NZ286443A - Treatment of inflammatory dermatoses other than psoriasis using a retinoid and a corticosteroid - Google Patents

Description

New Zealand Paient Spedficaiion for Paient Number £86443 New Zealand No 286443 International No PCT/ TO BE ENTERED AFTER ACCEPTANCE AND PUBLICATION Priority dates 07 02 1992, Complete Specification Filed 29 01 1993 Classification (6) A61K31/20,57,58 Publication date 28 October 1999 Journal No 1445 NO DRAWINGS NEW ZEALAND PATENTS ACT 1953 COMPLETE SPECIFICATION Title of Invention Methods of treating inflammatory dermatoses Name, address and nationality of applicant(s) as in international application form ALBERT M KLIGMAN, citizen of The Rittenhouse, 210 West Rittenhouse Square, Philadelphia, PA 19103, United States of America PCT/ US93/01043 - lcx- Field of the Invention This is a divisional application of New Zealand Patent Specification No 249379 which relates to cosmetic methods for the treatment of inflammatory dermatoses The present invention relates to the use of a synergistic composition in the manufacture of a medicament foi the treatment of inflammatory dermatoses More particularly, the invention is directed to the use of a synergistic composition in the manufacture of medicaments formulated for topical administration to an affected area of the skin for controlling, clearing and maintaining the clearance of inflammatory dermatoses Background of the Invention The most widely prescribed drugs to treat dermatologic disease are corticosteroids, also known as glucocorticosteroids or glucocorticoids. Approximately 50% of prescriptions written by dermatologists are for topical corticosteroids. Since the introduction of these substances m the early 1950s for dermatologic diseases,, topical corticosteroid therapy continues to be the mainstay for the management of a broad spectrum of inflammatory dermatoses. Although systemic SUBST(TUTE SHEET !Jy C1 f, ' O i /" WO 93/15740 PCT7DS93/0104 corticosteroids are often required m some severe dematologic diseases, topical treatment is preferred m most responsive cases because it causes fewer systemic adverse effects Topical corticosteroids are generally effective m the treatment of acute and chronic dermatoses such as seborrheic dermatitis, atopic dermatitis, contact dermatitis of the irritant and allergic type, localizec neurodermatitis (lichen simplex chronicus), lichen planus, 0 and psoriasis. Steroids are also used for a variety of other less common conditions, such as Darier's disease a~c ichthyosiform dermatitis A good overview of topical corticosteroid therapy appears m a series cf papers presented at tne Symposium on Topical Corticosteroids 5 Toaay and Tomorrow, sponsored by Schermg AG m Bali, June 16-20, 198 8, which were published in Drugs 36, Supplement 5, pp. 1-61 (Adis Press Ltd. 1988) Individual topical corticosteroid preparations vary m anti-inflammatory potency and clinical efficacy 0 Therapeutic efficacy of steroid therapy can often be enhanced by increasing the potency of the steroid or by using special enhancers, such as occlusive dressings general, efficacy is dependent on multiple factors, viz vehicle, site ard frequency of application, disease, the 3 individual patient, use cf occlusive dressings, etc. rj- Ch t< » PCl5us{3/Oq643 Potency of the corticosteroid preparation varies according to the particular corticosteroid selected, its concentration, and its vehicle. For convenience, topical corticosteroids, are classified into seven groups from 5 most (Group I) to least (Group VII) potent as shown, for example, in Table I below. Further, these classifications are ranked according to relative potency designations with Group I usually designated as ultra high potency, Groups II and II designated as high potency, Groups IV and V 10 designated mid potency, and Groups VI and VII designated low potency. Representative commercial corticosteroid preparations are set forth and classified according to this system in P.. 3. Stoogbton, "Percutaneous Absorption of Drugs," Annual Review of Pnarmacologic Toxicology, 15 pp 55-69 (1989) tv O, r«7 f - UO 93/15740 «- -I'ar/te93/010« TABLE I POTENCY RANKING 07 TOPICAL CORTICOSTEROIDS (Group I, most potent to Croup VII least potent) Group Generic Name Dosage Form Usual Potency Concentration Betamethasone dipropionate Clobetasol propionate Diflorasone diacetate cream, ointment cream, ointment ointment 0 054 0 05% 0 05% II Amcinonide Betamethasone dipropionate Diflorasone diacetate Halcmonide cream, ointment o mtment ointment cream, ointment 0 1% 0 051 0 05% 0 1% Fluocinonide Desoximetasone Triamcinolone acetonide Mometasone Fluocinolone acetonide cream, ointment, solution, gel 0 05s 0 05%-0 25-0 5% 0 1% 0 2% cream, gel, ointment cream, ointment ointment cream III Triamcinolone acetonide ointment Betamethasone dipropionate cream Diflorasone diacetate cream Betamethasone valerate ointment Mometasone cream 0 1% 0.05% 0 05% 0 1% 0 1% IV Flurandrenolide Triamcinolone acetonide Fluocinolone acetonide Desoximetasone Clocortolone pivalate ointment cream, lotion ointment cream cream 0.05% 0 1% 0.025% 0.05% 0 1% Flurandrenolide cream Betamethasone dipropionate Triamcinolone acetonide lotion Hydrocortisone butyrate cream, Fluocinolone acetonide cream Betamethasone valerate cream Hydrocortisone valerate cream ointment 0 05% 0.05% 0 1% 0 1% 0.025% 0 1% 0 2% VI Desonide Fluocinolone acetonide Betamethasone valerate Aciometasone dipropionate cream, ointment solution lotion cream, ointment 0 05% 0 01 0 05% 0 05% VII Topicals with hydrocortisone, dexamethasone, flumethalone, prednisolone, and methyprednisolone SUBSTITUTE SHEET n ^ liL.-I/USyi/01(M3 Though some steroids , particularly mid- to high-potency steroids, are efficacious m chronic dermatoses, long term use of steroids is associated vith serious local side effects. These include skm atrophy 5 (thmnng, telangiectasia, stiiae) and a prompt rebound flare when the steroid is stopped. Treatment of large areas of skm and use cf occlusive dressings can also increase the potential for adverse effects This is especially the case m children As discusstd more fully 10 below, U.S. Patents 4,BS9,847 and 5,019,569 disclose the use of retinoids, such as tretinoin, to prevent and reverse skin atrophy induced by corticosteroid therapy. retmoic acid or Vitamin A acid) nave been used by dermatologists for almost twenty years. For example, tretinoin is used topically m the treatment of acne vulgaris, primarily grades I-III, m which comedones, papules, and pustules predominate See, for example, U.S Patent No. 3,729,568 of Kligman.

