WO2007082542A1

WO2007082542A1 - Compositions comprising oxaprozin and a vitamin d3 analogue and their use for the manufacture of a medicament for the treatment of psoriasis

Info

Publication number: WO2007082542A1
Application number: PCT/DK2007/050002
Authority: WO
Inventors: Morten Sloth Weidner
Original assignee: Astion Pharma A/S
Priority date: 2006-01-17
Filing date: 2007-01-17
Publication date: 2007-07-26

Abstract

The invention provides novel compositions for the treatment of psoriasis and variants thereof. The compositions comprise a vitamin D3 analogue and Oxaprozin or a salt thereof.

Description

COMPOSITIONS COMPRISING OXAPROZIN AND A VITAMIN D3 ANALOGUE AND THEIR USE FOR THE MANUFACTURE OF A MEDICAMENT FOR THE

TREATMENT OF PSORIASIS

FIELD OF THE INVENTION

5 The present invention is in the field of pharmacology and relates to active ingredients, compositions and methods for treating skin diseases characterized by hyperproliferation and abnormal differentiation of keratinocytes and by the presence of inflammatory cell infiltrate, such as the diseases psoriasis.

10 BACKGROUND OF THE INVENTION

Psoriasis is a chronic inflammatory skin disease characterised by hyperproliferation of the epidermis. Psoriasis is difficult to manage and today, there is not one topical drug available that effectively treats all people with psoriasis. Mainstay topical treatment includes corticosteroids, vitamin D₃ analogues, coal tar, anthralin, or retinoids and combinations 15 thereof. Recent developments in the treatment of psoriasis include combining a vitamin D₃ analogue with a glucocorticosteroid to inhibit both the proliferation directly via the vitamin D₃ analogue and to slow down the immunological and inflammatory reaction via the steroidal effect.

20 However, treatment with glucocorticosteroids is associated with numerous side effects and is un-suitable for long-term use. vitamin D₃ analogues also have side effects, such as skin irritation, that often limit their use in facial treatment.

Accordingly, there is a significant need for topical treatment of hyperproliferative epidermal 25 diseases, such as psoriasis, wherein the dose of the topical vitamin D₃ derivative required is reduced or wherein the need for concomitant treatment with glucocorticosteroids is eliminated.

Combination therapy for the treatment of psoriasis is disclosed in WO04014387A1 30 (Boehringer Ingelheim). The therapy comprises administering one active agent "A" selected from an NSAID, an immunosuppressive, an angiogenesis inhibitor, a biological agent, a steroid, a vitamin D3 analogue, and a retinoid, together with a second active agent "B" that is a p38 MAP kinase inhibitor chosen from those disclosed in WO04014387A1. 35

The patent application WO0051554A2 relates to methods of regulating skin conditions by topically applying fluorinated vitamin D3 analogues, optionally in combination with a second active, such as an NSAID, to provide skin moisturization, barrier improvement/repair, photoprotection, wound repair, and skin pigmentation control benefits.

The patent application, WO0062790, relates to methods for treating various medical disorders that are characterised by abnormal or excessive TNFα levels, such as psoriasis and psoriasis arthritis, by administering compositions containing a TNFα antagonist. In addition to the TNFα antagonist further drug agents may be co-administered, such as pain medications, methotrexate, sulfasalazine, gold salts, azathioprine, cyclosporine, antimalarials, oral steroids, NSAIDS including among others Oxaprozin, newly developed anti- inflammatories, steroids, and many other drugs including vitamin D₃ analogues, such as calcipotriol.

SUMMARY OF THE INVENTION The present inventor has now discovered that Oxaprozin, which hitherto has been recognised as a non-steroidal anti-inflammatory drug (NSAID), exhibits several other pharmacodynamic properties than previously known.

Specifically, the present inventor has demonstrated that Oxaprozin, in dermatologically relevant doses, inhibits several pathways involved in the inflammatory process of inflamed skin tissue. To be mentioned is the inhibition of the enzymes; Protein tyrosine kinase Syk, Protein tyrosine kinase ZAP-70 and phosphodiesterase IV (PDE-IV). Therefore, Oxaprozin may no longer be considered as a conventional member of the NSAID group in that its principal pharmaco-dynamic properties in the skin do not include cyclooxygenase (cox- l/cox-2) inhibition. Notably, Oxaprozin is one of the NSAIDs with poorest Cox-2 inhibition and selectivity for Cox-2 inhibition (Kawai S. Cyclooxygenase selectivity and the risk of gastrointestinal complications of various non-steroidal anti-inflammatory drugs. A clinical consideration. In Inflamma. Res. Supplement 2 (1998) S102-S106).

Thus, Oxaprozin interferes with multiple enzymatic pathways of the inflammatory cascade that operate at higher hierarchic levels than the cyclo-oxygenase pathway.

Oxaprozin is today used clinically for the relief of pain, tenderness, swelling and stiffness caused by osteoarthritis and rheumatoid arthritis. However, according to the novel pharmacodynamic properties of Oxaprozin, this molecule may replace the steroid in the treatment therapy of psoriasis that combines a vitamin D₃ analogue and a steroid.

