US20160184431A1 - Topical compositions comprising a corticosteroid - Google Patents

Topical compositions comprising a corticosteroid Download PDF

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Publication number
US20160184431A1
US20160184431A1 US14/645,297 US201514645297A US2016184431A1 US 20160184431 A1 US20160184431 A1 US 20160184431A1 US 201514645297 A US201514645297 A US 201514645297A US 2016184431 A1 US2016184431 A1 US 2016184431A1
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US
United States
Prior art keywords
topical composition
alcohol
clobetasol
propylene glycol
composition according
Prior art date
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Abandoned
Application number
US14/645,297
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English (en)
Inventor
Sateesh Kandavalli
Madhusudhan BOMMAGANI
Vijendra Nalamothu
Franklin Okumu
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.)
Promius Pharma LLC
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Promius Pharma LLC
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
Application filed by Promius Pharma LLC filed Critical Promius Pharma LLC
Priority to US14/645,297 priority Critical patent/US20160184431A1/en
Priority to RU2017134440A priority patent/RU2690659C2/ru
Priority to JP2017547992A priority patent/JP2018507891A/ja
Priority to EA201791921A priority patent/EA037380B1/ru
Priority to BR112017019352-3A priority patent/BR112017019352B1/pt
Priority to CA2979051A priority patent/CA2979051C/en
Priority to US15/068,428 priority patent/US9855334B2/en
Priority to ES16712608T priority patent/ES2861374T3/es
Priority to KR1020177027989A priority patent/KR20170123335A/ko
Priority to CN201680027828.3A priority patent/CN107872972A/zh
Priority to UAA201709298A priority patent/UA121232C2/uk
Priority to EP16712608.5A priority patent/EP3267978B1/en
Priority to AU2016228574A priority patent/AU2016228574B2/en
Priority to PCT/US2016/022194 priority patent/WO2016145407A1/en
Priority to NZ735341A priority patent/NZ735341A/en
Priority to MX2017011521A priority patent/MX2017011521A/es
Priority to KR1020207012965A priority patent/KR20200051854A/ko
Publication of US20160184431A1 publication Critical patent/US20160184431A1/en
Priority to CONC2017/0010091A priority patent/CO2017010091A2/es
Priority to US15/820,601 priority patent/US11179465B2/en
Priority to US16/244,880 priority patent/US20190175735A1/en
Priority to JP2020170680A priority patent/JP2021008505A/ja
Abandoned legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds 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
    • A61K31/573—Compounds 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/04—Antipruritics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/38—Drugs for disorders of the endocrine system of the suprarenal hormones
    • A61P5/44—Glucocorticosteroids; Drugs increasing or potentiating the activity of glucocorticosteroids

Definitions

  • the present invention relates to a topical composition
  • a topical composition comprising a corticosteroid and at least one penetration enhancing agent, wherein the composition is substantially free of propylene glycol.
  • Topical corticosteroids are the most frequently prescribed drugs by dermatologists for treating psoriasis, relief of the inflammatory and pruritic manifestations of steroid responsive dermatoses, and associated diseases or disorders.
  • the corticosteroids are a class of compounds comprising 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.
  • steroids lipids that contain a hydrogenated cyclopentoperhydrophenanthrene ring system
  • corticosteroids are used primarily for their anti-inflammatory and/or immunosuppressive effects.
  • Topical corticosteroids such as clobetasol propionate
  • clobetasol propionate are effective in treatment of corticosteroid-responsive dermatoses primarily because of their anti-inflammatory, antipruritic and vasoconstrictive actions.
  • Clobetasol propionate is used to treat various other skin disorders including eczema and psoriasis. It is also highly effective for contact dermatitis caused by exposure to poison ivy/oak.
  • Clobetasol propionate is chemically known as [17-(2′-chloroacetyl)-9-fluoro-11-hydroxy-10,13,16-trimethyl-3-oxo-6,7,8,11,12,14,15,16-octahydrocyclopenta[a] phenanthren-17-yl] propanoate and is represented by structural Formula I:
  • Clobetasol propionate is commercially available in compositions for topical application in the form of aerosol foam, cream, ointment, gel, solution, lotion, spray or shampoo, in a weight concentration of 0.05%.
  • TEMOVATE Cream® is a commercially available product of clobetasol approved by U.S. Food and Drug Administration (FDA) on Dec. 27, 1985 and is currently being marketed by Fougera Pharms.
  • TEMOVATE Cream® contains Clobetasol propionate 0.5 mg/g in a cream base of propylene glycol, glyceryl monostearate, cetostearyl alcohol, glyceryl stearate, PEG 100 stearate, white wax, chlorocresol, sodium citrate, citric acid monohydrate and purified water.
  • TEMOVATE® E is another approved product by U.S. Food and Drug Administration (FDA) containing Clobetasol propionate (0.05% w/w) in a cream base of cetostearyl alcohol, isopropyl myristate, propylene glycol, ceteth-20, dimethicone 350, citric acid monohydrate, sodium citrate, imidurea, and purified water.
  • FDA Food and Drug Administration
  • U.S. Pat. No. 5,972,920 is related to a formulation characterized by a carrier compound formed of a combination of two components in a volume ratio of about 50/50, wherein a first carrier component is selected from the group consisting essentially of ethyl alcohol and isopropyl alcohol and a second carrier component is selected from the group consisting essentially of isopropyl myristate, isopropyl palmitate, octyl palmitate, octyl isononanoate, and isocetyl stearate.
  • the formulation also comprises an anionic surfactant.
  • PCT Application WO 2006/115987 is related to a method for treating psoriasis by spraying a pharmaceutical composition containing an effective amount of clobetasol propionate onto the skin with psoriasis, using a daily treatment for at least 4 weeks.
  • the preferred composition is a spray formulation of clobetasol propionate 0.05%, containing alcohol, isopropyl myristate, an anionic surfactant such as sodium lauryl sulfate, and optionally, an antimicrobial compound such as an antifungal compound, e.g., undecylenic acid.
  • U.S. Pat. Nos. 6,419,913 and 6,284,234 are related to topical delivery systems for active agents comprising micellar compositions.
  • U.S. Publication No. 2006/0099173 is related to a process of making a pharmaceutical composition for topical application, the composition being an emulsion comprising water and at least one active ingredient.
  • U.S. Publication No. 2007/0142343 is related to a composition comprising corticosteroids, penetration enhancers, solvents and emulsifiers.
  • the vehicle of this composition utilizes at least two penetration enhancers, including diisopropyl adipate, dimethyl isosorbide, propylene glycol, 1,2,6-hexanetriol, and benzyl alcohol.
  • US publication No. 2009/0104131 is related to a topically applicable compositions in the form of oil-in-water (O/W) emulsions contain a pro-penetrating system including at least one glycol and at least one additional pro-penetrating agent, a suitable emulsifying system and at least one active agent of the family of steroidal anti-inflammatory agents.
  • a pro-penetrating system including at least one glycol and at least one additional pro-penetrating agent, a suitable emulsifying system and at least one active agent of the family of steroidal anti-inflammatory agents.
  • Propylene glycol is disclosed as pro-penetrating agent.
