WO2011024027A1

WO2011024027A1 - Pharmaceutical combinations of diflucortolone and terbinafine

Info

Publication number: WO2011024027A1
Application number: PCT/IB2009/053700
Authority: WO
Inventors: Farhad Farshi; Fikret Koc; Serdar Soylemez
Original assignee: Abdi Ibrahim Ilac Sanayi Ve Ticaret Anonim Sirketi
Priority date: 2009-08-24
Filing date: 2009-08-24
Publication date: 2011-03-03

Abstract

This invention relates to pharmaceutical combinations, compositions and kits of diflucortolone and terbinafine and methods of using such combinations in the treatment of skin disease or diseases which respond to topical corticoid therapy where said skin disease or diseases are associated with one or more fungis or to prevent skin disease or diseases which respond to topical corticoid therapy where there is a likelihood of associating with one or more fungal diseases.

Description

Title of Invention: PHARMACEUTICAL COMBINATIONS OF

DIFLUCORTOLONE AND TERBINAFINE

[1] This invention is related to pharmaceutical combinations of diflucortolone and

terbinafine.

[2] Terbinafine is known from U.S. 4,755,534 and diflucortolone is known from BE

639708 and US 3426128.

[3] This invention embraces pharmaceutical combinations of therapeutically effective amount diflucortolone or its forms or derivatives and therapeutically effective amount terbinafine or its forms or derivatives and methods of using such combinations in the treatment of skin disease or diseases which respond to topical corticoid therapy where said skin disease or diseases are associated withone or morefungis or prevent skin disease or diseases which respond to topical corticoid therapy where there is a likelihood of associating withone or more fungis.

[4] The use of other antifungals such like isoconazole or its forms or derivatives an azole antifungal and diflucortolon or its forms or derivatives is known. This well established treatment can be progressed by using such a allylamine derivative antifungal with a broader spectrum of antifungal activity such like Terbinafin or its forms or derivatives. In contrast to azole derivatives such like isoconazole or its forms or derivatives antifungal agents which are primarily fungistatic in action, terbinafine or its forms or derivatives exhibits a primary fungicidal action in vitro against most fungal pathogens. The mechanism of action is via inhibition of the fungal enzyme squalene epoxidase, which is important early in the biosynthetic pathway of ergosterol. This results in accumulation of intracellular squalene and a modest decrease in ergosterol content.

Fungicidal actions of the drug appear related to development of high concentrations of intracellular squalene, as opposed to ergosterol deficiency, which interfere with fungal membrane function and cell wall synthesis. An exception is Candida albicans, where the action of terbinafine is fungistatic; growth inhibition of C albicans is probably the result of ergosterol deficiency.

[5] This invention is also embraces kits containing pharmaceutical combinations of therapeutically effective amount diflucortolone or its forms or derivatives and therapeutically effective amount terbinafine or its forms or derivatives and methods of using such combinations in the treatment of skin disease or diseases which respond to topical corticoid therapy where said skin disease or diseases are associated with one or more fungis or prevent skin disease or diseases which respond to topical corticoid therapy where there is a likelihood of associating withone or more fungis . [6] Accoording to this invention fungal diseases are tinea pedis and tinea cruris caused by trichophyton, epidermophyton floccosum,mixtures thereof and the like. Skin diseases which respond to topical corticoid therapy are contact dermatitis, contact eczema, occupational eczema vulgar, nummular, degenerative and seborrhoeic eczema, dyshidrotic eczema, eczema in varicose syndrome,anal eczema, eczema in children, neurodermatitis (endogenous eczema, atopic dermatitis), psoriasis, lichen ruber planus et verrucosus, lupus erythematosus discoides, first degree burns, sunburn, insect bites relief of inflammation, itching mixtures thereof and the like.

[7] Terbinafine is commercially marketed by Novartis under the trade name Lamisil ®.

