WO2003015789A2

WO2003015789A2 - A pharmaceutical composition for dermal application

Info

Publication number: WO2003015789A2
Application number: PCT/DK2002/000538
Authority: WO
Inventors: Erik Johannes Didriksen
Original assignee: Leo Pharma A/S
Priority date: 2001-08-15
Filing date: 2002-08-15
Publication date: 2003-02-27
Also published as: WO2003015789A3; AU2002333193A1

Abstract

A pharmaceutical composition for dermal application comprising, as an active component, a compound of general formula I And a pharmaceutically acceptable vehicle comprising a solvent for the active component capable of effecting penetration of the active component into the epidermis, and further comprising a polymeric emulsifier which is incapable of penetrating into the epidermis, may be used in the prevention or treatment of dermal inflammatory diseases or conditions such as dermatitis. Polymeric emulsifiers of the type preferably included in the present composition are generally classified as “carborners” but differ from the homopolymeric carbomers by being cross-linked copolymers and are preferably selected from the group consisting of (Permulen® TR1, Permulen ® TR2m carbomer 1342 (NF), ((Carbopol ® 1342, -Carbopol® 1382, Carbopol ® or Carbopol® ETD 2050. The solvent comprises a non-toxic glycol or glycol ether selected from the group consisting of propylene glycol, butylene glycol and ethoxy diglycol.

Description

A PHARMACEUTICAL COMPOSITION FOR DERMAL APPLICATION

FIELD OF INVENTION

The present invention relates to a pharmaceutical composition for dermal application as well as the use of the composition in the prophylaxis and treatment of dermal conditions.

BACKGROUND OF THE INVENTION

Dermal diseases affect a large number of patients with a prevalence (in the UK) of about 20%. Dermal inflammatory diseases are the most common dermal diseases, constituting about 50% of the skin diseases seen in general practice. Skin diseases may have profound psychosocial consequences, e.g. for patients suffering from extensive psoriasis or eczema. Dermal inflammatory conditions include dermatitis (eczema) typically involving redness or swelling of the skin or lesion which may be oozing, scaling or crusting. The inflamed areas of the skin are often also itchy (pruritic). Examples of dermatitis are atopic dermatitis, contact dermatitis or seborrheic dermatitis.

Atopic dermatitis is a chronic, relapsing, pruritic inflammatory skin disease occurring in genetically predisposed individuals. The onset of the disease is mostly in infancy or early childhood, 80% of the cases occurring before the age of 1 year. While there is a general tendency towards spontaneous improvement throughout childhood, approximately 60% of patients with severe atopic dermatitis and approximately 40% of patients with moderate atopic dermatitis contend with skin problems as adults, most frequently hand eczema.

The clinical manifestations of atopic dermatitis are erythema (redness), vesiculopapules, oozing or crusting, lichenification and general dryness of the skin. As the main complaint of atopic dermatitis is pruritus, excoriations are also prevalent.

Even though the disease has been under intense investigation with respect to pathogenesis and genetics in recent years, no pathognomic biochemical marker has been identified so far. There is general agreement that atopic dermatitis is a complex, multifactorial disease in which both genetic and environmental factors are involved. The role of allergens in the development of atopic dermatitis is controversial, and it has not been possible to demonstrate a consistent link between allergens and the disease. Atopic disease is regarded as a condition characterised by hyper-reactivity both at the clinical and the cellular level. One theory is that an unknown genetic predisposition leads to an imbalance of the immune system favouring the differentiation of T-helper-2(Th2)-type immunological characteristics such as enhanced IgE levels, blood eosinophilia and increased numbers of Th2-type cells. The cytokines involved are interleukin(IL)-4, IL-5 and IL-10 inducing secretion of IL-12 from eosinophils and macrophages. The IL-12 leads to activation of Thl and ThO cells which are responsible for the production of interferon γ (IFN-γ). The level of IFN-γ is correlated to the clinical severity of atopic dermatitis.

Recent studies indicate that patients suffering from atopic dermatitis have fundamental defects in their blood monocytes. Atopic leukocytes have an abnormally high activity of cyclic adenosine monophosphate phosphodiesterase (PDE) isoenzymes most prominent in monocytes, but an atopic PDE abnormality may also be present in multiple leukocyte subsets including basophils, B cells, T cells and eosinophils.

