WO1996002254A1

WO1996002254A1 - SYNERGISTIC PHARMACEUTICAL COMPOSITONS CONTAINING 16'alpha',17'alpha'-ISOPROPYLIDENEDIOXY SUBSTITUTED PREGNANES

Info

Publication number: WO1996002254A1
Application number: PCT/SE1994/000693
Authority: WO
Inventors: Michel Cohen; Georges Chriki
Original assignee: Michel Cohen
Priority date: 1994-07-15
Filing date: 1994-07-15
Publication date: 1996-02-01
Also published as: AU7510394A

Abstract

A pharmaceutical composition comprises a synergistic combination of about 0.01-0.15 % by wt. triamcinolone acetonide and about 0.04-0.3 % by wt. halcinonide as active ingredients, in combination with a pharmaceutically acceptable carrier.

Description

SYNERGISTIC PHARMACEUTICAL COMPOSITIONS CONTAINING 16α,17α-ISOPROPYLIDENEDIOXY SUBSTITUTED PREGNANES

The present invention rleates to a pharmaceutical composition for treating psoriasis. More particularly, the present invention relates to a composition containing 16α, 17α-substituted methylenedioxy steroids as active ingredients therein.

It has been known for over 25 years that 11-substituted 16α,17α-substituted methylene dioxysteroids of the pregnane series, as described, e.g., in U.S. Patent 2,990,401, have high anti-inflammatory activity and can be used topically in the treatment of burns, rheumatoid arthritis, allergies, psoriasis and other skin disorders.

Among the compounds taught in said patent, it is now well-known that triamcinolone acetonide, which is 9α-fluoro- llβ-21-dihydroxy-16α,17α-isopropylidenedioxy-l,4-pregnadiene -3,20-dione, has proved particularly useful in the treatment of dermatological conditions. The compound has been proved to have marked efficacy in the treatment of dermatosis, eczema, neurodermitis, impetigo, psoriasis, pruritis and other related diseases.

Similarly, in U.S. Patent 3,892,857 there is described and claimed a steroid formulation having enhanced properties for topical application, comprising 21-chloro-9-fluoro-11- hydroxy-16,17-[ (l-methyl-ethylidene)bis(oxy) ]pregn-4-ene- 3,20-dione in a vehicle containing as major ingredients propylene glycol and water. The present invention relates to a pharmaceutical composition for treating psoriasis. More particularly, the present invention relates to a composition containing 16α ,17α -substituted methylenedioxy steroids as active ingredients therein.

It has been known for over twenty-five years that 11-substituted 15x , 17 -substituted methylene dioxysteroids of the pregnane series, as described, e.g., in U.S. Patent 2,990,401, have high anti-inflammatory activity and can be used topically in the treatment of burns, rheumatoid arthritis, allergies, psoriasis and other skin disorders.

Among the compounds taught in said patent it is now well known that triamcinolone acetonide, which is 9<_ -fluoro-11 β 21-dihydroxy- 16 α, I7α -isopropylidenedioxy-1,4-pregnadiene- 3,20-dione, has proved particularly useful in the treatment of der atological conditions. The compound has been proved to have marked efficacy in the treatment of dermatosis, eczema, neurodermitis, impetigo, psoriasis, pruritis and other related diseases.

Similarly, in U.S. Patent 3,892,857 there is described and claimed a steroid formulation having enhanced properties for topical application comprising 21-chloro-9-fluoro-ll-hydroxy-16,17- [(1-methyl- ethylιdene)bis(oxy)]pregn-4-ene-3,20-dione in a vehicle containing as major ingredients propylene glycol arid water. Said compound has subsequently become known generally as halcinonide and is marketed as a topical anti- inflammatory compound.

While both of said compounds are successfully marketed and are known to ease the suffering caused by psoriasis by stopping the itching, and even cleaning the skin of crust, the basic psoriasis remains uncured.

It has now been surprisingly discovered that a combination of said compounds exhibits a synergistic effect which not only heals psoriasis but also cures said condition, so that even after treatment is completed, the psoriasis does not return.

The present invention provides a pharmaceutical composition comprising a synergistic combination of about 0.01-0.15% by wt. triamcinolone acetonide and about 0.04-0.3% by wt. halcinonide as active ingredients therein, in combination with a pharmaceutically acceptable carrier.

Preferably, according to the present invention, there is provided a pharmaceutical composition for treating psoriasis, comprising a synergistic combination of about 0.05-0.15% by wt. triamcinolone acetonide and about 0.2-0.3% by wt. halcinonide as active ingredients therein, in combination with a pharmaceutically acceptable carrier.

Said composition preferably comprises a pharmaceutical composition comprising about 0.1% triamcinolone acetonide and about 0.2% halcinonide. The pharmaceutically acceptable carrier can be any of those known and taught in the prior art. The formulation of this invention may also contain additives to improve the physical form and the release characteristics. Additives which may be used include diluents, thickness agents, preservatives and penetration enhancers.

The penetration enhancers suitable for the purpose of the invention are the therapeutically acceptable penetration enhancers that do not adversely affect the drug, the skin or the materials for using the ointment.

Examples of penetration enhancers include 1-dodecyl- azacycloheptan-2-one, propylene glyccl, surfactar.ts and others.

Thus it will be understood that the present invention also provides a pharmaceutical composition for treating psoriasis comprising a synergistic combination of about 0.01-0.15% by wt. triamcinolone acetonide and about 0.04-0.3% by wt. halcinonide as active ingredient therein when said active ingredients are used in combination with a penetration enhancer.

