WO2010048675A1 - Compositions pharmaceutiques anti-inflammatoires comprenant un corticostéroïde, de l'hexylène glycol et de l'eau - Google Patents

Compositions pharmaceutiques anti-inflammatoires comprenant un corticostéroïde, de l'hexylène glycol et de l'eau Download PDF

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Publication number
WO2010048675A1
WO2010048675A1 PCT/AU2009/001420 AU2009001420W WO2010048675A1 WO 2010048675 A1 WO2010048675 A1 WO 2010048675A1 AU 2009001420 W AU2009001420 W AU 2009001420W WO 2010048675 A1 WO2010048675 A1 WO 2010048675A1
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Prior art keywords
percent
composition according
pharmaceutical composition
water
agent
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PCT/AU2009/001420
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English (en)
Inventor
Kerryn Greive
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Ego Pharmaceuticals Pty Ltd
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Priority claimed from AU2008905582A external-priority patent/AU2008905582A0/en
Application filed by Ego Pharmaceuticals Pty Ltd filed Critical Ego Pharmaceuticals Pty Ltd
Priority to AU2009310634A priority Critical patent/AU2009310634B2/en
Priority to NZ591093A priority patent/NZ591093A/en
Publication of WO2010048675A1 publication Critical patent/WO2010048675A1/fr

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    • 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
    • A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
    • 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
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • 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

Definitions

  • the present invention relates to anti-inflammatory pharmaceutical compositions.
  • the invention also relates to cosmetically suitable gels capable of delivering pharmaceuticals, such as corticosteroids.
  • Corticosteroids are widely used as therapeutic agents for the treatment of inflammation, in particular for the treatment of inflammatory skin conditions.
  • U.S. Patent No. 4,472,393 discloses synthetic corticosteroids such as 3,20-dioxo-1,4- pregnadene-17- ⁇ -ol 17-aromatic heterqcycle carboxylate compounds. It also discloses pharmaceutical compositions containing said compounds and methods for the treatment and control of inflammatory conditions utilising said compounds.
  • These corticosteroids such as, for example mometasone furoate, are poorly soluble in water and have poor solubility in solvents frequently utilized in topical preparations.
  • the poor solubility characteristics_of corticosteroids such as mometasone furoate have hindered the development of cosmetically elegant anti-inflammatory corticosteroid compositions that are intended for topical application. Such compositions possess undesirable properties, such as greasiness, or may cause skin irritation.
  • AU 603837 discloses a cream composition of mometasone furoate.
  • the preferred composition contains 50 to 60% white petrolatum, 9 to 15% hexylene glycol, 6 to 10% lipophilic emulsifier, 8 to 12 % aluminium octenyl succinate and only 2 to 4% water.
  • the presence of 0.75 to 1.5% titanium dioxide serves to make the formulation white, giving it the appearance of a cream.
  • the disclosed composition is described as a cream, it is nearly water-less and the bulk of the excipients are either fatty materials or solids. Accordingly, it is more accurately described as an ointment.
  • Ointments generally display poor cosmetic properties including, for example, greasiness, inducing a heavy, clogging feeling on skin, poor absorption, visibility on the skin, the matting of hair on the skin and either sticking to and/or staining clothing.
  • anti-inflammatory formulations containing fatty materials and solids are discussed in US 20070265239 and US 20070264344.
  • the formulations described in these two applications comprise an anti-inflammatory agent (a preferred embodiment of which is clobetasol propionate), a pro-penetrating glycol, at least one other pro- penetrating agent, a polymeric emulsifier and a co-emulsifier.
  • the preferred embodiments include fatty materials and solids. The presence of an emulsifier is necessary in these compositions to blend the fatty and aqueous phases.
  • Other anti- inflammatory formulations containing fatty materials and solids, as well as emulsifiers are described in WO 1988/02257, WO 2003/097070, EP 0262681 and WO 1995/17196.
  • AU 616188 describes a topical lotion for the treatment of inflammation which comprises an anti-inflammatory corticosteroid in a hydro-alcoholic base consisting essentially of: 15 to 50% by weight of propylene glycol; 20 to 40% by weight of isopropyl alcohol; 20 to 60% by weight water; 0.1 to 3.0% by weight of a thickening agent, and sufficient buffer to maintain the pH of the composition within the range of 3.0 to 6.0.
