SK281616B6 - Topic pharmaceutical composition - Google Patents

Abstract

Disclosed is a topic pharmaceutical composition based on the antimycotically effective allyl amine of the formula (I) in the form of the soluble gel or lotion, substance of which consists in containing of the effective substance composed of the allyl amine of the formula (I) in the form of the free base or in the form of addition salt with an acid, oil phase composed of the isopropylmyristate, alcanol containing 1 to 4 carbon atoms and carbomeric thicke ning. The composition is intended for the treatment of the fungal infections.

Description

Technical field

The present invention relates to a topical pharmaceutical composition in the form of an emulsion gel or lotion, for the treatment of fungal infections, comprising, as an active ingredient, a compound of formula (I)

BACKGROUND OF THE INVENTION

The compound of formula (I) is known, for example, from BE-PS-853976 and EP-A-24587. The compound belongs to the class of antimycotically active allylamines. It has the generic name terbinafme and is commercially available under the name Lamisil. Although terbinafme is highly effective in topical and oral administration, it has been found that the only topical formulation for all-purpose use, a cream in which the active ingredient is dissolved in the organic phase, only partially meets the patient's requirements and is suitable for specific skin diseases and only some skin types.

In view of the foregoing, it is desirable to find a topical composition which, when compared to conventional topical formulations such as creams, provides some advantages when applied, including in particular that:

- releases the active substance more quickly and completely from the vehicle into the skin and is thus more effective,

- there is no grease or other undesirable residue on the skin after application and is therefore particularly suitable for application to the skin covered by hair,

- is more easily spreadable on the skin and is therefore suitable for application to larger areas of the skin, and

- cools when applied and is also suitable for application to seborrheic (seborrhoic) skin.

However, the preparation of topical compositions providing the above advantages is difficult because the compound of formula (I) has poor solubility in aqueous systems when used in the form of an acid addition salt or in the form of an oil-based emulsion gel or lotion. tends to separate from the composition as a free base in the form of droplets or even in crystalline form, since the free base has been found to be less soluble in water than the corresponding acid addition salt and that the active ingredient tends to interact with anionic excipients . Thus, the use of a compound of formula (I) in the form of an acid addition salt is desirable and is also a preferred embodiment of the invention since this can improve the solubility of the active ingredient in aqueous systems. Since the separation of the free base from the equilibrium state formed in the compositions of the invention presents a serious problem with regard to the reproducibility of the pharmaceutical effect and the durability of such a composition.

These difficulties are exacerbated when single-phase formulations such as fluid gels and gels containing the compound of formula (I) in free base form or in acid addition salt form in one and the same phase in combination with conventional carbomeric thickeners are to be prepared. (polyacrylic acid derivatives), which are typical gel adjuvants. It has now been found that there is an interaction of the components resulting in the formation of an insoluble complex or crystallization of the base. There is a need for improved topical forms of this type, for example, fluid gels and gels.

As indicated above, this problem may be solved by formulating an emulsion system in which the free base is dissolved in the oil phase. However, such systems may not be suitable for some skin types and some skin diseases, as in many cases, fat-free formulations such as fatty acids, fatty acid esters and fatty alcohols such as polyethylene stearates or palminates, cetyl stearates are preferred. or palminates, stearyl or cetyl alcohols. Also highly desirable is a topical formulation of a clear solution. Thus, there is a need for improved water-based formulations of the above type that are free of oils or fats and in which the free base present in equilibrium remains in solution.

SUMMARY OF THE INVENTION

The invention provides a topical pharmaceutical composition based on an antifungal active allylamine of formula (I)

in the form of an emulsion gel or lotion, which comprises an allylamine active compound of the formula (I) in the form of the free base or in the form of an acid addition salt, an isopropyl myristate oily phase, a C 1 -C 4 alkanol and a carbomer thickener .

This composition preferably comprises the allylamine of formula (I) and the oil phase in a weight ratio of 1: 5 to 1:40. Preferably, it comprises the compound of formula (1) in an amount of 0.1 to 5% by weight. It further preferably comprises water, the amount of alkanol, water and oil phase being 83 to 96% by weight, based on the weight of the composition. The composition preferably comprises ethanol as the alkanol and preferably contains the allylamine of formula (I) in the form of the free base.