A preferred formulation comprises a base of about 70% vaselin albun, 10% lanoline and 20% lanet wax and 325 ml water to form about 1 kilogram of ointment cream carrier for said active ingredients. While the invention will now be described in connection with certain preferred embodiments in the following examples so that aspects thereof may be more fully understood and appreciated, it is not intended to limit the invention to these particular embodiments. On the contrary, it is intended to cover all alternatives, modifi¬ cations and equivalents as may be included within the scope of the invention as defined by the appended claims. Thus, the following examples which include preferred embodiments will serve to illustrate the practice of this invention, it being understood that the particulars shown are by way of example and for purposes of illus¬ trative discussion of preferred embodiments of the present invention only and are presented in the cause of providing what is believed to be the most useful and readily understood description of formulation procedures as well as of the principles and conceptual aspects of the invention.

Example 1

Two compositions according to the present invention were prepared in the following manner:

Preparation of the Base:

Vaseline (70%) was mixed with lanolin (20%) and lanet wax (10%) was added while heating at a temperature not exceeding 70 C and mixing constantly in order to maximize the homogenicity of the base. 30% water was added at 70 C. Active Ingredients: la) Per 100g ointment - 200 mg haleinonide

- 100 mg triamcinolene

lb) Forte, per lOOg ointment - 300 mg haleinonide

100 mg tri mcinolone

The above amounts of active ingredients were respectively mixed together with a mortar and pestle with the help of a drop of parafin. While mixing constantly the base was added drop by drop at first, then more rapidly, until a total amount of 100 gm was obtained.

Comparative Example 2 a) A comparative composition was prepared as in example 1, however having only 0.1% halcinonide and 0.1% triamcinolone actamide in the final composition. b) A comparative composition was prepared as in Example 1, having 0.3% halcinonide. c) A comparative composition was prepared as in Example 1 having 0.3% triamcinolone acetonide.

A volunteer patient having severe psoriasis over the entire body was treated at different sites with compositions la, lb and comparative compositions 2a, 2b and 2c. The observed results were as follows: Composition 2a - Some spots of the psoriasis disappeared, but not all, and where they did fade, pink color remained.

Composition 2b - No results - no improvement.

Composition 2c - Mo results - no improvement.

Composition 1a - Within one week of treatment the psoriasis on the entire area of treatment disappeared with skin returning to normal color except for a few isolated spots of original long established psoriasis. (These spots also disappeared upon treatment with composition lb).

Composition lb - Within one week of treatment the spots completely disappeared with skin returning to normal color and with no sign of previous psoriasis.

It should be noted that this experiment was performed on a subject with a serious case of psoriasis covering parts of the entire body and that while the prior art formulations in their maximum permitted dose had no appreciable effect, the compositions of the present invention effected a complete cure. Exampl e 3

Several volunteer patients suffering from psoriasis were treated with composition la as prepared in Example 1. The treatment was as follows:

Composition is applied twice a day for two weeks, morning and evening. A very small amount is used each time, massaged very well into the skin. If the psoriasis disappeared by the end of these two weeks, the patient continued use once a day for three weeks. If psoriasis did not completely disappear patient was given composition lb and treament given two times a day for two weeks and then once per day for three weeks.

The following results were observed:

Total success of the above treatments was achieved in 70% of the cases in which the psoriasis disappeared completely and did not return for the two year observation period. In the remaining 30%, there was marked improvement but when treatment was stopped, the psoriasis returned.

It is to be noted that on the one hand a combination of 0.1% halcinonide and 0.1% triamcinolone acetonide is insufficient to effect a cure of psoriasis, and on the other hand, combined amounts of active ingredients above 0.4% are inadvisable because they repress adrenaline. Combinations within that range, however,provided that the amount of halcinonide is greater than the amount of triamcinolone acetonide, are effective and contemplated for use according to the present invention.

It will be evident to those skilled in the art that the invention is not limited to the details of the foregoing illustrative examples and that the present invention may be embodied in other specific forms without departing from the essential attributes thereof, and it is therefore desired that the present embodiments and examples be considered in all respects as illustrative and not restrictive, reference being made to the appended claims, rather than to the fore¬ going description, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein.

Claims

WHAT IS CLAIMED IS:

1. A pharmaceutical composition comprising a synergistic combination of about 0.01-0.15% by wt. triamcinolone acetonide and about 0.04-0.3% by wt. halcinonide as active ingredients therein, in combination with a pharmaceutically acceptable carrier.

2. A pharmaceutical composition for treating psoriasis, comprising a synergistic combination of about 0.05-0.15% by wt. triamcinolone acetonide and about 0.2-0.3% by wt. halcinonide as active ingredients therein, in combination with a pharmaceutically acceptable carrier.

3. A pharmaceutical composition according to claim 2 , comprising about 0.1% triamcinolone acetonide and about 0.2% halcinonide.

4. A pharmaceutical composition according to claim 1, comprising a base of about 70% vaselin albun, 10% lanolene and 20% lanet wax and 325 ml water, to form about 1 kilogram of ointment cream carrier for said active ingredients.

5. A pharmaceutical composition comprising a synergistic combination of about 0.01-0.15% by wt. triamcinolone acetonide and about 0.04-0.3% by wt. halcinonide as active ingredients therein, in combination with a penetration enhancer as defined herein.