  • a hydro-alcoholic base consisting essentially of: 15 to 50% by weight of propylene glycol; 20 to 40% by weight of isopropyl alcohol; 20 to 60% by weight water; 0.1 to 3.0% by weight of a thickening agent, and sufficient buffer to maintain the pH of the composition within the range of 3.0 to 6.0.
  • formulations containing high levels of isopropanol and propylene glycol prove to be irritating to the skin.
  • the present invention relates to cosmetically elegant anti-inflammatory pharmaceutical compositions that seek to minimise the problems associated with the compositions described above.
  • the present invention relates to a clear gel with anti-inflammatory activity.
  • the gel is a stable composition that is self-preserving. Typically it is water-washable. This provides a cosmetically elegant product for pharmaceutical delivery.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a water/hexylene glycol mixture having a weight ratio of 30 to 55:45 to 70 percent water to hexylene glycol and one or more functional components, each of which is soluble or dispersible in the water/hexylene glycol mixture, one of the components being a corticosteroid, corticosteroid ester or a pharmaceutically acceptable salt thereof.
  • the composition further includes a gelling or thickening agent.
  • a suitable agent is a cellulose derivative, such as hypromellose.
  • composition preferably further includes a pharmaceutically acceptable acid to adjust the pH of the final composition to from about pH 2.5 to about pH 5.5 at 25 0 C.
  • the present invention provides a pharmaceutical composition comprising:
  • the present invention provides a pharmaceutical composition comprising: a. water 30 to 55 percent (w/w); b. hexylene glycol 45 to 70 percent (w/w); and c. a corticosteroid, corticosteroid ester or a pharmaceutically acceptable salt thereof 0.01 to 0.25 percent (w/w).
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising: a. water 30 to 55 percent (w/w); b. hexylene glycol 45 to 70 percent (w/w); c. a corticosteroid, corticosteroid ester or a pharmaceutically acceptable salt thereof 0.01 to 0.25 percent (w/w); d. a gelling agent; and e. a pharmaceutically acceptable acid sufficient to adjust the pH of the final composition to from about pH 2.5 to about pH 5.5 at 25 0 C.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising: a. water 30 to 55 percent (w/w); b. hexylene glycol 45 to 70 percent (w/w); c. a corticosteroid, corticosteroid ester or a pharmaceutically acceptable salt thereof 0.01 to 0.25 percent (w/w); and d. a gelling agent.
  • the composition according to the present invention is a gelled continuous phase.
  • the composition is free or essentially free of emulsifier. This means that all components either have no emulsifying properties or are present in too small an amount to emulsify the composition. It is preferred that all components are miscible or dispersible within a water/hexylene glycol mixture. In this description hexylene glycol is not considered to be an emulsifier.
  • composition is also essentially free of white wax and petrolatum, and similar materials.
  • compositions according to the present invention include at least about 30 percent water (w/w).
  • the pharmaceutical compositions according to the present invention are substantially free of isopropanol and propylene glycol. They are also substantially free of other excipients or components that would cause the compositions to feel greasy on the skin. The absence of these greasy components in the compositions of the present invention means that emulsifiers do not need to be added to these compositions.
  • compositions of the present invention are achieved through the proportions of water and hexylene glycol. These proportions allow the corticosteroid to fully dissolve in the composition whilst also achieving a water-washable formulation.
  • a gelling agent affords desirable rheological properties in some embodiments of the pharmaceutical composition. Adjusting the pH of the composition to within the specified range is believed to assist in the long term stability of the active agent.
  • Preferred embodiments of the invention are free of propylene glycol and isopropanol.
  • the composition avoids the use of isopropanol and propylene glycol which are convenient formulation components but can be irritating to product users.
  • the composition of the invention only contains amounts of components that will dissolve or disperse within the water/alcohol (if present)/hexylene glycol mixture. Specifically, the use of emulsifiers is avoided. Equally, the use of longer chain hydrocarbon based components which may have a "greasy" feel on the skin after use of the product is avoided.
  • the corticosteroid is mometasone furoate included in the composition in an amount of from about 0.01 to about 0.25 percent (w/w). In a particularly preferred embodiment, the corticosteroid is mometasone furoate included in the composition in an amount of from about 0.05 to about 0.15 percent (w/w).
  • the gelling agent is hypromellose included in an amount of from about 0.5 to about 1.8 percent (w/w).
  • the hypromellose is a proprietary product available under the trade name METHOCEL KM100TM from Dow Chemical Limited.