Lamisil ® (terbinafine hydrochloride) cream is indicated for the treatment of tinea pedis (athlete's foot) and tinea cruris (dhobie itch/jock itch) caused by Trichophyton (e.g. T. rubrum, T. mentagrophytes, T. verrucosum, T. violaceum) and Epidermophyton floccosum.

[8] Diflucortoloneis used for all skin diseases which respond to topical corticoid therapy

: contact dermatitis, contact eczema, occupational eczema vulgar,nummular, degenerative and seborrhoeic eczema, dyshidrotic eczema, eczema in varicose syndrome (but not directly onto lower limb ulcers), anal eczema, eczema in children, neurodermatitis (endogenous eczema, atopic dermatitis), psoriasis, lichen ruberplanus et verrucosus, lupus erythematosus discoides,first degree burns, sunburn, insect bites relief of inflammation, itching associated with skin conditions and etc . Diflucortolone valerate is marketed by Intendis under trademark of Nerisone ®

[9] The wording "pharmaceutically acceptable derivative or/and forms" as used herein with reference to above mentioned therapeutic agents utilized in the present invention is aimed to include any pharmaceutically acceptable salt, solvent, ester or salt of such ester, or any other compound . The term terbinafine' as used herein includes terbinafine freebase as well as its pharmaceutically acceptable acid addition salts. For example, the acid addition salt may be terbinafine hydrochloride. Diflucortolone or any salt, solvate, prodrug, variant, derivative or form thereof may be used. Diflucortolone valerate is preferred.

[10] Combination is used in topical administration. Topical administration may be in the form of, but not limited to, lotion, gel, cream, solution, ointment, paste, powder, aerosol powder, aerosol solution, spray, foam, shampoo, mixtures thereof and the like.

[11] Eczema is an inflammatory skin condition. In principally, there is no any connection between eczema and fungi, however a fungal infection may develop on top of the weakened eczema skin. Therefore, it is needed new approach to produce more effectively new medicament.Accordingly, in this invention a pharmaceutical composition is disclosed comprising the combination of terbinafine and diflucortolone.

[12] The present invention is directed to a pharmaceutical composition comprising (i) therapeutically effective amount Terbinafine or its pharmaceutically acceptable forms or/and derivatives and (ii) therapeutically effective amount diflucortolone or its pharmaceutically acceptable forms or/and derivatives; and (iii) a pharmaceutically acceptable excipient or excipients.

[13] According to this invention using terbinafine HCI plus diflucortolone valerate

provides huge benefits to patients and physicians, and improves physician and pharmacist efficiencies. As the terbinafine HCI and diflucortolone valerate are formulated or packaged together, the physician would write a single prescription. The pharmacist would dispense a single combination rather than multiple pre- scriptions.Furthermore, terbinafine HCI plus diflucortolone valerate increase patient compliance.

[14] Pharmaceutical formulation used for topical administration may include various excipients such assolvents, alcohols, antimicrobial preservatives, alkalizing

agents,viscosity-increasing agent, emulsifying agent; solubilizing agent; wetting agent,chelating agents, stabilizingagents, stiff eningagents etc. For the kit, the compounds of the present invention are administered in the form of a seperately unit, one unit of pharmaceutical composition comprising Terbinafine HCI and a pharmaceutically acceptable excipent or excipients and other one unit of pharmaceutical composition comprising diflucortolone valerate with a pharmaceutically acceptable excipent or excipients.

[15] Pharmaceutical composition for cream may include excipients : mineral oil, ce- tostearyl alcohol, disodium edetate, carbomer 934, sodium hydroxide, polyoxyl 40 stearate, vaseline, purified water , methylparaben, mixtures thereof and the like .

[16] Pharmaceutical composition for pomade may include excipients : mineral oil,

vaseline, white beeswax, mixtures thereof and the like .

[17] Pharmaceutical composition for oily pomade may include excipients : hydrogenated castor oil, mineral oil, microcrystalline wax,vaseline,mixtures thereof and the like .