  • U.S. Pat. No. 6,579,512 is related to topical spray composition comprising clobetasol propionate, ethanol, propellant and isopropyl myristate.
  • U.S. Pat. Nos. 7,700,081 and 7,316,810 are related to clobetasol propionate (0.05 wt %) shampoo compositions used for washing and treating the ailments of scalp.
  • Dermatological corticosteroids in particular clobetasol propionate topical preparations face multiple problems, such as delivery efficiency, stability, and tolerability, in particular with respect to excipients that would not cause irritation.
  • corticosteroids can be absorbed through the skin and can cause systemic side effects, for example hypothalamic pituitary adrenal (HPA) axis suppression. Therefore, to avoid unwanted side effects, the corticosteroid is used at a concentration as low as possible.
  • HPA hypothalamic pituitary adrenal
  • topical preparations containing low concentrations corticosteroids cannot ensure a sufficient therapeutic effect.
  • U.S. Publication No. 2010/0249060 is related to a low dose clobetasol propionate composition in aqueous vehicle based on propylene glycol and macrogol-glycerol hydroxysterate.
  • compositions comprising clobetasol appears to show adverse effect on endocrine system as described in TEMOVATE Cream® and TEMOVATE E Cream® labels (Hypothalamic-pituitary-adrenal axis suppression).
  • the present invention provides a topical pharmaceutical composition comprising at least one corticosteroid and at least one penetration enhancing agent.
  • the composition of the present invention is substantially free of propylene glycol.
  • the present invention provides a topical pharmaceutical composition
  • a topical pharmaceutical composition comprising a low dose of clobetasol; an oil phase comprising: at least one penetration enhancing agent and a non-polymeric thickening agent; an aqueous phase; and optionally at least one pharmaceutically acceptable excipient, wherein the composition is substantially free of propylene glycol and substantially free of polymers; wherein the topical composition does not show significant adverse effects on endocrine system.
  • FIG. 1 shows drug release for a composition of the invention and a commercially available product.
  • FIG. 2 shows drug release for a composition of the invention and a commercially available product.
  • FIG. 3 shows percent of inhibition of redness for an untreated control, compositions of the invention, and a commercially available product.
  • FIG. 4 shows and AUC of skin redness for an untreated control, compositions of the invention, and a commercially available product.
  • Clobetasol as used herein encompasses pharmaceutically acceptable, pharmacologically active derivatives of clobetasol, including clobetasol propionate, clobetasol base form, its ester form, its isomer form, both individual enantiomers of clobetasol (dextrogyral and levogyral enantiomers) in their substantially pure form and their pharmaceutically acceptable salts, mixtures (in any ratio) of clobetasol enantiomers and their pharmaceutically acceptable salts, and active metabolites of clobetasol and their pharmaceutically acceptable salts, unless otherwise noted.
  • the solid state form of clobetasol used in the composition of the present invention is not critical.
  • clobetasol propionate can be amorphous or crystalline.
  • clobetasol(s) are corticosteroids.
  • active active agent
  • compound refers to corticosteroids, including clobetasol, or to pharmaceutically acceptable forms thereof.
  • low dose means an amount of corticosteroid, sufficient to induce a positive effect in the condition to be treated when provided in composition according to the present invention, but low enough to avoid serious side effects (at a reasonable benefit/risk ratio), within the scope of sound medical judgment.
  • the “low dose” is a dose which is below the optimal dose for that corticosteroid when used in a single-compound treatment.
  • the effective amount of the corticosteroid will vary with the particular condition being treated, the age and physical condition of the patient being treated, the severity of the condition, the duration of the treatment, the nature of concurrent therapy, the specific compound or composition employed, the particular pharmaceutically-acceptable carrier utilized, and like factors within the knowledge and expertise of the attending physician.
  • substantially free indicates that the specified substance referred to is present in amounts not more than 10% by weight of the total composition.
  • pharmaceutically-acceptable means that inert excipients are suitable for use in contact with the tissues of humans and lower animals without undue toxicity, incompatibility, instability, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio.
  • ranges can be expressed as from “about” one particular value, and/or to “about” another particular value. It is also understood that there are a number of values disclosed herein, and that each value is also herein disclosed as “about” that particular value in addition to the value itself. For example, if the value “10” is disclosed, then “about 10” is also disclosed. It is also understood that each unit between two particular units are also disclosed. For example, if 10 and 15 are disclosed, then 11, 12, 13, and 14 are also disclosed.
  • the present invention can comprise or consist essentially of the components of the present invention as well as other ingredients or elements described herein.
  • “comprising” means the elements recited, or their equivalent in structure or function, plus any other element or elements which are not recited.
  • the terms “having,” “including,” and “comprised of” are also to be construed as open ended unless the context suggests otherwise.
  • “consisting essentially of” means that the invention may include ingredients in addition to those recited in the claim, but only if the additional ingredients do not materially alter the basic and novel characteristics of the claimed invention.
  • improved efficacy or “improving efficacy” or “improving therapeutic efficacy” as used herein refers to the therapeutically beneficial effects of the topical active with reduction of systemic adverse effects as described in the present invention.
  • enhanced flux refers to increase in the skin permeation of the active in skin layers of the subject up to dermis with less systemic exposure. i.e., enhanced flux allows to utilize lower dose of active to treat disease condition effectively.
  • penetration enhancing agent(s) as used herein means compounds that enhance the penetration rate of a corticosteroid through the skin or mucous membrane, such as by temporarily diminishing the impermeability of the skin or mucous membrane.
  • a penetration enhancing agent is a component used to enhance the penetration rate of steroid through the skin or mucous membrane, such as by temporarily diminishing the impermeability of the skin or membrane.
  • Penetration enhancing agents are also been known as “accelerants” and “absorption promoters.”
  • Suitable penetration enhancing agents include, but are not limited to, polyols, glycols (except propylene glycol), ethers, glycol ethers, esters, sulfoxides, fatty acids, fatty acid esters, fatty alcohols, essential oils, terpenes, terpenoids, PEGylated fatty acids, PEGylated fatty acid esters, PEGylated fatty alcohols and mixtures thereof, including polyethylene glycol, polyethylene glycol monolaurate, and butanediol; sulfoxides, including dimethylsulfoxide and decylmethylsulfoxide; ethers, including diethylene glycol monoethyl ether and diethylene glycol monomethyl ether; fatty acids, including lauric acid, oleic acid, and valeric acid; fatty acid esters, including isopropyl myristate, isopropyl palmitate, methyl propionate, and ethyl oleate; nitrogenous compounds including
  • localized region refers to a discrete location on the body surface of the subject, such as a location experiencing a symptom of condition being treated.
  • subject includes both human and animal subjects.
  • veterinary therapeutic uses, as well as uses in connection with human subjects are provided in accordance with the present invention.
  • treatment relate to curing or substantially curing a condition, as well as ameliorating at least one symptom of the condition, and are inclusive of prophylactic treatment and therapeutic treatment.
  • treatment that is administered prior to clinical manifestation of a condition then the treatment is prophylactic (i.e., it protects the subject against developing the condition).
  • the treatment is therapeutic (i.e., it is intended to diminish, ameliorate, control, or maintain the existing condition and/or side effects associated with the condition).
