TECHNICAL FIELD OF THE INVENTION
The present invention relates to stable topical composition comprising a vitamin D analogue and a corticosteroid for the treatment of psoriasis.
BACKGROUND OF THE INVENTION
Psoriasis is a chronic inflammatory disease of the skin, affecting 1-3% of the world population. Psoriasis is a skin disorder that includes the presence of small elevations of the skin that may be characterized as elevated red lesions, plaques or pustules on the skin which eventually result in silvery scales. These silvery scales and plaques are the result of accelerated epidermal proliferation and the metabolic activity and proliferation of capillaries in the dermal region and the invasion of the dermis and epidermis by inflammatory cells.
The exact mechanism which triggers the abnormal cell proliferation is not known, though it is believed there may be biochemical stimuli and environmental factors. The seventy and course of psoriasis can vary greatly depending on the individual, but in general this chronic skin condition recurs throughout the life of the individual with varying intervals of one month to many years.
Therapeutic methods most commonly employed for the treatment of psoriasis include topical treatment using corticosteroids, vitamin D analogues or retinoids. First line treatment for the mild to moderate psoriasis includes monotherapies with a vitamin D analogue like calcipotnol (calcipotriene), calcitriol or tacalcitol or a corticosteroid like betamethasone, clobetasol or halobetasol. Paticularly, calcipotriol (calcipotriene) is the most preferred vitamin D analogue employed in the treatment of psoriasis It is being marketed under the brand name Dovonex since 1991 by Leo Pharma and is being described in the US patent no. 4,866,048. Further, corticosteroid most commonly employed in the treatment of psoriasis is betamethasone It is being marketed under the brand name Diprolene by Schering. US patent no. 4,070,462 describes an ointment comprising mono or diester of betamethasone in a non-aqueous base.
Monotherapies are not effective in the treatment of more severe forms of psoriasis. So a combined therapy using two anti-psoriatic agents, having different mechanisms of actions is preferred over the monotherapy in such a treatment. Particularly a combination of a vitamin D analogue and a corticosteroid is prefered. These two agents act through different mechanisms of action thereby providing a synergistic effect Corticosteroids have anti-inflammatory, immunosuppressive, antimitotic, and antipruritic actions, whereas vitamin D analogue reduces keratinocyte proliferation and acts as an immunomodulator. The side effects of each agent also can be reduced through use in a combination. A composition combining a vitamin D analogue and a corticosteroid provides synergy in the form of additional benefit to the patient apart from the direct therapeutic value of the active substances. It has been shown that the skin irritative side effects of a vitamin D analogue, such as calcipotriol (calcipotriene), is alleviated by the simultaneous application of a steroid, such as betamethasone, onto psoriatic skin.
These two agents have significantly different optimum stability pH values so earlier combination therapies invovled the sequential administration of these two antipsonaitic agents present in separate formulations. Vitamin D analogues require a pH value above 8 for maximum stability, whereas corticosteroids require pH value in the range of 4-6 for maximum stability. Since the base auxiliary materials and additives traditionally usee in preparing topical formulations, such as creams and/or ointments involve having some kind of acid or alkaline nature or reaction ability, it has therefore not been possible to combine the two active compounds in one single formulation while maintaining good stability of the active compounds.
But the sequential administration through separate formulations is not as effective and patient compliant as the therapy using a single composition containing both the active ingredients. So, attempts have been made in the prior art to design the compositions comprising a combination of a corticosteroid and a vitamin D analogue
having an improved stability
PCT application no WO2004/054588 filed by Galderma describes the combination of caicitriol with clobetasol propionate having synergistic effect in the treatment of
psoriasis
Further, US patent no. 6,753,013 assigned to Leo Pharma describes a pharmaceutical composition for dermal use including a combination of a vitamin D analogue and a corticosteroid admixed with a solvent component to coexist despite differing pH stability profiles. Solvent components being described in the said patent mainly concerned with the stabilization of the compositions containing these two incompatible active agents Furthermore, PCT application WO2008/027532 filed by Teva pharmaceuticals describes a pharmaceutical composition comprising a vitamin D analogue and a corticosteroid and a solvent component which tends to form a stabilized composition inspite of using the less stable anhydrous form of calcipotriol (calcipotriene).
