WO2009150408A2

WO2009150408A2 - Topical antimuscarinic formulations

Info

Publication number: WO2009150408A2
Application number: PCT/GB2009/001431
Authority: WO
Inventors: Alan Geoffrey Roach; Nigel Blackburn; Paul Goldsmith
Original assignee: Summit Corporation Plc
Priority date: 2008-06-13
Filing date: 2009-06-10
Publication date: 2009-12-17
Also published as: WO2009150408A3

Abstract

Topical compositions comprising muscarinic receptor antagonists and to methods of treating various skin disorders and diseases using the compositions are disclosed. In particular, the invention relates to compositions comprising muscarinic receptor antagonists for the treatment of acne, seborrhoea and for the reduction of excess sebum excretion. Preferred are hydrogel compositions comprising oxybutynin for topical application to the skin wherein the composition has a pH of 3.0 to 5.5 and compositions comprising a muscarinic receptor antagonist for topical application to the skin which yields a muscarinic receptor antagonist active plasma:dermis concentration ratio such that a non-spasmolytic concentration of muscarinic receptor antagonist active is produced after direct topical application to an area of ≤0.5 m² of skin.

Description

TOPICAL ANTIMUSCARINIC FORMULATIONS

The present invention relates to topical compositions comprising muscarinic receptor antagonists, and in particular the muscarinic receptor antagonist oxybutynin (as herein defined) and to methods of treating various skin disorders and diseases using the compositions. In particular, the invention relates to compositions comprising muscarinic receptor antagonists, and in particular the muscarinic receptor antagonist oxybutynin (as herein defined) for the treatment of acne, seborrhoea and for the reduction of excess sebum excretion.

Background to the Invention

Sebum is an oily secretion from sebaceous glands in the skin and serves many functions. Sebum is involved in the development of epidermal structure and maintains an epidermal permeability barrier, as well as transporting anti-oxidants to the surface of the skin and providing protection from microbial colonisation. An increased rate of sebum excretion is termed seborrhoea. Seborrhoea is a feature of many conditions including Parkinson's disease. Seborrhoeic dermatitis is characterised by the appearance of red, flaking, greasy areas of skin, most commonly on the scalp, nasolabial folds, ears, eyebrows and chest. Seborrhoeic dermatitis of the scalp is often referred to as dandruff and may range from mild scalp flaking to pronounced dense, diffuse, adherent scale on the scalp. In the clinical literature seborrhoeic dermatitis may be also referred to as "sebopsoriasis", "seborrhoeic eczema", "dandruff" and "pityriasis capitis". Treatments for seborrhoeic dermatitis include antifungal agents such as zinc pyrithione, cinnamic acid, azoles, cyclopirox, terbinafine, as well as non-specific topical agents such as selenium sulphide/sulphur, tar, lithium succinate, benzoyl peroxide, propylene glycol, and corticosteroids. Corticosteroids are effective topical anti-inflammatory treatments but have severe systemic side effects. Most compounds are given topically although if topical antifungals prove ineffective then agents such as ketoconazole, itraconazole or terbinafine can be given orally.

Acne vulgaris is accompanied with clinical seborrhoea and there is a direct relationship between the sebum excretion rate and the severity of acne vulgaris. Although sebum secretion increases during adolescence (particularly in boys, because of androgen stimulation), increased sebum alone does not cause acne. Bacteria, most importantly Propionibacterium acnes, are present in increased numbers in persons who have acne. Much of the inflammation that eventually occurs arises from the action of enzymes produced by the bacteria. Acne is divided into various categories, including comedonal, inflammatory, nodulocystic and conglobate acne. Conglobate acne describes a condition where there is a merging of deep abscesses to produce scarring channels in the skin. Nodulocystic acne is characterised by the appearance of hard lumps. Diagnosis of the condition into these categories determines the treatment schedule. Mild to moderate forms of comedonal and inflammatory acne are treated topically. Mild but significant comedonal acne responds well to topical retinoids (adapalene, tretinoin and isotretinoin) or benzoyl peroxide. Comedonal acne with inflammatory lesions is currently treated with topical antibiotics and antimicrobial agents (clindamycin, erythromycin, tetracycline, and azelaic acid). Moderate to severe inflammatory and nodulocystic acne are generally treated with oral antibiotics and retinoids. Severe side effects are associated with high dose retinoids and therefore treatment with these agents is often limited. Other forms of acne include acne that has not responded to standard treatment with oral antibiotics and topical medicines (referred to herein as "non-responsive acne") including post-retinoic acne (acne which develops after treatment with retinoic acids, such as isotretinoin (Roaccutane®)).

Glycopyrrolate and scopolamine are older generation anti-muscarinic drugs and block all five muscarinic receptor subtypes and centrally-mediated side effects have been reported, particularly with scopolamine. The older generation non-selective compounds are a mixture of compounds that enter the brain, and those that contain a quaternary ammonium function and therefore do not readily penetrate the blood brain barrier. Examples of compounds that contain a quaternary amine function are propantheline, methylscopolamine, homatropine methylbromide, poldine, ipratropium, trospium and glycopyrrolate. In recent years, a newer generation of muscarinic receptor antagonists, which possess some selectivity for and preferentially block muscarinic M3 receptors relative to the other M receptor subtypes have been introduced or are currently being developed for the treatment of bladder disorders. Examples of newer M3 muscarinic compounds, but not limited to, are darifenacin, solifenacin, fesoterodine, and zamifenacin. Oxybutynin is not a new generation muscarinic antagonist but it displays modest selectivity for M1 and M3 receptors over the other subtypes (and on this basis is classified as a partially selective antagonist). It is used extensively to treat overactive bladder disorders. However, compounds with differing selectivity profiles at muscarinic receptors have been developed to treat chronic obstructive pulmonary disease (COPD). WO01 /10427 discloses the use of certain anti-muscarinic agents having a dipole moment greater than 4D and having a defined degree of epithelial cell antiproliferative activity for the treatment of various forms of skin disorders including acne. However, this document does not disclose or suggest that certain anti-muscarinic agents may act to suppress sebum secretion or have antibacterial activity. Moreover, preferred antimuscarinic agents disclosed in WO01/10427 do not possess such properties: the present inventors have shown that the quaternary amine glycopyrrolate does not, for example, exhibit antibacterial activity. Our earlier WO2007/141530 describes the use of certain muscarinic receptor antagonists (including oxybutynin) in the treatment of various skin diseases associated with excess sebum production, including acne, seborrhoeic dermatitis and seborrhoea.