Current therapies of atopic dermatitis include topical treatment with emollients, topical corticosteroids and tar preparations, systemic treatment with corticosteroids, antibiotics, cyclosporine and antihistamines as well as phototherapy. The mainstay of therapy is topical corticosteroids which involve the risk of adverse cutaneous and systemic effects, including skin atrophy. New topical treatments have been proposed involving the application of ascomycin derivatives with an immunosuppressive effect. The long-term consequences of immunosuppressive treatment of atopic dermatitis have not been established, but some adverse effects including a higher incidence of infection in patients treated with ascomycin may be anticipated. Consequently, there is a need for an effective anti-inflammatory treatment of atopic dermatitis with fewer adverse effects.

Pruritus is a condition observed in a variety of dermal inflammatory diseases as well as in a number of systemic diseases such as malignant tumours, diabetes mellitus, hepatic diseases, renal failure, hemodialysis, thyroid diseases etc. Patients with pruritus experience a great deal of discomfort, and in severe cases it may cause significant disruption of daily life. In particular in connection with dermatitis, treatment for pruritus is required because scratching of the skin by the patient causes an aggravation of the symptoms.

Excoriation is the most exacerbating factor of dermatitis because scratching injures the skin resulting in defect of the barrier function and erosion by physical or chemical stimuli, and bacterial infection readily occurs. Due to extensive scratching of affected skin, even during sleep, patients affected by atopic dermatitis may develop atopic exanthema. Acne is a skin condition which is a multifactorial disease affecting the pilosebaceous follicles, characterised by increased sebum production and release of sebum from the sebaceous glands, the presence of excessive amounts of sebum in the duct of the pilosebaceous follicles leading to the formation of comedones (solidified sebum plugs in the follicular duct). Further closing of the ducts results in the formation of pustules, papules or cysts which are often subject to bacterial colonisation, especially by Propionibacterium acnes, and localised inflammation. Acne vulgaris is the most common skin disorder among teenagers, but substantial numbers of adults aged 20-40 are also affected by acne. Currently available drugs for the treatment of acne include benzoyl peroxide, azelaic acid, topical and systemic antibiotics, such as Fucidin®, clindamycin, erythromycin, and tetracyclin, retinoids, such as adapalene, tretinoin, isotretinoin, and hormones, such as estrogen. There are, however, serious drawbacks with these medications including teratogenicity, skin irritation, photosensibilisation, etc.

Because of the negative psychosocial consequences for affected individuals, and the relatively limited numbers of drugs available for topical treatment of dermal inflammatory diseases and the severity of the known side effects of some of these drugs, the provision of new medicaments for adequate therapy of dermal inflammatory diseases is very important.

SUMMARY OF THE INVENTION

The object of the present invention is to provide a topical formulation for application onto inflamed skin, such application resulting in effective penetration of an active anti- inflammatory component of the formulation into the epidermis while including other excipient materials in the vehicle which are not capable of penetrating the skin and therefore do not give rise to exacerbation of the skin irritation typically found in dermal inflammatory conditions.

Accordingly, the invention relates to a pharmaceutical composition for dermal application comprising, as an active component, a compound of general formula I

I wherein Ri and R₂ are each independently alkyl or a moiety of the formula -(CH₂)_m-A, wherein m is 0, 1, 2 or 3, and A is an optionally substituted cyclic hydrocarbon radical; R₃ is halogen, nitro or NR₄R₅ wherein R₄ and R₅ are independently hydrogen, alkyl, alkylcarbonyl, or together with the nitrogen atom to which they are attached form an optionally substituted heterocyclic ring; and pharmaceutically acceptable salts thereof; and a pharmaceutically acceptable vehicle comprising a solvent for the active component in an amount sufficient to effect penetration of the active component into the epidermis, and further comprising a polymeric emulsifier which is incapable of penetrating into the epidermis.

In another aspect, the invention relates to the use of said pharmaceutical composition for the manufacture of a medicament for the prophylaxis or treatment of dermal inflammatory diseases or conditions.

In a further aspect, the invention relates to a method of preventing or treating dermal inflammatory diseases or conditions, the method comprising dermally applying to a site of inflammation an effective amount of said pharmaceutical composition.

DETAILED DESCRIPTION OF THE INVENTION

Solvent

Compounds of formula I have a pronounced inner crystal bonding and some degree of hydrophobicity resulting in a high melting point (about 273°C). Consequently, the compounds of formula I are sparingly soluble, generally having a solubility in water of less than 0.05%. On the other hand, effective delivery of the active component into the epidermis where it can exert its effect requires that the compound be present in a dissolved state in said composition. In the course of research leading to the present invention, it has been found that certain semipolar alkylene glycols and alkylene glycol ethers are capable of dissolving a therapeutically effective amount of the active component.