The present inventors have developed an alternative formulation comprising a vitamin D analogue, more particularly calcipotriol (calcipotriene) and a corticosteroid, moie particularly betamethasone and a solvent carrier selected from the group comprising of (a) monoalkyl ether of diethylene glycol having a general formula C4H9O3(CnH2n+1) wherein n is 1-4 (b) propylene glycol monoesters (c) tocopherol derivatives
Solvent carriers used in the composition of the present invention provide enhanced stability of both the active agents and also improve their permeability through the skin These are also non-irritating and non-sensitizing to the skin thereby providing highly tolerable composition.
SUMMARY OF THE INVENTION
The present invention relates to stable topical composition comprising a vitamin D analogue and a corticosteroid for the treatment of psoriasis.
One of the aspects of the present invention relates to a topical pharmaceutical composition comprising
a) a therapeutically effective amount of a vitamin D analogue;
b) a therapeutically effective amount of a corticosteroid; and
c) at least one solvent carrier selected from the group comprising
sii monoalkyl ether of diethylene glycol having a general formula
C4H9O3(CnH2n+1). wherein n is 1-4; (ii) propylene glycol monoesters; and (in) tocopherol derivatives
According to one of the embodiments of the present invention vitamin D analogue is selected from the group comprising calcipotriol (calcipotriene), calcitriol, tacalcitol, maxacalcitol, 1(S).3(R)-dihydroxy-20(R)-[((3-(2-hydroxy-2-propyl)-phenyl)-methoxy)-methyl]-9.10-seco-pregna-5(Z).7(E),10(19)-triene. and mixtures thereof. Particularly the vitamin D analogue is calcipotriol (calcipotriene).
According to another embodiment of the present invention corticosteroid is selected from the group comprising betamethasone. clobetasol. clobetasone, desoximethasone, diflucortolone, diflorasone, fluocinonide, flumethasone, fluocinoione, fluticasone, fluprednidene halcinonide, hydrocortisone, momethasone, triamcinolone, and pharmaceutical^ acceptable esters and acetonides as well as mixtures thereof. Particularly the corticosteroid is betamethasone and esters thereof.
According to one of the embodiments the present invention relates to a topical
composition comprising
a) a therapeutically effective amount of calcipotriol;
b) a therapeutically effective amount of betamethasone or esters thereof;and
c) diethylene glycol monoethyl ether.
According to another embodiment the present invention relates to a topical
composition comprising
a) a therapeutically effective amount of calcipotriol;
b) a therapeutically effective amount of betamethasone or esters thereof; and
c) propylene glycol monostearate.
According to still another embodiment the present invention relates to a topical
composition comprising
a) a therapeutically effective amount of calcipotriol;
b) a therapeutically effective amount of betamethasone or esters thereof; and
c) D-alpha-tocopheryl polyethylene glycol 1000 succinate.
According to still another embodiment calcipotrioi is present in an amount of about 0.0001% to about 0.025% by weight of the composition. Particularly the composition of the present invention contains about 0.001% to about 0.01% by weight of calcipotrioi. More particularly the composition of the present invention contains about
0 004% to about 0.007% by weight of calcipotrioi.
According to yet another embodiment betamethasone or esters thereof is present in an amount of about 0.0005% to about 5% by weight of the composition. Particularly the composition of the present invention contains about 0.005% to about 0.5% by weight of the betamethasone or esters thereof. More particularly the composition of the present invention contains about 0.01% to about 0.1% by weight of the betamethasone or esters thereof.
According to still another embodiment solvent carrier is present in an amount of about 17D to about 30% by weight of the composition. Particularly the solvent carrier is present in an amount of about 2% to about 15% by weight of the composition. More particularly the composition of the present invention contains about 3% to aoout 10%, by weight of the solvent carrier.
