vary and are far less greasy than ointments but do not provide the same degree of hydration to the skin, and therefore may not have as high penetration as ointments. Lotions, which are suspensions of oil in water and are similar to creams, are vehicles which include agents to help solubilize the corticosteroids. Solutions have been used as vehicles and are water based with propylene glycol. Gels are solid components at room temperature but melt on the skin.
Lotions, gels and solutions have less penetration than ointments.

[151 Many vehicles for corticosteroids include propylene glycol for dissolving the corticosteroid in the vehicle. In general, compositions that contain higher amounts of propylene glycol tend to be more potent.

[161 Vehicles are so important in the potency of corticosteroids that different formulations containing the same amount of the same corticosteroid often are in different potency classes. For example, commercially available preparations of 0.05%
betamethasone dipropionate are classified as having Class 1, Class 2 or Class 3 potency, depending on their vehicles (as seen in Table 1).

Summary of the Invention [171 The present invention comprises a novel vehicle which is safe for topical application, stable, and provides increased potency for corticosteroid preparations, especially fluorinated corticosteroids.

[181 An embodiment of the present invention delivers the corticosteroid in a vehicle that comprises a corticosteroid, and (a) at least two penetration enhancers, including propylene glycol, dimethyl isosorbide or diisopropyl adipate, (b) solvents and/or emulsifiers for the corticosteroid and optionally the penetration enhancers and (c) optionally, non-solvent/emulsifier ingredients. The vehicle has a ratio of a:(a+b) that is greater than or equal to 0.70, preferably greater than or equal to 0.80 and most preferably greater than or equal to 0.90 or 0.95.

Detailed Description of the Preferred Embodiments [191 The present invention enhances the potency of corticosteroid preparations with a vehicle comprising at least two penetration enhancers, including diisopropyl adipate, dimethyl isosorbide, propylene glycol, 1,2,6-hexanetriol, and benzyl alcohol. The corticosteroids with which this invention may be used include, but are not limited to, fluorinated corticosteroids.

[20) Another embodiment of the present invention is a method for enhancing the potency of corticosteroids, preferably fluorinated corticosteroids. The corticosteroid is combined with two or more penetration enhancers (preferably propylene glycol and at least one other penetration enhancer), and one or more solvents and emulsifiers for the corticosteroid and optionally penetration enhancers, wherein the penetration enhancers are present in ratio to the total of the penetration enhancers, and solvents and emulsifiers of at least about 0.70, preferably at least 0.80 and most preferably 0.90 or 0.95.
Optionally, one or more inactive ingredients may also be combined with the corticosteroid.

[21] Another embodiment of the present invention is a method of delivering corticosteroids to skin, nails or hair, preferably mammalian skin, most preferably human, dog or cat skin. The corticosteroids are preferably fluorinated corticosteroids. The corticosteroid is combined with two or more penetration enhancers, and one or more solvents and emulsifiers for the corticosteroid, wherein the penetration enhancers are present in ratio to the total of the penetration enhancers, and solvents and emulsifiers of at least about 0.70, preferably at least 0.85 and most preferably 0.90 or 0.95. Optionally, one or more inactive ingredients may also be combined with the corticosteroid.

[221 As indicated above, this invention is broadly applicable to corticosteroids in general, and fluorinated corticosteroids in particular, most preferably fluocinonide or fluocinolone acetonide. The following examples show its application to preparations of fluocinonide, a commonly used fluorinated corticosteroid. Fluocinonide is a corticosteroid which is the 21-acetate ester of fluocinolone acetonide with the chemical name pregna-1,4-diene-3,20-dione,2 1 -(acetyloxy)-6,9-difluoro- 11 -hydroxy- 16, 17-[(1-methylethylidene)bis(oxy)]-,(6a,11(3, 16a)-. Compositions containing 0.05%
(all percentages are weight percentages) fluocinonide are commonly classified as Class 2.
Example 1 [23] Experiments were conducted with embodiments of the present invention and several control compositions. Compositions were prepared and the investigator was blinded with respect to the compositions. Thirty-six healthy volunteers were enrolled for two-day trials. On day 1, a single application of approximately 10 milligrams of at least eight compositions was made to 1 cm2 sites on the lower aspect of each volunteer's forearms in accordance with a computer generated randomization code. After applying the compositions, the sites were protected using a raised perforated guard.
The guard was secured to the arm with a non-occlusive tape and the subjects were scheduled to return the following day after being instructed to keep the sites dry.

[241 After approximately 16 hours of contact with the skin, the protective guards were removed and the compositions were removed from the test sites by gently washing with 1%O 031055-145 PCT/US02/39882 mild soap and water. Skin vasoconstrictor evaluations were performed on a four point scale (0-3) at approximately 1$ hours after application.

[251 Scores for skin vasoconstriction were sununed for each composition (each composition was applied to thirty-six volunteers and those thirty-six scores were sturimed). For each composition tested, the ratio of penetration enhancers (a) to the stud of penetration enhancers, and solvents and emulsifiers (ai b) was calculated (a:(a+b)). All of the compositions comprise 0,10% fluocinonide.

[26] Tablet Range of 1- 0.94- 0.89- 0.79- 0.69- 0.59-a.(a+b) 0.95 0.90 0.80 0.70 0.60 0.50 Average of 93 85 71 72 62 58 Summed Vasoconstrictor Scores _. __.
-------[27] ' means there were no samples with the range of 0.59 to 0.55.

[28] As seen in the above table, the average vasoconstrictor scores are significantly lower for ranges of a:(a+b)<0.70. The corticosteroid preparations with average vasoconstrictor scores of 58 and 62 are significantly less potent than those preparations with average vasoconstrictor scores of 72 and higher. Scores of 62 and 58 are not significantly different. This magnitude of increase in vasoconstrictor scores is typical of an increase in class.

[29] Several control compositions (with 0.10% fhtocinonide and no penetration enhancers, as defined below, were included) were also tested for their vasoconstrictor scores in the same manner. Therefore, the ratios of a:(a+b) are zero. The vasoconstrictor scores are 60.00 and 59.00, which are significantly lower than the present invention's embodiments' vasoconstrictor scores.

[301 Additionally, several other control compositions were tested for their vasoconstrictor scores ("vasoscores"). These compositions comprised 0.10% fluocinonide, and no diisoproyl adipate, propylene glycol or dunetbyl isosorbide. Their vasoscores were 49.00, 47.00 and 44.00.

[31] The experiments also included several Class 1 compositions as comparison points.
Psorcon ointment by Dermik Laboratories, Inc. of Collegeville, PA with 0.05%
diflorasone diacetate had a vasoscore of 101. Ultravate ointment by Westwood-Squibb of Evansville, IN with 0.05% halobetasol propionate had a vasoscore of 97, while Ultravate cream by Westwood-Squibb with 0.05% halobetasol propionate had a vasoscore of 92.