The present inventor has provided experimental data, clearly demonstrating the significant, immediate and complete alleviation of pruritus in a patient suffering from psoriasis. Notably, erythema and scaling were also improved during the first 1-2 weeks of treatment indicating a therapeutic effect on the underlying disease causing the pruritus (Example 2).

Furthermore, the combined application of calcipotriol and Oxaprozin to reconstructed human epidermis resulted in an over-additive anti-inflammatory effect compared to each of the single administered active ingredients (Example 4).

Accordingly, a first aspect of the present invention relates to a pharmaceutical composition comprising i) a vitamin D₃ analogue, such as calcipotriol; calcitriol, tacalcitol, maxacalcitol and mixtures thereof; and ii) Oxaprozin or a pharmaceutically acceptable salt thereof; and optionally iii) one or more pharmaceutically acceptable ingredients. In one embodiment thereof, the pharmaceutical composition is formulated for administration to a portion of the skin, such as to a diseased area of the skin.

In a second aspect, the invention provides a method for treating psoriasis or a clinically variant thereof. The method comprises, simultaneous or sequential, administration of a sufficient amount of a first therapeutically active ingredient i) a vitamin D₃ analogue, such as calcipotriol; calcitriol, tacalcitol, maxacalcitol and mixtures thereof; and ii) a sufficient amount of a second therapeutically active ingredient Oxaprozin or a pharmaceutically acceptable salt thereof, to a subject in need thereof.

In a alternative second aspect, the invention relates to the use of a combination of a first therapeutically active ingredient i) a vitamin D₃ analogue, such as calcipotriol; calcitriol, tacalcitol, maxacalcitol, and mixtures thereof; and a second therapeutically active ingredient ii) Oxaprozin or a pharmaceutically active salt thereof for the preparation of a medicament for the treatment of psoriasis or a clinically variant thereof.

In a still further aspect, the invention relates to a kit comprising i) one container comprising a composition of a vitamin D₃ analogue, such as calcipotriol; calcitriol, tacalcitol, maxacalcitol and mixtures thereof and ii) a second container comprising a composition of Oxaprozin or a pharmaceutically acceptable salt thereof.

DETAILED DESCRIPTION OF THE INVENTION

It has been recognised that the combination of active ingredients as disclosed herein provides a beneficial therapeutic effect, particularly an additive or synergistic effect, or an overall reduction of side effects of therapy, in the treatment of psoriasis. Combination of active ingredients

The present invention provides combinations of a vitamin D₃ analogue, such as calcipotriol and Oxaprozin or a pharmaceutically acceptable salt thereof for therapeutical use.

The term "vitamin D₃ analogue" refers to a synthetic compound comprising a vitamin D₃ (cholecalciferol) scaffold with side chain modifications and/or modifications of the vitamin D₃ scaffold itself and which inhibits hyperproliferation of dermis and epidermis.

A large number of vitamin D₃ analogues are known and can be used in practicing the invention. In various embodiments of the invention, the vitamin D₃ analogue may be selected from 24-Cyclopropyl-9,10-secochola-5,7,10(19),22-tetraene-l,3,24-triol (calcipotriol); 1,25-Dihydroxyvitamin D3 (calcitriol); 1,24-Dihydroxyvitamin D3 (tacalcitol), l,25-Dihydroxy-22-oxavitamin D3 (maxacalcitol); and mixtures thereof, including hydrates thereof.

In one particular embodiment of the invention, the vitamin D₃ analogue is calcipotriol. In another particular embodiment of the invention, the vitamin D₃ analogue is tacalcitol. In still another particular embodiment, the vitamin D₃ analogue is maxacalcitol.

Further examples of various modifications of a vitamin D₃ scaffold that could be used in the invention encompass the following vitamin D₃ analogues:

26,26-Difluoro-9,10-secocholesta-5,7,10(19)-triene-l,3,26-triol, such as 26,26- Difluoro-26-methoxyalfacalcidol)

■ 26,27-Dimethyl-9,10-secocholesta-5,7,10(19)-triene-3,25-diol, such as 25-Hydroxy- 26,27-dimethylvitamin D3

26,26,26,27,27,27-Hexafluoro-9,10-secocholesta-5,7,10(19)-triene-l,3,25-triol (26,26,26,27,27,27-Hexafluoro-l,25-dihydroxyvitamin D3 or Falecalcitriol) ■ 9,10-Secocholesta-5,7,10(19)-triene-l,3-diol, such as 1-Hydroxyvitamin D3

(Alfacalcidol)

9,10-Secocholesta-5,7,10(19)-triene-3,25-diol, such as 25-Hydroxycholecalciferol.