Oxybutynin is an anticholinergic agent currently widely used to relieve urinary and bladder difficulties, including frequent urination and urge incontinence, by decreasing muscle spasms of the bladder via antagonism at the M1 , M2, and M3 subtypes of the muscarinic acetylcholine receptor. It has also recently been shown to have sebum reducing properties - our earlier WO2007/141530 describes the use of certain muscarinic receptor antagonists (including oxybutynin) in the treatment of various skin diseases associated with excess sebum production, including acne, seborrhoeic dermatitis and seborrhoea. However, the use of oxybutynin is associated with various side effects. These include dry mouth, dizziness, blurred vision and constipation. In many cases these are so severe as to prompt termination of treatment. At least some of the side effects of oxybutynin therapy are attributed to its active metabolites, including in particular N-desethyloxybutynin. These side effects still occur with transdermal oxybutynin although the incidents such as dry mouth are reduced (Dmochowsky et a/. (2002) The Journal of Urology 168: 580-586). Appell et al. (2003) Mayo Clin. Proc. 78: 696-702 compared transdermal delivery and oral delivery of oxybutynin and reported that the transdermal formulation produced greater systemic availability and reduced production of its metabolite N-desethyloxybutynin and a lower incidence of dry mouth in healthy subjects. However, a common side effect with transdermal oxybutynin patches is pruritus at the application site. In addition, since systemic levels of oxybutynin are high with transdermal/topical application care must still be taken to avoid drug-drug interactions with other agents.

Interest in topical oxybutynin administration has led to the development of various topical formulations designed to reduce the side effects associated with the treatment of urinary and bladder disorders, as described for example in WO2004/041188, WO2005/032441 and WO2005/011683. Moreover, topical formulations containing various permeation enhancers have been described in the art, for example in US 5411740, US 5500222 and US 5614211 (monoglyceride fatty acids), US 5736577, US 5834010 and US 6555129 (triacetin), US 5747065 (monoglycerides and lactate esters), US 5843468 (mixtures of lauryl acetate and a glycerol monolaurate), US 6004578 (alkyl or aryl carboxylic acid esters of polyethyleneglycol monoalkyl ether and poiyethyleneglycol alkyl carboxymethyl ethers), US 6267984 (monoglyceride and ethyl palmitate) and US 6562368 (a hydroxide-releasing agent). In addition to the side effect considerations described above it is also generally recognized that topical or transdermal delivery systems for the administration of drugs offer other advantages over oral delivery, including convenience, continuous dosing, improved compliance, reversibility, elimination of "hepatic first pass" effect and a high degree of control over blood concentration of the drug. For these reasons, oxybutynin is now available as a transdermal patch under the brand-name Oxytrol™ and Kentera™as well as various sustained release oral formulations (the latter available generically and under the brand-names Ditropan™ and Lyrinel XL™) for the treatment of overactive bladder and urinary incontinence.

However, topical delivery of muscarinic receptor antagonists and oxybutynin in particular for the treatment of skin disorders as described in WO2007/141530 is complicated by problems arising from the need to avoid exacerbating the condition under treatment by irritating the skin and/or associated lesions. These problems are particularly acute in the case of formulations intended to treat diseases such as acne (where areas of inflamed and broken skin are typically present), and they may be summarized as follows:

• Topical application of oxybutynin to highly innervated (and so very sensitive) areas of skin (usually on the face) in the presence of inflammation, broken skin and infection can produce pain, discomfort, local irritation and even lead to potentially disfiguring complications.

• Because the areas to be treated often include areas of skin which are exposed to public view (such as the face), the cosmetic implications of topical administration greatly impact patient compliance. It is therefore of critical importance that the formulation does not leave a residue visible to the naked eye after application to the skin. None of the topical/transderrnal formulations of muscarinic receptor antagonists (or of oxybutynin in particular) described above avoids these problems and none is suitable for use in the treatment of skin disorders such as acne. Existing topical formulations are designed to achieve steady state systemic levels with a lower Cmax and not to achieve high skin concentrations and while WO2007/141530 discloses, in general terms, gel formulations of various muscarinic receptor antagonists (including oxybutynin) for topical application in the treatment of such diseases, it neither recognizes the aforementioned problems nor discloses or suggests specific topical oxybutynin formulations which overcome them. There is therefore a need for new therapies that reduce sebum excretion rates which are well tolerated for the treatment of seborrhoea in Parkinson's patients as well as producing effective combination treatments for seborrhoeic dermatitis and acne vulgaris as well as for transdermal/topical muscarinic receptor antagonist formulations, including formulations of oxybutynin, which are non-irritating to damaged and/or sensitive skin, low-residue and suitable for administration to subjects suffering from skin disorders such as acne.

Summary of the Invention

First aspect

According to a first aspect of the invention there is provided a composition comprising a muscarinic receptor antagonist for topical application to the skin which yields a muscarinic receptor antagonist active plasma:dermis concentration ratio such that a non-spasmolytic concentration of muscarinic receptor antagonist active is produced after direct topical application to an area of ≤0.5 m² of skin. Any suitable buffering agent may be used (as described herein), but preferred are citrate buffers (e.g. trisodium citrate dihydrate and anhydrous citric acid buffering agents). The composition may be a hydrogel, and may further comprise a non-ionic polymeric gelling agent as described herein. The gelling agent preferably has a molecular weight such that it is not visible to the naked eye after application to the skin. The gelling agent may be a cellulose polymer, for example a cellulose ether. Preferred is hydroxyethyl cellulose. The gelling agent preferably has an average molecular weight of less than 2,000,000, for example 1 ,000,000 to 2,000,000. Particularly preferred are gelling agents wherein the average molecular weight is: (a) less than 1 ,500,000; (b) 1 ,000,000 to 1 ,500,000; or (c) about 1 ,300,000. The composition of the invention preferably has a viscosity of 5,000 to 40,000 cps at 25° C, for example a viscosity of 10,000 to 35,000 cps at 25° C. Particularly preferred are compositions having a viscosity of 20,000 to 30,000 cps at 25° C. The composition of the invention may further comprise a humectant (as herein described). Preferred humectants are hygroscopic polyols such as propylene glycol. Particularly preferred humectants (such as propylene glycol) reduce or eliminate residue visible to the naked eye after application to the skin.

The muscarinic receptor antagonist may be incorporated into the compositions of the invention at any desired concentration. For applications involving the treatment of skin disorders such as acne it is present at a therapeutically effective amount. Lower quantities (that may for example be non-therapeutic) may be acceptable for cosmetic applications. Preferred compositions include muscarinic receptor antagonist at 0.01 to 10 percent by weight of the total weight of the composition, for example at: (a) 0.5 to 5 percent by weight of the total weight of the composition; (b) 0.5 to 2 percent by weight of the total weight of the composition; or (c) at about 1 percent by weight of the total weight of the composition.

Various adjunctive agents may be incorporated into the compositions of the invention. Such agents include antibacterial agents. Suitable antibacterial agents include antibiotics selected from, for example, clindamycin, erythromycin and tetracycline and benzoyl peroxide. Other adjunctive agents include combined agents, for example being selected from: erythromycin/zinc; erythromycin/tretinoin; erythromycin/isotretinoin; erythromycin/benzoyl peroxide and clindamycin/benzoyl peroxide. The compositions of the invention may include one or more preservatives. Preferred is ethanol, which may be present at a concentration at which it can also act as a permeation enhancer for the muscarinic receptor antagonist.