Tretinoin has been used effectively in the treatment of other skin conditions such a psoriasis, congenital ichthyosiform erythroderma, Darier's disease, epidermolvtic hyperkeratosis, actiric keratosis, trichostasis, flat warts, basal cell carcinomas, anc a Topical retinoids such as tretinoin (all-trans- VtO 93/15740 /"pcfr/us93/oio43 - u V ,1 Thomas et al. "The Therapeutic Uses of Topical Vitamin £ Acid," Journal of the American Acaderv of Dematolocr", 4.505-513 (1981) More recently, it has been found that retinoids, 5 such as tretinoin, particularly vhen used m separate, sequential topical applications with the corticosteroid, prevent and reverse skir atrophy m patients on long terr: corticosteroids for various skm diseases See, for exanple, U.S. patent Nos. 4,889,847 and 5,019,569 of 0 Xligmar, Mezick and Capetola, the disclosures of which are incorporated herein by reference However, that work was concerned with preventing and reversing the side effects cf corticosteroid therapy and did not address the possibility of enhanced efficacy, especially for those 5 patients whose disease has become resistant to corticosteroids Dermatologists call this acquired resistance "tachyphylaxis" and try to mitigate it by various strategies, such as rest periods (interval therapy) and switching to another drug These approaches 0 are only marginally helpful.

^ WO 93/15740 286 4 4 Brief Summary of the Invention According to the present invention inflammatory dermatoses, including both chronic and acute varieties, can be controlled and cleared more effectively than with 5 the use of corticosteroids or retinoids alone by the use of a composition compnsing a corticosteroid and a retinoid in the manufacture of a medicament formulated for topical administiation to an affected area of the skm for treating dermatoses That is, these rwo drugs have entirely different nodes cf 10 action ard, when combined m a single formulation, have synergistic effects which lead to more rapid clearing and are notably effective m dermatoses wh^ch have not responded to either corticosteroids cr retinoids alone Typically, tme dermatoses can be controlled and cleared by 15 once or twice daily applications of a medicament containing both the retinoid and the corticosteroid for about two to three weeks.

