AU2009310634B2

AU2009310634B2 - Anti-inflammatory pharmaceutical compositions comprising a corticosteroid, hexylene glycol and water

Info

Publication number: AU2009310634B2
Application number: AU2009310634A
Authority: AU
Inventors: Kerryn Greive
Original assignee: EGO PHARMACEUTICALS Pty Ltd
Current assignee: EGO PHARMACEUTICALS Pty Ltd
Priority date: 2008-10-30
Filing date: 2009-10-30
Publication date: 2013-05-09
Anticipated expiration: 2029-10-30
Also published as: NZ591093A; WO2010048675A1; AU2009310634A1

Abstract

The present invention relates to anti-inflammatory pharmaceutical compositions. The invention also relates to cosmetically suitable gels capable of delivering pharmaceuticals, such as corticosteroids. The compositions according to the present invention comprise 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.

Description

WO 2010/048675 PCT/AU2009/001420 ANTI-INFLAMMATORY PHARMACEUTICAL COMPOSITIONS COMPRISING A CORTICOSTEROID, HEXYLENE GLYCOL AND WATER Field of the invention The present invention relates to anti-inflammatory pharmaceutical compositions. The invention also relates to cosmetically suitable gels capable of delivering 5 pharmaceuticals, such as corticosteroids. Background of the invention 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 10 pregnadene-17-a-ol 17-aromatic heterocycle 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. 15 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. For example, AU 603837 discloses a cream composition of mometasone furoate. The 20 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. Although the disclosed composition is described as a cream, it is nearly water-less and the bulk of the excipients are either 25 fatty materials or solids. Accordingly, it is more accurately described as an ointment. Ointments generally display poor cosmetic properties including, for example, WO 2010/048675 PCT/AU2009/001420 2 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. Further examples of anti-inflammatory formulations containing fatty materials and solids are discussed in US 20070265239 and US 20070264344. The formulations described in 5 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 10 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 15 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. However, as acknowledged in AU603837, formulations containing high levels of isopropanol and propylene glycol prove to be irritating to the skin. There is therefore a desire to have a product suitable for carrying and delivering an anti 20 inflammatory pharmaceutical, such as a corticosteroid, to the skin for topical delivery that is non-irritating and non-greasy. Reference to any prior art in the specification is not, and should not be taken as, an acknowledgment or any form of suggestion that this prior art forms part of the common general knowledge in Australia or any other jurisdiction or that this prior art could 25 reasonably be expected to be ascertained, understood and regarded as relevant by a person skilled in the art.

WO 2010/048675 PCT/AU2009/001420 3 Summary of the invention The present invention relates to cosmetically elegant anti-inflammatory pharmaceutical compositions that seek to minimise the problems associated with the compositions described above. 5 Specifically, 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. In one embodiment, the present invention provides a pharmaceutical composition comprising a water/hexylene glycol mixture having a weight ratio of 30 to 55:45 to 70 10 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. Preferably, the composition further includes a gelling or thickening agent. A suitable agent is a cellulose derivative, such as hypromellose. 15 The 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 'C. In one aspect, 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); 20 c. a corticosteroid, corticosteroid ester or a pharmaceutically acceptable salt thereof 0.01 to 0.25 percent (w/w); and d. 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 *C. Preferably all the components that comprise the composition are soluble or dispersible 25 in the water/hexylene glycol mixture.