Preferred compositions comprise, consist of or consist essentially of: (a) oxybutynin chloride; (b) trisodium citrate dihydrate; (c) anhydrous citric acid; (d) hydroxyethyl cellulose; (e) propylene glycol; (f) ethanol; and (g) water. In such embodiments: (a) the muscarinic receptor antagonist may be present at 0.01 to 10 percent by weight of the total weight of the composition; and/or (b) the trisodium citrate dihydrate and anhydrous citric acid may be present at 2.0 to 2.5 percent by weight of the total weight of the composition and in relative proportions sufficient to achieve a pH of 3.0 to 5.5; and/or (c) the hydroxyethyl cellulose may be present at 1-4 percent by weight of the total weight of the composition; and/or (d) the propylene glycol may be present at 10-20 percent by weight of the total weight of the composition; and/or (e) the ethanol may be present at 5-15 percent by weight of the total weight of the composition; the balance being water.

Particularly preferred are compositions in which: (a) the muscarinic receptor antagonist is present at about 1 percent by weight of the total weight of the composition; and (b) the trisodium citrate dihydrate is present at about 1.5 percent by weight of the total weight of the composition; and (c) the anhydrous citric acid is present at about 1 percent by weight of the total weight of the composition; and (d) the hydroxyethyl cellulose is present at about 2 percent by weight of the total weight of the composition; and (e) the propylene glycol is present at about 15 percent by weight of the total weight of the composition; and (f) the ethanol is present at about 10 percent by weight of the total weight of the composition; the balance being water and the composition having a pH of about 4.5. Preferred compositions yield an muscarinic receptor antagonist active plasma:dermis concentration ratio of <1 or <0.75 or <0.5 or less than 0.1 after direct topical application to the skin.

Second aspect

According to a second aspect of the invention there is provided a hydrogel composition comprising oxybutynin for topical application to the skin wherein the composition has a pH of 3.0 to 5.5. Any suitable buffering agent may be used (as described herein), but preferred are citrate buffers (e.g. trisodium citrate dihydrate and anhydrous citric acid buffering agents). The composition may further comprise a non-ionic polymeric gelling agent as described herein. The gelling agent preferably has a molecular weight such that it is not visible to the naked eye after application to the skin. The gelling agent may be a cellulose polymer, for example a cellulose ether. Preferred is hydroxyethyl cellulose. The gelling agent preferably has an average molecular weight of less than 2,000,000, for example 1 ,000,000 to 2,000,000. Particularly preferred are gelling agents wherein the average molecular weight is: (a) less than 1 ,500,000; (b) 1 ,000,000 to 1 ,500,000; or (c) about 1 ,300,000.

Any form of oxybutynin (as described herein) may be used. Preferred is oxybutynin chloride, and particularly preferred is racemic oxybutynin chloride. The oxybutynin may be incorporated into the hydrogels of the invention at any desired concentration. For applications involving the treatment of skin disorders such as acne it is present at a therapeutically effective amount. Lower quantities (that may for example be non- therapeutic) may be acceptable for cosmetic applications. The hydrogel of the invention preferably has a viscosity of 5,000 to 40,000 cps at 25° C, for example a viscosity of 10,000 to 35,000 cps at 25° C. Particularly preferred are hydrogels having a viscosity of 20,000 to 30,000 cps at 25° C. The composition of the invention may further comprise a humectant (as herein described). Preferred humectants are hygroscopic polyols such as propylene glycol. Particularly preferred humectants (such as propylene glycol) reduce or eliminate residue visible to the naked eye after application to the skin. Preferred hydrogels include oxybutynin at 0.01 to 10 percent by weight of the total weight of the composition, for example at: (a) 0.5 to 5 percent by weight of the total weight of the composition; (b) 0.5 to 2 percent by weight of the total weight of the composition; or (c) at about 1 percent by weight of the total weight of the composition. Various adjunctive agents may be incorporated into the hydrogels of the invention. Such agents include antibacterial agents. Suitable antibacterial agents include antibiotics selected from, for example, clindamycin, erythromycin and tetracycline and benzoyl peroxide. Other adjunctive agents include combined agents, for example being selected from: erythromycin/zinc; erythromycin/tretinoin; erythromycin/isotretinoin; erythromycin/benzoyl peroxide and clindamycin/benzoyl peroxide.

The compositions of the invention may include one or more preservatives. Preferred is ethanol, which may be present at a concentration at which it can also act as a permeation enhancer for the oxybutynin. Preferred compositions comprise, consist of or consist essentially of: (a) oxybutynin chloride; (b) trisodium citrate dihydrate; (c) anhydrous citric acid; (d) hydroxyethyl cellulose; (e) propylene glycol; (f) ethanol; and (g) water. In such embodiments: (a) the oxybutynin chloride may be present at 0.01 to 10 percent by weight of the total weight of the composition; and/or (b) the trisodium citrate dihydrate and anhydrous citric acid may be present at 2.0 to 2.5 percent by weight of the total weight of the composition and in relative proportions sufficient to achieve a pH of 3.0 to 5.5; and/or (c) the hydroxyethyl cellulose may be present at 1-4 percent by weight of the total weight of the composition; and/or (d) the propylene glycol may be present at 10-20 percent by weight of the total weight of the composition; and/or (e)the ethanol may be present at 5-15 percent by weight of the total weight of the composition; the balance being water.

Particularly preferred are hydrogels in which: (a) the oxybutynin chloride is present at about 1 percent by weight of the total weight of the composition; and (b) the trisodium citrate dihydrate is present at about 1.5 percent by weight of the total weight of the composition; and (c) the anhydrous citric acid is present at about 1 percent by weight of the total weight of the composition; and (d) the hydroxyethyl cellulose is present at about 2 percent by weight of the total weight of the composition; and (e) the propylene glycol is present at about 15 percent by weight of the total weight of the composition; and (f) the ethanol is present at about 10 percent by weight of the total weight of the composition; the balance being water and the composition having a pH of about 4.5. Preferred compositions yield an oxybutynin active plasma:dermis concentration ratio of <1 or <0.75 or <0.5 or less than 0.1 after direct topical application to the skin. The compositions may also yield an oxybutynin active plasma:dermis concentration ratio such that a non- spasmolytic concentration of oxybutynin active is produced after direct topical application to an area of ≤0.5 m² of skin.

The compositions of the invention in both first and second aspects find application in various forms of therapy. For example, the composition of the invention may be used for reducing sebum excretion, for example facial sebum excretion. Other applications include the treatment of various skin diseases or disorders, including acne. Preferred applications include the treatment of: (a) comedonal acne with inflammatory lesions; (b) nodulocystic acne; (c) conglobate acne; and (d) non-responsive acne. Other preferred applications include the treatment of seborrhoea or seborrhoeic dermatitis, for example in a subject with Parkinson's disease. The compositions of the invention find application in a method of reducing sebum secretion, for example facial sebum excretion, comprising applying the composition of the invention directly to the skin of a subject in need thereof. They also find application in cosmetics, for example to reduce facial shine. Preferred applications include the treatment of: (a) comedonal acne with inflammatory lesions; (b) nodulocystic acne; (c) conglobate acne; and (d) non-responsive acne. Other preferred applications include the treatment of seborrhoea or seborrhoeic dermatitis, for example in a subject with Parkinson's disease.