Another aspect of the present invention provides a topical composition wherein said composition is in the form of an ointment, a cream, a lotion, a scalp lotion, a liniment or other spreadable liquid or semi liquid preparation.
According to another aspect, composition of present invention further comprises one or more pharmaceutically acceptable excipients selected from a group comprising solvents, preservatives, antioxidants, chelating agents, surfactants, pH-adjusting
agents ointment or lotion bases or mixtures thereof
Another aspect of the present invention provides a method of treating psoriasis by administering a therapeutically effective amount of topical composition of the present
invention
According to another aspect additional antifungal agents are included in the composition of the present invention for the treatment of psoriatic skin diseases, winch are complicated by fungal infections
The details of one or more embodiments of the invention are set forth in the description below Other features, objects and advantages of the invention will be apparent from the description and claims.
DESCRIPTION OF THE INVENTION
The present invention is directed to a stable topical pharmaceutical composition comprising a vitamin D analogue, a corticosteroid and at least one solvent carrier for
the treatment of psoriasis.
The phrase therapeutically effective amount" as used herein means the amount of a compound that, when administered to a subject for treating a state, disorder, condition or causing an action is sufficient to effect such treatment or action. The therapeutically effective amount" will vary depending on the compound, the disease and its severity and the age, weight, physical condition and responsiveness of the mammal to be treated.
Tiie term about' as used herein means up to plus or minus 10% of the particular
tenn
As used herein, the term "vitamin D analogue " includes vitamin D, its prodrugs,
naturai or synthetic analogues, and crystalline forms including anhydrate, hydrate,
solvate, or amorphous forms. Preferred vitamin D-containing compounds include
calcipotnol (calcipotnene), calcitriol, tacalcitol, maxacalcitol, or 1(S),3(R)-dihydroxy~
20(R)-[((3(2-hydroxy-2-propyl)-phenyl)-methoxy)-methy- l]-9,10-seco-pregna-
5(Z) 7(E) 10(19)-triene. Particularly the composition of the present invention contains calcipotnol (calcipotriene)
The calcipotriol used in the composition of the present invention may be present in crystalline, amorphous, anhydrous, hydrous form or mixtures thereof. More particularly anhydrous calcipotriol is used in the composition of the present invention.
Corticosteroids used in the composition of the present invention include betamethasone (9-fluoro-11,17,21-trihydroxy-16-methylpregna-1,4-diene-3,20-dione) and esters thereof such as the 21-acetate, 17-adamantoate, 17-benzoate, 17-valerate, and 17,21-dipropionate; alclomethasone and esters thereof such as the dipropionate; clobetasole and esters thereof such as the propionate; clobetasone ana esters thereof such as the 17-butyrate; diflorasone and esters thereof such as the diacetate; fluocinonide; flumetasone and esters thereof such as the pivalate; fluocinolone and ethers and esters thereof such as the acetonide; fluticasone and esters thereof such as the propionate; tluprednidene and esters thereof such as the acetate; halcinonide: hydrocortisone and esters thereof such as the -17-butyrate: mometasone and esters thereof such as the furoate; triamcinolone and ethers and esters thereof such as the acetonide; desoximetasone; diflucortolone and esters thereof Particularly the composition of the present invention contains betamethasone or esters thereof. More particularly the composition of the present invention contains betamethasone dipropionate or betamethasone valerate.
The solvent carrier included in the composition of the present invention is selected
from the group comprising
ta) monoalkyl ether of diethylene glycol having a general formula C4H9O3(CnH2n+1)
wherein n is 1-4.
ib) propylene glycol monoesters;
(c) tocopherol derivatives
Specific examples of monoalkyl ether of diethylene glycol having a general formula C4H9O3(CnH2n+1) wherein n is 1-4 include, but are not limited to, diethylene glycol monoethyl ether, diethylene glycol monomethyl ether or mixtures therof. Particularly me solvent is diethylene glycol monoethyl ether. It is marketed by Gattefosse under the trade name Transcutol-P®.