  • the terms relate to medical management of a subject with the intent to substantially cure, ameliorate, stabilize, or substantially prevent a condition, including but not limited to prophylactic treatment to preclude, avert, obviate, forestall, stop, or hinder something from happening, or reduce the severity of something happening, especially by advance action.
  • treatment or treating include, but are not limited to: inhibiting the progression of a condition of interest; arresting or preventing the development of a condition of interest; reducing the severity of a condition of interest; ameliorating or relieving symptoms associated with a condition of interest; causing a regression of the condition of interest or one or more of the symptoms associated with the condition of interest; and preventing a condition of interest or the development of a condition of interest.
  • the present invention includes a topical composition including a corticosteroid.
  • the present invention provides a topical pharmaceutical composition comprising at least one corticosteroid and at least one penetration enhancing agent.
  • the composition of the present invention is substantially free of propylene glycol.
  • the composition includes not more than 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1% by weight of the total composition.
  • the present invention provides a topical pharmaceutical composition comprising therapeutically effective amount of clobetasol propionate, at least one penetration enhancing agent and at least one pharmaceutically acceptable excipient, wherein the composition is substantially free of propylene glycol.
  • the present invention provides a method to provide an enhanced flux of clobetasol propionate through the localized region of the body surface to reach the dermis layer, comprising administering to an individual the effective amount of topical pharmaceutical composition comprising:
  • an oil phase comprising: at least one penetration enhancing agent and a non-polymeric thickening agent
  • composition is substantially free of propylene glycol and substantially free of polymers.
  • composition of the present application provides comparable or enhanced efficacy over the commercially available clobetasol propionate 0.05% w/w cream composition (TEMOVATE E® cream) and does not show significant adverse effect on endocrine system as described herein and as known to those of ordinary skill in the art.
  • Topical corticosteroids provide adverse effect on human endocrine system.
  • High potent corticosteroids show high incidence of systemic side effects such as suppression of hypothalamus-pituitary-adrenal (HPA) axis this effect is reversible.
  • Topical corticosteroids are absorbed systematically and show suppression of HPA axis.
  • the HPA axis suppression is critical safety issue in topical corticosteroid therapy.
  • the HPA axis suppression is generally evaluated by certain parameters such as levels of cortisol and levels of dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEAS) in a subject's blood during treatment schedule.
  • DHEA dehydroepiandrosterone
  • DHEAS dehydroepiandrosterone sulfate
  • the cortisol levels are determined by ACTH (cosyntropin) stimulation test.
  • the ACTH stimulation test measures how the adrenal glands respond to adrenocorticotropic hormone (ACTH).
  • ACTH is a hormone produced in the pituitary gland that stimulates the adrenal glands to release a hormone called cortisol.
  • cortisol The man-made form of ACTH is called cosyntropin.
  • the normal level of cortisol is less than 18 mcg/dL in a normal subject and cortisol level goes higher than 18 to 20 micrograms per deciliter (mcg/dL) after ACTH injection to the subject and similarly DHEA/DHEAS levels also changes in a subject who undergo treatment with topical corticosteroids, generally the standard reference range of DHEA is 280-640 ⁇ g/dL in men and 65-380 ⁇ g/dL is in women.
  • Clobetasol propionate is a highly potent topical corticosteroid, which is known to have effect on endocrine system which suppresses the HPA axis at doses as low as 2 grams per day.
  • Shortcomings of the previously-described therapy include necessity of periodic evaluation for HPA axis suppression and modification in dosing and administrating schedule due to the HPA axis suppression.
  • the topical composition of the present invention does not show significant adverse effect on endocrine system, when applied twice daily for 15 days (2 weeks) in the subjects having affected body surface area of at least 20% up to 50% excluding face, scalp, groin, axillae and other intertriginous areas.
  • the topical composition of the present invention comprises a therapeutically effective amount of clobetasol; an oil phase comprising at least one skin penetration enhancer; an aqueous phase and optionally one pharmaceutically acceptable excipient.
  • the present invention provides a method for prophylaxis, amelioration, or treatment of psoriasis, relief of the inflammatory and pruritic manifestations of steroid responsive dermatoses, erythema, contact sensitivity reactions, and other associated diseases or disorders, by administering to an individual the effective amount of topical composition comprising:
  • an oil phase comprising: at least one penetration enhancing agent and a non-polymeric thickening agent
  • composition is substantially free of propylene glycol and substantially free of polymers.
  • the clobetasol present in the composition amounts from about 0.005% to about 0.1% of the total weight of the composition. In an aspect, the clobetasol propionate is present in amounts from about 0.005% to about 0.05% of the composition, or in amounts up to about 0.025% of the total weight of the composition.
  • the clobetasol propionate is present in amounts up to about 0.005, 0.006, 0.007, 0.008, 0.009, 0.010, 0.011, 0.012, 0.013, 0.014, 0.015, 0.016, 0.017, 0.018, 0.019, 0.020, 0.021, 0.022, 0.023, 0.024, 0.025, 0.026, 0.027, 0.028, 0.029, 0.030, 0.031, 0.032, 0.033, 0.034, 0.035, 0.036, 0.037, 0.038, 0.039, 0.040, 0.041, 0.042, 0.043, 0.044, or 0.045% of the total weight of the composition.
  • the clobetasol propionate is present in amounts of less than 0.050% of the total weight of the composition. In some embodiments, the clobetasol propionate is present in amounts of about 0.010 to about 0.040% of the total weight of the composition. In some embodiments, the clobetasol propionate is present in amounts of about 0.015 to about 0.035% of the total weight of the composition. In some embodiments, the clobetasol propionate is present in amounts of about 0.020 to about 0.030% of the total weight of the composition.
  • the composition of the present invention comprises at least one penetration enhancing agent in an amount of from about 1% to about 30.0% of the weight of the composition, or in amounts of from about 0.01% to about 10.0% of the composition.
  • the at least one penetration enhancing agent is provided in amounts up to about 0.05, 0.10, 0.15, 0.20, 0.25, 0.30, 0.35, 0.40, 0.45, 0.50, 0.55, 0.60, 0.65, 0.70, 0.75, 0.80, 0.85, 0.90, 0.95, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, or 10% of the weight of the composition.
  • the present invention provides a topical pharmaceutical composition
  • a topical pharmaceutical composition comprising: a low dose of clobetasol propionate in an amount selected from about 0.005% to about 0.1% of the total weight of the composition; an oil phase comprising at least one penetration enhancing agent in an amount from about 0.01% to about 15.0% of the total weight of the composition and a non-polymeric thickening agent, an aqueous phase, and optionally, at least one pharmaceutically acceptable excipient, wherein the composition is substantially free of propylene glycol and substantially free of polymers.
  • the present invention provides a method for prophylaxis, amelioration or treatment of skin diseases or disorders such as psoriasis/psoriatic plaques, relief of the inflammatory and pruritic manifestations of steroid responsive dermatoses, erythema, contact sensitivity reactions, atopic dermatitis, seborrhoeic dermatitis, eczema, plaque psoriasis, erythrodermic psoriasis, psoriasis of thescalp, and other associated diseases or disorders, by administering to an individual an effective amount of a topical composition comprising: (a) clobetasol propionate in an amount of about 0.025% of the total weight of the composition, (b) an oil phase comprising: at least one penetration enhancing agent and a non-polymeric thickening agent, (c) an aqueous phase, and (d) at least one pharmaceutically acceptable excipient,
  • composition is substantially free of propylene glycol and the composition has comparable or improved efficacy compared to the commercially available clobetasol propionate 0.05% w/w cream composition (TEMOVATE® cream).