More specifically, the solvent comprises a non-toxic glycol or glycol ether selected from the group consisting of propylene glycol, butylene glycol and ethoxy diglycol. Of these solvent substances, propylene glycol has been found to result in a particularly favourable dissolution of the active component. Propylene glycol is a penetration enhancer, i.e. a substance which is capable of penetrating the stratum corneum and "draw" low-molecular components such as therapeutically active components in the vehicle into the epidermis. While in our research propylene glycol does not in itself give rise to any significant skin irritation, it is capable of "drawing" low-molecular and potentially irritative components of the vehicle into the epidermis, leading to an overall irritative effect of conventional vehicles including propylene glycol. For this reason, propylene glycol has previously been thought to be unsuitable for inclusion as a solvent in compositions intended for the treatment of atopic dermatitis. However, it has been found that when certain high molecular weight excipient materials which are not capable of penetrating into the epidermis are included in the vehicle, replacing conventional excipients, the resulting composition does not give rise to significant irritative reactions in skin on which the composition is applied even when the high molecular weight materials are only included in moderate amounts.

The solvent may comprise said non-toxic hydrophilic glycol or glycol ether in admixture with water. The ratio between hydrophilic glycol or glycol ether and water in the solvent phase may vary between wide limits, but is usually in the range of from about 90: 10 to about 40:60, more typically from about 70:30 to about 50:50, and more preferably about 60:40.

Polymeric emulsifier

In the course of research leading to the present invention, it has surprisingly been found that when the dissolved active component is formulated together with an emulsifier of a sufficiently high degree of polymerisation and molecular weight not to penetrate into the epidermis when applied on the skin, skin irritation problems otherwise encountered when a penetration enhancer is included in a vehicle containing conventional emulsifiers as a solvent for the active component may be substantially reduced or even completely avoided. This is particularly important for dermal formulations intended for application on inflamed, and therefore highly irritated skin so as to avoid a painful burning sensation at the site of application and more long-term irritation such as pain or itching. On the other hand, the inclusion of an excipient incapable of penetrating the skin should not impede the penetration of the active component into the epidermis.

The molecular weight of the polymeric emulsifier should be so selected that it is not capable of passing through biological membranes such as cell membranes. Therefore, the molecular weight of the polymeric emulsifier should generally be at least about 5000 Da, in particular at least about 6000 Da. In addition, the polymeric emulsifier should be structurally complex, e.g. cross-linked rather than linear. Preferably, the polymeric emulsifier should comprise ester groups capable of binding to the oil used as the cream or ointment base in the composition, thereby anchoring part of the molecule in the oil droplets to provide the emulsifying effect. A particularly favoured class of polymeric emulsifiers to be included in the present compositions is cross-linked polyacrylic acid derivatives. In particular, the polymeric emulsifier is selected from the class of polymers of acrylic acid cross-linked with allyl ethers of pentaerythritol or copolymers of acrylic acid and a long-chain alkyl (meth)acrylate cross- linked with allyl ethers of pentaerythritol. It has been found that while polymers of this type do not decrease surface tension and have no critical micelle concentration, they are nevertheless able to form the quasi-homogenous system of oil and water generally regarded as an emulsion. The polyacrylic acid forming the backbone of these polymers is generally composed of about 70-80 acrylic acid monomer units partially alkylated with Cι_0-3o alkyl. The molecular weight of the polymeric emulsifiers of this type is theoretically estimated to be in the range of from about 700,000 to about 3-4 billion ("theoretically" because no method of measuring the actual molecular weight of cross-linked polymers is currently available).

It has surprisingly been found that even when the polymeric surfactant is included in the present composition in quite modest amounts relative to the amount of solvent, it is possible to obtain the desired effect, i.e. preventing or substantially reducing skin irritation. Thus, the amount of polymeric surfactant required for this purpose may be in the range of about 0.1-0.5% w/w of the vehicle.

Polymeric emulsifiers of the type preferably included in the present composition are generally classified as "carbomers" but differ from the homopolymeric carbomers by being cross-linked copolymers and are preferably selected from the group consisting of Pemulen^® TRl, Pemulen^® TR2, carbomer 1342(NF), Carbopol^® 1342, Carbopol^® 1382 or Carbopol^® ETD 2050. Pemulen^® TRl and Pemulen^® TR2 are currently the more preferred polymeric emulsifiers for inclusion in the present composition.

Active component

The compounds of formula I shown above and methods of their preparation and use are disclosed in US 5,734,051 incorporated herein by reference in its entirety. In the compounds of formula I, Ri and R₂ preferably both represent -(CH₂)_m-A, wherein m is preferably 1 and A preferably represents an optionally substituted C_3-8 cycloalkyl, in particular cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. A is preferably cyclopropyl.