Detailed Description of the Invention

All publications, patents, patent applications and other references mentioned herein are hereby incorporated by reference in their entireties for all purposes as if each individual publication, patent or patent application were specifically and individually indicated to be incorporated by reference and the content thereof recited in full. Where used herein and unless specifically indicated otherwise, the following terms are intended to have the following meanings in addition to any broader (or narrower) meanings the terms might enjoy in the art:

Unless otherwise required by context, the use herein of the singular is to be read to include the plural and vice versa. The term "a" or "an" used in relation to an entity is to be read to refer to one or more of that entity. As such, the terms "a" (or "an"), "one or more," and "at least one" are used interchangeably herein.

As used herein, the term "comprise," or variations thereof such as "comprises" or "comprising," are to be read to indicate the inclusion of any recited integer (e.g. a feature, element, characteristic, property, method/process step or limitation) or group of integers (e.g. features, element, characteristics, properties, method/process steps or limitations) but not the exclusion of any other integer or group of integers. Thus, as used herein the term "comprising" is inclusive or open-ended and does not exclude additional, unrecited integers or method/process steps. The phrase "consisting essentially of" is used herein to require the specified integer(s) or steps as well as those which do not materially affect the character or function of the claimed invention. As used herein, the term "consisting" is used to indicate the presence of the recited integer (e.g. a feature, element, characteristic, property, method/process step or limitation) or group of integers (e.g. features, element, characteristics, properties, method/process steps or limitations) alone.

Concentrations, amounts and other numerical data may be presented herein in a range format. In these cases the range is used as a convenient and concise shorthand to specify not only the numerical values explicitly recited as the limits but also to include all the individual numerical values or sub-ranges encompassed within that range as if each numerical value and sub-range were explicitly recited. This holds irrespective of the breadth of the range or the parameter to which it is applied.

As used herein the term "hydrogel" is used to define semi-solid matrix comprising a network of polymer chains dispersed in water. Hydrogels are typically colloidal suspensions of non-ionic or insoluble polymers in water. They are plastic liquids that can be readily mobilized by shear forces and so have a jelly-like consistency. They may be viscous and/or thixotropic. The "yield value" as applied to the hydrogels of the invention defines their initial resistance to flow under an applied force.

As used herein, the term "muscarinic receptor antagonist active" is the sum of the concentrations of muscarinic receptor antagonist and its active metabolites. A "non- spasmolytic concentration of muscarinic receptor antagonist active" is used herein to define a concentration which is below that required to affect bladder muscle activity to a clinically significant degree. Thus, the non-spasmolytic concentrations of oxybutynin active used according to the invention may not affect urinary outflow to a clinically significant degree.

The term "direct topical application "used herein in relation to the hydrogels of the invention refers to application of the gel directly to the skin without the use of a supporting matrix, membrane, separate depot structure, material or structure (such as a bandage or dermal patch). Thus, direct topical application involves application of the gel to the skin in a free form.

As used herein, the term "treatment" or "treating" refers to an intervention (e.g. the administration of an agent to a subject) which cures, ameliorates or lessens the symptoms of a disease or removes (or lessens the impact of) its cause(s). In this case, the term is used synonymously with the term "therapy". Additionally, the terms "treatment" or "treating" refers to an intervention (e.g. the administration of an agent to a subject) which prevents or delays the onset or progression of a disease or reduces (or eradicates) its incidence within a treated population. In this case, the term treatment is used synonymously with the term "prophylaxis".

As used herein, the term acne includes all forms of acne, including acne vulgaris, comedonal, inflammatory and nodulocystic acne.

In this context "subject" (which is to be read to include "individual", "animal", "patient" or "mammal" where context permits) defines any subject, particularly a mammalian subject, for whom treatment is indicated. Mammalian subjects include, but are not limited to, humans, domestic animals, farm animals, zoo animals, sport animals, pet animals such as dogs, cats, guinea pigs, rabbits, rats, mice, horses, cattle, cows; primates such as apes, monkeys, orangutans, and chimpanzees; canids such as dogs and wolves; felids such as cats, lions, and tigers; equids such as horses, donkeys, and zebras; food animals such as cows, pigs, and sheep; ungulates such as deer and giraffes; rodents such as mice, rats, hamsters and guinea pigs; and so on. In preferred embodiments, the subject is a human, for example an infant human.

As used herein, the term "disease" is used to define any abnormal condition that impairs physiological function and is associated with specific symptoms. The term is used broadly to encompass any disorder, illness, abnormality, pathology, sickness, condition or syndrome in which physiological function is impaired irrespective of the nature of the aetiology (or indeed whether the aetiological basis for the disease is established). It therefore encompasses conditions arising from trauma, injury, surgery, radiological ablation, poisoning or nutritional deficiencies.

As used herein, an effective amount or a therapeutically effective amount of a compound defines an amount that can be administered to a subject without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio, but one that is sufficient to provide the desired effect, e.g. the treatment or prophylaxis manifested by a permanent or temporary improvement in the subject's condition. The amount will vary from subject to subject, depending on the age and general condition of the individual, mode of administration and other factors. Thus, while it is not possible to specify an exact effective amount, those skilled in the art will be able to determine an appropriate "effective" amount in any individual case using routine experimentation and background general knowledge. A therapeutic result in this context includes eradication or lessening of symptoms, reduced pain or discomfort, prolonged survival, improved mobility and other markers of clinical improvement. A therapeutic result need not be a complete cure.

In its broadest aspect, the present invention also contemplates all optical isomers, racemic forms and diastereomers of the compounds of the invention. Those skilled in the art will appreciate that, owing to the asymmetrically substituted carbon atom present in oxybutynin, it may exist and be synthesised and/or isolated in optically active and racemic forms. Thus, references to oxybutynin encompass the compounds as a mixture of diastereomers, as individual diastereomers, as a mixture of enantiomers as well as in the form of individual enantiomers. Therefore, the present invention contemplates all optical isomers and racemic forms thereof. The invention contemplates use of the isolated eutomer of oxybutynin (i.e. the (R)-isomer) and its corresponding salts, free base and derivatives. Muscarinic receptor antagonists for use according to the invention

Muscarinic receptors are members of the G-protein coupled receptors that are composed of a family comprising at least five receptor sub-types (M1 , M2, M3, M4 and M5). They are activated by the neurotransmitter acetylcholine. The receptors are widely distributed on multiple organs and tissues and are critical to the maintenance of central and peripheral cholinergic neurotransmission. The receptor subtypes are distributed in a tissue/organ specific manner: for example, the M3 subtype is located predominantly on smooth muscle and salivary glands. Glycopyrrolate and scopolamine are older generation anti-muscarinic drugs and block all five muscarinic receptor subtypes and centrally-mediated side effects have been reported, particularly with scopolamine. The older generation non-selective compounds are a mixture of compounds that enter the brain, and those that contain a quaternary ammonium function and therefore do not readily penetrate the blood brain barrier. Examples of compounds that contain a quaternary amine function are propantheline, methylscopolamine, homatropine methylbromide, poldine, ipratropium, trospium and glycopyrrolate. In recent years, a newer generation of muscarinic receptor antagonists, which possess some selectivity for and preferentially block muscarinic M3 receptors relative to the other M receptor subtypes have been introduced or are currently being developed for the treatment of bladder disorders. Examples of newer M3 muscarinic compounds, but not limited to, are darifenacin, solifenacin, fesoterodine, and zamifenacin. Oxybutynin is not a new generation muscarinic antagonist but it displays modest selectivity for M1 and M3 receptors over the other subtypes (and on this basis is classified as a partially selective antagonist). It is used extensively to treat overactive bladder disorders. However, compounds with differing selectivity profiles at muscarinic receptors have been developed to treat chronic obstructive pulmonary disease (COPD).