[321 In the ratio of (a): (a+b), penetration enhancers include at least two of. propylene glycol, diisopropyl adipate, dimethyl isosorbide, 1,2,6 hexanetriol, and benzyl alcohol (collectively referred to as "a"). The solvents and emulsifiers for the corticosteroid include one or more of dehydrated alcohol, alcohol (95% v/v) USP, 3-Cyclohexene-l-Methanol, oc4-Dimethyl-a-(4-Methyl-3-Pentenyl)-, Steareth-2, Steareth-21, citric acid, CPE-215, diisopropanolamine (1:9), DIPA/PG (1:9), ethoxydiglycol, Potassium hydroxide (10%), PEG-40 Stearate, PEG-7000, Polysorbate 60, potassium hydroxide (1%), propylene carbonate USP, propylethylene glycol 4, oleyl alcohol, sodium lauryl sulfate, sorbitan monostearate, sorbitan stearate, and 1,2,3-Propanetriol Ester (collectively referred to as "b").

[331 The compositions optionally comprise non-solvent/emulsifier ingredients, such as Glyceryl Stearate (and) PEG-100 Stearate, carbopol 980, cyclomethicone NF, glyceryl monostearate, hydroxyethyl cellulose, hydroxypropyl cellulose, isopropyl myristate, methyl paraben NF, mineral oil, oleic acid NF, PEG-100 Stearate, petrolatum, propyl paraben NF, purified water, stearyl alcohol, white petrolatum, and white wax.

[34] The combination of penetration enhancers used in the invention have a remarkable and unexpected result. Compounds using similar concentrations of a single penetration enhancer (e.g. propylene glycol as the sole penetration enhancer with 0.10%
fluocinonide yielded vasoscores of 72.00, and 50.00, depending on the solvents, emulsifiers and non-solvent/emulsifier ingredients used) do not have similarly high vaso scores. Compositions with the combination of penetration enhancers and formula scores of less than 0.65 also have low vaso scores. Therefore the invention results in an unexpected increase in potency of the fluocinonide.

Example 2 [351 One embodiment of the present invention is detailed in the chart below.
[361 Table 3 Component %w/w %w/w Fluocinonide 0.1 0.1 Micronized, USP

Propylene Glycol, 70.0 74.9 USP

Dimethyl isosorbide 15.0 Diisopropyl Adipate 3.0 Isopropyl Myristate, 5.0 NF

1,2,6 2.5 Trihydroxyhexane Carbopol 980 1.2 1.0 Diisopropanolamine 1.2 1.0 85%: propylene glycol (1:9) Citric Acid, USP 0.01 0.01 Purified Water, USP 2.49 2.49 Glyceryl 2.5 2.5 monostearate Glyceryl 7.5 7.5 monostearate & PEG

stearate Example 3 [371 Another embodiment of the present invention is detailed in the chart below.
[3 81 Table 4 Component %w/w %w/w Fluocinonide 0.1 0.1 Micronized, USP

Propylene Glycol, 66.8 69.9 USP

Dimethyl isosorbide 5.0 Diisopropyl Adipate 2.0 Isopropyl Myristate, 5.0 5.0 NF

Carbopol 980 0.5 0.5 Diisopropanolamine 0.5 0.5 85%: propylene glycol (1:9) White Petrolatum, 5.0 5.0 USP

Glyceryl 6.0 6.0 monostearate PEG 100 stearate 6.0 6.0 Stearyl alcohol, NF 5.0 5.0 Sodium Lauryl 0.1 Sulfate, NF

[391 It is to be understood that while the invention has been described in conjunction with the detailed description thereof, that the foregoing description is intended to illustrate and not limit the scope of the invention, which is defined by the scope of the appended claims. Other aspects, advantages, and modifications are evident from a review of the following claims.

Claims

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE PROPERTY
OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A composition comprising one or more corticosteroids;
two or more penetration enhancers; and one or more of the group consisting of solvents and emulsifiers, wherein the penetration enhancers are present in a ratio to a total of the penetration enhancers, and solvents and emulsifiers of at least about 0.90, and wherein the penetration enhancers comprise two or more of the group consisting of propylene glycol, diisopropyl adipate, dimethyl isosorbide, 1,2,6 hexanetriol, and benzyl alcohol and wherein said composition does not include a monoglyceride of a C6-C10 medium chain fatty acid.

2. The composition of claim 1 wherein the corticosteroid comprises a fluorinated corticosteroid.

3. The composition of claim 1 wherein the corticosteroid comprises fluocinonide.
4. The composition of claim 1 wherein the corticosteroid comprises fluocinolone acetonide.

5. The composition of any one of claims 1, 2, 3 or 4 wherein the corticosteroid is present at about 0.10%.

6. The composition of any one of claims 1, 2, 3 or 4 wherein the corticosteroid is present at at least about 0.50%.

7. The composition of any one of claims 1, 2, 3 or 4 wherein the corticosteroid is present at at least about 0.25%.

8. The composition of any one of claims 1, 2, 3 or 4 wherein the penetration enhancers comprise two or more of the group consisting of propylene glycol, diisopropyl adipate and dimethyl isosorbide.

9. The composition of any one of claims 1, 2, 3, or 4 wherein one penetration enhancer comprises propylene glycol.

10. The composition of claim 1 wherein the ratio is at least about 0.95.

11. The composition of claim 1 wherein the solvents and emulsifiers comprise one or more of the group consisting of dehydrated alcohol, alcohol (95% v/v)USP, 3-Cyclohexene-1-Methanol, oc4-Dimethyl-a-(4-Methyl-3-Pentenyl)-, Steareth-2, Steareth-21, citric acid, CPE-215, diisopropanolamine (1:9), DIPA/PG (1:9), ethoxydiglycol, Potassium hydroxide (10%), PEG-40 Stearate, PEG-7000, Polysorbate 60, potassium hydroxide (1%), propylene carbonate USP, propylethylene glycol 4, oleyl alcohol, sodium lauryl sulfate, sorbitan monostearate, sorbitan stearate, and 1,2,3-Propanetriyl Ester.

12. The composition of claim 1 further comprising one or more non-solvent/emulsifier ingredients.

13. The composition of claim 12 wherein the non-solvent/emulsifier ingredients comprise one or more of the group consisting of Glyceryl Stearate (and) PEG-100 Stearate, carbopol 980, cyclomethicone NF, glyceryl monostearate, hydroxyethyl cellulose, hydroxypropyl cellulose, isopropyl myristate, methyl paraben NF, mineral oil, oleic acid NF, PEG-100 Stearate, petrolatum, propyl paraben NF, purified water, stearyl alcohol, white petrolatum, and white wax.

14. The composition of claim I wherein the solvents and emulsifiers are present at about 4-5%.

15. The composition of claim 12 wherein the non-solvent/emulsifier ingredients are present at about 11% to about 53%.

16. The composition of claim 12 wherein the non-solvent/emulsifier ingredients are present at about 11% to about 27%.

17. A composition comprising about 0.10% fluocinonide, about 74.9% propylene glycol, about 3.0% diisopropyl adipate, about 5.0% isopropyl myristate, about 2.5%
1,2,6 trihydroxyhexane, about 1.0% carbopol 980, about 1.0% diisopropanolamine 85%:
propylene glycol (1:9), about 0.01% citric acid, about 2.49% purified water, about 2.5%
glyceryl monostearate, and about 7.5% glyceryl monostearate & PEG stearate.

18. A composition comprising about 0.10% fluocinonide, about 70.0% propylene glycol, about 15.0% dimethyl isosorbide, about 1.2% carbopol 980, about 1.2%
diisopropanolamine 85%: propylene glycol (1:9), about 0.01% citric acid, about 2.49%
purified water, about 2.5% glyceryl monostearate, and about 7.50% glyceryl monostearate & PEG stearate.