  • topical composition is administered twice-a-day for a period of 4 weeks or topical composition is administered twice-a-day for a period of at least 2 weeks.
  • the penetration enhancing agent used in the present invention is selected from the group consisting of polyols, glycols (except propylene glycol), ethers, glycol ethers, esters, sulfoxides, fatty acids, fatty acid esters, fatty alcohols, essential oils, terpenes, terpenoids, PEGylated fatty acids, PEGylated fatty acid esters, PEGylated fatty alcohols, and mixtures thereof
  • the penetration enhancing agent is diethylene glycol monoethylether.
  • composition of the present invention comprises one or more additional active agents that are useful in the management of psoriasis and associated pathological conditions including synthetic, semi-synthetic, or naturally obtained active agents.
  • composition of the present invention can be used for prophylaxis, amelioration, or treatment of skin diseases and disorders, by administering a pharmaceutically effective amount of the composition to a subject in need thereof.
  • compositions of the present invention are also useful in conjunction with other therapies, such as phototherapy.
  • the present invention provides a process for preparing a topical pharmaceutical composition, comprising:
  • step (iii) preparing an emulsion by adding the oil phase of step (i) to the aqueous phase of step (ii) or vice versa under constant homogenization
  • step (v) adding the clobetasol solution obtained in step (iv) to the emulsion prepared in step (iii) followed by homogenization and cooling to obtain a cream composition.
  • the present invention provides a process for preparing topical pharmaceutical composition comprising:
  • step (iii) preparing an emulsion by adding the oil phase of step (i) to the aqueous phase (ii) or vice versa under homogenization, dissolving a premixed solution of clobetasol propionate in a diethylene glycol monoethyl ether and the followed by addition of BHT and homogenizing to obtain a clobetasol propionate solution, and
  • step (iv) adding the steroid solution obtained in step (iv) to the emulsion prepared in step (iii) followed by homogenization to obtain a cream composition.
  • compositions of the present invention using one or more other corticosteroids can be prepared by using a process similar to that described above.
  • the topical pharmaceutical composition of the present invention is useful in the prophylaxis, amelioration or treatment of skin diseases or disorders such as psoriasis/psoriatic plaques, relief of the inflammatory and pruritic manifestations of steroid responsive dermatoses, erythema, contact sensitivity reactions, atopic dermatitis, seborrhoeic dermatitis, eczema, plaque psoriasis, erythrodermic psoriasis, psoriasis of the scalp, and other associated diseases or disorders.
  • skin diseases or disorders such as psoriasis/psoriatic plaques, relief of the inflammatory and pruritic manifestations of steroid responsive dermatoses, erythema, contact sensitivity reactions, atopic dermatitis, seborrhoeic dermatitis, eczema, plaque psoriasis, erythrodermic psoriasis, psorias
  • the topical compositions of the invention containing an oil phase that comprises at least one penetration enhancing agent, and an aqueous phase provides an enhanced flux of clobetasol through the localized region of the body surface to reach the dermis layer; this advantageously allows for the use of a lower concentration of clobetasol, i.e., about 50% less than the commercially available dosage form TEMOVATE Cream® (which contains 0.05% of clobetasol propionate), while providing a similar or improved efficacy and provides no significant effect on endocrine system i.e., HPA axis suppression.
  • TEMOVATE Cream® which contains 0.05% of clobetasol propionate
  • the pharmaceutical composition of the present invention containing 3% of penetration enhancing agent provides similar or improved efficacy as compared to TEMOVATE Cream® (which contains 0.05% of clobetasol propionate).
  • the pharmaceutical composition of the present invention containing 10% of penetration enhancing agent.
  • topical pharmaceutical composition of the present invention which is free of propylene glycol, is non-irritating, non-toxic, and well-tolerated and are free of any undesired attributes, thereby providing a high degree of patient compliance.
  • compositions of the present application present invention are physically and chemically stable.
  • topical pharmaceutical compositions of the present invention are useful in the relief of the inflammatory and pruritic manifestations of steroid responsive dermatoses, and further can provide a moisturizing and/or soothing effect at the site of application to the skin.
  • the composition of the application reduces the dryness that accompanies the build-up of skin in psoriatic plaques.
  • composition of the application can be applied directly to the psoriatic lesions or dermatoses and can help reduce inflammation, remove built-up scale, reduce skin turnover, and/or clear affected skin of plaques.
  • compositions of the present invention can utilize any topical corticosteroids, either alone or in combination of others.
  • suitable examples of topical corticosteroids include, but not limited to, clobetasol propionate, alclometasone dipropionate, amcinonide, beclomethasone dipropionate, betamethasone benzoate, betamethasone dipropionate, betamethasone sodium phosphate, betamethasone valerate, budesonide, clocortolone pivalate, desonide, desoximetasone, dexamethasone, dexamethasone acetate, dexamethasone nicotinate, dexamethasone propionate, dexamethasone sodium phosphate, dexamethasone valerate, diflorasone diacetate, diflucortolone valerate, fluandrenolide, flumethasone pivalate, fluocinolone acetonide, fluocinon
  • compositions of the present invention may be in the form of solution, suspension, emulsions, creams, ointments, lotions, microemulsions, nanoemulsions, emulgels, liposomes, micelle, reverse micelle, gels, hydrogels, sprays and the like.
  • the topical composition of the present invention may be in form of compositions, comprising two phases: an oil phase and an aqueous phase and compositions of the present invention may be in the form of emulsions, creams, lotions, microemulsions, nanoemulsions, emulgels, liposomes, micelles, reverse micelle, spray and the like.
  • compositions may be in the form of an emulsion.
  • the emulsion can be in the form of an oil-in-water type of emulsion or a water-in-oil type of emulsion.
  • An aqueous-based emulsion such as an oil-in-water emulsion, frequently has lower viscosity than other emulsion types and exhibits appreciable storage stability and patient compliance.
  • oil-in-water emulsions have better skin feel properties, when applied to the skin, as these give sensations similar to an aqueous material.
  • compositions of the present invention are formulated as emulsions, comprising an oily or hydrophobic phase, an aqueous or hydrophilic phase, and an emulsifier.
  • oily phase is dispersed as droplets within an aqueous continuous phase, this is called an “oil-in-water” type of emulsion.
  • aqueous phase is dispersed as droplets within an oily continuous phase, this is called a “water-in-oil” type of emulsion.
  • a pharmaceutical composition of the present invention is aqueous-based topical oil-in-water emulsion.
  • the “aqueous-based” term is defined as an emulsion which comprises high percentage of water.
  • the aqueous-based oil-in-water emulsion composition of the present invention comprises at least 60% of water in the final composition, or comprises at least 70% of water in the final composition.