  • METHOCEL KM100 PREMIUM
  • the hypromellose is a proprietary product available under the trade name METHOCEL KM100 (PREMIUM) TM, also available from Dow Chemical Limited.
  • METHOCEL KM100 (PREMIUM)TM hypromellose is characterised by having a viscosity value of approximately 80,000 to 120,000 centipoises (cps) for a 2 percent solution (w/w) in water at 20 0 C, a methoxyl content of from about 19 to about 24 percent and a hydroxypropyl content of from about 7 to about 12 percent.
  • Other hypromelloses with similar characteristics are also contemplated as being preferred gelling agents according to the present invention.
  • the degree of gelling required depends on the mode of administration for different embodiments of the invention. For a gel, sufficient gelling agent is added so the composition is readily retained on the skin for absorption of the active corticosteroid. In a liquid form, little or no gelling agent is included.
  • the composition according to the present invention has a viscosity of about 10,000 cps to about 100,000 cps at 25 0 C, and preferably has a viscosity of between about 30,000 cps to about 60,000 cps at 25 0 C as determined using a
  • a non-gelling, pharmaceutically acceptable thickening agent is used to increase the viscosity of the pharmaceutical composition to a similar level but which is otherwise inert in the composition.
  • such an agent is cosmetically acceptable and non-greasy on the skin.
  • the pH value of the pharmaceutical composition according to the present invention is preferably within the range of about pH 2.5 to about pH 5.5 at 25 0 C.
  • the pH value of the pharmaceutical composition is within the range of pH 3.0 to pH 5.0 at 25
  • the pH value of the pharmaceutical composition according to the present invention is in the range of from about pH 3.5 to about pH 4.5 at 25 °C.
  • the preferred pharmaceutically acceptable acid used to adjust the pH of the compositions according to the present invention is citric acid. Acetic, lactic, phosphoric and carbonic acids could also be used, as could other pharmaceutically suitable pH adjusters.
  • any pharmaceutically acceptable acid may be employed to adjust the pH of the pharmaceutical composition of the present invention.
  • the identity of such acids are known to those of ordinary skill in the art, and include, but are not limited to those described in the International Cosmetic Ingredient Dictionary and Handbook 12 th Edition, 2008, Volume 3, pp 3221-3222.
  • Preferred acids are lactic acid, citric acid, hydrochloric acid and sulfuric acid.
  • a particularly preferred acid is citric acid.
  • the present invention provides a pharmaceutical composition consisting essentially of:
  • the present invention provides a pharmaceutical composition consisting essentially of:
  • the composition optionally further includes a colouring agent and/or fragrances, which are soluble in the water/hexylene glycol mixture.
  • the composition according to the present invention may contain a pharmaceutically acceptable amount of a lower alkyl alcohol.
  • the lower alkyl alcohol may either partially or completely replace the water in the composition.
  • Lower alcohols will form a suitable pharmaceutical composition according to the invention.
  • pure methanol is not a suitable solvent for pharmaceutical use but a water/ethanol/methanol mixture would be (i.e. pharmaceutical-grade methylated spirits, which is usually 2 to 5% methanol, 90 to 95% ethanol and the rest being water).
  • Ethanol and ethanol/water mixtures are known to be suitable also.
  • the invention therefore extends to suitable lower alcohol/water solvents in place of pure water as exemplified in the embodiments of the invention above.
  • the composition further includes a humectant.
  • a humectant Suitable examples are glycerine and dexpanthenol.
  • the present invention provides a method of treating an inflammatory disorder comprising topical administration of a therapeutically effective amount of a composition according to the present invention.
  • the present invention provides use of a therapeutically effective amount of a pharmaceutical composition according to the present invention in the preparation of a medicament for the topical treatment of an inflammatory disorder.
  • the present invention provides a composition for the topical treatment of an inflammatory disorder comprising as an active ingredient a pharmaceutical composition according to the invention.
  • the present invention provides a composition comprising a therapeutically effective amount of a pharmaceutical composition according to the invention as a main active ingredient.
  • the present invention provides a composition comprising a therapeutically effective amount of a pharmaceutical composition according to the invention for use in the topical treatment of an inflammatory disorder.
  • the present invention provides use of a pharmaceutical composition according to the present invention for the topical treatment of an inflammatory disorder.