Examples of propylene glycol monoesters include, but are not limited to, propylene glycol monostearate, propylene glycol monolaurate or mixtures therof. Particularly propylene glycol monostearate is used in the composition of the present invention. It helps in formulating a stable composition. Further it improves penetration characetnstics and tolerance of the composition
As used herein the term "tocopherol derivatives" includes all natural and synthetic tocopherol or Vitamin E compounds. Particularly preferred tocopherol derivatives include tocopherol esters. More particularly Vitamin E TPGS (D- a- tocopheryl polyethylene glycol 10000 succinate) is used. It is a water-soluble derivative of Vitamin E prepared by esterifying D- a -tocopheryl acid succinate with polyethylene glycol 1000. It acts as excellent solvent and has a very low irritative potential.
It has been found that in such combination composition containing a solvent carrier, the active components can co-exist without degradation, despite their different pH/stability profiles The tendencies of the active compounds to affect one another with regard to pH is minimized or eliminated.
The topical pharmaceutical composition of the present invention is in the form of an ointment, a cream, a lotion, preferably a scalp lotion, a liniment or other spreadable liquid or semi liquid preparation which is, preferably, non-aqueous or in the form of an oil-in-water or water-in-oil emulsion. Particularly the composition of the present invention is a monophasic composition, i.e. a composition comprising a single solvent system, such as an ointment
The topical pharmaceutical composition of the present invention further comprises one or more pharmaceutical^ acceptable excipients selected from a group comprising solvents, preservatives, antioxidants, chelating agents, surfactants, pH-adjusting agents, ointment or lotion bases or mixtures thereof.
The composition of the present invention may be prepared in accordance with methods well known to the person skilled in the field of pharmacy. Thus, the composition may be prepared by incorporating the components into a well-known ointment or lotion base excipients such as white petrolatum (white soft paraffin) or PiastibaseTM (a base prepared from polyethylene (average MW about 21,000) and paraffin liquid) or ESMA-P™ (a microcrystalline wax)
According to one of the embodiments composition of the present invention is prepared by melting the ointment base, adding a solution of the vitamin D analogue in the required amount of solvent component, followed by addition of a dispersion of the corticosteroid in another ointment base, and then cooling the mixture. The composition may also contain other pharmaceutically acceptable excipients.
Examples of ointment bases used in the present invention include, but are not limited to paraffins or a combination of paraffins ranging from liquids for example mineral oii; to semisolids for example petrolatum and white petrolatum; to solids for example paiaffin wax, silicones, lanolins, or mixtures thereof.
The invention also relates to a method of treatment of psoriasis and related skin diseases by administering an effective amount of a composition of the present invention to a patient in need of such treatment. Said method preferably comprises topical application once or twice daily of a medically sufficient dosage of said
composition.
The topical composition of the present invention may further comprise an additional antifungal agent selected from the group comprising of miconazole, clotrimazole, terbinafine ciclopirox, bifonazole, nystatin, ketoconazole, econazole or amorolfine for the treatment of psoriat.c skin diseases complicated by fungal infections.
The following examples further describe and demonstrate embodiments within the scope of the present invention. The examples are given solely for the purpose of illustration and are not to be construed as limitations of the present invention, as many variations thereof are possible without departing from the spirit and scope of
the invention
EXAMPLE 1
Ql ntment containing calcipotriol (calcipotriene) and betamethasone dipropionate

(Table Removed)
1) Diethyiene glycol monoethyl ether was heated to 70°C and calcipotriol
(calcipotriene) was dissolved in it with stirring.
2) White petrolatum was melted and then cooled to 70°C.
3) Solution of step 1 was added drop wise to melted white petrolatum of step 2 while maintaining the temperature at 70°C.
4) Betamethasone dipropionate was dispersed in mineral oil.
5) dl-alpha tocopherol and dispersion of step 4 was added to step 3 with stirring.