  • an aqueous-based topical oil-in-water emulsion composition of the present invention comprises: a therapeutically effective amount of a corticosteroid and at least one pharmaceutically acceptable excipient, wherein the composition is substantially free of propylene glycol and substantially free of polymers.
  • an aqueous-based topical oil-in-water emulsion composition of the present invention comprises: (a) a therapeutically acceptable amount of clobetasol (b) a discontinuous oil phase comprising: a solvent and at least one penetration enhancing agent; (c) a continuous aqueous phase; and (d) at least one pharmaceutically acceptable excipient, wherein the composition is substantially free of propylene glycol and substantially free of polymers.
  • the topical composition comprises: (a) a therapeutically acceptable amount of clobetasol of about 0.025% w/w; (b) an oil phase comprising: at least one penetration enhancing agent, and a non-polymeric thickening agent; (c) an aqueous phase; and (d) optionally one pharmaceutically acceptable excipient; wherein the said topical composition is substantially free of propylene glycol and substantially free of polymers; wherein the topical composition provides no significant adverse effect on endocrine system.
  • an aqueous based topical oil-in-water emulsion composition of the present invention has viscosity in the range of from about 10 cP to about 100000 cP.
  • the viscosities of the aqueous-based emulsion compositions of the present invention may be in the range of about 0.01-100 Pascal second, “Pa ⁇ s” (10-1,00,000 cP), or about 0.1 to 100 Pa ⁇ s (100-1,00,000 cP) or about 1-50 Pa ⁇ s (1000-50,000 cP), or about 0.01-15 Pa ⁇ s (10-15,000 centipoise, “cP”), or about 0.02-1.5 Pa ⁇ s (20-1,500 cP), or about 0.05-1 Pa ⁇ s (50-1,000 cP).
  • the viscosity of topical compositions of the present invention is in the range of from about 0.1 cP to about 500 cP when measured by Brookfield viscometer Cap 2000+ with spindle no. 1 at 530 rpm at 25° C.
  • composition of the present invention includes one or more pharmaceutically acceptable excipient, which may act as carrier(s), emulsifier(s), co-emulsifier(s) solvent(s), co-solvents(s), emollient(s), antioxidant(s), preservative(s), gelling or thickening agent(s), polymer(s), surfactant(s), soothing agent(s), pH modifier(s), solubilizer(s), humectants(s), moisturizer(s), oily base(s), and the like.
  • pharmaceutically acceptable excipient may act as carrier(s), emulsifier(s), co-emulsifier(s) solvent(s), co-solvents(s), emollient(s), antioxidant(s), preservative(s), gelling or thickening agent(s), polymer(s), surfactant(s), soothing agent(s), pH modifier(s), solubilizer(s), humectants(s), moisturizer(s), oily base(s), and
  • carrier denotes organic or inorganic ingredients, natural or synthetic, with which an active ingredient is combined to facilitate application of a composition.
  • carriers include, but not limited to, water, acetone, alone or in combination with materials such as silicone fluids.
  • the carrier can comprise, in addition to water, water-immiscible substances such as any pharmaceutically acceptable fatty esters of natural fatty acids, triglycerides of animal or vegetable, medium chain triglycerides, mixtures of mono-, di- and/or triglycerides, waxes, hydrogenated vegetable oils, and mixtures thereof
  • emulsifying agents include, but not limited to, disodium cocoampho diacetate, oxyethylenated glyceryl cocoate (7 EO), PEG-20 hexadecenyl succinate, PEG-15 stearyl ether, ricinoleic monoethanolamide monosulfosuccinate salts, oxyethylenated hydrogenated ricinoleic triglyceride containing 60 ethylene oxide units such as the products marketed by BASF under the trademarks CREMOPHOR® RH 60 or CREMOPHOr® RH 40 (polyoxyl 40 hydrogenated castor oil), polymers such as poloxamers, which are block copolymers of ethylene oxide and propylene oxide, and the nonsolid fatty substances at room temperature (that is to say, at temperatures ranging from about 20 to 35° C.) such as sesame oil, sweet almond oil, apricot stone oil, sunflower oil, octoxyglyceryl palmitate (or 2-ethyl
  • Sorbitan fatty acid esters are a series of mixtures of partial esters of sorbitol and its mono- and dianhydrides with fatty acids. Sorbitan esters include products marketed as ARLACEL® 20, ARLACEL 40, ARLACEL 60, ARLACEL 80, ARLACEL83, ARLACEL 85, ARLACEL 987, ARLACEL C, PEG-6 stearate and glycol stearate and PEG-32 stearate (TEFOSE® 63), and PEG-6 stearate and PEG-32 stearate (TEFOSE® 1500), glyceryl stearate and PEG 100 stearate (TEFOSE® 165) and any mixtures thereof.
  • Sorbitan esters include products marketed as ARLACEL® 20, ARLACEL 40, ARLACEL 60, ARLACEL 80, ARLACEL83, ARLACEL 85, ARLACEL 987, ARLACEL C, PEG-6 stearate
  • Polyethylene glycol ethers of stearic acid are in another group of emulsifiers that can be used in the emulsions.
  • examples of polyethylene glycol ethers of stearic acid include, but not limited to, steareth-2, steareth-4, steareth-6, steareth-7, steareth-10, steareth-11, steareth-13, steareth-15, steareth-20, polyethylene glycol ethers of stearyl alcohol (steareth 21), and any mixtures thereof.
  • Other emulsifying agents include sodium lauryl sulphate, cetyl trialkyl ammonium bromide, polyoxyethylene sorbitan fatty acid esters, and any mixtures thereof
  • Nonionic emulsifying agents include those that can be broadly defined as condensation products of long chain alcohols, e.g., C8-30 alcohols, with sugar or starch polymers, i.e., glycosides.
  • Various sugars include, but not limited to, glucose, fructose, mannose, and galactose
  • various long chain alcohols include, but are not limited to, decyl alcohol, cetyl alcohol, stearyl alcohol, lauryl alcohol, myristyl alcohol, oleyl alcohol, and any mixtures thereof
  • nonionic emulsifying agents include condensation products of alkylene oxides with fatty acids such as alkylene oxide esters of fatty acids.
  • Other nonionic surfactants are the condensation products of alkylene oxides with 2 moles of fatty acids such as alkylene oxide diesters of fatty acids.
  • Emulsifying agents can also include any of a wide variety of cationic, anionic, zwitterionic, and amphoteric surfactants that are known in the art.
  • anionic emulsifying agents include, but not limited to, alkyl isethionates, alkyl and alkyl ether sulfates and salts thereof, alkyl and alkenyl ether phosphates and salts thereof, alkyl methyl taurates, and soaps (e.g., alkali metal salts and sodium or potassium salts) of fatty acids.
  • amphoteric and zwitterionic emulsifying agents include those which are broadly described as derivatives of aliphatic secondary and tertiary amines in which the aliphatic radical can be straight or branched chain, wherein one of the aliphatic substituents contains from about 8 to about 22 carbon atoms and one contains an anionicwater solubilizing group, e.g., carboxy, sulfonate, sulfate, phosphate, or phosphonate. Specific examples include, but not limited to, alkylimino acetates, iminodialkanoates and aminoalkanoates, imidazolinium and ammonium derivatives.