Preferred compounds of formula I are those in which R₃ is halogen, nitro or NR₄R₅, wherein R₄ and ₅ are independently hydrogen, alkyl, alkylcarbonyl or, together with the nitrogen atom to which they are attached, form an optionally substituted heterocyclic ring. When R₃ is halogen, it is preferably fluorine, chlorine or bromine. When R₃ is NR₄R₅, R₄ is preferably hydrogen, and R₅ is hydrogen or alkylcarbonyl, in particular hydrogen. Suitable heterocyclic moieties include saturated or unsaturated heterocyclic groups with single or fused rings, each ring comprising 5-7 atoms including 1-3 heteroatoms selected from 0, S or N. The heterocyclic moiety is preferably a single ring with 5-6 atoms, in particular 6 atoms such as pyrrolidinyl, piperidinyl or morpholinyl.

In the present context, the term "alkyl" is intended to indicate a straight or branched radical of 1-10 carbon atoms, in particular 1-6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl or hexyl.

Specific examples of compounds of formula I are

1,3-d -cyclopropylmethyl-8-amino xanthine, 1,3-d -cyclobutylmethyl-8-amino xanthine, 1,3-d -cyclopentylmethyl-8-amino xanthine, 1,3-d -cyclohexylmethyl-8-amino xanthine, 1,3-d -cyclopropylmethyl-8-nitro xanthine, 1,3-d -cyclobutylmethyl-8-nitro xanthine, 1,3-d -cyclopentylmethyl-8-nitro xanthine, 1,3-d -cyclohexylmethyl-8-nitro xanthine, 1,3-d -cyclopropyl-8-amino xanthine, 1,3-d -cyclopropylmethyl-8-chloro xanthine, 1,3-d -cyclopropylmethyl-8-morpholino xanthine, 1,3-d -cyclopropylmethyl-8-pyrrolidinyl xanthine, 1,3-d -cyclopropylmethyl-8-piperidinyl xanthine, 1,3-d -cyclohexylmethyl-8-piperidinyl xanthine, 1,3-d -cyclohexylmethyl-8-bromo xanthine, 1,3-d -cyclohexyl-8-nitro xanthine, and 1,3-d -cyclohexyl-8-chloro xanthine.

A currently preferred compound of formula I for inclusion as an active component in the present composition is l,3-di-cyclopropylmethyl-8-amino xanthine (known under the generic name cipamfylline) and pharmaceutically acceptable salts thereof. In in vitro studies, this compound has been shown to be a potent and selective inhibitor of PDE₄ and the secretion of proinflammatory cytokines such as tumour necrosis factor α (TNF-α), IL-10, IL-12 and IFN-γ, but has no effect on lymphocyte proliferation contrary to rapamycin and tacrolimus (both immunosuppressive agents currently in clinical trials for atopic dermatitis).

Pharmaceutical formulation

Formulations suitable for dermal application include liquid or semi-liquid preparations such as liniments, lotions, gels, oil-in-water or water-in-oil emulsions such as creams, ointments or pastes; or solutions or suspensions such as drops.

In addition to the polymeric emulsifier described above, the present composition may further comprise a second emulsifier. This may be included to adjust the size of the droplets of oil in the oil phase, which may have a diameter of up to 200 μm, to a smaller size than that obtainable with the polymeric emulsifier alone, i.e. the size obtainable by using a traditional emulsifier (size range 1-25 μm), thereby improving the cosmetic appearance of the composition. The second emulsifier may suitably be a water-in-oil emulsifier, e.g. selected from the group consisting of water-in-oil emulsifiers such as, for example, sorbitan oleate, sorbitan isostearate, sorbitan sesquioleate, polyglyceryl-3-diisostearate and polyglyceryl-6-hexaricinoleate.

Furthermore, the vehicle may suitably comprise a viscosity-increasing agent. This, like the polymeric emulsifier, should preferably be selected from high molecular weight polymeric substances to substantially avoid penetration thereof into the epidermis. The viscosity- increasing agent may suitably be selcted from carbomer homopolymers, e.g. carbomer 934NF, carbomer 934P NF, carbomer 940, Carbopol^® 974P NF, Carbopol^® 5984, Carbopol^® 2984, Carbopol^® 940, Carbopol^® 980, Carbopol^® ETD 2001 and Carbopol^® ETD 2050. Unlike the polymeric emulsifier discussed above, the viscosity-increasing agent does not contain any ester groups and is consequently unable to bind to the oil droplets in the composition.

The present composition may additionally include an agent capable of ionising carbomer- type components thereof so as to increase the gelling and structuralizing capabilities of such components. Examples of suitable agents include trometamol, Ph.Eur. (tromethamine, USP).