19. A composition comprising about 0.10% fluocinonide, about 66.8% propylene glycol, about 5.0% dimethyl isosorbide, about 5.0% isopropyl myristate, about 0.5%
carbopol 980, about 0.5% diisopropanolamine 85%: propylene glycol (1:9), about 5.0%
white petrolatum USP, about 6.0% glyceryl monostearate, about 6.0% PEG 100 stearate, about 5.0% stearyl alcohol, and about 0.10% sodium lauryl sulfate.

20. A composition comprising about 0.10% fluocinonide, about 69.9% propylene glycol, about 2.0% diisopropyl adipate, about 5.0% isopropyl myristate, about 0.5%
carbopol 980, about 0.5% diisopropanolamine 85%: propylene glycol (1:9), about 5.0%
white petrolatum USP, about 6.0% glyceryl monostearate, about 6.0% PEG 100 stearate, and about 5.0% stearyl alcohol.

21. A composition comprising one or more corticosteroids;
two or more penetration enhancers;
one or more solvents/emulsifiers; and one or more non-solvent/emulsifier ingredients, wherein the one or more non-solvent/emulsifier ingredients include purified water, and wherein the non-solvent /emulsifier ingredients are different than the one or more solvents/emulsifiers and.
wherein the penetration enhancers are present in a ratio to a total of the penetration enhancers, and solvents/emulsifiers of at least about 0.90, and wherein said composition does not include a monoglyceride of a C6-C10 medium-chain fatty acid.

22. The composition of claim 21 wherein the corticosteroid comprises a fluorinated corticosteroid.

23. The composition of claim 21 wherein the corticosteroid comprises fluocinonide.
24. The composition of claim 21 wherein the corticosteroid comprises fluocinolone acetonide.

25. The composition of any one of claims 21, 22, 23 or 24 wherein the corticosteroid is present at about 0.10%.

26. The composition of any one of claims 21, 22, 23 or 24 wherein the corticosteroid is present at at least about 0.50%.

27. The composition of any one of claims 21, 22, 23 or 24 wherein the corticosteroid is present at at least about 0.25%.

28. The composition of any one of claims 21, 22, 23 or 24 wherein the penetration enhancers comprise two or more of the group consisting of propylene glycol, diisopropyl adipate and dimethyl isosorbide, 1,2,6 hexanetriol and benzyl alcohol.

29. The composition of any one of claims 21, 22, 23 or 24 wherein the penetration enhancers comprise two or more of the group consisting of propylene glycol, diisopropyl adipate and dimethyl isosorbide.

30. The composition of any one of claims 21, 22, 23, or 24 wherein one penetration enhancer comprises propylene glycol.

31. The composition of claim 21 wherein the ratio is at least about 0.95.

32. The composition of claim 21 wherein the solvents and emulsifiers comprise one or more of the group consisting of dehydrated alcohol, alcohol (95% v/v)USP, 3-Cyclohexene-1-Methanol, oc4-Dimethyl-a-(4-Methyl-3-Pentenyl)-, Steareth-2, Steareth-21, citric acid, CPE-215, diisopropanolamine (1:9), DIPA/PG (1:9), ethoxydiglycol, Potassium hydroxide (10%), PEG-40 Stearate, PEG-7000, Polysorbate 60, potassium hydroxide (1%), propylene carbonate USP, propylethylene glycol 4, oleyl alcohol, sodium lauryl sulfate, sorbitan monostearate, sorbitan stearate, and 1,2,3-Propanetriyl Ester.

33. The composition of claim 21 wherein the non-solvent/emulsifier ingredients comprise one or more of the group consisting of Glyceryl Stearate (and) PEG-100 Stearate, carbopol 980, cyclomethicone NF, glyceryl monostearate, hydroxyethyl cellulose, hydroxypropyl cellulose, isopropyl myristate, methyl paraben NF, mineral oil, oleic acid NF, PEG-100 Stearate, petrolatum, propyl paraben NF, purified water, stearyl alcohol, white petrolatum, and white wax.

34. The composition of claim 21 wherein the solvents and emulsifiers are present at about 4-5%.

35. The composition of claim 21 wherein the non-solvent/emulsifier ingredients are present at about 11% to about 53%.

36. The composition of claim 21 wherein the non-solvent/emulsifier ingredients are present at about 11 % to about 27%.

37. A composition comprising:
one or more corticosteroids;
two or more penetration enhancers, wherein the first penetration enhancer is propylene glycol and the second penetration enhancer is selected from the group consisting of diisopropyl adipate, dimethyl isosorbide, 1,2,6 hexanetriol and benzyl alcohol;
one or more solvents/emulsifiers; and one or more non-solvent/emulsifier ingredients wherein the one or more non-solvent/emulsifier ingredients include purified water, and wherein the non-solvent/emulsifier ingredients are different than the one or more solvents/emulsifiers, and wherein the penetration enhancers are present in a ratio to a total of the penetration enhancers, and solvents/emulsifiers of at least about 0.90 wherein the propylene glycol is at least 66.8% of the composition.

38. The composition of claim 37 wherein the propylene glycol is between 66.8%
and 74.9% of the composition.

39. A composition comprising:
one or more corticosteroids;
two or more penetration enhancers wherein the first penetration enhancer is dimethyl isosorbide and the second penetration enhancer is selected from the group consisting of diisopropyl adipate, propylene glycol, 1,2,6-hexanetriol, and benzyl alcohol;
and one or more of the group consisting of solvents and emulsifiers, wherein the penetration enhancers are present in a ratio to a total of the penetration enhancers, and solvents and emulsifiers of at least about 0.90.

44. The composition of claim 39 wherein the corticosteroid comprises a fluorinated corticosteroid.

41. The composition of claim 39 wherein the corticosteroid comprises fluocinonide.
42. The composition of claim 39 wherein the corticosteroid comprises fluocinolone acetonide.

43. The composition of claim 39, 40, 41, or 42 wherein the corticosteroid is present at about 0.10%.

44. The composition of claim 39, 40, 41, or 42 wherein the corticosteroid is present at at least about 0.50%.

45. The composition of claim 39, 40, 41 or 42 wherein the corticosteroid is present at at least about 0.25%.

46. The composition of claim 39, 40, 41, or 42 wherein the second penetration enhancer comprises propylene glycol.

47. The composition of claim 39 wherein the ratio is at least about 0.95.

48. The composition of claim 39 wherein the solvents and emulsifiers comprise one or more of the group consisting of dehydrated alcohol, alcohol (95% v/v)USP, 3-Cyclohexene-1-Methanol, 4-Dimethyl-a-(4-Methyl-3-Pentenyl)-, Steareth-2, Steareth-21, citric acid, CPE-215, diisopropanolamine (1:9), DIPA/PG (1:9), ethoxydiglycol, Potassium hydroxide (10%), PEG-40 Stearate, PEG-7000, Polysorbate 60, potassium hydroxide (1%), propylene carbonate USP, propylethylene glycol 4, oleyl alcohol, sodium lauryl sulfate, sorbitan monostearate, sorbitan stearate, and 1,2,3-Propanetriyl Ester.