WO 2010/048675 PCT/AU2009/001420 4 In another aspect, 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 5 c. a corticosteroid, corticosteroid ester or a pharmaceutically acceptable salt thereof 0.01 to 0.25 percent (w/w). In another aspect, the present invention provides a pharmaceutical composition comprising: a. water 30 to 55 percent (w/w); 10 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 15 composition to from about pH 2.5 to about pH 5.5 at 25 *C. In another aspect, 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); 20 c. a corticosteroid, corticosteroid ester or a pharmaceutically acceptable salt thereof 0.01 to 0.25 percent (w/w); and d. a gelling agent. In a preferred embodiment, the composition according to the present invention is a gelled continuous phase. 25 In preferred embodiments, 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 WO 2010/048675 PCT/AU2009/001420 5 miscible or dispersible within a water/hexylene glycol mixture. In this description hexylene glycol is not considered to be an emulsifier. The composition is also essentially free of white wax and petrolatum, and similar materials. 5 The pharmaceutical 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 10 the compositions of the present invention means that emulsifiers do not need to be added to these compositions. Without wishing to be bound by theory or mode of action, it is considered that cosmetic elegance of the compositions of the present invention is achieved through the proportions of water and hexylene glycol. These proportions allow the corticosteroid to 15 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. 20 The composition avoids the use of isopropanol and propylene glycol which are convenient formulation components but can be irritating to product users. Again, without being bound by theory or mode of action, 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, 25 the use of longer chain hydrocarbon based components which may have a "greasy" feel on the skin after use of the product is avoided. In preferred embodiments, 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 WO 2010/048675 PCT/AU2009/001420 6 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). In preferred embodiments, the gelling agent is hypromellose included in an amount of from about 0.5 to about 1.8 percent (w/w). In a particularly preferred embodiment, the 5 hypromellose is a proprietary product available under the trade name METHOCEL KM1OO TM from Dow Chemical Limited. Most preferably, the hypromellose is a proprietary product available under the trade name METHOCEL KM 100 (PREMIUM) TM, also available from Dow Chemical Limited. METHOCEL KM100 (PREMIUM) T M hypromellose is characterised by having a viscosity 10 value of approximately 80,000 to 120,000 centipoises (cps) for a 2 percent solution (w/w) in water at 20 *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. 15 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. In another aspect, the composition according to the present invention has a viscosity of 20 about 10,000 cps to about 100,000 cps at 25 "C, and preferably has a viscosity of between about 30,000 cps to about 60,000 cps at 25 *C as determined using a Brookfield DV-i+ Viscometer with Spindle S64 at 6 RPM. The skilled addressee will recognise that viscosity values will vary according to the measurement method and instrumentation employed and these values are intended to be interpreted with this 25 variation in mind. In an alternative embodiment, a non-gelling, pharmaceutically acceptable thickening agent is used to increase the viscosity of the pharmaceutical composition to a similar WO 2010/048675 PCT/AU2009/001420 7 level but which is otherwise inert in the composition. Preferably, 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 0C. Preferably, the pH 5 value of the pharmaceutical composition is within the range of pH 3.0 to pH 5.0 at 25 C. Most preferably, 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 0C. 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 10 acids could also be used, as could other pharmaceutically suitable pH adjusters. As described above, 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 15 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. In another aspect, the present invention provides a pharmaceutical composition consisting essentially of: a. mometasone furoate 0.01 to 0.25 percent (w/w); 20 b. hypromellose; c. hexylene glycol 45 to 70 percent (w/w); d. citric acid sufficient to adjust the pH of the final composition to from about pH 2.5 to about pH 5.5 at 25 'C; and e. water 20 to 55 percent (w/w). 25 In another aspect, the present invention provides a pharmaceutical composition consisting essentially of: a. mometasone furoate 0.1 percent (w/w); WO 2010/048675 PCT/AU2009/001420 8 b. hypromellose 1.2 percent (w/w); c. hexylene glycol 60 percent (w/w); d. citric acid 0.03 percent (w/w); and e. water. 5 In the above two aspects, the composition optionally further includes a colouring agent and/or fragrances, which are soluble in the water/hexylene glycol mixture. In another preferred embodiment 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. 10 Lower alcohols will form a suitable pharmaceutical composition according to the invention. However, as would be understood by a pharmaceutical formulator, 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 15 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. In another preferred embodiment, the composition further includes a humectant. Suitable examples are glycerine and dexpanthenol. 20 In yet another aspect, 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. In yet another aspect, the present invention provides use of a therapeutically effective amount of a pharmaceutical composition according to the present invention in the 25 preparation of a medicament for the topical treatment of an inflammatory disorder. In a further aspect, 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.