In a currently favoured embodiment of the present composition, the vehicle comprises (a) a solvent for the active component in an amount of about 25-55 % w/w,

(b) a polymeric emulsifier in an amount of about 0.1-0.5% w/w,

(c) a viscosity-increasing agent in an amount of about 0.1-1% w/w, (d) a second emulsifier in an amount of about 0.05-0.4% w/w,

(e) an oil in an amount of about 10-50% w/w,

(f) water in an amount of about 20-40% w/w.

The amount of the individual ingredients in the composition will, to some extent, depend on the concentration of the active component incorporated therein. By way of example, at a concentration of the active component of 1.5 mg/g of vehicle, the amount of propylene glycol solvent required to dissolve this amount of active component is typically in the range of from about 45% w/w to about 50% w/w of the vehicle. At lower concentrations of the active component, the amount of propylene glycol solvent may be correspondingly reduced, e.g. to about 35-40% w/w of the vehicle.

The amount of active component in the composition may vary according to the severity of the condition to be treated, but will generally be in the range of from about 0.5 to about 2.5 mg/g of vehicle, in particular about 1.5 mg/g of vehicle.

The composition of the present invention may be prepared in accordance with methods well known to the person skilled in the art of pharmaceutical formulation. Thus, the composition may be prepared by incorporating the ingredients into a well known cream or ointment base comprising an oil, preferably an oil which is not soluble in the solvent for the active component and which is therefore not "drawn" into the epidermis, thereby potentially causing skin irritation. Examples of suitable oils include liquid paraffin, petrolatum or straight or branched hydrocarbons of, for instance, 14-18 carbon atoms, such as isohexadecane. In general, a cream composition is preferred as it is less highly viscous and has a less oily appearance on the skin than an ointment, thereby improving patient compliance.

In addition to the above-mentioned ingredients, the present composition may include one or more additional ingredients such as other therapeutically active substances applied in the tratment of dermal inflammatory conditions, including corticosteroids such as hydrocortisone, salicylic acid or topical antibiotics such as clindamycin. Furthermore, the present composition may include a topical anesthetic such as bupivacaine, chlorprocaine, dibucaine, ketamine, pramoxine or the like.

The present composition may also comprise other components commonly used in dermal formulations, e.g. antioxidants (e.g. alpha-tocopherol), preservatives, emollients, pigments, skin soothing agents, skin healing agents and skin conditioning agents such as urea, glycerol, allantoin or bisabolol, cf. CTFA Cosmetic Ingredients Handbook, 2^nd Ed., 1992. The dermal inflammatory disease or condition to be treated by the present method or medicament is, in particular, dermatitis (eczema), such as atopic dermatitis, seborrheic dermatitis or contact dermatitis, urticaria, pruritis, or acne.

The dosage in which the active component is administered may vary between wide limits, depending on the age and condition of the patient, the severity of the condition to be treated and the discretion of the physician. A suitable dose of the present composition comprising a compound of formula I will, however, generally be in the range of about 1-3 mg/cm² applied on the affected area or areas of the skin one or more times a day.

The present invention is described in further detail in the following examples which are not in any way intended to limit the scope of the invention as claimed.

Examples

Example 1

Preparation of a dermal cream composition

A. Trometamol (2.5 mg/g vehicle) was dissolved in purified water (300 mg/g vehicle). Cipamfylline (1.5 mg/g vehicle) was dissolved in propylene glycol (480 mg/g vehicle) and purified water (20 mg/g vehicle) was added. Pemulen^® TRl (2 mg/g vehicle) and Carbopol^® 974P (5 mg/g vehicle) were dispersed in liquid paraffin (195 mg/g vehicle) and sorbitan oleate (2 mg/g vehicle) was added. The oil phase was slowly added to the cipamfylline solution, and the resulting cream was thoroughly homogenised. The trometamol solution was then added and mixed thoroughly with the cream. The resulting formulation was filled into 50 g tubes and stored at room temperature.

B. A reference cream formulation was prepared by by dissolving cipamfylline (1.5 mg/g vehicle) in propylene glycol (480 mg/g vehicle). Sodium citrate (1.5 mg/g vehicle) and citric acid monohydrate (1 mg/g vehicle) were dissolved in purified water (316 mg/g vehicle) and the pH adjusted to 4.5. The buffer solution was added to the cipamfylline solution followed by heating to 70-75°C. Arlacel^® 165 (20 mg/g vehicle), cetostearyl alcohol (40 mg/g vehicle) and liquid paraffin (140 mg/g vehicle) were mixed and heated to 70-75°C. The aqueous phase was slowly added to the oil phase. The resulting cream was thoroughly homogenised followed by cooling to room temperature with mild agitation. The resulting formulation was filled into 50 g tubes and stored at room temperature.