(Calcifediol)

9,10-Secocholesta-5,7,10(19)-triene-l,3,22,25-tetrol such as 1S,22R,25- Trihydroxyvitamin D3 and the 22 methoxy derivative, 22R-Methoxycalcitriol

9,10-Secocholesta-5,7,10(19)-triene-l,3,22,25-tetrol, such as 1S,22R,25-

Trihydroxyvitamin D3

■ 9,10-Secocholesta-5,7,10(19)-triene-3,24,25-triol, such as 24,25-Dihydroxyvitamin D3 (Secalciferol). 9,10-Secocholesta-5,7,10(19)-triene-l,3,22,25-tetrol, _such _as is,22R,25- Trihydroxyvitamin D3 or the 22R methoxy derivative

■ 26,27-Dimethyl-9,10-secocholesta-5,7,10(19)-triene-3,25-diol, such as 25-Hydroxy- 26,27-dimethylvitamin D3 ■ 20-[3-(2-Hydroxypropan-2-yl)benzyloxymethyl]-9,10-secopregna-5,7,10(19)-triene- 1,3-diol, such as Atocalcitol

■ l-(l,3-Dihydroxy-24-oxo-9,10-secochola-5,7,10(19)-trien-24-yl)piperidine, such as Ecalcidene. 20-[(4-Ethyl-4-hydroxyhexyl)oxy]-9,10-secopregna-5,7,10(19)-triene-l,3-diol, such as Lexacalcitol

■ 4-Methylene-5-[[octahydro-l-[2-[3-(l-hydroxy-l-methylethyl)phenoxy]-l- methylethyl]-7a-methyl-4H-inden-4-ylidene]ethylidene]-l,3-cyclohexanediol;

■ 22-Oxa-9,10-secocholesta-5,7,10(19)-triene-l,3,25-triol, such as 1,25-Dihydroxy- 22-oxavitamin D3. 22-Oxacalcitriol. ■ l,3,24-Trihydroxy-9,10-secocholesta-5,7,10(19),22-tetraene-25-carboxylic acid

■ 24a,26a,27a-Trihomo-9,10-secocholesta-5,7,10(19),22,24-pentaene-l,3,25-triol (Seocalcitol)

■ Ia, 24S-dihydroxy-vitamin D2

1 (S), 3 (R)dihydroxy-20 (R)-[((3-(2-hydroxy-2-propyl)-phenyl)-methoxy)-methyl]- 9, 1 0-seco- pregna-5 (Z), 7 (E), 10 (19)-triene

The second therapeutically active ingredient of the present invention encompasses Oxaprozin (4,5-diphenyl-2-oxazole-propionic acid) or a pharmaceutically acceptable salt thereof.

In the present context, the phrase "a pharmaceutically acceptable salt" encompasses a base addition salt derived from the reaction of the free propionic acid entity of Oxaprozin with inorganic bases (hydroxides) or organic bases or/and an acid addition salt derived from the reaction of the basic oxazole ring nitrogen with pharmaceutically acceptable acids. Thus, it might be understood that Oxaprozin may be provided in the form of an acid addition salt or a base addition salt or in the form of a double salt of mixed acid addition and base addition salt.

Examples of base addition salts encompass Na, K, Ca, Mg, Cu, Zn and Mn salts. Typical organic bases for use in the preparation of a base addition salt are primary, secondary or tertiary amines including alkylphenylamine, ammonia, 2-aminoethanol, aminopyrimidine, aminopyridine, arginine, benethamine, benzathine, betaine, caffeine, choline, deanol, diethanolamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethylenediamine, N- ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, glycinol, hydrabamine, imidazol, isopropylamine, meglumine, methylglucamine, morpholine, piperazine, piperidine, procaine, purine, pyrrolidine, theobromine, thiamine, triethanolamine, triethylamine, trimethylamine, tripropylamine, tromethamine, spermidine, and the like. Furthermore, base addition salts may be derived from the reaction with natural amino acids such as with glycine, alanine, valine, leucine, isoleucine, norleucine, tyrosine, cystine, cysteine, methionine, proline, hydroxy proline, histidine, ornithine, lysine, arginine, serine, threonine, and phenylalanine and with unnatural amino acids such as D-isomers or substituted amino acids; guanidine, substituted guanidine wherein the substituents are selected from nitro, amino, alkyl, alkenyl, alkynyl, ammonium or substituted ammonium salts, and aluminum salts.

Examples of pharmaceutically acceptable salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic or phosphorous acids and the like, as well as the salts derived from relatively non-toxic organic acids like acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like. Also included are salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galacturonic acids and the like.

Where Oxaprozin or a derivative thereof is provided in the form of a salt, it is meant to include a pharmaceutically acceptable solvate, which may be a hydrate (comprising from half a mole of H₂O up to about 10 moles of H₂O per mole of salt) or comprise other solvents of crystallization such as alcohols.

It is anticipated that the novel pharmaco-dynamic effect of Oxaprozin may also be exhibited by closely related derivatives and bioisosters of Oxaprozin. Several derivatives of Oxaprozin with anti-inflammatory effect have been described in the patent literature. General derivatives as well as the manufacturing thereof are described in US 3,578,671. Specific derivatives and the manufacturing thereof are described in US 5,380,738 (4- fluorophenyl and 4-methylsulfonylphenyl), US 4,659,728 (hydroxy substituted derivatives), US 6,090,834 (sulfonyl derivatives), US 3,506679 (4,5-diarylthiazol derivatives).