WO 2010/048675 PCT/AU2009/001420 9 In another aspect, the present invention provides a composition comprising a therapeutically effective amount of a pharmaceutical composition according to the invention as a main active ingredient. In yet another aspect, the present invention provides a composition comprising a 5 therapeutically effective amount of a pharmaceutical composition according to the invention for use in the topical treatment of an inflammatory disorder. In another aspect, the present invention provides use of a pharmaceutical composition according to the present invention for the topical treatment of an inflammatory disorder. In yet another aspect, the present invention provides use of 30 to 55 percent (w/w) 10 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. Detailed description of the embodiments It will be understood that various terms employed in the specification, examples and 15 claims have meanings that will be understood by one of ordinary skill in the art. However, for convenience, certain terms are defined below. As used herein, except where the context requires otherwise, the term "comprise" and variations of the term, such as "comprising", "comprises" and "comprised", are not intended to exclude further additives, components, integers or steps. 20 The term "pharmaceutical 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.

WO 2010/048675 PCT/AU2009/001420 10 The term "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. The term "hypromellose" as used throughout the specification is understood to mean a 5 hydroxypropyl methylcellulose. Throughout the specification, the two terms are used interchangeably. The term "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 10 state in a biological system. The term "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 15 subject, and the ability of the substance to elicit a desired response in the subject. The present invention provides 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) I to 3 percent (w/w) and sufficient acid to adjust the pH of the 20 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. According to one embodiment of the present invention, the corticosteroid is a halogenated corticosteroid. Preferably, the corticosteroid is a chlorinated corticosteroid. Most preferably, the corticosteroid is 25 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 WO 2010/048675 PCT/AU2009/001420 11 doses authorised by regulatory agencies, and the physicochemical properties of the corticosteroid (such as, for example, its solubility). In one embodiment, the 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 5 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. In another embodiment, the corticosteroid of the present invention is a corticosteroid or 10 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, 15 aclometasone dipropionate, flurandrenolide, methylprednisolone acetate and their pharmaceutically acceptable salts, hydrates and solvates. The 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 20 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 25 described herein as an example. In a preferred embodiment, the gelling agent is hypromellose. In a particularly preferred embodiment, 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 WO 2010/048675 PCT/AU2009/001420 12 such as, for example, Sigma-Aldrich or Dow Chemical Company. METHOCEL K1OM

(PREMIUM)

T M as manufactured by Dow Chemical Limited is also a preferred embodiment. This grade complies with the British Pharmacopeia 2009 Monograph for Hypromellose. 5 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 10 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). In one embodiment, METHOCEL KM100 (PREMIUM) TM is used in the composition in an amount ranging from about 0.5 to about 1.8 percent (w/w). According to another aspect of the present invention, the composition may include a 15 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. It will be recognised by one of ordinary skill in the art that the inclusion of additional 20 therapeutic agents in the 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. It will further be recognised by one of ordinary skill in the art that the disclosed 25 therapeutic agents may be administered to afford more than one therapeutic effect. In one embodiment, the composition according to the present invention comprises a therapeutically effective amount of at least one additional anti-inflammatory agent. In one embodiment, the additional anti-inflammatory agent is another corticosteroid or WO 2010/048675 PCT/AU2009/001420 13 corticosteroid ester. Examples include betamethasone dipropionate, betamethasone valerate, clobetasol propionate, clobetasone butyrate, diflurasone diacetate, halobetasol propionate, amcinonide, desoximetasone, fluocinonide, fluocinolone acetonide, halcinonide, triamcinolone acetate, hydrocortisone, hydrocortisone valerate, 5 hydrocortisone butyrate, aclometasone dipropionte, flurandrenolide and methylprednisolone. In another embodiment, the additional anti-inflammatory agent is a non-corticosteroid anti-inflammatory agent. Examples of non-corticosteroid anti inflammatory agents include ibuprofen, salicylates, indomethacin, diclofenac, pranoprofen, tiaprofenic acid, dipottasium glycyrrhizinate, allantoin, epsilon 10 aminocaproic acid, berberine chloride, berberine sulfate, sodium azulenesulfonate, lysozyme chloride and tolfenamic acid. In another embodiment, 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, 15 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. In another embodiment, the composition according to the present invention may 20 comprise a therapeutically effective amount of at least one antibiotic or antiseptic agent, such as, for example, mupirocin, neomycin sulfate, bacitracin, polymyxin B, I-ofloxacin, tetracyclines (chlortetracycline hydrochloride, oxytetracycline hydrochloride and tetracycline hydrochloride), clindamycin phosphate, gentamicin sulfate, benzalkonium chloride, benzethonium chloride, cetrimide, hexylresorcinol, methylbenzethonium 25 chloride, phenol, quaternary ammonium compounds, triclocarbon, triclosan, tea tree oil, benzoyl peroxide and their pharmaceutically acceptable salts. In yet another embodiment, the 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.