Example 2

In vitro activity of cipamfylline

Inhibition of PDE activity

The ability of cipamfylline to inhibit PDE₄ activity was determined by in vitro assays using enzymes isolated from human blood monocytes. Specific isoenzyme inhibition was determined by measuring the ability of the compound to inhibit the hydrolysis of cAMP. As shown in Table 1, cipamfylline was shown to be a potent and selective inhibitor of PDE₄.

Table 1

Effect on cvtokines

The effect of cipamfylline on cytokine release was tested in human peripheral blood mononuclear cells. Superoxide generation was determined in human polymorphonuclear granulocytes stimulated with TNF-α. Two known PDE₄ inhibitors, CP-80633 and rolipram, were used as reference compounds. The results are shown in Table 2 from which it appears that cipamfylline and other PDE₄ inhibitors are potent inhibitors of proinflammatory cytokine release. Cipamfylline has no effect on IL-lβ and IL-2. Table 2

Immunosuppressive effects

The effect of cipamfylline on T-cell proliferation was determined by the reduction in uptake of labelled thymidine over two days following stimulation with an anti-CD3 antibody. Tacrolimus and rapamycin were used as reference compounds.

Cipamfylline had no effect on T-cell proliferation whereas both tacrolimus and rapamycin caused as strong inhibition of thymidine uptake with IC₅₀ values in the subnanomolar range. It was concluded that cipamfylline has no effect on lymphocyte proliferation.

Example 3

In vivo topical effects

TPA induced chronic skin inflammation in the mouse ear

Skin inflammation was induced by 12-0-tetradecanoylphorbol-13-acetate (TPA) application to the right ear on alternate days for a 10-day period. Cipamfylline or reference compounds, both dissolved in acetone, were applied twice daily from day 8 to day 11. Ear swelling was determined six hours after the last application and ear tissue was histologically prepared for determination of epidermal thickness.

A dose of 10 μg/ear of cipamfylline inhibited ear swelling by 22%, while a maximum inhibition of 36% was obtained at a dose of 100 μg/ear. No additional effect was observed with higher doses. Epidermal hyperplasia was inhibited by 45% and 51% at cipamfylline doses of 10 and 100 μg/ear, respectively. A 45% inhibition of epidermal hyperplasia was observed at a dose of 10 μg/ear of hydrocortisone. It was concluded that cipamfylline inhibited ear swelling and epidermal hyperplasia in TPA-induced chronic skin inflammation in mice. The magnitude of the effect was comparable to that of hydrocortisone.

Chronic oxazolone-indiced murine atopic dermatitis

Mice were sensitised with oxazolone on the right ear, and seven days later they were challenged on the same ear every other day for twenty days. Challenged ear were treated 5 times once daily from day 16 to day 20. Ear swelling was determined 3 hours after the last dose (day 20). IL-lβ and IL-4 were determined in lyophilised, homogenised and extracted ear tissue by commercially available murine ELISA kits. Two PDE₄ inhibitors (rolipram and CP-80633) and betamethasone were used as reference compounds. It was concluded that cipamfylline inhibited ear swelling as well as IL-lβ and IL-4 in this model of atopic dermatitis. The anti-inflammatory effect of cipamfylline was comparable to that of betamethasone and better than that of the two PDE₄ inhibitors.

Acute arachidonic acid induced pruritus and inflammation

Application of arachidonic acid to mouse ears causes an intense inflammatory response characterised by pruritus and oedema. Counting of scratching episodes and measurement of ear swelling are the endpoints use din this model. Cipamfylline 0.03 mg/ear was tested in two different vehicles: propylene glycol: acetone (1: 1) and propylene glycol :ethanol: water (2:2: 1). Both vehicles yielded similar results, i.e. a mean maximum inhibition of pruritus of 54% and a 37% inhibition of ear swelling when compared to controls. It was concluded that cipamfylline showed antipruritic and anti-inflammatory activity in arachidonic acid induced dermatitis in mice.

Example 4

In vivo effects on atopic dermatitis in humans of topical application of cipamfylline

In a phase II, multi-centre, randomised, double-blind left/right study comparing cipamfylline cream 1.5 mg/g in reference vehicle (formulation B) with the vehicle without cipamfylline and with Locoid cream 0.1% (hydrocortisone-17-butyrate 0.1% cream) in patients suffering from atopic dermatitis, patients were randomised to either group (1) cipamfylline cream 1.5 mg/g in reference vehicle vs vehicle or (2) cipamfylline cream 1.5 mg/g in reference vehicle vs Locoid cream. One g of each cream were applied twice daily for two weeks.