  • the present invention provides use of 30 to 55 percent (w/w) water; 45 to 70 percent (w/w) hexylene glycol; and 0.01 to 0.25 percent (w/w) of a corticosteroid, corticosteroid ester or a pharmaceutically acceptable salt thereof; for the manufacture of a medicament for the treatment of a topical inflammatory disorder.
  • composition as used throughout the specification is understood to mean a composition comprising a therapeutically effective amount of at least one therapeutic agent and at least one pharmaceutically acceptable carrier, excipient, diluent, additive or vehicle consistent with the intended form of topical administration and consistent with conventional pharmaceutical practices.
  • pharmaceutically acceptable carrier excipient, diluent, additive or vehicle consistent with the intended form of topical administration and consistent with conventional pharmaceutical practices.
  • corticosteroid as used throughout the specification is understood to mean a naturally derived, semi-synthetic or synthetic steroid that possesses biological activity, in particular anti-inflammatory activity.
  • hypothalamic material as used throughout the specification is understood to mean a hydroxypropyl methylcellulose. Throughout the specification, the two terms are used interchangeably.
  • therapeutic agent biologically active agent or simply “agent” or “active” as used throughout the specification are understood to mean any substance that is intended for the diagnosis, cure, mitigation, treatment, prevention or modification of a state in a biological system.
  • therapeutically effective amount relates to the amount or dose of a therapeutic agent or a composition thereof that will lead to one or more desired effects, in particular the reduction of an inflammatory state.
  • a therapeutically effective amount will vary according to factors such as the disease state, age, sex, and weight of a subject, and the ability of the substance to elicit a desired response in the subject.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising: water 30 to 55 percent (w/w); hexylene glycol 45 to 70 percent (w/w), a corticosteroid, corticosteroid ester or a pharmaceutically acceptable salt thereof 0.01 to 0.25 percent (w/w); a gelling agent (thickening agent) 1 to 3 percent (w/w) and sufficient acid to adjust the pH of the final composition to a value of from about pH 2.5 to about pH 5.5 at 25 0 C.
  • the composition according to the present invention comprises a therapeutically effective amount of at least one corticosteroid.
  • the corticosteroid is a halogenated corticosteroid.
  • the corticosteroid is a chlorinated corticosteroid.
  • the corticosteroid is mometasone or mometasone furoate.
  • the amount of corticosteroid included in the compositions according to the present invention will depend upon a number of factors that are known to those skilled in the art, such as, for example the therapeutic dose, the doses authorised by regulatory agencies, and the physicochemical properties of the corticosteroid (such as, for example, its solubility).
  • compositions according to the present invention comprise mometasone furoate in an amount of about 0.01 to 0.25 percent (w/w). In a preferred embodiment, the compositions according to the present invention comprise mometasone furoate in an amount of about 0.05 to 0.15 percent (w/w). In a particularly preferred embodiment, the composition comprises about 0.1 percent (w/w) mometasone furoate.
  • the corticosteroid of the present invention is a corticosteroid or its pharmaceutically acceptable ester selected from the group consisting of betamethasone dipropionate, betamethasone valerate, clobetasol propionate, clobetasone butyrate, diflurasone diacetate, halobetasol propionate, amcinonide, desoximetasone, fluocinonide, fluocinolone acetonide, halcinonide, triamcinolone acetate, hydrocortisone, hydrocortisone valerate, hydrocortisone butyrate, aclometasone dipropionate, flurandrenolide, methylprednisolone acetate and their pharmaceutically acceptable salts, hydrates and solvates.
  • betamethasone dipropionate betamethasone valerate
  • clobetasol propionate clobetasone butyrate
  • composition according to the present invention further comprises at least one gelling agent.
  • Gelling agents suitable for use in pharmaceutical compositions are well known to those of ordinary skill in the art and include, for example, xanthan gum and its derivatives, carbomer and its derivatives, acrylate based copolymers and cross polymers, sodium polyacrylate and its derivatives, cellulose and its derivatives, and starch and agar and their derivatives.
  • the selection of the gelling agent according to the present invention is important in providing a cosmetically elegant composition, especially a clear gel.
  • Hypromellose is described herein as an example.
  • the gelling agent is hypromellose.
  • the gelling agent is a proprietary product sold under the names of Methocel E, Methocel F, Methocel J, Methocel K or Methocel HG by industry suppliers such as, for example, Sigma-AIdrich or Dow Chemical Company.