Preferred muscarinic receptor antagonists for use in the invention are darifenacin, solifenacin, tolterodine, fesoterodine, zamifenacin, oxybutynin, Ro-3202904 (PSD-506), propantheline, methylscopolamine, homatropine, methylbromide or trospium. Preferential (or partially selective) M3 muscarinic receptor antagonists such as darifenacin, solifenacin, tolterodine, fesoterodine, zamifenacin, oxybutynin and Ro-3202904 (PSD-506), are particularly preferred. Darifenacin and oxybutynin (and/or the active metabolite(s) tehreof, for example N-desethyloxybutynin) are also preferred. The advantage of using preferential M3 muscarinic receptor antagonists is that they do not cause the numerous side-effects associated with blockade of all the muscarinic receptor subtypes (such as severe stomach pain or constipation, reduced micturation, dry mouth, eye accommodation abnormalities, sleep disturbances, confusion and hallucinations).

As used herein, the term "oxybutynin" is used to define the compound having the general structure:

The oxybutynin addition salt, oxybutynin chloride (or oxybutynin HCI), is known by several IUPAC names such as α-cyclohexyl-hydroxy-benzenacetic acid 4- (diethylamino)-2-butynyl ester hydrochloride; α -phenylcyclohexaneglycolic acid 4- (diethylamino)-2-butynyl ester hydrochloride and 4-diethylamino-2-butynylphenylcyclohexylglycolate hydrochloride. As used herein, the term "oxybutynin" is to be interpreted broadly to include oxybutynin free base, acid addition salts (for example oxybutynin chloride) together with analogues of the foregoing and related compounds, isomers, polymorphs, complexes and prodrugs thereof. Also specifically contemplated is the use of one or more of the active metabolite(s) of oxybutynin. Particularly preferred in this respect is N-desethyloxybutynin. Oxybutynin is a chiral molecule and (R)- and (S)-isomers exist. When metabolised, oxybutynin gives rise to metabolites such as N-desethyloxybutynin, which may also be present as (R)- and (S)- isomers or combinations thereof. A reference to oxybutynin is to be interpreted to cover: (a) (S)-oxybutynin; (b) (R)-oxybutynin and (c) racemic mixtures thereof. Similarly, a reference to N-desethyloxybutynin is to be interpreted to cover: (a) (S)- N- desethyloxybutynin; (b) (R)- N-desethyloxybutynin and (c) racemic mixtures thereof. References herein to oxybutynin therefore include the isomeric forms discussed above and their mixtures are therefore within the scope of this invention. Preferred for use in the hydrogel compositions of the invention is oxybutynin chloride. The oxybutynin may be provided in a micronised form or other powdered form.

Testing for dual antibacterial and sebum excretion reducing activity

Muscarinic receptor antagonists for use according to the invention preferably exhibit dual antibacterial and anti-sebum secretion activity. Such antagonists (which may be referred to herein as "muscarinic receptor antagonists having dual antibacterial and anti-sebum secretion activity") may be readily identified by determining the minimum inhibitory concentration (MIC) and/or minimum bactericidal concentration (MBC) using any of a wide variety of standard techniques known to those skilled in the art (and described in general terms in the Study, below). Preferably, the muscarinic receptor antagonists for use according to the invention are tested for antibacterial activity against Propionibacterium spp. (e.g. P. acnes).

The term antibacterial activity is used herein to define the ability to destroy bacteria or inhibit or prevent bacterial growth or metabolism. Those skilled in the art will be aware of many different tests for detecting and/or quantifying antibacterial activity, including for example cup plate or paper disc bioassays based on the detection/measurement of zones of inhibition in seeded agar plates. The antibacterial muscarinic receptor antagonists for use according to the invention may be bacteriocidal or bacteriostatic. Preferably, the antibacterial muscarinic receptor antagonist is bacteriocidal, since such agents (examples being oxybutynin and darifenacin) reduce the emergence of resistance. Antibacterial activity may be expressed in terms of the minimum inhibitory concentration (MIC) of the test compound required to produce a bacteriostatic effect in vitro. In general, MIC values of less than 1000 mg/L (or 500 mg/L or less) define thresholds that identify antibacterial activity. The in vitro tests typically involve serial dilution and liquid culture or the impregnation of absorbent discs with various concentrations of test agent followed by zone clearing tests with the discs on solid media. In the former case, the tests are typically broth microdilution tests performed according to the National Committee for Clinical Laboratory Standards (NCCLS) method using RPMI 1640 as the test medium or its European equivalent , the AFST-EUCAST procedure (see Cuenca-Estrella et al. (2002) Antimicrobial Agents and Chemotherapy, 46(11): 3644-3647 and the methods described herein). In the latter case, the assay format typically involves a series of agar plates, each having the test compound incorporated at a particular concentration. The plates are then inoculated with a standard culture of, for example, a propionibacterium and the plates then incubated for 48 hours at 37^°C. The plates are then examined for the presence or absence of growth of the bacterium. Both of these assay formats are common general knowledge in the art. Preferred antibacterial muscarinic receptor antagonists for use according to the invention have MIC values of less than 1000 mg/L (preferably 500 mg/L or less) in broth microdilution tests against at least one species of Propionibacterium. The term anti-sebum secretion activity is used herein to define the ability to reduce serum secretion by sebocytes (e.g. facial sebocytes). Muscarinic receptor antagonists having such activity may be identified using any of a wide variety of standard techniques known to those skilled in the art (and described in general terms in the Study, below), for example by measuring skin sebum excretion rates with a Sebumeter®. Thus, tertiary amine muscarinic receptor antagonists (such as oxybutynin and darifenacin) may be preferred for use according to the invention, and particularly preferred are selective (or partially selective) M3 tertiary amine muscarinic receptor antagonists (such as oxybutynin and darifenacin). Of these preferred selective M3 tertiary amine muscarinic receptor antagonists are those which exhibit dual antibacterial and sebum reducing activity as defined herein and identified according to the teachings set out herein.

Buffering agents

Any buffering agent may be used provided that it can achieve a pH of between 3 and 5.5 in the finished hydrogel. Suitable buffering agents include inorganic and organic buffering agents such as phosphate, borate, citrophosphate, acetate, glutamate, citrate, tartrate, benzoate, lactate, gluconate and glycine buffers. Preferred for use in the compositions of the invention is sodium citrate/citric acid. Since buffering agents increase the total solids content of the composition the amounts used are kept to a minimum to avoid or minimize any visible residue after application. The pH of the compositions of the invention is critical and the present inventors have surprisingly found that a pH in the range of between 3 and 5.5 is compatible with facial and/or acne-covered skin, does not compromise the stability of the muscarinic receptor antagonist and does not degrade or compromise the gel structure and so lead to undesirably low viscosities.