It is further anticipated that the invention might be carried out by metabolites of Oxaprozin or suitable prodrugs of Oxaprozin, or bioisosters of Oxaprozin. Typical examples of suitable prodrugs of Oxaprozin include formiate, acetate, propionate, ascorbyl and benzoylate esters of Oxaprozin. Examples of metabolites of Oxaprozin are hydroxy substituted Oxaprozin, namely 5-(4-hydroxyphenyl)-4-phenyl-2-oxazolepropanoic acid, 4-(4- hydroxyphenyl)-5-phenyl-2-oxazolepropanoic acid and 4-(4-hydroxyphenyl)-5-(4- hydroxyphenyl)-2-oxazolepropanoic acid as described in US 4,659,728. Typical examples of bioisosters include those where the oxazole ring oxygen atom of Oxaprozin is replaced by a sulfur atom or a nitrogen atom.

Uses, methods and kits

Methods, use kits and compositions described herein relate to the treatment of psoriasis and a variant thereof.

The term "psoriasis" refers to all variations of psoriasis including plaque psoriasis, guttate psoriasis, flexural psoriasis, palmoplanar pustulosis, acrodermatitis of hallopeau, scalp psoriasis (sebo-psoriasis of the scalp), napkin psoriasis, generalised pustular psoriasis, and nail involvement.

In some embodiments of the invention, the two active ingredients are administered or formulated for the administration to a portion of the skin, such as to the diseased area of the skin, in that it is the intention to achieve local availability of the two classes of therapeutically active ingredients mentioned herein in the skin, such as in the epidermis or dermis. It is not the intention to administer the active ingredients transdermally to achieve systemic absorption of the actives, but only to penetrate stratum corneum. Thus, in various embodiments of the invention, transdermal administration of the actives is excluded.

The phrase "local availability" or "administration to a portion of the skin" are interchangeable terms, which are meant to include cutaneous administration of the Oxaprozin or a salt thereof and the Vitamin D₃ analogue to the skin surface of the body, which can be on any part of the body, including but not limited to the epidermis, or any other dermis. Cutaneous administration or application means the direct contact of one or both of the two classes of actives with skin to provide local treatment of the diseased area of the skin with substantially no concomitant systemic delivery and/or systemic administration of the actives. Thus, it is intended that less than 15% by weight, such as less than 10%, 8%, 5% and 3% by weight, of the cutaneous administered actives of the invention enter the blood stream or is recovered in urine and faeces.

As mentioned, the active ingredients mentioned herein may together be applied to a portion of the skin, such as to a diseased area of the skin. The phrase "diseased area of the skin" is meant to defined skin affected by a skin disease, such as psoriasis or a variant thereof. The active ingredient may be applied in the form of a pharmaceutical formulation suitable for being applied to skin, such as a cream, ointment, gel, solution (spray-on- solution), emulsion, liniment, foam, pasta, powder and other suitable forms.

A combination of a vitamin D₃ analogue as mentioned herein and Oxaprozin or a salt thereof may be cutaneously administered in the form of a blend containing both of the active ingredients in a single preparation. Alternatively, the actives may be processed into separate preparations and then administered. The separate preparations may be administered either at the same time or at a definite time interval. In the case of administering at a definite time interval, the Oxaprozin or a salt thereof may be administered first followed by the administration of the other active. Alternatively, the vitamin D₃ analogue may be administered first followed by the administration of the Oxaprozin or a salt thereof. The administration methods may be either the same or different. Typically, the time intervals are of at least 2, 4, 6, 8 or 12 hours in between the administration of the one and the other active ingredient.

The separate administration of the therapeutically active ingredients encompass the kit aspect of the invention in that the each of the single active ingredients is contained individually in a container or individually formulated into separate pharmaceutical compositions or dosage forms, such as a cream, liniment, ointment, spray, foam, gel or any other dosage form intended for being applied to skin. The kit of the invention comprises at least two individual containers or pharmaceutical compositions, wherein at least one container/pharmaceutical composition comprises a Vitamin D₃ analogue of the invention, and at least another container/pharmaceutical composition comprises Oxaprozin or a pharmaceutical acceptable salt thereof or a closely related derivative thereof. The containers/pharmaceutical compositions of the kit may be assembled together in a packet, container or the like.

The active ingredients of the invention are administered in therapeutically sufficient amounts. The term "sufficient amount" refers to the amount of the combination of the active ingredients that will elicit the biological or medical response of the skin of a human that is being sought by the medical doctor or other clinician. The term "sufficient amount" includes that amount of the combination of active ingredients that, when administered, is sufficient to prevent development of, or alleviate to some extent, one or more of the symptoms of the condition or disorder being treated. The therapeutically effective amount will vary depending on the compound, the disease and its severity and the age, weight, etc., of the human to be treated. With respect to applying an effective amount of Oxaprozin or a derivative thereof, it is considered to apply a dermatological formulation comprising between 0.1% to 20% by weight of Oxaprozin or a salt thereof to the affected skin areas for 1 to 4 times daily. In one embodiment, the dermatological formulation comprises between 2 and 15% by weight of Oxaprozin or a salt thereof. In one embodiment, the dermatological formulation comprises between 4 and 12% by weight of Oxaprozin or a salt thereof, such as about 5%, 6%, 6.5%, 7%, 7.5% 8%, 8.5% 9%, 9.5%, 10%, 11% and 12% by weight of Oxaprozin or a salt thereof. The vitamin D₃ analogue of the invention may be applied cutaneously once or twice a day in a therapeutically sufficient dosage. Typically, the dose of the vitamin D₃ analogue is between 0.0001 - 5 mg/g or ml, preferably 0.0001 - 2 mg/g or ml, even more preferably contains about 0.001-0.5mg/g or ml, such as about 0.001-0,25mg/g or ml, of the vitamin D3 analogue.