[18] Another aspect of this invention is relevant to kits comprising (i) therapeutically effective amount of terbinafine or its pharmaceutically acceptable forms or/and derivatives and a pharmaceutically acceptable excipient or excipients and (ii) therapeutically effective amount of diflucortolone or a pharmaceutically acceptable forms or/and derivatives and its pharmaceutically acceptable excipent or excipients and (iii) a container.

[19] The kits of the invention may include container as separately compositions such as a divided bottle or a divided packet. Seperately unit dosage forms may also be contained undivided container. Unit dosage forms can each be discrete dosage forms that are packaged together. The pharmaceutical kits can include instructions as a separate sheet or optionally printed on the containers. [20] In the kits, unit dosage forms are generally administered in the form of a pharmaceutical composition and each unit dosage form additionally comprising a pharmaceutically acceptable excipient or excipients.

[21] According to the present invention, combination can be administered simul- taneously,separately or sequentially.

Claims

[Claim 1] A pharmaceutical composition comprising ;

(i) therapeutically effective amount of terbinafine or its pharmaceutically acceptable forms or derivatives; and

(ii) therapeutically effective amount of diflucortolone or its pharmaceutically acceptable forms or derivatives; and

(iii) pharmaceutically acceptable excipient or excipients.

[Claim 2] A pharmaceutical composition according to Claim 1, wherein (i)

terbinafine is HCI and ( ii) diflucortolone is valerate.

[Claim 3] A pharmaceutical composition according to claims of 1 to 3 for use as a medicament.

[Claim 4] According to claim 3, pharmaceutical composition is used ;

(i) in the treatment of where skin disease or diseases, which respond to topical corticoid therapy, are associated withone or morefungal disease or,

(ii) to prevent skin disease or diseases, which respond to topical corticoid therapy, where there is a likelihood of associating withone or more fungal diseases .

[Claim 5] As claimed in claim 4, fungal diseases are tinea pedis and tinea cruris caused by trichophyton or epidermophyton floccosum or mixtures thereof .

[Claim 6] As claimed in claim 4, skin diseases which respond to topical corticoid therapy are contact dermatitis, contact eczema, occupational eczema vulgar, nummular, degenerative and seborrhoeic eczema, dyshidrotic eczema, eczema in varicose syndrome,anal eczema, eczema in children, neurodermatitis (endogenous eczema, atopic dermatitis), psoriasis, lichen ruber planus et verrucosus, lupus erythematosus discoides,first degree burns, sunburn, insect bites relief of inflammation, itching or mixtures thereof .

[Claim 7] A kit comprising

(i) first pharmaceutical formulation comprising therapeutically effective amount of diflucortolone or its pharmaceutically acceptable forms or derivatives and a pharmaceutically acceptable carrier and/or diluent ; and

(ii) second pharmaceutical formulation comprising therapeutically effective amount of terbinafin or its pharmaceutically acceptable forms or derivatives and a pharmaceutically acceptable carrier and/or diluent ; and

(iii) container includes first and second pharmaceutical formulations.

[Claim 8] According to claim 7, kit is used ;

(i) in the treatment of where skin disease or diseases, which respond to topical corticoid therapy, are associated withone or morefungal diseases or,

(ii) to prevent skin disease or diseases, which respond to topical corticoid therapy, where there is a likelihood of associating withone or more fungal diseases.

[Claim 9] As claimed in claim 8, fungal disease are tinea pedis and tinea cruris caused by trichophyton or epidermophytonfloccosum or mixtures thereof.

[Claim 10] As claimed in claim 8, skin diseases which respond to topical corticoid therapy are contact dermatitis, contact eczema, occupational eczema vulgar, nummular, degenerative and seborrhoeic eczema, dyshidrotic eczema, eczema in varicose syndrome,anal eczema, eczema in children, neurodermatitis (endogenous eczema, atopic dermatitis), psoriasis, lichen ruber planus et verrucosus, lupus erythematosus discoides,first degree burns, sunburn, insect bites relief of inflammation, itching or mixtures thereof .