A total number of 108 patients with a clinical diagnosis of atopic dermatitis, with symmetrical lesions of atopic dermatitis on their arms with a minimum score of 6 in the total severity score (ratings of erythema, oedema/papulation, oozing/crusting, excoriations and lichenification on a scale from 0-3) were included. Excluded were patients with suspected infection in the treatment areas, patients who were receiving other treatment for atopic dermatitis or who were pregnant or planning to become pregnant in the course of the study.

At the end of the study, the total severity score had decreased by 17% on the vehicle treated side and by 38% on the cipamfylline treated side, the difference being statistically significant (p<0.001). At the end of treatment, the total severity score had decreased by 59% on the Locoid treated side and by 30% on the cipamfylline treated side, the difference being statistically significant (p<0.001).

The most frequently reported adverse effects were local adverse reactions such as burning, stinging and pruritus, most predominant on the side treated with vehicle only (25% of the patients vs 15% on the side treated with cipamfylline). Two patients withdrew from the study due to unacceptable adverse events (flare-up of eczema). The adverse reaction are thought to be the result of irritative components of the reference vehicle penetrating into the epidermis of the patients.

Example 5

Cutaneous tolerance of cipamfylline formulations in hairless guinea pigs

The dermal tolerability of cipamfylline formulated in a cream formulation (A) containing 1.5 mg/g of cipamfylline and in a reference formulation (B) containing 1.5 mg/g of cipamfylline was compared.

The study was carried out in hairless guinea pigs. Comparisons of the formulations were based on results obtained within groups of 8 hairless guinea pigs. Vehicles without cipamfylline (placebos) were also included and compared with the cipamfylline formulations based on a right/left comparison within animals. Cumulative non-occluded applications twice daily for 5 days were used. Clinical evaluation of test sites was carried out every day. Evaluation of test sites was based on an objective measurement of erythema (a*, ChromaMeter), skin hydration (electrical capacitance, Corneometer) and skin water barrier function (TEWL, Evaporimeter). Non- invasive measurements were performed at baseline and at the end of the treatment period. Furthermore, skin biopsies were taken at the end of the treatment period for histological preparation and subsequent histopathological evaluation with measurement of epidermal thickness.

From the comparison of cipamfylline-containing formulations and corresponding placebos, it appears that no differences were found in dermal tolerability between the formulations containing cipamfylline and the respective placebos. Thus, no local skin irritation could be attributed to the active component of the formulations.

Further results are shown in the appended Figs. 1-4.

It appears from Fig. 1 that the reference formulation (B) induced moderate erythema and scaling at the end of the treatment period. The skin water barrier was affected as indicated by the increase in TEWL (Fig. 2). The skin hydration level was unchanged (Fig. 3). Some increase in epidermal thickness (acanthosis) was observed (Fig. 4).

By way of comparison, cream formulation A induced no or very slight erythema and no scaling (Fig. 1). Formulation A did not affect the skin water barrier (Fig. 2) and the skin hydration level was unchanged (Fig. 3). Furthermore, the epidermal thickness was normal (Fig. 4).

Based on these results, it was concluded that formulation A of the present invention was significantly less irritative than reference formulation B in that repeated application of formulation A resulted in no or very slight erythema, no change in skin barrier function and normal epidermal thickness.

Claims

1. A pharmaceutical composition for dermal application comprising, as an active component, a compound of general formula I

wherein Ri and R₂ are each independently alkyl or a moiety of the formula -(CH₂)_m-A, wherein m is 0, 1, 2 or 3, and A is an optionally substituted cyclic hydrocarbon radical; R₃ is halogen, nitro or N ^Rs, wherein R₄ and R₅ are independently hydrogen, alkyl, alkylcarbonyl, or together with the nitrogen atom to which they are attached form an optionally substituted heterocyclic ring; and pharmaceutically acceptable salts thereof; and a pharmaceutically acceptable vehicle comprising a solvent for the active component capable of effecting penetration of the active component into the epidermis, and further comprising a polymeric emulsifier which is incapable of penetrating into the epidermis.

2. A composition according to claim 1, wherein the solvent comprises a substance selected from the group consisting of propylene glycol, butylene glycol and ethoxy diglycol.

3. A composition according to claim 1 or 2, wherein the polymeric emulsifier is a cross- linked polyacrylic acid derivative.

4. A composition according to claim 3, wherein the polymeric emulsifier is a polymer of acrylic acid cross-linked with allyl ethers of pentaerythritol or a copolymer of acrylic acid and a long-chain alkyl (meth)acrylate cross-linked with allyl ethers of pentaerythritol.