Dermatological Formulations

As mentioned, in one embodiment of the invention, the active ingredients of the invention are to be administered to a portion of the skin, such as to the portion of skin affected by a skin disease, such as psoriasis or a variant thereof. Thus, the active ingredients may together or separately be formulated into cutaneously administrable pharmaceutical compositions. Such embodiments of the invention encompasses compositions in liquid, semi-solid form or solid form, for example formulated as a cream, an ointment, a gel, a liniment, a foam, a powder, a solution, a spray-on-solution, a paste or they may be provided in combination with a "finite" carrier, for example a non-spreading material that retains its form, including, for example, a patch, bioadhesive, dressing or bandage. Furthermore, the active ingredients may be formulated in aqueous or non-aqueous vehicles, or mixtures thereof, such as in the form of a solution, emulsion, dispersion, suspension and ointment.

The pharmaceutical compositions of the invention may be formulated in any solid, semisolid or fluid form suitable for being administered topically according to conventional pharmaceutical practice, see e.g. "Remington: The science and practice of pharmacy" 20th ed. Mack Publishing, Easton PA, 2000 ISBN 0-912734-04-3 and "Encyclopaedia of Pharmaceutical Technology", edited by Swarbrick, J. & J. C. Boylan, Marcel Dekker, Inc., New York, 1988 ISBN 0-8247-2800-9 or a newer edition.

In one embodiment of the invention, the two classes of therapeutically active ingredients are formulated together as a cream. Creams of the invention are oil-in-water emulsions that typically contain more than 50% water. As oily base material especially fatty alcohols, for example lauryl, cetyl or stearyl alcohol, fatty acids, for example palmitic or stearic acid, liquid to solid waxes, for example isopropyl myristate, wool wax or beeswax, and/or hydrocarbons, for example vaseline (petrolatum) or paraffin oil is used. Suitable emulsifiers are surface-active substances having predominantly hydrophilic properties, such as corresponding non-ionic emulsifiers, for example fatty acid esters of polyalcohols or ethylene oxide adducts thereof, such as polyglycerol fatty acid esters or polyoxyethylene sorbitan fatty acid esters (Tweens), also polyoxyethylene fatty alcohol ethers or fatty acid esters, or corresponding ionic emulsifiers, such as alkali metal salts of fatty alcohol sulphates, for example sodium lauryl sulphate, sodium cetyl sulphate or sodium stearyl sulphate, which are customarily used in the presence of fatty alcohols, for example cetyl alcohol or stearyl alcohol. Additives to the aqueous phase are, inter alia, active ingredients that reduce drying out of the creams, for example polyalcohols, such as glycerol, sorbitol, propylene glycol and/or polyethylene glycols, and also preservatives, perfumes, etc.

In another embodiment, the two actives are formulated as an ointment. Ointments are water-in-oil emulsions that contain up to 70%, but preferably from approximately 20% to approximately 50%, water or aqueous phases. Suitable as fatty phase are especially hydrocarbons, for example vaseline, paraffin oil and/or hard paraffins, which preferably contain suitable hydroxy compounds, such as fatty alcohols or esters thereof, for example cetyl alcohol or wool wax alcohol or wool wax, in order to improve their capacity to bind water. Emulsifiers are corresponding lipophilic substances, such as sorbitan fatty acid esters (Spans), for example sorbitan oleate and/or sorbitan isostearate. Additives to the aqueous phase are, inter alia, moisture-retaining agents, such as polyalcohols, for example glycerol, propylene glycol, sorbitol and/or polyethylene glycol, and preservatives, perfumes, etc.

In another embodiment, the two actives are formulated as fatty ointments that are anhydrous and contain as base material, especially hydrocarbons, for example paraffin, vaseline and/or liquid paraffins, and natural or partially synthetic fats, for example coconut fatty acid triglyceride, or preferably hardened oils, for example hydrogenated groundnut or castor oil, and fatty acid partial esters of glycerol, for example glycerol mono- or di- stearate, and also, for example, the fatty alcohols that increase the water absorption capacity and the emulsifiers and/or additives mentioned in connection with the ointments.