  • Other suitable amphoteric and zwitterionic emulsifying agents include betaines, sultaines, hydroxysultaines, alkyl sarcosinates, and alkanoyl sarcosinates.
  • Silicone emulsifying agents are typically organically modified organopoly siloxanes, sometimes called silicone surfactants.
  • Useful silicone emulsifying agents include dimethicone copolyols. These materials are polydimethyl siloxanes, which have been modified to include polyether side chains such as polyethylene oxide chains, polypropylene oxide chains, mixtures of these chains, and polyether chains containing moieties derived from both ethylene oxide and propylene oxide.
  • Co-emulsifiers or secondary emulsifying agents include, but not limited to, polyoxylglycerides such as oleoyl macrogolglycerides (LABRAFIL® M 1944CS), linoleoyl macrogolglycerides (LABRAFIL® M 2125CS), caprylocaproyl macrogolglycerides (LABRASOL®), cetyl alcohol (and) ceteth-20 (and) steareth-20 (EMULCIRETM 61 WL 2659), glyceryl stearate (and) PEG-75 stearate (GELOT® 64), d-alpha tocopheryl polyethylene glycol 1000 succinate (TPGS) and any mixtures thereof.
  • polyoxylglycerides such as oleoyl macrogolglycerides (LABRAFIL® M 1944CS), linoleoyl macrogolglycerides (LABRAFIL® M 2125CS), caprylocaproyl macrogolglycerides (LABRASOL®),
  • solvent refers to components that aid in the dissolution of the drug in the formulation. Solvents serve to maintain a solution of the drug in the composition. Some solvents can also enhance percutaneous penetration of drug and/or act as humectants.
  • solvents can include water-immiscible substances such as fatty esters of natural fatty acids, triglycerides of animal or vegetable, medium chain triglycerides, mixtures of mono-, di- and/or triglycerides, waxes, hydrogenated vegetable oils, and mixtures thereof.
  • Some specific examples include, but not limited to, castor oil, isopropyl myristate, dimethyl isosorbide, oleyl alcohol, labrafil, labrasol, medium chain triglyceride, diethyl sebacate, lanolin oil, citrate triisocetyl triglycerides having 10-18 carbon atoms, caprylic/capric triglycerides, coconut oil, corn oil, cottonseed oil, linseed oil, oil of mink, olive oil, palm oil, sunflower oil, nut oil, saturated paraffin oils, mineral oils, vegetable oils or glycerides, and the like.
  • Solvent can also be selected from the group comprising monoalkyl ether of diethylene glycol such as diethylene glycol monomethyl ether, diethylene glycol monoethyl ether or mixtures thereof.
  • the solvent is diethylene glycol monoethyl ether. It is marketed by Gattefosse under the trade name TRANSCUTOL®, TRANSCUTOL-P®, TRANSCUTOL-CG®, and TRANSCUTOL-HP®.
  • a solvent is selected from the group consisting of: mineral oil, isopropyl myristate, dimethyl isosorbide, oleyl Alcohol, labrafil, labrasol, medium chain triglyceride, diethyl sebacate, ammonium lauryl sulfate, lauramine oxide, sodium laureth sulfate, n-methyl-2-pyrrolidinone, octanoic — acid, cocobetaine, dimethylsulfoxide, sodium laureth 2 sulfate, benzyl_alcohol, ethylacetate, lactic acid, oleic acid, ethylacetate, spearmint oil, isostearic acid, ethanol, propylene glycol diacetate, dimethyl isosorbide, 1-butanol, methyl gluceth-10, sodium lauroylsarcosinate, polysorbate 20, isopropyl alcohol, 1-butanol, Capryol 90, sorbitan
  • emollients are substances that soften and soothe the skin. They are used to prevent dryness and scaling of the skin.
  • emollients that can be used in the present invention include, but not limited to, oils of natural origin such as almond oil, coconut oil, olive oil, palm oil, peanut oil and the like, fatty acids such as lauric acid, myristic acid, palmitic acid, and stearic acid, monohydric alcohol esters of the fatty acids such as ethyl laurate, isopropyl laurate, ethyl myristate, n-propyl myristate, isopropyl myristate, ethyl palmitate, isopropyl palmitate, methyl palmitate, methyl stearate, ethyl stearate, isopropyl stearate, butyl stearate, isobutyl stearate, amyl stearate, and isoamyl stearate, glycol
  • Exemplary emollients include caprylic/capric triglyerides, castor oil, ceteareth-20, ceteareth-30, cetearyl alcohol, ceteth 20, cetostearyl alcohol, cetyl alcohol, cetyl stearyl alcohol, cocoa butter, diisopropyl adipate, glycerin, gyceryl monooleate, glyceryl monostearate, glyceryl stearate, isopropyl myristate, isopropyl palmitate, lanolin, lanolin alcohol, hydrogenated lanolin, liquid paraffins, linoleic acid, mineral oil, oleic acid, white petrolatum, polyethylene glycol, polyoxyethylene glycol fatty alcohol ethers, silicones and mixtures thereof.
  • Silicones are typically organically modified organopoly siloxanes, sometimes called silicone surfactants.
  • Useful polysiloxane or silicone emollients include, but not limited to, polysiloxane polymer, dimethicone copolyols, cyclomethicones. These materials are polydimethyl siloxanes, which have been modified to include polyether side chains such as polyethylene oxide chains, polypropylene oxide chains, mixtures of these chains, and polyether chains containing moieties derived from both ethylene oxide and propylene oxide.
  • antioxidants are substances which inhibit oxidation or suppress reactions promoted by oxygen or peroxides. Antioxidants, especially lipid-soluble antioxidants, can be absorbed into the cellular membrane to neutralize oxygen radicals and thereby protect the membrane. Suitable antioxdants that can be used in the present invention include, but not limited to, ascorbic acid (vitamin C), glutathione, lipoic acid, uric acid, sorbic acid, carotenes, a-tocopherol (vitamin E), TPGS, ubiquinol, butylated hydroxyanisole, butylated hydroxytoluene, sodium benzoate, propyl gallate (PG, E310), and tertiary-butylhydroquinone.
  • vitamin C ascorbic acid
  • PG propyl gallate
  • E310 tertiary-butylhydroquinone
  • preservative refers to a natural or synthetic chemical that prevents the decomposition of the composition by microbial growth or by undesirable chemical changes. Preservatives can desirably be incorporated into a composition for protecting against the growth of potentially harmful microorganisms. While microorganisms tend to grow in an aqueous phase and can also reside in a hydrophobic or oil phase. Examples of preservatives that can be used in the present invention include, but not limited to, methylparaben, propylparaben, benzyl_alcohol, chlorocresol, benzalkonium chloride, cetrimonium chloride, sodium edetate, boric acid, sorbic acid, or any mixtures thereof.
  • thickening agents or “gelling agents” are used to give bulkiness to the composition.
  • thickening agents or gelling agents include, but not limited to carbomers, polyethylene glycols, acrylate polymers, methacrylate polymers, polyvinylpyrrolidones, copolymers based on butyl methacrylate and methyl methacrylate povidone, vinyl acetates, polyvinyl acetates, celluloses, gums, alginates, cellulose acetate phthalates, cellulose acetate butyrates, hydroxypropyl methyl cellulose phthalates, and the like.