Thereafter, clearance can be maintained by less 2 0 frequent and/cr less potent applications of one or both of the active ingredients, such as a corticosteroid several times per week or a daily application of a retinoid.

Moreover, oice the disease has been brought under control, lower potency steroids can be used to maintain the 25 re-issior cr ether ncr-stercidal regirer.s can be used tj h which are safer, though usually less effective, viz tars, topical antibiotics or anti-bactenals, and other conventional therapies The physician is given more choices m handling inflammatory dermatoses, particularly 5 chronic inflammatory dermatoses, which are merely controlled but not cured by corticosteroids.

Detailed Description of the Preferred Embodiments The medicament manufactured according to the present invention may be administered for treating inflammatory dermatoses which are well known in the 10 art They include chronic and stubborn, as well as acute, afflictions of the skin which have previously been treated with various anti-inflammatory drugs, including oral corticosteroids and sometimes oral retinoids. While these prior therapies are sometimes effective, the side effects of each are numerous and severe.

There have been reports of using tretinoin and certain corticosteroids in combination, either sequentially or mixed together, for various forms of psoriasis. See, for example, K H. Kaidbey et al., 20 "Treatment of Psoriasis with Topically Applied Tretinoin and Steroid Ointment," Archives cf Derratoloav, 111:1001-1003 (2975) and P Frost et al., "Retiroic Acid for the Tnerapy cf Psoriasis", Acta Derratovener, Suppl 74:15-- \1 r* r T " ^ vj! - "V ^ 160 (Stockholm, 1975) However, effective treatment of inflammatory dermatoses in general has not previously been indicated The medicaments manufactured according to the present 5 invention may be administered for treatment of disorders such as the various forms of inflammatory acne. These include the most devastating type, acne conglobata or nodulocvstic acne Additionally, inflammatory acne with numerous pustules and deep persistent papules responds dramatically 10 Severely inflammatory acne, notably acne conglobata, responds to an oral retinoid, 13-cis retmoic acid (available commercially as ACCUTAJTE®) . However, the side effects of this drug are very serious, including teratogenicity, elevated blood lipids, fragile skm, 15 conjunctivitis, etc It has been found that acne conglobata as well as severely inflammatory acne vulgaris, m particular, can be brought under control or show excellent responses in as little as two to three weeks of twice daily applications of the medicament manufactured in 20 the present invention Persistent papulo-pustular acne also responds well to the combination medicament herein described It is noted that acne vulgaris is actually a mixture of inflammatory and non-inflammatory acnes, and while the medicaments manufactured according to the present invention f 1 ^ \ P Qj would probably be unnecessary in most cases due to the effectiveness of retinoids alone.

Rosacea is another common disease which can be 5 very inflammatory and is resistant to therapy except for oral retinoids. Severe rosacea mimics acne conglobata These fulminating types of rosacea also respcnd to the combination of a retinoid and a corticostf.ro id described herein Other inflammatory disorders which may be controlled and cleared by the medicament manufacture-1 in the present invention include lichen planus, especially the hypertrophic variety; chronic discoid lupus erytheratoscs, chronic atopic dermatitis, including lichen simplex 15 chronicus which is a persistent, itchy dermatosis that is common in patients with atopic dermatitis; chronic contact or allergic dermatitis, which is due to a great variety of environmental allergens; chronic hand dermatitis; lichen amyloidosis; alopecia areata; pseudofolliculitis barbae; 20 pityriasis rubra pilaris; mycosis fungcides; drug reactions (acute); and others.

The corticosteroids useful in the medicaments manufactured according to the present invention include all of tne large nuir-cer of corticosteroids which are knc*n for tneir 25 anti-ir.flarjzatcr1' properties See, fcr exarcle, those \ o WO 93/15740 PCT/US93/01043 lasted m Table I above Preferably, the mid- to high- or ultra high-potency corticosteroids are used m the invention. Examples of preferred mid-potency corticosteroids are betamethasone valerate, triamcinolone 5 acetonide, and fluocinolone acetonide. Clobetasol propionate is presently unrivalled in potency. Other preferred high-potency steroids include, for example, betamethasone dipropionate It is also possible to use low-potency corticosteroids such as hydrocortisone, 10 dexamethasone and prednisolone m those particular chronic dermatoses, such as atopic dermatitis, which do not require high-potency steroids for control.