5. A composition according to claim 4, wherein the polymeric emulsifier is a carbomer selected from the group consisting of Pemulen^® TRl, Pemulen^® TR2, carbomer 1342(NF), Carbopol^® 1342, Carbopol^® 1382 or Carbopol^® ETD 2050.

6. A composition according to any of claims 1-5, wherein the vehicle further comprises a viscosity-increasing agent.

7. A composition according to claim 6, wherein the viscosity-increasing agent is a carbomer homopolymer.

8. A composition according to claim 7, wherein the viscosity-increasing agent is carbomer 934NF, carbomer 934P NF, carbomer 940, Carbopol^® 974P NF, Carbopol^® 5984, Carbopol^® 2984, Carbopol^® 940, Carbopol^® 980, Carbopol^® ETD 2001 and Carbopol^® ETD 2050.

9. A composition according to any of claims 1-8, wherein the vehicle further comprises a second emulsifier.

10. A composition according to claim 9, wherein the second emulsifier is selected from the group consisting of water-in-oil emulsifiers such as, for example, sorbitan oleate, sorbitan isostearate, sorbitan sesquioleate, polyglyceryl-3-diisostearate and polyglyceryl-6-hexaricinoleate.

11. A composition according to any of claims 1-10, wherein the vehicle comprises

(g) a solvent for the active component in an amount of about 25-55 % w/w,

(h) a polymeric emulsifier in an amount of about 0.1-0.5% w/w,

(i) a viscosity-increasing agent in an amount of about 0.1-1% w/w,

(j) a second emulsifier in an amount of about 0.05-0.4% w/w, (k) an oil in an amount of about 10-50% w/w,

(I) water in an amount of about 20-40% w/w.

12. A composition according to claim 11, wherein the amount of active substance is in the range of from about 0.5 mg/g to about 2.0 mg/g of vehicle, in particular about 1.5 mg/g of vehicle.

13. A composition according to any of claims 1-12, wherein Ri in formula I is -(CH₂)_m-A.

14. A composition according to any of claims 1-12, wherein both Ri and R₂ in formula I are -(CH₂)_m-A.

15. A composition according to claim 14, wherein A is optionally substituted C_3-8 cycloalkyl.

16. A composition according to claim 14, wherein m is 1.

17. A composition according to claim 16, wherein A is optionally substituted cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

18. A composition according to claim 17, wherein R₃ in formula I is nitro or -NR₄R₅, wherein R₄ is hydrogen and R₅ is hydrogen or alkylcarbonyl.

19. A composition according to claim 18, wherein both R₄ and R₅ are hydrogen.

20. A composition according to claim 19, wherein A is cyclopropyl.

21. A composition according to claim 20, wherein the compound of formula I is selected from the group consisting of

1,3-d -cyclopropylmethyl-8-amino xanthine 1,3-d -cyclobutylmethyl-8-amino xanthine, 1,3-d -cyclopentylmethyl-8-amino xanthine, 1,3-d -cyclohexylmethyl-8-amino xanthine, 1,3-d -cyclopropylmethyl-8-nitro xanthine, 1,3-d -cyclobutylmethyl-8-nitro xanthine, 1,3-d -cyclopentylmethyl-8-nitro xanthine, 1,3-d -cyclohexylmethyl-8-nitro xanthine, 1,3-d -cyclopropyl-8-amino xanthine, 1,3-d -cyclopropylmethyl-8-chloro xanthine, 1,3-d -cyclopropylmethyl-8-morpholino xanthine, 1,3-d -cyclopropylmethyl-8-pyrrolidinyl xanthine, 1,3-d -cyclopropylmethyl-8-piperidinyl xanthine, 1,3-d -cyclohexylmethyl-8-piperidinyl xanthine, 1,3-d -cyclohexylmethyl-8-bromo xanthine, 1,3-d -cyclohexyl-8-nitro xanthine, and 1,3-d -cyclohexyl-8-chloro xanthine.

22. Use of a pharmaceutical composition according to any of claims 1-21 for the manufacture of a medicament for the prophylaxis or treatment of dermal inflammatory diseases or conditions.

23. The use of claim 22, wherein the dermal disease or condition is dermatitis, such as atopic dermatitis, seborrheic dermatitis or contact dermatitis, urticaria, pruritis, eczema or acne.

24. A method of preventing or treating dermal inflammatory diseases or conditions, the method comprising dermally applying to a site of inflammation, an effective amount of a pharmaceutical composition according to any of claims 1-21.

25. The method of claim 24, wherein the dermal inflammatory disease or condition is dermatitis, such as atopic dermatitis, seborrheic dermatitis or contact dermatitis, urticaria, pruritis, eczema or acne.