WO 2010/048675 PCT/AU2009/001420 14 In another embodiment, the 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 5 acids), benzoyl peroxide, antibiotics and compounds or plant extracts that regulate sebum. In another embodiment, the 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 10 (e.g. Tazarotene) and anthraline. In yet another embodiment, the composition according to the present invention may comprise a therapeutically effective amount of at least one anti-allergic agent. Examples of anti-allergic agents include, but are not limited to: ketotifen, oxatomide, cetirizine, and sodium cromoglycate. 15 In yet another embodiment, the composition according to the present invention may comprise a therapeutically effective amount of at least one local anaesthetic. Examples of local anaesthetics include, but are not limited to, lidocaine, cinchocaine, tetracaine, procaine and dibucaine, and their pharmaceutically acceptable salts. According to another aspect of the present invention, the composition may include at 20 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. 25 Again, it will be recognised that the inclusion of skin active agents in the composition according to the present invention will depend upon their physical, chemical and therapeutic compatibility with the other components of the composition.

WO 2010/048675 PCT/AU2009/001420 15 In one embodiment, the composition according to the present invention further comprises an effective amount of at least one sunscreen. Examples of sunscreens include, but are not limited to, octyl methoxycinnamate, oxybenzone and butyl methoxydibenzoylmethane. Some such sunscreens may retain a more greasy feel but 5 the composition still provides a suitable delivery vehicle for a therapeutic, such as mometasone furoate. In another embodiment the sunscreen is phenylbenzimidazol sulfonic acid or disodium phenyl dibenzimidazole tetrasulfonate or similar. In this embodiment, the sunscreen has a non-greasy feel, but the sunscreen is more stable when the pH of the composition is 6 or above. To achieve a composition according to 10 this embodiment of the present invention, 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. Similarly, different therapeutic or other components may require the composition to have different optimum pH values. It will be recognised by one of ordinary skill in the art 15 that 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. It will also be recognised by a person skilled in the art that an increase in the pH of the 20 composition of the present invention may also lead to a decrease in the stability of certain components of the composition of the present invention. Hence, 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. 25 In one embodiment, the composition according to the present invention may include at least one anti-wrinkling or anti-aging agent. Examples of 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 30 acid, and ascorbic acid derivatives (for example ascorbyl palmitate and ascorbyl polypeptide).

WO 2010/048675 PCT/AU2009/001420 16 In another embodiment, 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 5 example, tocophery 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 10 extracts and legume extracts. Antioxidants may also minimize skin irritation. In another embodiment, the 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. In another embodiment, the composition according to the present invention may include 15 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). In another aspect according to the present invention, the composition comprises at least one other component intended to improve the appearance, stability or consumer appeal 20 of the composition. Such 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. Again, it will be recognised that the inclusion of other components intended to improve 25 the appeal or stability of the composition according to the present invention will depend upon their physical, chemical and therapeutic compatibility with the other components of the composition.