Retinoids have been defined narrowly as comprising vitamin A (retinol) and its derivatives, such 15 as vitamin A aldehyde (retinal) and vitamin A acid (retmoic acid) , which are metabolites of natural vitamin A. However, subsequent research has resulted m a larger class of chemical compounds that are termed retinoids because they have biological actions similar to 2 0 the parent vitamin A, even though there may be great structural dissimilarities. Compounds useful m the present invention mcluae dJ 1 natural and/or synthetic analogs of vitamin A or retinol-like compounds which have sinlar tnerapeutic activities as demonstrated for a r* / / 0 ,Ji purposes of the present invention, the term "retinoid" '~2.11 be understood to mean a natural or synthetic substance that elicits all or some of the biologic responses of retinoic acid or retinol by binding to and 5 subsequently activating known and unknown cutaneous retinoic acid receptors. Examples of suitable retinoids useful in the present invention are set forth in Table I, although it will be understood that the invention is not limited thereto.

TABLE I all-trans-retinoic acid 13-cis-retmoic acid 11-cis-retmoic acid 9-cis-retinoic acid 15 retinol retinal retmoyl palmitate retmyl palmitate retinyl propionate 20 (all-I)-9-(4-nethoxy-2,3,6- trirethylphenyl)-3,7-dinethyl-2,4,6,8-nonatetraenoic acid eth>l ester \ \ 1 WO 93/15740 PCT/US93/01043 - 13 - CO (all-E) -9- (4 -methory-2 ,3,6-tnmethylphenyl) -3 , 7-dinethyl-2 ,4 ,6,8-nonatetraenoic acid N-ethyl-9- (4-methox-y-2 , 3 , 6-tnmethyl-5 phenyl)-3,7,-dimethyl-2,4,6,B- ncnatetrsena-ide (E,E)-9-(2,6-dichloro-4-nethoyy-3-rethylphenyl)-3,7-dimethyl-2,4,6,8-nonatetraenoic acid ethyl ester 7,B-didehydroretinoic acid (E,E)-4-[2-roethyl-4-(2,6,6-tnmethyl-1-cyclohexen-l-yl)-1,3-butadienyl]benzoic acid p J 1 / (E)-4-[4-methyl-6-(2,6,6-triemthyl-1-cyclohexen-l-yl)-1,3,5-hexa-tnenyl] benzoic acid PCT/US93/010 43 "'0 fy 1 / rv ^ t J { .. , (all-E)-3,7-dimethyl-(3-thienyl)-2,4,6,B—nonatetraencic acid (E,E,E)-3-methy1-7-(5,6,7,8-tetrahydro-5,5,8,8y-tetramethyl-2-naphthalenyl)-2,4,6—octatrienoic acid (E)-6-[2-(2,6,6-tnmethyl-l-cyclohexen-1-yl)ethyenyl]-2-naphthalenecarboxylic acid (E,E,E)-7-(2,3-dihydro-l,1,3,3-tetra-methyl-lH-mden-5-yl) -3-methyl-2,4,6-octatrienoic acid (E)-4-[2-(2,3,-dihydro-1,1,3,3,-tetramethyl-lH-mden-5-yl) -l-propenyl]benzoic acid (E)-4-[2-(5,6,7,8-tetrahyaro-5,5,8,8-tetramethyl-2-naphthalenyl-l-propenyl]benzoic acid ' > ! ^ /.