In another embodiment, the two actives are formulated as a gel. In the case of gels, a distinction is made between aqueous and anhydrous or low-water-content gels which consist of swellable, gel-forming materials. Especially transparent hydrogels based on inorganic or organic macromolecules are used. High molecular weight inorganic components having gel-forming properties are predominantly water-containing silicates, such as aluminium silicates, for example betonite, magnesium aluminium silicate, for example veegum, or colloidal silica, for example aerosil. As high molecular weight organic substances, e.g. natural, semi-synthetic or synthetic macromolecules are used. Natural and semi-synthetic polymers are derived, for example, from polysaccharides having very varied carbohydrate building blocks, such as celluloses, starches, tragacanth, gum arabic, agar-agar, gelatine, alginic acid and salts thereof, for example sodium alginate, and derivatives thereof, such as lower alkylcelluloses, for example methyl- or ethyl-celluloses, and carboxy-or hydroxy lower alkylcelluloses, for example carboxymethyl-or hydroxyethyl- celluloses. The building blocks of synthetic, gel-forming macromolecules are, for example, correspondingly substituted unsaturated aliphatic compounds, such as vinyl alcohol, vinylpyrrolidine, acrylic acid or methacrylic acid. As examples of such polymers, polyvinyl alcohol derivatives, such as polyviol, polyvinylpyrrolidines, such as collidine, polyacrylates and polymethacrylates, such as Rohagit S or Eudispert may be mentioned. Customary additives, such as preservatives or perfumes, may be added to the gels.

In another embodiment, the two actives are formulated as a foam. Foams are administered, for example, from pressurised containers and are oil-in-water emulsions in aerosol form, there being used as propellants halogenated hydrocarbons, such as chlorofluoro-lower alkanes, for example dichlorodifluoromethane or dichlorotetrafluoroethane. As oily phase there are used, inter alia, hydrocarbons, for example paraffin oil, fatty alcohols, for example cetyl alcohol, fatty acid esters, for example isopropylmyristate, and/or other waxes. As emulsifiers there are used, inter alia, mixtures of those having predominantly hydrophilic properties, such as polyoxyethylene sorbitan fatty acid esters (Tweens), and those having predominantly lipophilic properties, such as sorbitan fatty acid esters (Spans). The customary additives, such as preservatives, etc. are added thereto.

Tinctures and solutions have in most cases an aqueous-ethanolic base to which have been added, inter alia, polyalcohols, for example glycerol, glycols and/or polyethylene glycol, as moisture-retaining agents to reduce evaporation, and fat-restoring substances, such as fatty acid esters with low molecular weight polyethylene glycols, that is to say lipophilic substances that are soluble in aqueous mixture, as a replacement for the fatty substances removed from the skin with the ethanol, and, if necessary, other adjuncts and additives.

The dermatologically administrable pharmaceutical preparations are prepared in a manner known per se by mixing with pharmaceutical adjuncts that are customary for that purpose, for example by dissolving or suspending the active ingredient in the base material or in a portion thereof, if necessary. In order to prepare emulsions in which the active ingredient is dissolved in one of the liquid phases, the active ingredient is, as a rule, dissolved therein before the emulsification; in order to prepare suspensions in which the active ingredient is suspended in the emulsion, the active ingredient is mixed with a portion of the base material after the emulsification and then added to the remainder of the formulation. In dermatological compositions of the invention, the active ingredients will usually be distributed in a liquid carrier system such as water or any aqueous solution containing organic or inorganic materials. Additionally, the compositions may contain one or more ingredients to modify or enhance their texture, appearance, scent performance or stability. Illustrative additives to the compositions include: ointment bases, solvents, buffering agents, pH-adjusting agents, preservatives, humectants, chelating agents, antioxidants, stabilizers, emulsifying agents, suspending agents, gel-forming agents, perfumes, skin protective agents, Lubricants, such as silicones or isopropyl myristate, astringents such as lactic acid or zinc phenolsulfonate, fragrances such as bay oil, rose water, orange oil, myrrh or musk, antiseptics such as menthol and camphor, emollients such as glycerols and sorbitols, and preservatives such as ascorbic acid, parahydroxybenzoic acid esters and tocopherols.

Typical ointment bases may be selected from the group comprising white vaseline, beeswax, paraffin, cetanol, cetyl palmitate, vegetable oils, sorbitan esters of fatty acids (Span), polyethylene glycols, and condensation products between sorbitan esters of fatty acids and ethylene oxide, e.g. polyoxyethylene sorbitan monooleate (Tween, such as Tween 80).

Typical hydrophobic ointment bases may be selected from the group comprising paraffin's, vegetable oils, animal fats, synthetic glycerides, waxes, lanolin, and liquid polyalkylsiloxanes. Typical hydrophilic ointment bases are but not limited to solid macrogols (polyethylene glycols).

Typical solvents may be selected from the group comprising water; alcohols such as, polyethylene glycols; propylene glycols; glycerol; liquid polyalkylsiloxanes; and mixtures thereof.

Typical buffering agents may be selected from the group comprising of citric acid, acetic acid, tartaric acid, lactic acid, hydrogen phosphoric acid, diethylamine etc. Typical pH- adjusting agents are organic and inorganic acids and bases, such as potassium or sodium hydroxide, monoethanolamine, triethanolamine and hydrochloric acid.