WO 2010/048675 PCT/AU2009/001420 17 According to the present invention 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 5 content of the active shows very little variation over time relative to the initial content. In one embodiment, the composition according to the present invention comprises at least one humectant. Examples of 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. 10 In another embodiment, the composition according to the present invention may comprise at least one preservative. Examples of 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 para hydroxybenzoate, ethyl para-hydroxybenzoate, propyl para-hydroxybenzoate and butyl 15 para-hydroxybenzoate. In a particularly preferred embodiment, 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 20 "C using a Brookfield DV-l+ Viscometer with Spindle S64 at 6 RPM. It has a density as determined at 25 *C of from about 0.94 to about 1.04 g/mL. In this preferred embodiment, 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. 25 The formulations of the present invention are manufactured in a conventional manner by thoroughly mixing the ingredients at ambient or elevated temperatures. Preferably, 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 WO 2010/048675 PCT/AU2009/001420 18 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 5 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, 10 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. 15 Preferably, 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, surnburn irritation, erythema induced by extrinsic factors, acne inflammation, psoriasis, seborrheic dermatitis, eczema, poison ivy, insect bites, folliculitus, alopecia, and 20 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 25 systems commonly used in the prior art.

WO 2010/048675 PCT/AU2009/001420 19 Table 1 Solvent Mometasone furoate Mometasone furoate dissolved (%w/w) at 5 dissolved (%w/w) at 25 *C "C Hexylene glycol 0.75 0.97 Propylene glycol 0.12 0.16 Isopropyl alcohol 0.30 0.43 Industrial methylated alcohol 0.59 0.78 Propylene glycol : isopropyl 0.36 0.52 alcohol 3:4 (w/w) Propylene glycol : industrial 0.41 0.56 methylated alcohol 3:4 (w/w) Hexylene glycol : water 12:3 0.47 0.63 (w/w) Hexylene glycol : water 0.14 0.21 60:38.67 (w/w) The example that follows is intended to illustrate but in no way limit the present invention. A composition according to the invention has: 5 mometasone furoate 0.1 percent (w/w) hypromellose 1.2 percent (w/w) hexylene glycol 60 percent (w/w) citric acid 0.03 percent (w/w) water to 100 percent (w/w) 10 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 0C to dissolve the mometasone furoate and form a second clear solution. The mometasone furoate-hexylene glycol solution was cooled to 70 0C and the hypromellose was added to obtain a uniform "bulk dispersion". The 15 water-acid solution was then added to the bulk dispersion and the resultant composition WO 2010/048675 PCT/AU2009/001420 20 was mixed until the composition had thickened and a clear gel was obtained. The composition was then homogenised to ensure gel uniformity. Repeat Insult Patch Testing data demonstrated that Composition 1 is not irritating or sensitizing. 5 The composition is applied as a thin film to the affected area once daily. It will be understood that the invention disclosed and defined in this specification extends to all alternative combinations of two or more of the individual features mentioned or evident from the text. All of these different combinations constitute various alternative aspects of the invention.

Claims

1. A pharmaceutical composition consisting essentially of a water/hexylene glycol mixture having 30 to 55 percent (w/w) water, 45 to 70 percent (w/w) hexylene glycol and one or more functional components, each of which is soluble or dispersible in the 5 water/hexylene glycol mixture, one of the components being a corticosteroid, corticosteroid ester or a pharmaceutically acceptable salt thereof.

2. A pharmaceutical composition according to claim 1 consisting essentially of: a. water 30 to 55 percent (w/w); b. hexylene glycol 45 to 70 percent (w/w); and 0 c. a corticosteroid, a corticosteroid ester or a pharmaceutically acceptable salt thereof 0.01 to 0.25 percent (w/w).

3. A pharmaceutical composition according to any one of the preceding claims consisting essentially of: 5 a. water 30 to 55 percent (w/w); b. hexylene glycol 45 to 70 percent (w/w); c. a corticosteroid, a corticosteroid ester or a pharmaceutically acceptable salt thereof 0.01 to 0.25 percent (w/w); and d. a pharmaceutically acceptable acid sufficient to adjust the pH of the final 20 composition to from about pH 2.5 to about pH 5.5 at 25 *C.