(E)-4 -[2 -(5,6,7,B-tetrahydro-3-mcthyl-5,5,6,6-tetranethyl-2-naphthalenyl~l-propenyl]benzoic acid (E)-1,2,3,4-tetrahydro-l,1,4,4-tetramethyl-6- (l-niethyl~2~phenylethenyl) naphthalene 6-(1,2,3,4-tetrahydro-l,1,4,4-tetramethy2-6-naphthyl-2-naphthalenecarboyylac acid (E)—6-[2-(4-ethylsulfonyl)phenyl]-1-methylethenylj-1,2,3,4-tetrahydro-1,1,4,4 -tetrainethylnaphthalene 4-f(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)ethynyl]ben2oic acid (E)-2-(1,1,4,4-tetramethyl-1,2,3,4-tetra-hydronaphth-7-yl)-1-[4-tetrazol-5-yl)phenyl]-1-propene - 16 (E)—4 — [2—(5,6,7,8-tetrahvdro-7-hydrovy-5,5,8,8-tetranethyl-2-naphthaleny1)-1-propenyl]benzyl alcohol (6—(3-(1-adamantyl)—4 —raethoxypheny1)-5 2-naphthoic acid) 11-cis, 13-cis-12-hydroJcyn\ethylretinoic acid /"-lactone 4-acetanxdophenyl retmoate 1-(4-carboxyphenyl)-4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethy1-2-naphthalenyl)pyrazole 1-(4-carboxyphenyl)-5-hydroxy-3-(5,6,7,8-tetrahydro- ,5,8,8-tetramethyl-2-naphthalenyl)pyrazole 4-[(5, 6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-ethynyl]methylsulfonylbenzene 1.0 [// ■ retmoyl ^-glucuronide wo 03/15740 PCI7US93/01043 1 f A-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)carbamoyl]benzcic acid 4 - [ (5, 6 , 7 ,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)carooxamido]benzoic acid Also enccrpassed within the tern "retinoid" are geometric and stereoisomers of the retinoids, as well as pro-drugs thereof Preferably, the corticosteroid and retinoid are applied simultaneously m a single composition which uses 10 a carrier pharmaceutically acceptable for both the retinoid and corticosteroid. Since tretinoin and some other actives are relatively unstable, such as being subject to photodecomposition, the particular combination of corticosteroid, retinoid, vehicle and any other 15 ingredients must be selected so as to be compatible, but such selection is vithm the skill of the art given the present disclosure. The amounts or concentrations of the corticosteroid and retinoid which are present m the composition will vary widely depending upon such factors 20 as the particular corticosteroid and retinoid chosen, the disorder beirg treated, the frequency of applications to be maae, whether cr net the aonimstration will induce @ WO 93/15740 -1 f) ' " Pharmaceutical compositions containing a retinoid as an active ingredient m intimate admixture with a pharmaceutical carrier are known m the art and can be prepared according to conventional pharmaceutical 5 compounding techniques, such as those used for formulating topical all-trans-retinoic acid (tretinoin) The carrier may take a wide variety of physical forms such as creams, dressings, gels, lotions, ointments or liquids The particular retinoid, which may be more or less potent tha-1 10 tretinoin, will be present m an amount from about 0.00001% by weight to about 3% by weight, depending on the potency of the retinoid. Suitable topical retinoid preparations v<hich are commercially available are Retin-A1 gels which contain 0.01% to 0.025% by weight tretinoin, 15 and Retin-A® creams, which contain 0.025% to 0.1% by weight tretinoin, both produced by Ortho Pharmaceutical Corporation.

Typically, the corticosteroid will be present m the composition m amounts of about 0.00001 to 3 weight 20 percent, mainly depending on desired potency Using tretinoin as the standard for retinoids, tretinoin will typically be present m the composition in an amount of about 0.0001 to 1 weight percent, and other mere cr less potent retinoids will be used in corresponding amounts wo 93/15740 PCT7US93/01043 19 1Pi 6 % f' r Low potency corticosteroids, such as hydrocortisone, vill generally reguire concentrations cf about 2 o or higher, whereas mid- to high-potency corticosteroids are generally satisfactory at the 5 concentrations recommended by their manufacturers, such as 0.1% for betamethasone valerate or triamcinolone acetonde, and 0.05% for clobetasol propionate. These concentrations can of course be altered to obtain an optimal formulation for a particular condition. Moreover, 10 a particular advantage of the combinations of the present invention is that the corticosteroid can often be used in concentrations half of those in present formulations (not containing a retinoid) in the manufacture of medicaments This is an added safety factor treated conditions, the enhanced efficacy provided by the combination with the retinoid allows the use of lower concentrations of the corticosteroid. On the other hand, for particularly resistant disorders which would not normally be controlled or cleared by either the 2 0 corticosteroid or retinoid alone, higher concentrations of the corticosteroid may be desired and may be more easily tolerated due to the presence of the retinoid. contain additional ingredients Known m the art, sucn as Thus, on the one hand for relatively easily The corpositions of the invention may also stabilizers, er.ollier.ts, penetration enhancers, and U _ \1 •*> WO 93/15740 PCT/US93/01043 286 44 like Also, the compositions may be used with various means of application including, for example, occlusive dressings and drug delivery systems such as sponges, patches, liposomes, etc 5 - The general therapeutic regimen or strategy described herein usually involves once or twice daily applications, preferably twice daily, of the conbmation for several weeks to bring the dermatoses under control Thereafter, depending on 10 the characteristics of the disease it is possible to maintain clearance by judicious application of the corticosteroid alone several times weekly or by daily application of the retinoid alone, or by lower concentrations, and/or less frequent applications of the 15 combination or of a less potent combination.