If it is desirable to obtain a carbomeric thickening emulsion gel or lotion to administer a compound of formula (1) to the skin, there are problems resulting from the interaction of the free base with the anionic polymer, which are substantially the same as those described above. solutions. It has been found that these interactions can be avoided and that stable emulsion gels and lotions can be obtained when an oil phase such as isopropyl myristate is added to the compound of formula (I), preferably in the form of the free base and the carbomer thickener. This results in the formation of a stable emulsion gel and lotion having all the good gel properties while avoiding undesired interaction of the active ingredient with the carbomer thickener.

In the emulsion gels and lotions of the invention, the compound of formula (I) and the oil phase are present in a weight ratio of from about 1: 5 to about 1:40, preferably from about 1: 7 to about 1:20. The oil phase is preferably isopropyl myristate. This phase is preferably present at a concentration of 10% by weight.

The compound of formula (I) constitutes about 0.1 to about 5%, more preferably about 0.5 to about 3% by weight of the total weight of the composition. The preferred amount of the lower alkanol, water and optionally oil phase present is about 83 to about

286% by weight of the total weight of the composition. Other conventional excipients are, in particular, thickeners, such as carbomeric thickeners (polyacrylic acid derivatives), which are known and commercially available under the designation Carbopol (Fiedler 1, pp. 206-207), for example Carbopol 934 P or Carbopol 1342. Other excipients are, for example, emulsifiers such as sorbitan monolaurate (Span 20) and polysorbate 20 (Tween 20). Since carbomers have been observed to stabilize the emulsion with the compound of formula (I) to a sufficient extent, only a small amount of emulsifier or no emulsifier is required to achieve a stable emulsion gel or lotion, particularly when using Carbopol 1342 carbomeric thickener. absolutely necessary.

The resulting emulsion gels and lotions have improved cosmetic properties, in particular in that they more easily spread on the skin and do not leave grease on the skin; due to the reduced content or absence of conventional emulsifiers, these emulsion gels or lotions have better pharmacological properties, in particular better skin tolerance, especially when applied to infected or inflamed skin. A further advantage achieved by the invention is that the appearance and consistency of the final formulation can be easily and extensively controlled by the content of a thickening agent (carbomer) in the formulation.

The emulsion gels and lotions of the invention may be obtained by a process comprising dissolving the compounds of formula (I) in free base or acid addition salt form and optionally other excipients in, for example, a suitable oil phase such as isopropyl myristate.

The oily phase may be emulsified in a suitable aqueous phase and then incorporated into a preformed gel concentrate containing the carbomer and other optional excipients. In this way, the interaction between the compound of formula (I) and the carbomer during the preparation of emulsion gels and lotions is avoided. Preferably, the carbomer is neutralized with an oil phase prior to mixing.

Said additives may contain further additives, for example

- complexing agents, such as ethylenediaminetetraacetate (disodium salt),

flavoring additives, and

coloring additives.

The compositions of the invention may also contain conventional ingredients to adjust the pH to a value that is acceptable for skin care. This can be achieved by adding a pharmaceutically acceptable base or acid and adjusting the pH or adding a pharmaceutically acceptable buffer system to the composition. In addition, these compositions may contain preservatives and / or antioxidants such as ascorbyl palmitate, sodium bisulfite, butylhydroxyanisole (BHA), butylhydroxytoluene (BHT), tocopherols such as α-tocopherol (vitamin E), benzyl alcohol and propyl or methyl-p- hydroxybenzoate, the amount of these additives being, for example, from 0.05 to 1%, based on the total weight of the composition.

The compositions of the invention are indicated for the same types of diseases for which other topical compositions are used, for example, for the treatment of fungal infections, and are used at doses as determined, for example, by standard clinical trials. Typical dosages are obtained when the concentration of active ingredient on the treated skin is in the range of 10 to 10,000 ng per centimeter of square skin. Preferred concentrations of the active ingredient on the skin are in the range of 500 to 2000 ng per centimeter of square skin, for example 1000 ng of active ingredient per centimeter of square skin. Higher or lower doses of the active ingredient can also be effective, which can be determined by standard tests. For example, an effective concentration of the active ingredient in the treated skin may be achieved when a compound of formula (I) is applied to the infected skin, for example in the form of a 1% composition, e.g. 5 mg of active ingredient per day and a skin area of about 100 square centimeters.