49. The composition of claim 39 further comprising one or more non-solvent/emulsifier ingredients.

50. The composition of claim 49 wherein the non-solvent/emulsifier ingredients comprise one or more of the group consisting of Glyceryl Stearate (and) PEG-Stearate, carbopol 980, cyclomethicone NF, glyceryl monostearate, hydroxyethyl cellulose, hydroxypropyl cellulose, isopropyl myristate, methyl paraben NF, mineral oil, oleic acid NF, PEG-100 Stearate, petrolatum, propyl paraben NF, purified water, stearyl alcohol, white petrolatum and white wax.

51. The composition of claim 39 wherein the solvents and emulsifiers are present at about 4-5%.

52. The composition of claim 49 wherein the non-solvent/emulsifier ingredients are present at about 11% to about 53%.

53. The composition of claim 49 wherein the non-solvent/emulsifier ingredients are present at about 11 % to about 27%.
54. A composition comprising:
one or more corticosteroids;
two or more penetration enhancers wherein the first penetration enhancer is dimethyl isosorbide and the second penetration enhancer is selected from the group consisting of diisopropyl adipate, propylene glycol, 1,2,6-hexanetriol, and benzyl alcohol;
one or more solvents/emulsifiers; and one or more non-solvent/emulsifier ingredients, wherein the one or more non-solvent/emulsifier ingredients include purified water, and wherein the non-solvent/emulsifier ingredients are different than the one or more solvents/emulsifiers, and wherein the penetration enhancers are present in a ratio to a total of the penetration enhancers, and solvents/emulsifiers of at least about 0.90.

55. The composition of claim 54 wherein the corticosteroid comprises a fluorinated corticosteroid.

56. The composition of claim 54 wherein the corticosteroid comprises fluocinonide.
57. The composition of claim 54 wherein the corticosteroid comprises fluocinolone acetonide.

58. The composition of claim 54, 55, 56, or 57 wherein the corticosteroid is present at about 0.10%.

59. The composition of claim 54, 55, 56, or 57 wherein the corticosteroid is present at at least about 0.50%.

60. The composition of claim 54, 55, 56 or 57 wherein the corticosteroid is present at at least about 0.25%.

61. The composition of claim 54, 55, 56, or 57 wherein the second penetration enhancer comprises propylene glycol.

62. The composition of claim 54 wherein the ratio is at least about 0.95.

63. The composition of claim 54 wherein the solvents and emulsifiers comprise one or more of the group consisting of dehydrated alcohol, alcohol (95% v/v)USP, 3-Cyclohexene-1 -Methanol, 4-Dimethyl-a-(4-Methyl-3-Pentenyl)-, Steareth-2, Steareth-21, citric acid, CPE-215, diisopropanolamine (1:9), DIPA/PG (1:9), ethoxydiglycol, Potassium hydroxide (10%), PEG-40 Stearate, PEG-7000, Polysorbate 60, potassium hydroxide (1%), propylene carbonate USP, propylethylene glycol 4, oleyl alcohol, sodium lauryl sulfate, sorbitan monostearate, sorbitan stearate, and 1,2,3-Propanetriyl Ester.

64. The composition of claim 54 wherein the non-solvent/emulsifier ingredients comprise one or more of the group consisting of Glyceryl Stearate (and) PEG-Stearate, carbopol 980, cyclomethicone NF, glyceryl monostearate, hydroxyethyl cellulose, hydroxypropyl cellulose, isopropyl myristate, methyl paraben NF, mineral oil, oleic acid NF, PEG-100 Stearate, petrolatum, propyl paraben NF, purified water, stearyl alcohol, white petrolatum and white wax.

65. The composition of claim 54 wherein the solvents and emulsifiers are present at about 4-5%.

66. The composition of claim 54 wherein the non-solvent/emulsifier ingredients are present at about 11% to about 53%.

67. The composition of claim 54 wherein the non-solvent/emulsifier ingredients are present at about 11 % to about 27%.

68. The composition of claim 61 wherein the propylene glycol is at least 66.8%
of the composition.

69. The composition of claim 61 wherein the propylene glycol is between 66.8%
and 74.9% of the composition.

70. A method for enhancing potency of corticosteroids comprising Combining one or more corticosteroids with two or more penetration enhancers, and one or more of the group consisting of solvents and emulsifiers, wherein the penetration enhancers are present in a ratio to a total of penetration enhancers, and solvents and emulsifiers of at least about 0.90, and wherein the penetration enhancers comprise two or more of the group consisting of propylene glycol, diisopropyl adipate, dimethyl isosorbide, 1,2,6 hexanetriol, and benzyl alcohol.

71. The method of claim 70 wherein the corticosteroid comprises a fluorinated corticosteroid.

72. The method of claim 70 wherein the corticosteroid comprises fluocinonide.

73. The method of claim 70 wherein the corticosteroid comprises fluocinolone acetonide.
74. The method of any one of claims 70, 71, 72 or 73 wherein the corticosteroid is present at about 0.10%.

75. The method of any one of claims 70, 71, 72 or 73 wherein the corticosteroid is present at at least about 0.50%.

76. The method of any one of claims 70, 71, 72 or 73 wherein the corticosteroid is present at at least about 0.25%.

77. The method of any one of claims 70, 71, 72 or 73 wherein the penetration enhancers comprise two or more of the group consisting of propylene glycol, diisopropyl adipate and dimethyl isosorbide.

78. The method of any one of claims 70, 71, 72 or 73 wherein one penetration enhancer comprises propylene glycol.

79. The method of claim 70 wherein the ratio is at least about 0.95.

80. The method of claim 70 wherein the solvents and emulsifiers comprise one or more of the group consisting of dehydrated alcohol, alcohol (95% v/v) USP, 3-Cyclohexene-1-Methanol, oc4-Dimethyl-a-(4-Methyl-3-Pentenyl)-, Steareth-2, Steareth-21, citric acid, _ cellulose, isopropyl myristate, methyl paraben NF, mineral oil, oleic acid NF, Stearate, petrolatum, propyl paraben NF, purified water, stearyl alcohol, white petrolatum, and white wax.

83. The method of claim 70 wherein the solvents and emulsifiers are present at about 4-5%.

84. The method of claim 82 wherein the non-solvent/emulsifier ingredients are present at about 11% to about 53%.

85. The method of claim 82 wherein the non-solvent/emulsifier ingredients are present at about 11% to about 27%.

86. A method for enhancing potency of corticosteroids, comprising: Combining one or more corticosteroids with two or more penetration enhancers, and one or more of the group consisting of solvents and emulsifiers, wherein the penetration enhancers are present in a ratio to a total of penetration enhancers, and solvents and emulsifiers of at least about 0.90, and wherein the first penetration enhancer is propylene glycol and the second penetration enhancer is selected from the group consisting of diisopropyl adipate, dimethyl isosorbide 1,2,6 hexanetriol, and benzyl alcohol, and wherein the propylene glycol is at least 66.8% of the composition.

87. A method for enhancing potency of corticosteroids, comprising: Combining one or more corticosteroids with two or more penetration enhancers, and one or more of the group consisting of solvents and emulsifiers, wherein the penetration enhancers are present in a ratio to a total of penetration enhancers, and solvents and emulsifiers of at least about 0.90, and wherein the first penetration enhancer is propylene glycol and the second penetration enhancer is selected from the group consisting of diisopropyl adipate, dimethyl isosorbide 1,2,6 hexanetriol, and benzyl alcohol, and wherein the propylene glycol is between 66.8% and 74.9% of the composition.