Atopic dermatitis is an example of a disorder m which the clearance can be maintained by application of a low-potency corticosteroid alone, while inflammatory acne vulgaris is an example of a disorder in which clearance 20 can be maintained by application of a retinoid, e.g. tretinoin, alone Controlled studies on a significant number of patients have shown that the combined medicament manufactured according to tne present invention is not only additive, but nay ce -21 - 0 o ft A h C o 0 ^ ^ effective than and produces responses not obtained by the usual treatment regimens with either the corticosteroid or the retinoid alone Thus, inflammatory dermatoses clear more rapidly and there is rapid resolution of scaling, 5 induration and edema with the combination. This leads to greater patient compliance. Moreover, relapses are delayed and less severe. Significantly, improvement has been demonstrated m conditions which have become refractory to standard cr conventional treatments, such as 10 corticosteroid therapy alone, and rebound, often found after stopping steroid therapy, is eliminated.

It is important to note that the function of the retinoid component in this combination is not simply that of preventing or reversing atrophogenicity of 15 the corticosteroid, as described and claimed an U S Patents 4,889,847 and 5,019,569. According to the discovery of the present invention, the retinoid enhances the efficacy of the corticosteroid in suppressing inflammation which is characteristic of these chronic and 2 0 acute dermatoses. It as known that tretinoin and other retinoids have some anti-inflammatory effects, though the mechanisn of action is very different fron that of corticosteroids. It is also known that tretinoin makes the skm mere permeable, enabling a greater amount of 2 5 steroid to rea-h tne diseased stan.

L> 1 ^ - While applicant does not wish to be bound by any particular theory of action, it is believed that the retinoid enhances the efficacy of the corticosteroid in at least two particular ways: (1) by thinning the outer 5 horny layer (the so-called permeability "barrier" of the skm), thus enabling more of the drug to penetrate into the target tissue and yielding a greater local concentration of the corticosteroid (equivalent to increasing the dose of the corticosteroid); and (2) the 10 capacity of the retinoid to prevent and reduce inflammation m its own right.

The possible explanations for the antiinflammatory effects relate to the kno.cn ability of retinoids to inhibit migration of white cells 15 (neutrophils) from the blood vessels into the tissue (cheraotaxis). Moreover, retinoids influence immune processes; for example, activation of T-cells and the release of cytokines at the site of inflammation.

Retinoids also inhibit migration of macrophages into 20 diseased areas. These cells produce a variety of toxic products, including interleukins and proteins. One can cite other anti-mflarjtatory effects for which there is as yet no obvious explanation Tretinoin brings about faster resolution of chronic granulomas that are the result of foreign body reactions such as those elicited after the injection of collagen, elastin and carrageenin.

It must be emphasized that the modes of action 5 of corticosteroids and retinoids are completely different, and hence the combination of the two has unexpected beneficial therapeutic effects One mechanism by which tne corticosteroid works is by inhibiting the release of enzymes that initiate the inflammatory cascade, whereas the effect of the retinoid is less specific and dependent on a multiplicity of unrelated effects. Among these is the ability of retinoids to promote wound healing and to stimulate the formation of new blood vessels (angiogenesis), thus increasing the local blood supply.