4. A pharmaceutical composition according to any one of the preceding claims consisting essentially of: a. water 30 to 55 percent (w/w); 25 b. hexylene glycol 45 to 70 percent (w/w); c. a corticosteroid, a corticosteroid ester or a pharmaceutically acceptable salt thereof 0.01 to 0.25 percent (w/w); 22 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 C.

5 5. A pharmaceutical composition according to claim 4 wherein the composition is a gelled continuous phase.

6. A pharmaceutical composition according to any one of the preceding claims consisting essentially of: 10 a. water 30 to 55 percent (w/w); b. hexylene glycol 45 to 70 percent (w/w); c. hypromellose 0.5 to 1.8 percent (w/w); d. mometasone furoate 0.01 to 0.25 percent (w/w); and e. a pharmaceutically acceptable acid sufficient to adjust the pH of the final 15 composition to from about pH 2.5 to about pH 5.5 at 25 *C.

7. A pharmaceutical composition according to any one of the preceding claims consisting essentially of: a. water 35 to 50 percent (w/w); 20 b. hexylene glycol 50 to 65 percent (w/w); c. hypromellose 0.7 to 1.5 percent (w/w); d. mometasone furoate 0.05 to 0.15 percent (w/w); and e. a pharmaceutically acceptable acid sufficient to adjust the pH of the final composition to from about pH 3 to about pH 5 at 25 *C. 25

8. A pharmaceutical composition according to any one of claims 1 to 6 further containing a pharmaceutically acceptable acid sufficient to adjust the pH of the final composition to from about pH 3 to about pH 5 at 25 *C. 23

9. A pharmaceutical composition according to any one of the preceding claims consisting essentially of: a. mometasone furoate 0.1 percent (w/w); 5 b. hypromellose 1.2 percent (w/w); c. hexylene glycol 60 percent (w/w); d. citric acid 0.03 percent (w/w); and e. water.

10 10. A pharmaceutical composition according to any one of the preceding claims wherein the composition also contains a lower alkyl alcohol, wherein the lower alkyl alcohol is selected from methanol, ethanol, and mixtures thereof.

11. A pharmaceutical composition according to any one of claims 1 to 9 wherein the 15 water in the composition is replaced with a lower alkyl alcohol, wherein the lower alkyl alcohol is selected from methanol, ethanol, and mixtures thereof.

12. A pharmaceutical composition according to any one of claims 1 to 9 wherein the composition does not contain a lower alkyl alcohol. 20

13. A pharmaceutical composition according to any one of the preceding claims further containing one or more additives selected from the group consisting of an antifungal agent, antibiotic agent, antiseptic agent, an immunomodulator, anti-acne agent, antipsoriatic agent, anti-allergic agent, an anaesthetic, a skin active agent, a sunscreen, 25 an anti-wrinkling agent, an anti-aging agent, antioxidant, a skin lightening agent and an agent intended to inhibit or minimise skin irritation.

14. A pharmaceutical composition according to any one of the preceding claims further containing one or more additives selected from the group consisting of fragrances, 24 emollients, preservatives, vitamins and vitamin derivatives, colours, humectants, plant extracts and surface active agents.

15. Use of a therapeutically effective amount of a pharmaceutical composition according 5 to any one of claims 1 to 14 in the preparation of a medicament for the topical treatment of an inflammatory disorder.

16. A composition for the topical treatment of an inflammatory disorder comprising as an active ingredient a pharmaceutical composition according to any one of claims 1 to 14.

17. A composition comprising a therapeutically effective amount of a pharmaceutical 10 composition according to any one of claims 1 to 14 as a main active ingredient.

18. A composition comprising a therapeutically effective amount of a pharmaceutical composition according to any one of claims 1 to 14 for use in the topical treatment of an inflammatory disorder.

19. A pharmaceutical composition according to claim 1, substantially as herein 15 described.