Gelling agents for use according to the invention

Preferred for use in the compositions of the invention are non-ionic polymeric gelling agents, particularly cellulose polymers (such as cellulose ether polymers). Particularly preferred is hydroxyethyl cellulose. Polymeric polymers for use according to the invention may have an average molecular weight (and/or other physicochemical properties) sufficient to produce a gel of suitable viscosity for topical application to facial skin. Preferably, the average molecular weight (and/or other physicochemical properties) of the gelling agent is such that a viscosity of 5000 to 40000 cps at 25° C can be achieved. Viscosities below 5000 cps may be in the liquid state when applied and may therefore not properly cover the areas to be treated and/or be effectively retained at such sites. A viscosity of greater than 40000 cps can feel sticky to the touch and this property can reduce patient compliance.

Preferably, the average molecular weight (and/or other physicochemical properties) of the gelling agent is such that a gel composition having a yield value of at least 5 dyn/cm² can be achieved. Gels with yield values of less than about 5 dyn/cm² may not be effectively localized to the site of treatment. Preferably, the average molecular weight (and/or other physicochemical properties) of the gelling agent is 1 ,000,000 to 1 ,500,000, more preferably about 1 ,300,000. Preferably, the average molecular weight (and/or other physicochemical properties) of the gelling agent is such that it does not leave a residue visible to the naked eye after drying on the skin. Other suitable cellulose polymers include hydroxypropyl cellulose (e. g. KLUCEL™), hydroxypropylmethyl cellulose (e. g. KLUCEL HF™, METHOCEL™), hydroxypropylethyl cellulose, hydroxypropylbutyl cellulose, hydroxypropylpentyl cellulose, hydroxyethyl cellulose (Natrosol® and in particular the 250HHX grade)), ethylcellulose, carboxymethyl cellulose, hydroxypropylmethyl cellulose phthalate, and cellulose acetate. NatrosolOHEC is a non-ionic water-soluble cellulose ether, formed by reaction of cellulose with ethylene oxide. Inatrosol® is easily dispersed in cold or hot water to give solutions of varying viscosities and desired properties, yet it is insoluble in organic solvents. The PHARM grades of Natrosol®HEC (including the 250HHX grade preferred for use according to the invention comply with the requirements of the National Formulary and European Pharmacopoeia.

The gel formulation may be prepared by providing a gelling agent, usually in a powdered form, and adding water. The gel then swells and may then be pH adjusted. In a separate vessel, the muscarinic receptor antagonist may be dissolved in an appropriate solvent. The dissolved muscarinic receptor antagonist and the gel may then be mixed to form the final gel formulation. Other methods of producing a drug-containing gel will be recognized by those of ordinary skill in the art and relevant teaching may be found, for example, in US 2909462, US 4340706, US 4652441 , US 5516808, US5643584, US5840338, US5912009 and US 6258830 (the contents of which are incorporated herein by reference). To prepare a uniform gel, dispersing agents such as alcohol can be added, or the gelling agent can be dispersed by trituration, mechanical mixing or stirring (or combinations thereof). Those skilled in the art will recognize that many other methods of incorporating the muscarinic receptor antagonist and other components into the gel may be employed. Humectants

Humectants for use in the compositions of the invention are hygroscopic and act to slow or prevent drying out of the gel and may in use moisturize the skin to which the composition is applied. Since they function to increase the water content of the gel film after application to the skin, they may also modify the optical characteristics of the film and this can be used to improve the cosmetic performance of the compositions of the invention (see below). Examples of humectants useful in this invention include glycerine, sorbitol, polyethylene glycol, propylene glycol, polysaccharides (such as fructose, glucose, maltose, etc.), corn syrup, polyols, urea and derivatives and natural honey.

Preferred humectants for use in the compositions of the invention are hygroscopic polyols. Suitable polyol humectants include glycerol, diglycerol, triglycerol, polyglycerol, polyalkylene glycols and more preferably alkylene polyols and their derivatives, including propylene glycol, dipropylene glycol, polypropylene glycol, polyethylene glycol and derivatives thereof, sorbitol, hydroxypropyl sorbitol, hexylene glycol, 1,3-butylene glycol, isoprene glycol, 1 ,2,6- hexanetriol, ethoxylated glycerol, propoxylated glycerol and mixtures thereof. Preferred is propylene glycol. Particularly preferred are humectants which reduce or eliminate residue visible to the naked eye after application to the skin. Propylene glycol has surprisingly been found to exhibit this property, for example when used at appropriate concentrations in conjunction with hydroxyethyl cellulose as gelling agent.

Preservatives

The compositions of the invention may comprise one or more preservatives. These increase shelf-life and prevent or inhibit the growth of potentially harmful microorganisms. Preservatives suitable for use in the compositions of the invention include alkyl esters of para-hydroxybenzoic acid, sorbic acid (and its salts), alcohols, hydantoin derivatives, propionate salts, various quaternary ammonium compounds, phenoxyethanol, methyl paraben, propyl paraben, imidazolidinyl urea, octanedio, sorbitol, p-oxybenzoic acid esters (e. g. methyl paraben, ethyl paraben and propyl paraben), benzyl alcohol, isopropyl alcohol, chlorobutanol, betahydroxytoluene and thimerosal. Preferred is ethanol, which also acts as a permeation enhancer (see below). Preservatives are preferably employed in amounts ranging from 0.01% to 2% by weight of the composition, but as a dual acting preservative and permeation enhancer (see below), ethanol may be used at higher concentrations. Permeation enhancers

The compositions of the invention may comprise one or more permeation enhancer(s). These agents increase the permeability of the skin to the muscarinic receptor antagonist. Suitable permeation enhancers are described in Osborne and Henke (1998) "Skin Penetration Enhancers Cited in the Technical Literature", in "Pharmaceutical Technology" which is incorporated herein by reference. More particularly, permeation enhancers known to enhance the delivery of oxybutynin include but are not limited to: fatty acids, fatty acid esters, fatty alcohols, fatty acid esters of lactic acid or glycolic acid, glycerol tri-, di-and monoesters, triacetin, short chain alcohols, and mixtures thereof Various permeation enhancers have been reported for transdermal or topical delivery of oxybutynin, including for example US 5411740, US 5500222 and US 5614211 (monoglyceride fatty acids), US 5736577, US 5834010 and US 6555129 (triacetin), US 5747065 (monoglycerides and lactate esters), US 5843468 (mixtures of lauryl acetate and a glycerol monolaurate), US 6004578 (alkyl or aryl carboxylic acid esters of polyethyleneglycol monoalkyl ether and polyethyleneglycol alkyl carboxymethyl ethers), US 6267984 (monoglyceride and ethyl palmitate) and US 6562368 (a hydroxide-releasing agent). Specific species or combinations of species may be selected from the above listed classes of compounds by one skilled in the art, in order to optimise enhancement of the particular muscarinic receptor antagonist composition employed. Preferred permeation enhancers for use in the compositions of the invention are short chain alcohols. Particularly preferred is ethanol, which has dual activity as a preservative and which is non-greasy.

Other optional components

The compositions of the invention may also include additional components including (but not limited to) one or more of the following: adjunctive active agents (see below), excipients, solvents, emulsifiers, chelating agents, surfactants, emollients, antioxidants, lubricants, adjuvants, dyes and perfumes.