Typical preservatives may be selected from the group comprising parabens, such as methyl, ethyl, propyl p-hydroxybenzoate, butylparaben, isobutylparaben, isopropylparaben, potassium sorbate, sorbic acid, benzoic acid, methyl benzoate, phenoxyethanol, bronopol, bronidox, MDM hydantoin, iodopropynyl butylcarbamate, EDTA, benzalconium chloride, and benzyl alcohol, or mixtures of preservatives. Typical humectants may be selected from the group comprising glycerin, propylene glycol, sorbitol, lactic acid, urea, and mixtures thereof. Typical chelating agents are but not limited to sodium EDTA and citric acid. Typical antioxidants may be selected from the group comprising butylated hydroxy anisole (BHA), ascorbic acid and derivatives thereof, tocopherol and derivatives thereof, cysteine, and mixtures thereof. Suitable emulsifying agents may be selected from the group comprising naturally occurring gums, e.g. gum acacia or gum tragacanth; naturally occurring phosphatides, e.g. soybean lecithin; sorbitan monooleate derivatives; wool fats; wool alcohols; sorbitan esters; monoglycerides; fatty alcohols, fatty acid esters (e.g. triglycerides of fatty acids); and mixtures thereof.

Suitable suspending agents may be selected from the group comprising celluloses and cellulose derivatives, such as, e.g., carboxymethyl cellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carrageenan, acacia gum, arabic gum, tragacanth, and mixtures thereof.

Suitable gel bases and viscosity-increasing components may be selected from the group comprising liquid paraffin, polyethylene, fatty oils, colloidal silica or aluminium, zinc soaps, glycerol, propylene glycol, tragacanth, carboxyvinyl polymers, magnesium-aluminium silicates, Carbopol®, hydrophilic polymers, such as e.g. starch or cellulose derivatives, such as, e.g., carboxymethylcellulose, hydroxyethylcellulose and other cellulose derivatives, water-swellable hydrocolloids, carrageenans, hyaluronates (e.g. hyaluronate gel optionally containing sodium chloride), and alginates including propylene glycol alginate.

EXAMPLES

Example 1

A topical pharmaceutical composition according to the invention was prepared by 5 dissolving 2.5% of a monoethanolamine salt of Oxaprozin in a liniment of calcipotriol marketed under the name Daivonex® Liniment, which contains Calcipotriol 50μg/ml in a carrier consisting of hydroxypropylcellulose, isopropyl alcohol, levomenthol, sodium citrate, propylenglycol and purified water. Hydrochloric acid is added.

10

Example 2

A 32 years old male subject had been suffering from plaque psoriasis for more than two years. The disease was apparent on the elbows with erythema, scaling and significant pruritus. During an aggravation of the symptoms the subject initiated a week of twice daily

15 treatment with an emulsion containing 5.0% of the monoethanolamine salt of Oxaprozin. The subject experienced an immediate significant relief of pruritus after the first treatment. This level of efficacy was maintained for the entire week of treatment. Furthermore a significant reduction of erythema and scaling was observed. This indicates a surprisingly good therapeutic effect not only on the pruritus, but also on the underlying disease.

20

Example 3

The combined effect of Oxaprozin and calcipotriol on a model of psoriatic reconstructed epidermis (RHE) can be tested according to the procedure described in Boniface K et al,

25 2005. (Boniface K, Bernard FX, Garcia M, Gurney AL, Lecron JC, Morel F. IL-22 inhibits epidermal differentiation and induces proinflammatory gene expression and migration of human keratinocytes. J Immunol. 2005 Mar 15; 174(6). -3695-702) and may be conducted by "DERMSCAN Group Headquarters" at the following address: 27, Bd. du 11 Novembre 1918, B.P. 2132 - 69603 VILLEURBANNE Cedex - FRANCE.

30

In this model, the psoriatic profile is induced by a set of pro-inflammatory cytokines in that a mix of interleukins-specific cytokine mixtures can induce a profile of RHE closer to that of psoriasis-like phenotype of human epidermis than from psoriatic skin models.

35 The tested compounds are topically applied onto RHE, and then the inflammatory mix of interleukins is introduced in the culture medium underneath the epidermis. For a complete study, additional epidermis can be treated by the tested formulations in the absence of inflammatory stimulation (controls). After incubation, the level of expression (mRNA) of markers of psoriasis is measured using the quantitative RT-PCR method. If positive results are obtained in the first step, the structure of the epidermis can be examined using histology and immuno-histochemistry.

For the quantitative RT-PCR, a culture of reconstructed human epidermis (0.5 cm²) are incubated for 24 h at 37⁰C, 5% CO₂. The reconstructed epidermis is topically treated with the test compounds in a concentration of 2 mg/cm². The samples are then incubated overnight at 37⁰C, 5% CO₂. A mix of interleukins (IL mix) is then introduced to the culture medium and the samples are incubated for 24 hours at 37⁰C, 5% CO₂. Finally, the total

RNA is extracted, treatment with DNAse, then inactivation of DNAse followed by Q-PCR analysis.

For testing the histology of the psoriatic epidermis following treatment with the combination of agents of the invention, reconstructed human epidermis (0.5 cm²) is incubated for 24 h at 37⁰C, 5% CO₂. The reconstructed epidermis is topically treated with the test compounds in a concentration of 2 mg/cm². The samples are then incubated overnight at 37⁰C, 5% CO₂. A mix of interleukins (IL mix) is then introduced to the culture medium and the samples are incubated for 96 hours at 37⁰C, 5% CO₂. Epidermis is then rinced, fixed in a balanced 10% formalin solution and embedded in paraffin. Vertical sections (2 per epidermis and per marker) are stained with H&E or with specific antibodies and peroxidase-conjugated antibodies and counterstained with hematoxylin according to standard protocols.