  • Examples include CARBOPOL® products, PEG 400, EUDRAGIT® 100, EUDRAGIT® RSPO, EUDRAGIT® RLPO, EUDRAGIT® ND40, PLASDONE®, copolymers based on butyl methacrylate and methyl methacrylate (PLASTOID® B), alkyl celluloses such as ethyl celluloses and methyl celluloses, hydroxyalkyl celluloses such as hydroxyethyl cellulose and hydroxypropyl cellulose, hydroxyalkyl alkyl celluloses such as hydroxypropyl methyl celluloses and hydroxybutyl methyl celluloses, gums such as xanthan gum, tragacanth, guar gum, locust bean gum, acacia, and the like.
  • PLASTOID® B alkyl celluloses such as ethyl celluloses and methyl celluloses
  • hydroxyalkyl celluloses such as hydroxyethyl cellulose and
  • the thickening agents are non-polymeric thickening agents
  • examples of non-polymeric thickening agent are fatty alcohol selected from group comprising: cetyl alcohol, paraffin, stearyl alcohol, white wax, wax cetyl esters, microcrystalline wax, anionic emulsifying wax, nonionic emulsifying wax, yellow wax, castor oil, ceresin, cetostearyl alcohol, cyclomethicone, glyceryl behenate, hectorite, myristyl alcohol, cetylstearyl alcohol, triolein, and lanolin.
  • Fatty alcohols that can be used as non-polymeric thickening agent include but not limited to stearyl alcohol, oleyl alcohol, cetyl alcohol, cetostearyl alcohol are long chain fatty alcohols.
  • Stearyl Alcohol is a white, waxy solid with a faint odor, while oleyl alcohol and octyl dodecanol are clear, colorless liquids.
  • Oleyl alcohol is an unsaturated fatty alcohol, similar to the saturated fatty alcohols stearyl alcohol and cetyl alcohol.
  • the topical compositions of the present invention are substantially free of polymers.
  • thickening agents or gelling agents or polymers that are useful in the present invention include, but not limited to, polyamides, polycarbonates, polyalkylenes, polyalkylene glycols, polyalkylene oxides, polyalkylene terepthalates, polyvinyl alcohols, polyvinyl ethers, polyvinyl esters, polyvinyl halides, polyglycolides, polysiloxanes, polyurethanes and copolymers thereof, cellulose ethers, cellulose esters, nitrocelluloses, polymers of acrylic and methacrylic esters, cellulose acetates, cellulose propionates, cellulose acetate butyrates, cellulose acetate phthalates, carboxylethyl celluloses, cellulose triacetates, cellulose sulphate sodium salts, poly(methyl ethacrylate), poly(ethylmethacrylate), poly(butylmethacrylate), poly(isobutylmethacrylate), poly(hexy
  • Examples of other useful polymers that can act as thickening agents or gelling agents include, but not limited to, synthetic polymers, such as polymers of lactic acid and glycolic acid, polyanhydrides, poly(ortho ester), polyurethanes, poly(butyric acid), poly(valeric acid), poly(caprolactone), poly(hydroxybutyrate), poly(lactide-co-glycolide), poly(lactide-co-caprolactone), and natural polymers such as alginate and other polysaccharides that include but not limited to arabinans, fructans, fucans, galactans, galacturonans, glucans, mannans, xylans (such as, for example, inulin), levan, fucoidan, carrageenan, galactocarolose, pectic acid, pectin, amylose, pullulan, glycogen, amylopectin, cellulose, dextran, pustulan, chitin, agarose, kerat
  • humectant refers to a hygroscopic substance that is often a molecule with several hydrophilic groups, most often hydroxyl groups, but amines and carboxyl groups, sometimes esterified, can be encountered as well; the affinity to form hydrogen bonds with molecules of water is crucial here.
  • humectants include, but not limited to, glycerol, and glyceryl triacetate (E1518).
  • Others can be sugar polyols like sorbitol (E420), xylitol and maltitol (E965), polymeric polyols like polydextrose (E1200), or natural extracts like quillaia (E999), lactic acid or urea.
  • excipients described above can have more than one function in a composition.
  • an excipient can be both a solvent and a penetration enhancer, or both a solvent and a carrier.
  • the categorizations of excipients described above are not to be construed as limiting or restricting in any manner.
  • composition of the present application can be applied directly onto affected areas of the skin, such as psoriatic plaques or dermatoses.
  • Cream compositions are applied in the form of film on the affected areas and, in embodiments, can provide release of the active agent for an extended duration of time.
  • the topical composition of the present invention comprising: (a) a low dose of clobetasol; (b) an oil phase comprising: at least one penetration enhancing agent, and a non-polymeric thickening agent; (c) an aqueous phase; and (d) optionally, at least one pharmaceutically acceptable excipient; wherein the said topical composition comprising low dose of clobetasol has dose proportionate release rate as to be equivalent or more than the release rates of TEMOVATE® 0.05% cream.
  • dose proportionate release rate means the topical composition of the present invention releases clobetasol such that concentration of clobetasol is equivalent to or more than the concentration delivered by 0.05% w/w topical clobetasol compositions such as TEMOVATE® cream.
  • the dose proportionate release rate is cumulative percentage of drug release is at least about 6% of applied dose of clobetasol in about 9 hours.
  • the topical composition of the present invention forms a depot on the skin forming an occlusive film, thereby extending the duration of active agent action while allowing “breathing” of the skin.
  • compositions of the present invention may have pH values ranging from about 3.0 to about 7.0, or from about 3.5 to about 6.0.
  • compositions of the present invention can be dispensed in any dispensing device such as laminated tubes or lacquered aluminum tubes.
  • Laminated tubes contains propylene glycol-free topical compositions, wherein the device is a lamitube comprised of 5 layers White PE, Ethylene acrylic acid (EAA), Aluminum foil, EAA, Virgin natural PE such that the composition is consistently discharge on application. Used.
  • the compositions of the present invention are dispensed in lacquered aluminum tubes which are very useful and very effective in storing the cream.
  • step (i) preparing an emulsion by adding the oil phase of step (i) to the aqueous phase (ii) or vice versa under homogenization
  • step (iv) adding the clobetasol propionate solution obtained in step (iv) to the emulsion prepared in step (iii) followed by homogenization to obtain a cream composition.
  • step (i) preparing an emulsion by adding the oil phase of step (i) to the aqueous phase (ii) or vice versa under homogenization
  • step (iv) adding the clobetasol propionate solution obtained in step (iv) to the emulsion prepared in step (iii) followed by homogenization to obtain a cream composition.
  • a composition of the present example was prepared by following Manufacturing Process-I using the following ingredient amounts.
  • a composition of the present example was prepared by following Manufacturing Process-I using the following ingredient amounts.
  • a composition of the present example was prepared by following Manufacturing Process-I using the following ingredient amounts.
  • a composition of the present example was prepared by following Manufacturing Process-I using the following ingredient amounts.
  • a composition of the present example was prepared by following Manufacturing Process-II using the following ingredient amounts.
  • a composition of the present example was prepared by following Manufacturing Process-II using the following ingredient amounts.