  • METHOCEL K100M (PREMIUM)TM as manufactured by Dow Chemical Limited is also a preferred embodiment. This grade complies with the British Pharmacopeia 2009 Monograph for Hypromellose.
  • the amount of gelling agent added to the composition may be readily determined by one of ordinary skill in the art with a minimum of experimentation, and will depend upon factors known to those skilled in the art, such as the properties of the gelling agent and the desired properties of the pharmaceutical composition.
  • a particularly preferred embodiment according to the present invention is the use of Methocel E, Methocel F, Methocel J, Methocel K or Methocel HG in the composition in an amount ranging from about 0.5 to about 1.8 percent (w/w).
  • METHOCEL KM100 (PREMIUM)TM is used in the composition in an amount ranging from about 0.5 to about 1.8 percent (w/w).
  • the composition may include a therapeutically effective amount of at least one additional therapeutic agent.
  • Additional therapeutic agents include, but are not limited to, additional anti-inflammatory agents, antifungal agents, antibiotic or antiseptic agents, immunomodulators, anti-acne agents, anti-psoriatic agents, anti-allergic agents and local anaesthetic agents.
  • compositions according to the present invention will depend upon their inherent physicochemical and therapeutic properties, and their physicochemical and therapeutic compatibility with the other components of the composition.
  • the disclosed therapeutic agents may be administered to afford more than one therapeutic effect.
  • the composition according to the present invention comprises a therapeutically effective amount of at least one additional anti-inflammatory agent.
  • the additional anti-inflammatory agent is another corticosteroid or corticosteroid ester.
  • examples include betamethasone dipropionate, betamethasone valerate, clobetasol propionate, clobetasone butyrate, diflurasone diacetate, halobetasol propionate, amcinonide, desoximetasone, fluocinonide, fluocinolone acetonide, haicinonide, triamcinolone acetate, hydrocortisone, hydrocortisone valerate, hydrocortisone butyrate, aclometasone dipropionte, flurandrenolide and methylprednisolone.
  • the additional anti-inflammatory agent is a non-corticosteroid anti-inflammatory agent.
  • non-corticosteroid antiinflammatory agents include ibuprofen, salicylates, indomethacin, diclofenac, pranoprofen, tiaprofenic acid, dipottasium glycyrrhizinate, allantoin, epsilon- aminocaproic acid, berberine chloride, berberine sulfate, sodium azulenesulfonate, lysozyme chloride and tolfenamic acid.
  • the composition according to the present invention may comprise a therapeutically effective amount of at least one antifungal agent, such as, for example, miconazole, terbinafine, nystatin, clotrimazole, econazole, itraconazole, fluconazole, bifoconazole, terconazole, butoconazole, tioconazole, ketoconazole, saperconazole, sulconazole, oxiconizole, tolnaftate, nystatin, ciclopirox olamine, naftifine, butenafine, undecylenic acid, amorolfine, naftifine, elubiol, griseofulvin, and their pharmaceutically acceptable salts.
  • at least one antifungal agent such as, for example, miconazole, terbinafine, nystatin, clotrimazole, econazole, itraconazole, fluconazole,
  • the composition according to the present invention may comprise a therapeutically effective amount of at least one antibiotic or antiseptic agent, such as, for example, mupirocin, neomycin sulfate, bacitracin, polymyxin B, l-ofloxacin, tetracyclines (chlortetracycline hydrochloride, oxytetracycline hydrochloride and tetracycline hydrochloride), clindamycin phosphate, gentamicin sulfate, benzalkonium chloride, benzethonium chloride, cetrimide, hexylresorcinol, methylbenzethonium chloride, phenol, quaternary ammonium compounds, triclocarbon, triclosan, tea tree oil, benzoyl peroxide and their pharmaceutically acceptable salts.
  • antibiotic or antiseptic agent such as, for example, mupirocin, neomycin sulfate, bacitracin, polymy
  • composition according to the present invention may comprise a therapeutically effective amount of at least one immunomodulator, such as, for example, cyclosporin A, pimecrolimus and tacrolimus.
  • composition according to the present invention may comprise a therapeutically effective amount of at least one anti-acne agent.
  • Anti-acne agents may include, but are not limited to, agents that normalize epidermal differentiation (e.g. retinoids), keratolytic agents (e.g. salicylic acid and alpha hydroxy acids), benzoyl peroxide, antibiotics and compounds or plant extracts that regulate sebum.