The following samples of reconstructed epidermis are made: A: untreated epidermis, normal controls B: untreated epidermis + IL mix, "psoriatic" controls

C: epidermis treated with a vehicle according to example 1 + IL mix D: epidermis treated with calciprotriol in a vehicle according to example 1 + IL mix E: epidermis treated with with a combination of Oxaprozin and Calcipotriol dissolved in a vehicle according to example 1 + IL mix F: epidermis treated with oxaprozin in a vehicle according to example 1 + IL mix

The result indicates an additive effect of Oxaprozin and Calcipotriol on the treatment of psoriatic reconstructed epidermis in that the expression of psoriasis markers were significantly more depressed in such samples than in samples treated with the single compounds. Example 4

The anti-inflammatory potential of Oxaprozin was determined by evaluating the inhibitory activity of Oxaprozin against the following enzymes;

Phosphodiesterase PDEIV₁ using a test method described in Nicholson CD, Challiss RA, Shahid M. Differential modulation of tissue function and therapeutic potential of selective inhibitors of cyclic nucleotide phosphodiesterase isoenzymes. Trends Pharmacol Sci 1991 January; 12(1): 19-27 and in Cortijo J, Bou J, Beleta J, Cardelus I, Llenas J, Morcillo E et al. Investigation into the role of phosphodiesterase IV in bronchorelaxation, including studies with human bronchus. Br J Pharmacol 1993 February; 108(2): 562-8.

Protein Tyrosine Kinase SYK using a test method described in Shichijo M, Yamamoto N, Tsujishita H, Kimata M, Nagai H, Kokubo T. Inhibition of syk activity and degranulation of human mast cells by flavonoids. Biol Pharm Bull 2003 December;26(12): 1685-90 and in Zhang J, Berenstein E, Siraganian RP. Phosphorylation of Tyr342 in the linker region of Syk is critical for Fc epsilon RI signaling in mast cells. MoI Cell Biol 2002 December;22(23):8144-54.

Protein Tyrosine kinase ZA70 (ZAP-70) using a method described in Huckle WR, Dy RC, Earp HS. Calcium-dependent increase in tyrosine kinase activity stimulated by angiotensin II. Proc Natl Acad Sci U S A 1992 September 15;89(18):8837-41 and in Isakov N, Wange RL, Watts JD, Aebersold R, Samelson LE. Purification and characterization of human ZAP- 70 protein-tyrosine kinase from a baculovirus expression system. J Biol Chem 1996 June 28;271(26):15753-61.

The enzyme assays may be conducted by MSD Pharma Services .

The following concentration of Oxaprozin (as the monoethanolamine salt) resulted in 50% inhibition of the following enzymes (IC₅₀);

Enzyme MDS Pharma IC₅₀

Service No:

Phosphodiesterase PDE IV 154000 22 μM

Protein Tyrosine Kinase , SYK 155761 28 μM

Protein Tyrosine Kinase , ZA70 (ZAP-70) 155987 38 μM

Claims

1. A pharmaceutical composition comprising; i) a vitamin D₃ analogue selected from the group consisting of calcipotriol; calcitriol, tacalcitol, maxacalcitol and mixtures thereof; ii) Oxaprozin or a pharmaceutically acceptable salt thereof; iii) optionally one or more dermatologically acceptable ingredients.

2. The composition according to claim 1, wherein the vitamin D₃ analogue is calcipotriol.

3. The composition according to claim 1, wherein the composition is formulated for the application to a portion of the skin.

4. The composition according to claim 1, wherein the composition is formulated for the application to a portion of skin affected by a skin disease.

5 The composition according to claim 1, wherein the composition is formulated as a cream, ointment, gel, solution, emulsion, liniment, foam, pasta, powder, and spray.

6. Use of i) a first therapeutically active ingredient vitamin D₃ analogue selected from the group consisting of calcipotriol; calcitriol, tacalcitol, maxacalcitol and mixtures thereof; and ii) a second therapeutically active ingredient Oxaprozin or a pharmaceutically salt thereof for the preparation of a medicament for the treatment of psoriasis or a clinical variant thereof.

7. The use according to claim 6, wherein the vitamin D₃ analogue is calcipotriol.

8. The use according to claim 6, wherein the medicament is formulated for the application to a portion of the skin affected by psoriasis or a variant thereof.

9. A method for treating psoriasis or a clinically variant thereof comprising administering a sufficient amount of a first therapeutically active ingredient i) a vitamin D₃ analogue selected from the group consisting of calcipotriol; calcitriol, tacalcitol, maxacalcitol and mixtures thereof; and ii) a sufficient amount of a second therapeutically active ingredient Oxaprozin or a pharmaceutically acceptable salt thereof, to a subject in need thereof.

10. The method according to claim 9, wherein the vitamin D₃ analogue is calcipotriol.