  • a composition of the present example was prepared by following Manufacturing Process-II using the following ingredient amounts.
  • compositions of the present invention All the compositions were evaluated for the physical changes such as color during the studies and all the compositions were remained in the off white to white cream throughout the study and did not show any significant changes.
  • Example 1 The prepared formulation of example 1, example 2, example 3, example 5, example 6 and example 7 were filled into closed container and exposed to the various stability testing conditions such as 25° C. and 60% relative humidity (RH), 30° C. and 65% RH, and 40° C. and 75% RH for twelve months, and analyses at various storage points are shown in Tables.
  • various stability testing conditions such as 25° C. and 60% relative humidity (RH), 30° C. and 65% RH, and 40° C. and 75% RH for twelve months, and analyses at various storage points are shown in Tables.
  • a Franz diffusion cell was fitted with a 0.45 ⁇ m nylon membrane clamped between the donor and receptor compartments.
  • the receptor media was a mixture of water and acetone (35:65 by volume) with a replacement volume of 11.0 mL, a sampling volume of 2.0 mL was drawn at 30 min, 1, 2, 4, 6, and 8 hours respectively, and the temperature was maintained at 32 ⁇ 0.5° C. About 200 mg of the formulation was applied uniformly over the membrane.
  • the donor compartment was covered using PARAFILM® (hydrocarbon wax and polyolefin blend).
  • Receptor fluid was analyzed for the drug, using high performance liquid chromatography (HPLC).
  • the UV erythema test is a suitable and accepted procedure for standardized comparison of anti-inflammatory action of topical medications.
  • individual sensitivity to UV were determined followed by performance of a light scale to determine the minimal erythemal dose (MED).
  • MED minimal erythemal dose
  • UV exposure was performed using 1.5 MED, with less than 30 cm 2 skin surface was irradiated.
  • the pharmaceutical compositions given in the examples and TEMOVATE E® cream were applied at the dose approximately 10 mg/cm 2 over the UV exposed skin surface.
  • the assessment of erythema suppression will be determined by chromametric measurement.
  • the percent of inhibition of redness and AUC in comparison with TEMOVATE E® cream is shown in FIGS. 3 and 4 , respectively.
  • the HPA axis suppression study enrolled 50 subjects with moderate to severe plaque psoriasis from 10 investigational sites in a ratio of 1:1 to test compositions (Example 5) to TEMOVATE cream.
  • the subjects enrolled in the study were above 18 years to 90 years with body surface, having affected area (psoriasis) of at least 20% to 50% BSA (body surface area) on the body, not including the face, scalp, groin, axillae and other intertriginous areas.
  • the subjects were having an IGA (investigator's global assessment score) grade of at least 3 (moderate) at the baseline visit.
  • ACTH (cosyntropin) stimulation test were carried out in all the subjects.
  • Cosyntropin is synthetic derivative of adrenocorticotropic hormone (ACTH) and Cosyntropin was injected to the subjects.
  • ACTH adrenocorticotropic hormone
  • the products were applied twice daily for 15 days to all affected areas on the body (20-50% BSA) 7 gm per day and results of cortisol levels, DHEA/DHEAS levels and changes in IGA score were evaluated on Day 1, Day 8, and Day 15. The change in IGA score from 3 to 0-1 was considered success in the treatment.

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US14/645,297 US20160184431A1 (en) 2014-03-11 2015-03-11 Topical compositions comprising a corticosteroid
EP16712608.5A EP3267978B1 (en) 2014-03-11 2016-03-11 Topical compositions comprising a corticosteroid
AU2016228574A AU2016228574B2 (en) 2014-03-11 2016-03-11 Topical compositions comprising a corticosteroid
JP2017547992A JP2018507891A (ja) 2014-03-11 2016-03-11 コルチコステロイドを含む局所用組成物
BR112017019352-3A BR112017019352B1 (pt) 2014-03-11 2016-03-11 Composições tópicas compreendendo um corticosteróide
CA2979051A CA2979051C (en) 2014-03-11 2016-03-11 Topical compositions comprising a corticosteroid
US15/068,428 US9855334B2 (en) 2014-03-11 2016-03-11 Topical compositions comprising a corticosteroid
ES16712608T ES2861374T3 (es) 2014-03-11 2016-03-11 Composiciones tópicas que comprenden un corticosteroide
KR1020177027989A KR20170123335A (ko) 2014-03-11 2016-03-11 코르티코스테로이드를 포함하는 국소용 조성물
PCT/US2016/022194 WO2016145407A1 (en) 2014-03-11 2016-03-11 Topical compositions comprising a corticosteroid
UAA201709298A UA121232C2 (uk) 2014-03-11 2016-03-11 Композиції для місцевого застосування, що містять кортикостероїд
RU2017134440A RU2690659C2 (ru) 2014-03-11 2016-03-11 Композиции для местного применения, содержащие кортикостероид
EA201791921A EA037380B1 (ru) 2014-03-11 2016-03-11 Композиция для местного применения, содержащая кортикостероид
CN201680027828.3A CN107872972A (zh) 2014-03-11 2016-03-11 包含皮质类固醇的外用组合物
NZ735341A NZ735341A (en) 2014-03-11 2016-03-11 Topical compositions comprising a corticosteroid
MX2017011521A MX2017011521A (es) 2014-03-11 2016-03-11 Composiciones topicas que comprenden un corticosteroide.
KR1020207012965A KR20200051854A (ko) 2014-03-11 2016-03-11 코르티코스테로이드를 포함하는 국소용 조성물
CONC2017/0010091A CO2017010091A2 (es) 2014-03-11 2017-10-04 Composiciones tópicas que comprenden un corticosteroide
US15/820,601 US11179465B2 (en) 2014-03-11 2017-11-22 Topical compositions comprising a corticosteroid
US16/244,880 US20190175735A1 (en) 2014-03-11 2019-01-10 Topical compositions comprising a corticosteroid
JP2020170680A JP2021008505A (ja) 2014-03-11 2020-10-08 コルチコステロイドを含む局所用組成物

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WO2016145407A1 (en) 2016-09-15
CO2017010091A2 (es) 2018-01-05
EP3267978B1 (en) 2021-01-20
US9855334B2 (en) 2018-01-02
US20190175735A1 (en) 2019-06-13
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EP3267978A1 (en) 2018-01-17
US20180078643A1 (en) 2018-03-22
US11179465B2 (en) 2021-11-23
NZ735341A (en) 2019-05-31
JP2018507891A (ja) 2018-03-22
JP2021008505A (ja) 2021-01-28
AU2016228574B2 (en) 2019-05-02
RU2017134440A3 (es) 2019-04-11
KR20200051854A (ko) 2020-05-13
RU2017134440A (ru) 2019-04-11
US20160199493A1 (en) 2016-07-14
AU2016228574A1 (en) 2017-09-28
EA037380B1 (ru) 2021-03-22
EA201791921A1 (ru) 2018-03-30
CN107872972A (zh) 2018-04-03
CA2979051A1 (en) 2016-09-15
BR112017019352A2 (pt) 2018-06-05
KR20170123335A (ko) 2017-11-07
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CA2979051C (en) 2019-09-17
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