Overall, retinoids, while initially inflammatory, seem to moderate inflammatory processes. In sum, the corticosteroid-retinoid combinations of the invention blunt inflammation by two entirely different mechanisms, acting m concert 2 0 Another advantage of the combination jls the prevention of rebound flare when the steroid is withdrawn. Dramatic examples cf rebound flare are well known to derratologists For example, the treatment of rosacea b} topical steroids leads to a svrdrome called "steroid 28b 44 After cessation of treatment, a ferocious, intense, pustular eruption develops which is very difficult to control In other diseases too, the treated sites show a "rebound dermatitis" when the steroid is stopped The 5 site becomes tender, red, cracked, edematous and peeling.

This rebound is completely prevented with combinations used in the manufacture of medicaments according to the present invention Still further, tachyphylaxis has not been observed with the combinations used in the manufacture of medicaments according to the present invention 10 The present invention will now be described m more detail with reference to the following specific, non-limiting examples. In these examples, two formulations have been extensively evaluated (1) 0.1% triamcinolone acetonide combined with 0.1% tretinoin in a 15 cream base; and (2) 0.05% clobetasol propionate combined with 0.1% tretinoin m a cream base. As expected, the therapeutic response to the latter formulation was swifter, because clobetasol is the most potent corticosteroid known Unless otherwise indicated in the 2 0 following examples, the combination brought about rapid resolution (control and clearing) within two to three weeks cf twice daily applications. \ 1 Example 1 Approximately 3 0 cases of highly mflannatory acne vulgaris were treated with a combination of 0 05% clobetasol propionate and 0.1% tretinoin m a cream base 5 Almost every instance of this condition was brought under control within two to three weeks of twice daily applications Example 2 About 2 0 patients having severely lr.flannatory acne conglobata were treated with the same combination as m Example 1 These patients have shown excellent responses m three weeks of twice daily applications. The response (clearing) is faster and more dramatic than with oral 13-cis-retmoic acid.

Example 3 Nine cases of severe papulo-pustular inflammatory acne were treated for two to three weeks with twice daily applications of 0.1% triamcinolone acetonide and either 0 05 or 0.1% tretinoin in a water-m-oil cream. 2 0 The lesicr.s coded down quickly and were then switched to daily applications of 0.025% tretinoin cream alore 26 Another alternative after stopping the combination treatment is a topical antibiotic such as erythromycin or an anti-bacterial such as benzoyl peroxide rosacea of the face have been treated with a combination of 0.1% tretinoin and 0.05% clobetasol propionate m a cream base This combination was remarkably effective lr clearing granulomatous rosacea, pyoderma faciale, and 10 rosacea fulmmans. Thereafter, remission could be maintained by topical metronidazole or oral tetracycline. the legs responded rapidly (within three weeks) from twice 15 daily applications of the same combination as m Example 4 Clearing could be maintained by mid-strength corticosteroids applied every second to third day.

Example 6 Ten adults with the adult form of cnromc atopic 20 dermatitis, which appeared as licnen simplex chronicus of the lo^er legs were treatec with a ccnoir.ation cf 0. 025% cr C 05% tretinoin ard 2 0% h/drrccrtiscre :r a crsar Example 4 Approximately 14 patients with severely inflamed Example 5 Six patients with hypertrophic lichen planus of WO 93/15740 PCT/US93/01043 y< ft) p /_ ' • - 27 - C k ' - vehiclc The itchy, thick plaques which characterize this condition essentially disappeared within three weeks of twice daily applications of the combination Thereafter, 1.0% hydrocortisone cream, applied once daily, was 5 sufficient to prevent relapse.

Example 7 A dozen patients suffering from chronic allergic contact dermatitis of occupational origin responded quickly to treatment with applications of the combination 10 of 0.1% triamcinolone acetonide and 0.1% tretinoin in a cream base.

Example 8 Twenty black males with long-standing, severely inflammatory pseudofolliculitis barbae were treated with 15 the combination of 0.1% triamcinolone acetonide and 0.1% or 0.05% tretinoin m a petrolatum vehicle (water-m-oil emulsion containing 46% petrolatum). In this disease tips of highly curved, stiff beard hairs which grow downwards into the skin create an inflammatory foreign body 2 0 granuloma. After about two to three weeks of treatment with the combination, the inflammatory lesions flattened ard became inactive, after which tretinoin alone was used

Claims (10)