  • composition according to the present invention may comprise a therapeutically effective amount of at least one antipsoriatic agent, such as, for example, a corticosteroid, Vitamin D and its analogues (e.g. calcipotriene), a retinoid (e.g. Tazarotene) and anthraline.
  • at least one antipsoriatic agent such as, for example, a corticosteroid, Vitamin D and its analogues (e.g. calcipotriene), a retinoid (e.g. Tazarotene) and anthraline.
  • composition according to the present invention may comprise a therapeutically effective amount of at least one anti-allergic agent.
  • anti-allergic agents include, but are not limited to: ketotifen, oxatomide, cetirizine, and sodium cromoglycate.
  • composition according to the present invention may comprise a therapeutically effective amount of at least one local anaesthetic.
  • local anaesthetics include, but are not limited to, lidocaine, cinchocaine, tetracaine, procaine and dibucaine, and their pharmaceutically acceptable salts.
  • the composition may include at least one additional "skin active agent".
  • Skin active agents may afford an improvement in the appearance, tone or texture of the skin, and may include, but are not limited to, sunscreens, anti-wrinkling or anti-aging agents, antioxidants, vitamins, depigmentating or skin lightening agents, moisturizing agents, emollients, metal chelators, retinoids and retinoid derivatives, agents intended to reduce skin irritation, and alpha-hydroxy acids.
  • the composition according to the present invention further comprises an effective amount of at least one sunscreen.
  • sunscreens include, but are not limited to, octyl methoxycinnamate, oxybenzone and butyl methoxydibenzoylmetha ⁇ e. Some such sunscreens may retain a more greasy feel but the composition still provides a suitable delivery vehicle for a therapeutic, such as mometasone furoate.
  • the sunscreen is phenylbenzimidazol sulfonic acid or disodium phenyl dibenzimidazole tetrasulfonate or similar.
  • the sunscreen has a non-greasy feel, but the sunscreen is more stable when the pH of the composition is 6 or above.
  • the composition is stabilised to a pH of about 6, such as by addition of arginine. As mometasone furoate is less stable at a pH above 5, a balance of the stability of different components is required in some embodiments.
  • the pH of the composition of the present invention can be raised to, for example, pH 7, by the addition of pharmaceutically acceptable agents.
  • the pH of the composition of the present invention may need to be buffered at about pH 5 to, for example, improve the stability of certain components of the composition.
  • an increase in the pH of the composition of the present invention may also lead to a decrease in the stability of certain components of the composition of the present invention.
  • the need to raise the pH of the composition of the present invention to increase the stability of one or more components will need to be balanced with the desire to obtain a cosmetically elegant composition, in accordance with the present invention.
  • the composition according to the present invention may include at least one anti-wrinkling or anti-aging agent.
  • anti-wrinkling or anti-aging agents include, but are not limited to, retinoids (for example, retinoic acid, retinol, retinal, retinyl acetate, and retinyl palmitate), alpha hydroxy acids, galactose sugars (for example, melibiose and lactose), lipoic acid and dihydrolipoic acid, lactoferrin, ascorbic acid, and ascorbic acid derivatives (for example ascorbyl palmitate and ascorbyl polypeptide).
  • retinoids for example, retinoic acid, retinol, retinal, retinyl acetate, and retinyl palmitate
  • alpha hydroxy acids for example, galactose sugars (for example, melibiose and lactose)
  • lipoic acid and dihydrolipoic acid lactoferr
  • the composition according to the present invention may include at least one antioxidant or a natural extract that contains antioxidants.
  • Antioxidants may be water or oil-soluble.
  • Oil soluble antioxidants suitable for use in the composition of this invention include, but are not limited to, tocopherols and tocopherol derivatives (for example, tocopheryl acetate, alpha-tocopherol), tocotrienols and ubiquinone.
  • Natural extracts containing antioxidants suitable for use in the composition of this invention include, but are not limited to, extracts containing flavonoids, phenolic compounds, flavones, flavanones, isoflavonoids, mono-, di- and tri-terpenes, sterols and their derivatives. Examples of such natural extracts include grape seed, green tea, pine bark extracts and legume extracts. Antioxidants may also minimize skin irritation.
  • composition according to the present invention may include at least one skin lightening agent, such as, for example, kojic acid, ascorbic acid and ascorbic acid derivatives such as ascorbyl palmitate.