88. A method for enhancing potency of corticosteroids comprising Combining one or more corticosteroids with two or more penetration enhancers, and one or more of the group consisting of solvents and emulsifiers, wherein the penetration enhancers are present in a ratio to a total of penetration enhancers, and solvents and emulsifiers of at least about 0.90, and wherein the first penetration enhancer is dimethyl isosorbide and the second penetration enhancer is selected from the group consisting of propylene glycol, diisopropyl adipate, 1,2,6 hexanetriol, and benzyl alcohol.

89. The method of claim 88 wherein the corticosteroid comprises a fluorinated corticosteroid.

90. The method of claim 88 wherein the corticosteroid comprises fluocinonide.

91. The method of claim 88 wherein the corticosteroid comprises fluocinolone acetonide.
92. The method of claim 88, 89, 90 or 91 wherein the corticosteroid is present at about 0.10%.

93. The method of claim 88, 89, 90 or 91 wherein the corticosteroid is present at at least about 0.50%.

94. The method of claim 88, 89, 90 or 91 wherein the corticosteroid is present at at least about 0.25%.

95. The method of claim 88 wherein the ratio is at least about 0.95.

96. The method of claim 88 wherein the solvents and emulsifiers comprise one or more of the group consisting of dehydrated alcohol, alcohol (95% v/v) USP, 3-Cyclohexene-1-Methanol, 4-Dimethyl-a-(4-Methyl-3-Pentenyl)-, Steareth-2, Steareth-21, citric acid, CPE-215, diisopropanolamine (1:9), DIPA/PG (1:9), ethoxydiglycol, Potassium hydroxide (10%), PEG-40 Stearate, PEG-7000, Polysorbate 60, potassium hydroxide (1%), propylene carbonate USP, propylethylene glycol 4, oleyl alcohol, sodium lauryl sulfate, sorbitan monostearate, sorbitan stearate, and 1,2,3-Propanetriyl Ester.

97. The method of claim 88 wherein the composition further comprises one or more non-solvent/emulsifier ingredients.

98. The method of claim 97 wherein the non-solvent/emulsifier ingredients comprise one or more of the group consisting of Glyceryl Stearate (and) PEG-100 Stearate, carbopol 980, cyclomethicone NF, glyceryl monostearate, hydroxyethyl cellulose, hydroxypropyl cellulose, isopropyl myristate, methyl paraben NF, mineral oil, oleic acid NF, Stearate, petrolatum, propyl paraben NF, purified water, stearyl alcohol, white petrolatum, and white wax.

99. The method of claim 88 wherein the solvents and emulsifiers are present at about 4-5%.

100. The method of claim 98 wherein the non-solvent/emulsifier ingredients are present at about 11% to about 53%.

101. The method of claim 98 wherein the non-solvent/emulsifier ingredients are present at about 11% to about 27%.

102. The method of claim 88 wherein the second penetration enhancer is propylene glycol and wherein the propylene glycol is at least 66.8% of the composition.

103. The method of claim 88 wherein the second penetration enhancer is propylene glycol and wherein the propylene glycol is between 66.8% and 74.9% of the composition.

104. A method of delivering corticosteroids to skin comprising Topically applying a composition comprising one or more corticosteroids with two or more penetration enhancers, and one or more of the group consisting of solvents and emulsifiers, wherein the penetration enhancers are present in ratio to a total of the penetration enhancers, and solvents and emulsifiers of at least about 0.90, and wherein the penetration enhancers comprise two or more of the group consisting of propylene glycol, diisopropyl adipate dimethyl isosorbide, 1,2,6 hexanetriol, and benzyl alcohol and wherein the composition does not include a monoglyceride of C6-C10 medium chain fatty acid.

105. The method of claim 104 wherein the corticosteroid comprises a fluorinated corticosteroid.

106. The method of claim 104 wherein the corticosteroid comprises fluocinonide.
107. The method of claim 104 wherein the corticosteroid comprises fluocinolone acetonide.

108. The method of any one of claims 104, 105, 106 or 107 wherein the corticosteroid is present at about 0.10%.

109. The method of any one of claims 104, 105, 106 or 107 wherein the corticosteroid is present at at least about 0.50%.

110. The method of any one of claims 104, 105, 106 or 107 wherein the corticosteroid is present at at least about 0.25%.

111. The method of claim 104 wherein the solvents and emulsifiers comprise one or more of the group consisting of dehydrated alcohol, alcohol (95% v/v)USP, 3-Cyclohexene-1-Methanol, oc4-Dimethyl-a-(4-Methyl-3-Pentenyl)-; Steareth-2, Steareth-21, citric acid, CPE-215, diisopropanolamine (1:9), DIPA/PG (1:9), ethoxydiglycol, Potassium hydroxide (10%), PEG-40 Stearate, PEG-7000, Polysorbate 60, potassium hydroxide (1%), propylene carbonate USP, propylethylene glycol 4, oleyl alcohol, sodium lauryl sulfate, sorbitan monostearate, sorbitan stearate, and 1,2,3-Propanetriyl Ester.

112. The method of claim 104 wherein the composition further comprises one or more non-solvent/emulsifier ingredients.

113. The method of claim 112 wherein the non-solvent/emulsifier ingredients comprise one or more of the group consisting of Glyceryl Stearate (and) PEG-100 Stearate, carbopol 980, cyclomethicone NF, glyceryl monostearate, hydroxyethyl cellulose, hydroxypropyl cellulose, isopropyl myristate, methyl paraben NF, mineral oil, oleic acid NF, PEG-100 Stearate, petrolatum, propyl paraben NF, purified water, stearyl alcohol, white petrolatum, and white wax.

114. The method of claim 104 wherein the solvents and emulsifiers are present at about 4-5%.

115. The method of claim 113 wherein the non-solvent/emulsifier ingredients are present at about 11 % to about 53%.

116. The method of claim 113 wherein the non-solvent/emulsifier ingredients are present at about 11 % to about 27%.

117. A method of delivering corticosteroids to skin comprising:
topically applying a composition comprising one or more corticosteroids with two or more penetration enhancers, and one or more of the group consisting of solvents and emulsifiers, wherein the penetration enhancers are present in ratio to a total of the penetration enhancers, and solvents and emulsifiers of at least about 0.90, and wherein the first penetration enhancer is propylene glycol and the second penetration enhancer is selected from the group consisting of diisopropyl adipate, dimethyl isosorbide, 1,2,6 hexanetriol, and benzyl alcohol, and wherein the propylene glycol is at least 66.8% of the composition.

118. A method of delivering corticosteroids to skin comprising:
topically applying a composition comprising one or more corticosteroids with two or more penetration enhancers, and one or more of the group consisting of solvents and emulsifiers, wherein the penetration enhancers are present in ratio to a total of the penetration enhancers, and solvents and emulsifiers of at least about 0.90, and wherein the first penetration enhancer is propylene glycol and the second penetration enhancer is selected from the group consisting of diisopropyl adipate, dimethyl isosorbide, 1,2,6 hexanetriol, and benzyl alcohol, and wherein the propylene glycol is between 66.8% and 74.9% of the composition.