Adjunctive active agents

Various adjunctive agents may be incorporated into the compositions of the invention. Such agents include antibacterial agents. Suitable antibacterial agents include antibiotics selected from, for example, clindamycin, erythromycin, lymecycline, minocycline and tetracycline and benzoyl peroxide. Other adjunctive agents include combined agents, for example being selected from: erythromycin/zinc; erythromycin/tretinoin; erythromycin/isotretinoin; erythromycin/benzoyl peroxide and clindamycin/benzoyl peroxide. Preferred are basic antibiotics (including for example erythromycin, clindamycin, tetracycline, lymecycline and minocycline) which do not interact with muscarinic receptor antagonist.

The patient to be treated according to the invention may also be administered: (a) an antifungal or an antiproliferative; and/or (b) benzoyl peroxide, azelaic acid, a retinoid (e.g. adapalene, tretinoin or isotretinoin), salicyclic acid, nicotinamide, a histone deacetylase inhibitor or an antibacterial agent; and/or (c) a retinoid, an anti-androgen, a histone deacetylase inhibitor, or an antibiotic agent. In the case of adapalene, tretinoin and isotretinoin, these organic acids may interact with the muscarinic receptor antagonist to form salts which readily dissociate after application and may also enhance absorption and retention of actives in the skin. Other adjuntive active agents include those used in the treatment of seborrhoeic dermatitis (see below), for example antifungal agents such as zinc pyrithione, cinnamic acid, azoles, cyclopirox, terbinafine, as well as non-specific topical agents such as selenium sulphide/sulphur, tar, lithium succinate, benzoyl peroxide, propylene glycol, corticosteroids, ketoconazole, itraconazole or terbinafine.

Medical uses

The compositions of the invention find application in a wide variety of medical applications, including acne, various diseases, conditions and indications associated with excess sebum production, seborrhoea and seborrhoeic dermatitis. It is accepted in the clinical community that acne vulgaris is accompanied with clinical seborrhoea and there is a direct relationship between the sebum excretion rate and the severity of acne vulgaris. Although sebum excretion increases during adolescence (particularly in boys, because of androgen stimulation), increased sebum alone does not cause acne. Bacteria, most importantly Propionibacterium acnes, are present in increased numbers in persons who have acne. Much of the inflammation that eventually occurs arises from the action of enzymes produced by the bacteria.

Acne is divided into various categories, including comedonal, inflammatory, nodulocystic and conglobate acne. Conglobate acne describes a condition where there is a merging of deep abscesses to produce scarring channels in the skin. Nodulocystic acne is characterised by the appearance of hard lumps. Diagnosis of the condition into these categories determines the treatment schedule. Mild to moderate forms of comedonal and inflammatory acne are treated topically. Mild but significant comedonal acne responds well to topical retinoids (adapalene, tretinoin and isotretinoin) or benzoyl peroxide. Comedonal acne with inflammatory lesions is currently treated with topical antibiotics and antimicrobial agents (clindamycin, erythromycin, tetracycline, and azelaic acid). Moderate to severe inflammatory and nodulocystic acne are generally treated with oral antibiotics and retinoids. Severe side effects are associated with high dose retinoids and therefore treatment with these agents is often limited. Other forms of acne include acne that has not responded to standard treatment with oral antibiotics and topical medicines (referred to herein as "non- responsive acne") including post-retinoic acne (acne which develops after treatment with retinoic acids, such as isotretinoin (Roaccutane®)).

The compositions of the invention may also be used to treat excess sebum excretion. Sebum is an oily secretion from sebaceous glands in the skin and serves many functions. Sebum is involved in the development of epidermal structure and maintains an epidermal permeability barrier, as well as transporting anti-oxidants to the surface of the skin and providing protection from microbial colonisation. An increased rate of sebum excretion is termed seborrhoea. Seborrhoea is a feature of many conditions including Parkinson's disease. Seborrhoeic dermatitis is characterised by the appearance of red, flaking, greasy areas of skin, most commonly on the scalp, nasolabial folds, ears, eyebrows and chest. Seborrhoeic dermatitis of the scalp is often referred to as dandruff and may range from mild scalp flaking to pronounced dense, diffuse, adherent scale on the scalp. In the clinical literature seborrhoeic dermatitis may be also referred to as "sebopsoriasis", "seborrhoeic eczema", "dandruff" and "pityriasis capitis".

Cosmetic uses

Healthy skin is coated with a thin film of lipids composed of triglycerides, diglycerides, fatty acids, wax esters, squalene, sterols, sterol esters and phospholipids known as sebum. Sebum is excreted by the sebaceous glands. These are most numerous on the face (where they typically occur at a density of 400-800 glands/cm²). The film of sebum is usually at least 4 μm thick and it functions to prevent undue water loss through the skin, protect against sunburn, maintain the dermal microflora and deliver antioxidants to the skin surface. While playing an important role in the maintenance of healthy skin, the presence of sebum on the face is responsible for facial shine (sometimes referred to as facial gloss). Facial shine is considered to be aesthetically unattractive, imparting the appearance of unclean greasiness suggestive of poor hygiene and/or health. A demographic study showed that facial shine is a common concern of 70% of the US female population and 62% of the Japanese female population (see e.g. Draelos et al. (2006) Journal of Cosmetic and Laser Therapy 8: 96-101). Sebum control is therefore a goal of many over-the-counter (non-prescription) skin care products. However, most currently available products function by absorbing sebum from the face rather than modulating its production and/or excretion. This can lead to problems associated with residue build-up and the need for daily facial scrubbing, as well as requiring frequent application in cases where sebum excretion rates are high. The compositions of the invention reduce sebum excretion and so can be used as cosmetic agents for reducing facial shine.

Exemplification

The invention will now be described with reference to specific Examples. These are merely exemplary and for illustrative purposes only: they are not intended to be limiting in any way to the scope of the monopoly claimed or to the invention described. These examples constitute the best mode currently contemplated for practicing the invention. The exemplary formulations were prepared by dissolving the oxybutynin HCI in water, any required buffer salts and ethanol while dispersing the hydroxyethyl cellulose (HEC) in the propylene glycol. The HEC slurry was then poured into the aqueous solution and stirred while it hydrated and gelled.

Example 1

Preservative efficacy tests confirmed that the formulation complied with the criteria of the European Pharmacopoeia for topical products. Stability testing over a three month period revealed no qualitative change in viscosity and the oxybutynin was stable. Example 2

Preservative efficacy tests confirmed that the formulation complied with the criteria of the European Pharmacopoeia for topical products. Stability testing over a three month period revealed no qualitative change in viscosity and the oxybutynin was stable.

Equivalents

The foregoing description details presently preferred embodiments of the present invention. Numerous modifications and variations in practice thereof are expected to occur to those skilled in the art upon consideration of these descriptions. Those modifications and variations are intended to be encompassed within the claims appended hereto.

Claims

CLAIMS:

1. A hydrogel composition comprising oxybutynin for topical application to the skin wherein the composition has a pH of 3.0 to 5.5.