  • skin lightening agent such as, for example, kojic acid, ascorbic acid and ascorbic acid derivatives such as ascorbyl palmitate.
  • composition according to the present invention may include at least one agent intended to inhibit or minimise potential skin irritation, such as an emollient, a vitamin, an antioxidant (e.g., vitamin E) and a herbal extract (e.g. aloe vera).
  • an emollient such as a vitamin, an antioxidant (e.g., vitamin E) and a herbal extract (e.g. aloe vera).
  • the composition comprises at least one other component intended to improve the appearance, stability or consumer appeal of the composition.
  • components include, but are not limited to: fragrances, emollients, preservatives, vitamins and vitamin derivatives, antioxidants, colours, humectants, antioxidants, plant extracts, surface active agents, and other ingredients to further soothe and protect the skin.
  • the term 'stability' refers to a composition that does not present any macroscopic change of appearance (e.g. change in colour) or microscopic change of appearance (e.g. recrystallization of the active agent) over time and where the active component (e.g. corticosteroid) remains stable - that is, the content of the active shows very little variation over time relative to the initial content.
  • the active component e.g. corticosteroid
  • the composition according to the present invention comprises at least one humectant.
  • humectants include, but are not limited to: glycerol, dexpanthenol, sorbitol, propylene glycol, 1,3-butylene glycol, polypropylene glycol, xylitol, maltitol, lactitol, oat protein, allantoin, acetamine MEA and hylauronic acid.
  • the composition according to the present invention may comprise at least one preservative.
  • preservatives which may be used in the composition of this invention include, but are not limited to, salicylic acid, chlorhexidine hydrochloride, phenoxyethanol, sodium benzoate, methyl parahydroxybenzoate, ethyl para-hydroxybenzoate, propyl para-hydroxybenzoate and butyl para-hydroxybenzoate.
  • the composition according to the present invention is free of added fragrances, colours and preservatives.
  • the pH of the final composition is between from about pH 3.5 to about pH 4.5 as determined at 25 0 C. It has a viscosity of from about 30,000 to about 60,000 centipoises as determined at 25 0 C using a Brookfield DV-I+ Viscometer with Spindle S64 at 6 RPM. It has a density as determined at 25 0 C of from about 0.94 to about 1.04 g/mL.
  • the composition may or may not be aerated.
  • the composition according to this preferred embodiment is a clear, colourless gel that has an odour characteristic of hexylene glycol.
  • the formulations of the present invention are manufactured in a conventional manner by thoroughly mixing the ingredients at ambient or elevated temperatures.
  • the corticosteroid is dissolved in the hexylene glycol to form a clear solution.
  • the acid is combined with the water to form a clear solution.
  • the hypromellose is dispersed in the hexylene glycol/corticosteroid solution to which the water/acid solution is added.
  • the composition is then mixed until a uniform gel is obtained.
  • Another aspect of this invention provides a method for treating inflammatory disorders comprising administering a therapeutically effective amount of the composition according to the present invention.
  • Inflammatory disorders and related conditions which may be treated or inhibited by topical use of the compositions of this invention include inflammatory and pruritic manifestations of corticosteroid-responsive dermatoses. These include, but are not limited to, arthritis, contact dermatitis, atopic dermatitis, psoriasis, seborrheic dermatitis, eczema, allergic dermatitis, polymorphous light eruption, inflammatory dermatoses, folliculitis, alopecia, poison ivy, insect bites, acne inflammation, sunburn, irritation induced by extrinsic factors such as chemicals, trauma, pollutants and sun exposure, and secondary conditions resulting from inflammation including but not limited to xerosis, hyperkeratosis, pruritus, post-inflammatory hyperpigmentation and scarring.
  • the inflammatory disorders and related conditions which may be treated or prevented using the methods of the present invention are inflammatory dermatoses, contact dermatitis, allergic dermatitis, atopic dermatitis, polymorphous light eruptions, surnbum irritation, erythema induced by extrinsic factors, acne inflammation, psoriasis, seborrheic dermatitis, eczema, poison ivy, insect bites, folliculitus, alopecia, and secondary conditions and the like.
  • One of the advantages of the present invention is that the active ingredient of the composition, mometasone furoate, is completely solubilised in the water/hexylene glycol mixture. Therefore, the addition of emulsifying agents is avoided.
  • Table 1 illustrates the solubility of mometasone furoate in water/hexylene glycol mixtures and in solvent systems commonly used in the prior art.