119. A method of delivering corticosteroids to skin comprising:
topically applying a composition comprising one or more corticosteroids with two or more penetration enhancers, and one or more of the group consisting of solvents and emulsifiers, wherein the penetration enhancers are present in ratio to a total of the penetration enhancers, and solvents and emulsifiers of at least about 0.90, and wherein the first penetration enhancer is dimethyl isosorbide and the second penetration enhancer is selected from the group consisting of propylene glycol, diisopropyl adipate, 1,2,6 hexanetriol, and benzyl alcohol.

120. The method of claim 119 wherein the corticosteroid comprises a fluorinated corticosteroid.

121. The method of claim 119 wherein the corticosteroid comprises fluocinonide.
122. The method of claim 119 wherein the corticosteroid comprises fluocinolone acetonide.

123. The method of claim 119, 120, 121 or 122 wherein the corticosteroid is present at about 0.10%.

124. The method of claim 119, 120, 121 or 122 wherein the corticosteroid is present at at least about 0.50%.

125. The method of claim 119, 120, 121 or 122 wherein the corticosteroid is present at at least about 0.25%.

126. The method of claim 119 wherein the solvents and emulsifiers comprise one or more of the group consisting of dehydrated alcohol, alcohol (95% v/v)USP, 3-Cyclohexene-1-Methanol, 4-Dimethyl-a-(4-Methyl-3-Pentenyl)-, Steareth-2, Steareth-21, citric acid, CPE-215, diisopropanolamine (1:9), DIPA/PG (1:9), ethoxydiglycol, Potassium hydroxide (10%), PEG-40 Stearate, PEG-7000, Polysorbate 60, potassium hydroxide (1 %), propylene carbonate USP, propylethylene glycol 4, oleyl alcohol, sodium lauryl sulfate, sorbitan monostearate, sorbitan stearate, and 1,2,3-Propanetriyl Ester.

127. The method of claim 119 wherein the composition further comprises one or more non-solvent/emulsifier ingredients.

128. The method of claim 127 wherein the non-solvent/emulsifier ingredients comprise one or more of the group consisting of Glyceryl Stearate (and) PEG-Stearate, carbopol 980, cyclomethicone NF, glyceryl monostearate, hydroxyethyl cellulose, hydroxypropyl cellulose, isopropyl myristate, methyl paraben NF, mineral oil, oleic acid NF, PEG-100 Stearate, petrotatum, propyl paraben NF, purified water, stearyl alcohol, white petrolatum, and white wax.

129. The method of claim 119 wherein the solvents and emulsifiers are present at about 4-5%.

130. The method of claim 127 wherein the non-solvent/emulsifier ingredients are present at about 11% to about 53%.

131. The method of claim 127 wherein the non-solvent/emulsifier ingredients are present at about 11 % to about 27%.

132. The method of claim 119 wherein the second penetration enhancer is propylene glycol and wherein the propylene glycol is at least 66.8% of the composition.

133. The method of claim 119 wherein the second penetration enhancer is propylene glycol and wherein the propylene glycol is between 66.8% and 74.9% of the composition.
CA2471041A 2001-12-21 2002-12-12 Compositions and methods for enhancing corticosteriod delivery Expired - Lifetime CA2471041C (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US10/037,360 US6765001B2 (en) 2001-12-21 2001-12-21 Compositions and methods for enhancing corticosteroid delivery
US10/037,360 2001-12-21
PCT/US2002/039882 WO2003055445A2 (en) 2001-12-21 2002-12-12 Compositions and methods for enhancing corticosteriod delivery

Publications (2)

Publication Number Publication Date
CA2471041A1 CA2471041A1 (en) 2003-07-10
CA2471041C true CA2471041C (en) 2012-07-03

Family

ID=21893928

Family Applications (1)

Application Number Title Priority Date Filing Date
CA2471041A Expired - Lifetime CA2471041C (en) 2001-12-21 2002-12-12 Compositions and methods for enhancing corticosteriod delivery

Country Status (9)

Country Link
US (8) US6765001B2 (en)
EP (2) EP2363150A1 (en)
JP (2) JP2005524614A (en)
CN (1) CN1617730A (en)
BR (1) BR0215254A (en)
CA (1) CA2471041C (en)
IL (1) IL162581A0 (en)
MX (1) MXPA04006014A (en)
WO (1) WO2003055445A2 (en)