2. The composition of claim 1 further comprising a non-ionic polymeric gelling agent.

3. The composition of claim 1 or claim 2 wherein the oxybutynin is oxybutynin chloride.

4. The composition of any one of the preceding claims having a pH of 3.0 to 5.0.

5. The composition of any one of the preceding claims having a pH of 4.0 to 5.0.

6. The composition of any one of the preceding claims having a pH of about 4.5.

7. A composition comprising a muscarinic receptor antagonist for topical application to the skin which yields a muscarinic receptor antagonist active plasma:dermis concentration ratio such that a non-spasmolytic concentration of muscarinic receptor antagonist active is produced after direct topical application to an area of ≤0.5 m² of skin.

8. The composition of claim 7 which is a hydrogel, for example comprising a non-ionic polymeric gelling agent.

9. The composition of claim 7 or claim 8 wherein the muscarinic receptor antagonist is a preferential M3 receptor antagonist.

10. The composition of any one of claims 7 to 10 wherein the muscarinic receptor antagonist is a tertiary amine.

11. The composition of any one of claims 7 to 10 wherein the muscarinic receptor antagonist is selected from: darifenacin, solifenacin, tolterodine, fesoterodine, zamifenacin, oxybutynin, Ro-3202904 (PSD-506), propantheline, methylscopolamine, homatropine, methylbromide or trospium, for example oxybutynin (e.g. oxybutynin chloride) or darifenacin.

12. The composition of any one of claims 7 to 11 having a pH of 3.0 to 5.5, for example 3.0 to 5.0.

13. The composition of claim 12 having a pH of 4.0 to 5.0, for example about 4.5.

14. The composition of any one of claims 2 to 13 wherein the gelling agent has a molecular weight such that it is not visible to the naked eye after application to the skin.

15. The composition of any one of claims 2 to 14 wherein the gelling agent is a cellulose polymer, for example a cellulose ether, e.g. hydroxyethyl cellulose.

16. The composition of any one of claims 2 to 15 wherein the average molecular weight of the gelling agent is less than 2,000,000, for example being in the range 1 ,000,000 to 2,000,000.

17. The composition of claim 16 wherein the average molecular weight of the gelling agent is less than 1 ,500,000, for example being in the range 1 ,000,000 to 1 ,500,000.

18. The composition of claim 17 wherein the average molecular weight of the gelling agent is about 1 ,300,000.

19. The composition of any one of the preceding claims having a viscosity of 5,000 to 40,000 cps at 25° C, for example a viscosity of 10,000 to 35,000 cps at 25° C, e.g. a viscosity of 20,000 to 30,000 cps at 25° C.

20. The composition of any one of the preceding claims further comprising a humectant, for example a hygroscopic polyol (e.g. propylene glycol).

21. The composition of claim 20 wherein the humectant reduces or eliminates residue visible to the naked eye after application to the skin.

22. The composition of any one of the preceding claims wherein the muscarinic receptor antagonist is present at a therapeutically effective amount.

23. The composition of any one of the preceding claims wherein the muscarinic receptor antagonist is present at 0.01 to 10 percent by weight of the total weight of the composition, for example at 0.5 to 5 percent by weight of the total weight of the composition, e.g. at 0.5 to 2 percent by weight of the total weight of the composition.

24. The composition of claim 23 wherein the muscarinic receptor antagonist is present at about 1 percent by weight of the total weight of the composition.

25. The composition of any one of the preceding claims further comprising an antibacterial agent, for example an antibiotic (e.g. selected from clindamycin, erythromycin and tetracycline).

26. The composition of claim 25 wherein the antibacterial agent is benzoyl peroxide.

27. The composition of claim 25 wherein the antibacterial agent is a combined agent selected from: erythromycin/zinc; erythromycin/tretinoin; erythromycin/isotretinoin; erythromycin/benzoyl peroxide and clindamycin/benzoyl peroxide.

28. The composition of any one of the preceding claims further comprising a preservative, for example ethanol, optionally wherein the ethanol also acts as a permeation enhancer.

29. The composition of any one of the preceding claims further comprising a buffering agent, for example a buffering agent comprising, or consisting of, sodium citrate/citric acid.

30. The composition of any one of the preceding claims which consists essentially of: : (a) a muscarinic receptor antagonist; (b) buffering agents sufficient to achieve a pH of 3.0 to 5.5; (c) hydroxyethyl cellulose; (d) propylene glycol; (e) ethanol; and (f) water.

31. The composition of claim 30 wherein the muscarinic receptor antagonist is oxybutynin, e.g. oxybutynin chloride.

32. The composition of any one of the preceding claims wherein the composition comprises, consists of or consists essentially of: (a) oxybutynin chloride; (b) trisodium citrate dihydrate; (c) anhydrous citric acid; (d) hydroxyethyl cellulose; (e) propylene glycol; (f) ethanol; and (g) water.

33. The composition of claim 90 wherein: (a) the oxybutynin chloride is present at 0.01 to 10 percent by weight of the total weight of the composition; and/or (b) the trisodium citrate dihydrate and anhydrous citric acid are present at 2.0 to 2.5 percent by weight of the total weight of the composition and in relative proportions sufficient to achieve a pH of 3.0 to 5.5; and/or (c) the hydroxyethyl cellulose is present at 1-4 percent by weight of the total weight of the composition; and/or (d) the propylene glycol is present at 10-20 percent by weight of the total weight of the composition; and/or (e) the ethanol is present at 5-15 percent by weight of the total weight of the composition; the balance being water.

34. The composition of claim 33 wherein: (a) the oxybutynin chloride is present at about 1 percent by weight of the total weight of the composition; and (b) the trisodium citrate dihydrate is present at about 1.5 percent by weight of the total weight of the composition; and (c) the anhydrous citric acid is present at about 1 percent by weight of the total weight of the composition; and (d) the hydroxyethyl cellulose is present at about 2 percent by weight of the total weight of the composition; and (e) the propylene glycol is present at about 15 percent by weight of the total weight of the composition; and (f) the ethanol is present at about 10 percent by weight of the total weight of the composition; (g) the balance being water and the composition having a pH of about 4.5.

35. The composition of any one of the preceding claims which yields an muscarinic receptor antagonist active plasma:dermis concentration ratio of <1 or <0.75 or <0.5 or less than 0.1 after direct topical application to the skin.

36. The composition of any one of the preceding claims for reducing sebum excretion, for example facial sebum excretion.

37. The composition of any one of the preceding claims for treatment of a skin disease or disorder.

38. The composition of any one of the preceding claims for the treatment of acne.

39. The composition of claim 38 wherein the acne is selected from: (a) comedonal acne with inflammatory lesions; (b) nodulocystic acne; (c) conglobate acne; and (d) non- responsive acne.

40. The composition of any one of the preceding claims for the treatment of seborrhoea or seborrhoeic dermatitis, for example in a subject with Parkinson's disease.

41. A method of reducing sebum excretion, for example facial sebum excretion, comprising applying the composition of any one of claims 1 to 35 directly to the skin of a subject in need thereof.

42. A method of treating any of the diseases or disorders as defined in claims 36 to 41 comprising applying the composition of any one of claims 1 to 35 directly to the skin of a subject in need thereof.

43. A method of reducing facial shine comprising applying the composition of any one of claims 1 to 35 directly to the skin of a subject in need thereof.