WO 93/15740 PCT/US93/01043 Example 9 Small numbers of patients with various chronic dermatoses characterized by chronic, resistant, inflammatory lesions responded favorably to daily 5 applications of the combination of 0.053, clobetasol propionate and 0.1% tretinoin in a cream base for three to four weeks These disorders included chronic discoid lupus erythematosus, lichen planus, Darier's disease, alopecia areata, and persistent seborrheic dermatitis. 10 The present invention may be embodied m other specific forms without departing from the spirit or essential attributes thereof and, accordingly, reference should be made to the appended claims, rather than to the foregoing specification as indicating the scope of the 15 invention. WO 93/15740 PCT/US93/01043 - 29 - 9 p ft /» loO i CLAIMS

1 The use of a synergistic composition comprising a corticosteroid and a retinoid, in the manufacture of a medicament formulated for topical administration to an affected area of the skin 5 for controlling and clearing inflammatory dermatoses except psoriasis

2 A use according to claim 1 wherein said dermatosis is selected from the group consisting of 10 inflammatory acne vulgaris, severe mflammtory acne conglobata, lichen planus, discoid lupus erythematosus, alopecia areata, pseudofolliculitis barbae, pityriasis rubra pilaris, mycosis fungoides, inflammatory rosacea, chronic atopic dermatitis, chronic contact dermatitis, 15 chronic hand dermatitis, and acute drug reactions

3. A use according to claim 1 wherein said corticosteroid is present m said composition m an amount of substantially 0.00001 to 3 weight percent

4. A use according to claim 1 wherein said 2 0 retinoid is present m said corposition m an amount equivalent to substantially 0 0001 to 1 weight percent tretinoin ^ ' I / WO 93/15740 PCT/US 93/01043 -30- 286 ^^

5 A use according to claim 1 wherein said medicament is applied to the skin once or twice daily until the dermatosis is controlled and cleared, and thereafter clearance is maintained by less frequent 5 application or lower concentration application of the medicament or of a corticosteroid or a retinoid alone.

6 A use according to claim 5 wherein said less frequent application comprises substantially several applications per week of a corticosteroid or substantially once 10 daily applications of a retinoid.

7. A use according to claim 1 wherein said corticosteroid is a group I to group V potency corticosteroid.

8 . A use according to claim 7 wherein said 15 corticosteroid is selected from the group consisting of betamethasone valerate, triamcinolone acetonide, and clobetasol propionate.

9. A use according to claim 1 wherein said retinoid is tretinoin. H - WO 93/15740 PCT/US93/01013 31

10. *;use according to clnim 1 wherein said medicament comprises substantially 0 05 to 0 1 weight porcont tretinoin and substantially 0 05 to 0 1 weight percent of n corticosteroid selected from the group consisting of 5 betamethasone valerate, triamcinolone acetonide and clobetasol propionate.;retinoid is selected from the group consisting of all-trans-retinoic acid, 13-cis-retmoic acid, ll-cis-reti noic 10 acid, 9-cis-retinoic acid, retinol, retinal, (all-E)-9-(4-methoxy-2,3,6-tnmethylphenyl)-3 , 7-dimethyl-2,4,6,6-nonatetraenoic acid ethyl ester, (all-E)-9-(4-metho>*y-2,3,6-trimethvlphenyl)-3,7-dimethyl-2,4,6,8-nonatetraenoic acid, N-ethyl-9-(4-methoxy-2, 3, 6-trimethylphenyl)-3,7-15 dimethyl-2,4,6,B-nonatetraenamide, (E,E)-9-(2,6-dichloro-4-methoxy-3-methylphenyl)-3,7-dimethyl-2,4,6,8-nonatetraenoic acid ethyl ester, 7,8-didehydroretinoic acid, (E,E) -4-[2-methyl-4- (2,6, 6-tnioethyl-l-cyclohexen-1-yl)-l,3-butadienyl]benzoic acid, (E)-4-[4-methyl-6-20 (2,6,6-trimethyl-l-cyclohexen-l-yl)-1,3,5- hexatnercyl ]benzcic acid, (all-Z) -3 , 7-dimethy 1-3-thienyl)-2,4,6,8-nonatetraenoic acid, (E, E, E)-3-neth/2-7-(5,6,7,S-tetrahyaro-5,5,8,8-tetramethyl-2-naphthalenyl)-^ , -t , 6 —oc ^atner.c ic acid, (x.)—6 — — (2,6,6—tririethyl — — — 11 A use according to claim ] wherein said / / END OF CLAIMS V