Families Citing this family (76)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6630152B2 (en) * 1999-04-07 2003-10-07 Shen Wei (Usa), Inc. Aloe vera glove and manufacturing method
US8512718B2 (en) 2000-07-03 2013-08-20 Foamix Ltd. Pharmaceutical composition for topical application
US6765001B2 (en) * 2001-12-21 2004-07-20 Medicis Pharmaceutical Corporation Compositions and methods for enhancing corticosteroid delivery
IL152486A0 (en) 2002-10-25 2003-05-29 Meir Eini Alcohol-free cosmetic and pharmaceutical foam carrier
US10117812B2 (en) 2002-10-25 2018-11-06 Foamix Pharmaceuticals Ltd. Foamable composition combining a polar solvent and a hydrophobic carrier
US8486376B2 (en) 2002-10-25 2013-07-16 Foamix Ltd. Moisturizing foam containing lanolin
US9211259B2 (en) 2002-11-29 2015-12-15 Foamix Pharmaceuticals Ltd. Antibiotic kit and composition and uses thereof
US7704518B2 (en) 2003-08-04 2010-04-27 Foamix, Ltd. Foamable vehicle and pharmaceutical compositions thereof
US9668972B2 (en) 2002-10-25 2017-06-06 Foamix Pharmaceuticals Ltd. Nonsteroidal immunomodulating kit and composition and uses thereof
US8900554B2 (en) 2002-10-25 2014-12-02 Foamix Pharmaceuticals Ltd. Foamable composition and uses thereof
US8119109B2 (en) 2002-10-25 2012-02-21 Foamix Ltd. Foamable compositions, kits and methods for hyperhidrosis
US8119150B2 (en) * 2002-10-25 2012-02-21 Foamix Ltd. Non-flammable insecticide composition and uses thereof
US7820145B2 (en) 2003-08-04 2010-10-26 Foamix Ltd. Oleaginous pharmaceutical and cosmetic foam
US9265725B2 (en) 2002-10-25 2016-02-23 Foamix Pharmaceuticals Ltd. Dicarboxylic acid foamable vehicle and pharmaceutical compositions thereof
US7700076B2 (en) 2002-10-25 2010-04-20 Foamix, Ltd. Penetrating pharmaceutical foam
US20080138296A1 (en) 2002-10-25 2008-06-12 Foamix Ltd. Foam prepared from nanoemulsions and uses
MXPA05004278A (en) 2002-10-25 2005-10-05 Foamix Ltd Cosmetic and pharmaceutical foam.
US7575739B2 (en) 2003-04-28 2009-08-18 Foamix Ltd. Foamable iodine composition
US8486374B2 (en) 2003-08-04 2013-07-16 Foamix Ltd. Hydrophilic, non-aqueous pharmaceutical carriers and compositions and uses
US8795693B2 (en) 2003-08-04 2014-08-05 Foamix Ltd. Compositions with modulating agents
US20050238672A1 (en) * 2004-04-27 2005-10-27 Nimni Marcel E Antifungal drug delivery
US7897587B2 (en) 2004-09-03 2011-03-01 Nycomed Us Inc. Topical dermatological formulations and use thereof
WO2007054818A2 (en) 2005-05-09 2007-05-18 Foamix Ltd. Foamable vehicle and pharmaceutical compositions thereof
ES2313670T3 (en) * 2005-05-10 2009-03-01 Alcon Inc. Ophthalmic suspension comprising an ophthalmic drug, a polyoxamine and a glycolic agent adjusting the tone, use of such a compound for the manufacture of a medication to treat ophthalmic disorders.
PL1885336T3 (en) * 2005-05-10 2009-08-31 Alcon Inc Suspension formulations comprising an active principle, a poloxamer or meroxapol surfactant and a glycol, its use for the manufacture of a medicament for treating ophthalmic disorders
WO2007046315A1 (en) * 2005-10-17 2007-04-26 Nisshin Kyorin Pharmaceutical Co., Ltd. External preparation for skin
US9486408B2 (en) 2005-12-01 2016-11-08 University Of Massachusetts Lowell Botulinum nanoemulsions
MX2008007439A (en) * 2005-12-09 2009-01-22 Nycomed Inc Topical glucocorticosteroid formulations.
US20070179121A1 (en) * 2006-02-02 2007-08-02 Plott R T Method of treating pediatric patients with corticosteroids
US20090053290A1 (en) * 2006-03-08 2009-02-26 Sand Bruce J Transdermal drug delivery compositions and topical compositions for application on the skin
FR2898499B1 (en) * 2006-03-15 2008-11-28 Galderma Sa NOVEL TOPIC COMPOSITIONS IN THE FORM OF O / W EMULSION COMPRISING PRO-PENETRANT GLYCOL
WO2008015583A1 (en) * 2006-06-13 2008-02-07 Wescast Industries, Inc. Exhaust manifolds including heat shield assemblies
PL2494959T3 (en) * 2006-07-05 2015-06-30 Foamix Pharmaceuticals Ltd Dicarboxylic acid foamable vehicle and pharmaceutical compositions thereof
GB2443162B (en) * 2006-10-28 2011-02-09 Nupharm Lab Ltd Betamethasone spray
GB2443161B (en) * 2006-10-28 2011-03-23 Nupharm Lab Ltd Clobetasol spray
US20080260655A1 (en) 2006-11-14 2008-10-23 Dov Tamarkin Substantially non-aqueous foamable petrolatum based pharmaceutical and cosmetic compositions and their uses
KR20090106493A (en) 2006-12-01 2009-10-09 안테리오스, 인코퍼레이티드 Micellar nanoparticles comprising botulinum toxin
US20080152592A1 (en) * 2006-12-21 2008-06-26 Bayer Healthcare Llc Method of therapeutic drug monitoring
JP2010514789A (en) * 2006-12-27 2010-05-06 アベール ファーマシューティカルズ インコーポレイテッド Transdermal methods and patches for corticosteroid administration
WO2008115224A2 (en) * 2007-03-20 2008-09-25 Bayer Healthcare Llc Method of analyzing an analyte
US8636982B2 (en) 2007-08-07 2014-01-28 Foamix Ltd. Wax foamable vehicle and pharmaceutical compositions thereof
US9439857B2 (en) 2007-11-30 2016-09-13 Foamix Pharmaceuticals Ltd. Foam containing benzoyl peroxide
WO2010041141A2 (en) 2008-10-07 2010-04-15 Foamix Ltd. Oil-based foamable carriers and formulations
WO2009090495A2 (en) 2007-12-07 2009-07-23 Foamix Ltd. Oil and liquid silicone foamable carriers and formulations
AU2009205314A1 (en) 2008-01-14 2009-07-23 Foamix Ltd. Poloxamer foamable pharmaceutical compositions with active agents and/or therapeutic cells and uses
US20090298803A1 (en) * 2008-05-28 2009-12-03 Glenmark Generics Ltd. Pharmaceutical composition comprising fluocinonide
CN105147608B (en) * 2008-06-26 2019-12-10 安特里奥公司 Dermal delivery
TW201035054A (en) * 2009-02-27 2010-10-01 Lundbeck & Co As H Methods of administering (4aR, 10aR)-1-n-propyl-1,2,3,4,4a,5,10,10a-octahydro-benzo[g]quinoline-6,7-diol and pharmaceutical compositions thereof
US20120087872A1 (en) 2009-04-28 2012-04-12 Foamix Ltd. Foamable Vehicles and Pharmaceutical Compositions Comprising Aprotic Polar Solvents and Uses Thereof
AR077490A1 (en) * 2009-07-21 2011-08-31 Novartis Ag TOPICAL PHARMACEUTICAL COMPOSITIONS FOR THE TREATMENT OF A HYPERPROLIFERATIVE SKIN CONDITION
WO2011013008A2 (en) 2009-07-29 2011-02-03 Foamix Ltd. Non surface active agent non polymeric agent hydro-alcoholic foamable compositions, breakable foams and their uses
CA2769625C (en) 2009-07-29 2017-04-11 Foamix Ltd. Non surfactant hydro-alcoholic foamable compositions, breakable foams and their uses
US9364485B2 (en) 2009-08-31 2016-06-14 Dr. Reddy's Laboratories Ltd. Topical formulations comprising a steroid
MX359879B (en) 2009-10-02 2018-10-12 Foamix Pharmaceuticals Ltd Topical tetracycline compositions.
US9849142B2 (en) 2009-10-02 2017-12-26 Foamix Pharmaceuticals Ltd. Methods for accelerated return of skin integrity and for the treatment of impetigo
US8685381B2 (en) 2010-10-23 2014-04-01 Joel Schlessinger Topical base and active agent-containing compositions, and methods for improving and treating skin
US8968755B2 (en) 2010-10-23 2015-03-03 Joel Schlessinger Topical base and active agent-containing compositions, and methods for improving and treating skin
US8809307B2 (en) * 2010-11-22 2014-08-19 Dow Pharmaceutical Sciences, Inc. Pharmaceutical formulations containing corticosteroids for topical administration
US20180243420A1 (en) 2010-11-22 2018-08-30 Dow Pharmaceutical Sciences, Inc. Pharmaceutical formulations containing corticosteroids for topical administration
BR112013018919A2 (en) * 2011-01-24 2016-10-04 Anteriors Inc empty nanoparticle compositions and their use to treat dermatological problems
GB201110632D0 (en) * 2011-06-22 2011-08-03 King S College London Drug delivery formulations
JP5820206B2 (en) * 2011-09-13 2015-11-24 日東電工株式会社 Transdermal absorption enhancing composition and patch preparation
US20140112959A1 (en) 2012-10-18 2014-04-24 MiCal Pharmaceuticals LLC - H Series, a Series of MiCal Pharmaceuticals LLC, a Multi-Division Limite Topical steroid composition and method
US10111956B2 (en) 2013-06-03 2018-10-30 Tolmar, Inc. Corticosteroid compositions
ES2836132T3 (en) 2013-08-08 2021-06-24 Novan Inc Topical compositions and methods of using them
CA2920859A1 (en) * 2013-08-09 2015-02-12 The Chemours Company Fc, Llc Skin care compositions having cyclic diesters and methods thereof
US20160184431A1 (en) 2014-03-11 2016-06-30 Promius Pharma Llc Topical compositions comprising a corticosteroid
US10322082B2 (en) 2014-07-11 2019-06-18 Novan, Inc. Topical antiviral compositions and methods of using the same
SI3310389T1 (en) 2015-06-18 2020-11-30 Bausch Health Ireland Limited Topical compositions comprising a corticosteroid and a retinoid for treating psoriasis
US11684567B2 (en) 2015-08-05 2023-06-27 Cmpd Licensing, Llc Compositions and methods for treating an infection
US11793783B2 (en) 2015-08-05 2023-10-24 Cmpd Licensing, Llc Compositions and methods for treating an infection
EP3143986A1 (en) * 2015-09-21 2017-03-22 Zimmer MedizinSysteme GmbH Hydrophilic gel for topical delivery of 5-aminolevulinic acid and production thereof
US10398641B2 (en) 2016-09-08 2019-09-03 Foamix Pharmaceuticals Ltd. Compositions and methods for treating rosacea and acne
MX2019005833A (en) 2016-11-21 2019-10-30 Eirion Therapeutics Inc Transdermal delivery of large agents.
JP2021534161A (en) * 2018-08-16 2021-12-09 ドクター・レディーズ・ラボラトリーズ・リミテッド Topical oily composition
WO2020176754A1 (en) * 2019-02-27 2020-09-03 Oticara, Inc. Method for treating nasal, sinonasal, and nasopharyngeal tissue infection and/or inflammation