6) Stirring was continued until a smooth ointment was obtained. 7) Finally the ointment was packed into the collapsible tubes.
EXAMPLE 2
Ointment containing calcipotnol (calcipotriene) and betamethasone dipropionate

(Table Removed)
1) Propylene glycol monostearate was melted at 70°C and calcipotriol (calcipotriene) was dissolved in it with stirring.
2) White petrolatum was melted and then cooled to 70°C.
3) Solution of step 1 was added drop wise to melted white petrolatum of step 2 while maintaining the temperature at 70°C.
4) Betamethasone dipropionate was dispersed in mineral oil.
5) dl-alpha tocopherol and dispersion of step 4 was added to step 3 with stirring.
6) Stirring was continued until a smooth ointment was obtained. 7) Finally the ointment was packed into the collapsible tubes.
EXAMPLE 3
Ointment containing calcipotriol (calcipotriene) and betamethasone dipropionate

(Table Removed)
1) Vitamin E TPGS was mielted at 70°C and calcipotriol (calcipotriene) was dissolved in it with stirring
2) White petrolatum was melted and then cooled to 70°C
3) Solution of step 1 was added drop wise to melted white petrolatum of step 2 while maintaining the temperature at 70°C.
4) Betamethasone dipropionate was dispersed in mineral oil.
5) dl-alpha tocopherol and dispersion of step 4 was added to step 3 with stirring.
6) Stirring was continued until a smooth ointment was obtained.
7) Finally the ointment was packed into the collapsible tubes.

WE CLAIM:
1. A topical pharmaceutical composition comprising:
a) a therapeutically effective amount of a vitamin D analogue;
b) a therapeutically effective amount of a corticosteroid; and
o at least one solvent component selected from the group comprising of (i) monoalkyl ether of diethylene glycol having a general formula
C4H9O3(CnH2n+1) wherein n is 1-4. (n) propylene glycol monoesters; (lii) tocopherol derivatives.
2. The topical pharmaceutical composition of claim 1 wherein vitamin D analogue is selected from the group comprising calcipotriol, calcitriol, tacalcitol. maxacalcitol, 1 (S),3(R)-dihydroxy-20(R)-[((3-(2-hydroxy-2-propyl)-phenyl)-methoxy)-methyl]-9,10-seco-pregna-5(Z),7(E), 10(19)-triene, and mixtures thereof
3. The topical pharmaceutical composition of claim 1 wherein corticosteroid is selected from the group comprising betamethasone, clobetasol, clobetasone, desoximethasone, diflucortolone, diflorasone, fluocinonide, flumethasone, fluocinolone, fluticasone, fluprednidene. halcinonide, hydrocortisone, momethasone, triamcinolone, and pharmaceutically acceptable esters and acetonides and mixtures thereof.
4. The topical pharmaceutical composition of claim 1 wherein the solvent carrier is selected from the group comprising diethylene glycol monoethyl ether, diethylene glycol monomethyl ether, propylene glycol monostearate, vitamin E TPGS or mixtures thereof.
5. The topical pharmaceutical composition of claim 2. wherein calcipotriol is
composition.

6. The topical pharmaceutical composition of claim 3 wherein betamethasone dipropionate is present in an amount of about 0.005% to about 0.1% by weight of the composition.
7. The topical pharmaceutical composition of claim 1 wherein solvent carrier is present in an amount of about 1% to about 30% by weight of the composition.
8. The topical pharmaceutical composition of claim 1 wherein said composition is in the form of an ointment, a cream, a lotion, a scalp lotion, a liniment or other spreadable liquid or semi liquid preparation
9. The topical pharmaceutical composition of claim 1 wherein said composition further comprises one or more pharmaceutically acceptable excipients selected from a group comprising water miscible solvents, preservatives, antioxidants, chelating agents, surfactants, pH-adjusting agents, ointment or lotion bases and mixtures thereof.
10. A topical pharmaceutical composition comprising a vitamin D analogue and a corticosteroid substantially as described and illustrated herein.