  • a composition according to the invention has:
  • composition 1 The components of composition 1 were mixed as follows: Water and citric acid were combined to form a first clear solution. Mometasone furoate was combined with hexylene glycol and heated to 75 0 C to dissolve the mometasone furoate and form a second clear solution. The mometasone furoate-hexylene glycol solution was cooled to 70 0 C and the hypromellose was added to obtain a uniform "bulk dispersion”. The water-acid solution was then added to the bulk dispersion and the resultant composition was mixed until the composition had thickened and a clear gel was obtained. The composition was then homogenised to ensure gel uniformity.
  • composition is applied as a thin film to the affected area once daily.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Dermatology (AREA)
  • Inorganic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

La présente invention porte sur des compositions pharmaceutiques anti-inflammatoires. L'invention porte également sur des gels cosmétiquement appropriés capables d'administrer des produits pharmaceutiques, tels que des corticostéroïdes. Les compositions selon la présente invention comprennent un mélange eau/hexylène glycol ayant un rapport en masse de 30 à 55:45 à 70 % entre l'eau et l'hexylène glycol et un ou plusieurs composants fonctionnels, dont chacun est soluble ou miscible dans le mélange eau/hexylène glycol, l'un des composant étant un corticostéroïde, un ester de corticostéroïde ou un sel pharmaceutiquement acceptable de ceux-ci.
PCT/AU2009/001420 2008-10-30 2009-10-30 Compositions pharmaceutiques anti-inflammatoires comprenant un corticostéroïde, de l'hexylène glycol et de l'eau WO2010048675A1 (fr)

Priority Applications (2)

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AU2009310634A AU2009310634B2 (en) 2008-10-30 2009-10-30 Anti-inflammatory pharmaceutical compositions comprising a corticosteroid, hexylene glycol and water
NZ591093A NZ591093A (en) 2008-10-30 2009-10-30 Anti-inflammatory pharmaceutical compositions comprising a corticosteroid, hexylene glycol and water

Applications Claiming Priority (2)

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AU2008905582 2008-10-30
AU2008905582A AU2008905582A0 (en) 2008-10-30 Anti-inflammatory compositions

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WO2010048675A1 true WO2010048675A1 (fr) 2010-05-06

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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1988002257A1 (fr) * 1986-10-02 1988-04-07 Schering Corporation Composition de creme anti-inflammatoire
WO1995017196A1 (fr) * 1993-12-21 1995-06-29 Schering Corporation Traitement du psoriasis
WO2003097070A1 (fr) * 2002-05-17 2003-11-27 Orva Ilaç Sanayi Ve Ticaret A.S. Composition pharmaceutique comportant un corticosteroide et un antiseptique
US20070264344A1 (en) * 2006-03-15 2007-11-15 Galderma S.A. Topically applicable anti-inflammatory O/W emulsions comprising pro-penetrating glycols
US20070265239A1 (en) * 2006-03-15 2007-11-15 Galderma S.A. Topically applicable anti-inflammatory O/W emulsions comprising pro-penetrating glycols
WO2009063493A2 (fr) * 2007-09-10 2009-05-22 Glenmark Pharmaceuticals Limited Composition pharmaceutique topique pour la combinaison de l'acide fusidique avec un corticostéroïde

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1988002257A1 (fr) * 1986-10-02 1988-04-07 Schering Corporation Composition de creme anti-inflammatoire
WO1995017196A1 (fr) * 1993-12-21 1995-06-29 Schering Corporation Traitement du psoriasis
WO2003097070A1 (fr) * 2002-05-17 2003-11-27 Orva Ilaç Sanayi Ve Ticaret A.S. Composition pharmaceutique comportant un corticosteroide et un antiseptique
US20070264344A1 (en) * 2006-03-15 2007-11-15 Galderma S.A. Topically applicable anti-inflammatory O/W emulsions comprising pro-penetrating glycols
US20070265239A1 (en) * 2006-03-15 2007-11-15 Galderma S.A. Topically applicable anti-inflammatory O/W emulsions comprising pro-penetrating glycols
WO2009063493A2 (fr) * 2007-09-10 2009-05-22 Glenmark Pharmaceuticals Limited Composition pharmaceutique topique pour la combinaison de l'acide fusidique avec un corticostéroïde

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AU2009310634A1 (en) 2010-05-06
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