Family Cites Families (23)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3592930A (en) * 1968-07-19 1971-07-13 Syntex Corp Moisture-deterioratable topical medicaments,particularly anti-inflammatory steroids,in a substantially non-aqueous fatty alcohol-propylene glycol vehicle
US4017615A (en) 1970-10-29 1977-04-12 Syntex Corporation Propylene carbonate ointment vehicle
US3934013A (en) * 1975-02-21 1976-01-20 Syntex (U.S.A.) Inc. Pharmaceutical composition
EP0020794B1 (en) * 1979-06-08 1983-01-12 Toko Yakuhin Kogyo Kabushiki Kaisha Creamy preparation containing steroid and process for the preparation thereof
JPS58225009A (en) 1982-06-23 1983-12-27 Shionogi & Co Ltd Pharmaceutical preparation of corticosteroid for external use
JPS6136219A (en) * 1984-07-27 1986-02-20 Shiseido Co Ltd External drug for skin
US4879119A (en) * 1984-02-21 1989-11-07 Yamanouchi Pharmaceutical Co., Ltd. Patch
US4831023A (en) * 1986-06-27 1989-05-16 Thames Pharmacal Co., Inc. Water washable vehicles for topical use
JPH0676328B2 (en) * 1987-04-14 1994-09-28 株式会社大塚製薬工場 Steroid cream formulation
US4855294A (en) * 1988-09-06 1989-08-08 Theratech, Inc. Method for reducing skin irritation associated with drug/penetration enhancer compositions
US5422361A (en) * 1989-12-20 1995-06-06 Schering Corporation Stable cream and lotion bases for lipophilic drug compositions
JP3655305B2 (en) * 1992-11-23 2005-06-02 エスティー ローダー インコーポレーテッド Self-tanning cosmetic composition and method of using the same
US6300326B1 (en) 1994-11-02 2001-10-09 Michael R. Dobbs Composition and method for control and treatment of cutaneous inflammation
KR970064620A (en) 1996-03-05 1997-10-13 임성기 Cyclosporin-containing external-use pharmaceutical composition
JPH10204001A (en) * 1996-11-15 1998-08-04 Kao Corp Percutaneous absorption accelerator
US6075056A (en) 1997-10-03 2000-06-13 Penederm, Inc. Antifungal/steroid topical compositions
JPH11158060A (en) * 1997-11-18 1999-06-15 Bristol Myers Squibb Co Method and composition for increasing transdermal permeation of drugs by using permeation enhancer in the case that the drugs and/or the permeation enhancer is unstable in the composition to be stored for long period of time
US6066281A (en) * 1998-06-16 2000-05-23 Velcro Industries B.V. Fastener products and their production
WO2000040250A1 (en) * 1999-01-06 2000-07-13 Taisho Pharmaceutical Co.,Ltd. Amelometasone lotion
US6656928B1 (en) * 1999-09-02 2003-12-02 Mccadden Michael E. Composition for the topical treatment of rashes, dermatoses and lesions
US20020013294A1 (en) * 2000-03-31 2002-01-31 Delong Mitchell Anthony Cosmetic and pharmaceutical compositions and methods using 2-decarboxy-2-phosphinico derivatives
US6765001B2 (en) * 2001-12-21 2004-07-20 Medicis Pharmaceutical Corporation Compositions and methods for enhancing corticosteroid delivery
TW200522932A (en) * 2003-09-15 2005-07-16 Combinatorx Inc Methods and reagents for the treatment of diseases and disorders associated with increased levels of proinflammatory cytokines

Also Published As

Publication number Publication date
EP1465636A4 (en) 2006-04-05
US7217422B2 (en) 2007-05-15
US20120289490A1 (en) 2012-11-15
US7771733B2 (en) 2010-08-10
US20030130247A1 (en) 2003-07-10
US20030186951A1 (en) 2003-10-02
US8232264B2 (en) 2012-07-31
EP1465636A2 (en) 2004-10-13
CN1617730A (en) 2005-05-18
US20090176750A1 (en) 2009-07-09
WO2003055445A3 (en) 2003-10-09
MXPA04006014A (en) 2005-07-13
EP2363150A1 (en) 2011-09-07
US20100210609A2 (en) 2010-08-19
US20100210614A2 (en) 2010-08-19
JP2005524614A (en) 2005-08-18
US20030176408A1 (en) 2003-09-18
US7794738B2 (en) 2010-09-14
US20100210615A2 (en) 2010-08-19
US20070142343A1 (en) 2007-06-21
CA2471041A1 (en) 2003-07-10
US6765001B2 (en) 2004-07-20
WO2003055445A2 (en) 2003-07-10
AU2002360589B2 (en) 2007-03-15
JP2010280689A (en) 2010-12-16
BR0215254A (en) 2005-02-01
IL162581A0 (en) 2005-11-20
US7220424B2 (en) 2007-05-22
AU2002360589A1 (en) 2003-07-15
US20040198709A1 (en) 2004-10-07
US20070142344A1 (en) 2007-06-21

Similar Documents

Publication Publication Date Title
CA2471041C (en) Compositions and methods for enhancing corticosteriod delivery
US9918960B2 (en) Topical oily foam compositions
US20190000977A1 (en) Corticosteroid compositions
WO2014197398A1 (en) Corticosteroid compositions
STOUGHTON The vasoconstrictor assay in bioequivalence testing: practical concerns and recent developments
AU2002360589B9 (en) Compositions and methods for enhancing corticosteriod delivery
US20070179121A1 (en) Method of treating pediatric patients with corticosteroids
McKenzie Percutaneous absorption of steroids

Legal Events

Date Code Title Description
EEER Examination request
MKEX Expiry

Effective date: 20221212