In the following, the invention will be explained in more detail by means of specific examples thereof, the examples being for the purpose of illustration only and are not to be construed as limiting the scope of the invention as defined by the claims.

DETAILED DESCRIPTION OF THE INVENTION

Example 1% emulsion gel

Component Content (g / 100 g)

A. A compound of formula (I) in the form of 1.00 free base

C. Butylhydroxytoluene 0.02

I. Sodium hydroxide pellets0.10

D. Benzyl alcohol0,50

G. Carbomer 934 (e.g. Carbomer 934 P) 1.00

E. Sorbitan monolaurate (e.g. Span 20) 1.00

F. Polysorbite 20 (e.g., Tween 20) 5.00

H. 94% Ethanol (w / w) 10.00

B. Isopropyl myristate 10.00

Demineralized water71,33

A pharmaceutically acceptable emulsion gel is prepared from the above ingredients as follows:

I. components A, B, C, D, E and F are combined and mixed under gentle heating until all solid particles are dissolved;

II. about half of the total water is heated to 60-70 ° C in a suitable vessel equipped with a stirrer and homogenizer;

III. I is slowly added to II with stirring and homogenization until a homogeneous emulsion with a suitable emulsion droplet size is obtained; the concentrated emulsion is then cooled to room temperature;

IV. in a separate vessel, a base carbomer gel is prepared by dispersing said carbomer thickener in component Hav with the other half of the water and neutralizing component I;

The base emulsion III is added to the base gel and the resulting mixture is stirred at room temperature until a homogeneous emulsion gel is obtained.

Example 2 1% lotion

component Content (g / 100 g) A. A compound of formula (I) in the form 1.00 free principle C. Propyl p-hydroxybenzoate 0.03 D. Methyl p-hydroxybenzoate 0.10 G. 25% ammonia solution (w / w) 0.36 F. Carbomer (eg Carbopol 1342) 0.60 B. Isopropyl myristate 5.00 H. 94% Ethanol (w / w) 10.00 E. Demineralized water 82.91

The topical pharmaceutical composition of claims 1 to 3, further comprising water, wherein the amount of alkanol, water and oil phase is 83 to 96% by weight based on the weight of the composition.

A topical pharmaceutical composition according to claims 1 to 4, wherein the alkanol is ethanol.

Topical pharmaceutical composition according to claims 1 to 5, characterized in that it contains the allylamine of formula (I) in the form of the free base.

End of document

A pharmaceutically acceptable lotion is prepared from the above ingredients as follows:

I. component A is dissolved in component B at room temperature;

II. in a suitable vessel equipped with a stirrer and an efficient homogenizer, components C and D are dissolved in component E with heating up to 90 ° C; the solution obtained is then cooled to a temperature of about 30 to 40 ° C;

III. component F is dispersed in the solution obtained in step II; the homogeneous dispersion is then neutralized with component G to give a opalescent, concentrated solution;

IV. the organic solution of step I is then emulsified in the thickened solution of step III by stirring and homogenizing until a lotion with an appropriate emulsion droplet size is obtained;

V. Finally, component H is added to the lotion of step IV and the mixture is stirred until the final product is obtained.

Examples 3 and 4

Topical pharmaceutical compositions are prepared which are analogous to the compositions prepared in Examples 1 and 2, which differ from these compositions in that isopropanol is used instead of ethanol in their preparation.

Claims (3)

PATENT CLAIMS A topical pharmaceutical composition based on an antifungal active allylamine of formula (I) in the form of an emulsion gel or lotion, characterized in that it comprises an active substance consisting of allylamine of formula (I) in free base or acid addition salt form, an oily phase formed isopropyl myristate, a C 1 -C 4 alkanol, and a carbomer thickener. Topical pharmaceutical composition according to claim 1, characterized in that it contains the allylamine of formula (I) and the oil phase in a weight ratio of 1: 5 to 1:40. Topical pharmaceutical composition according to claims 1 and 2, characterized in that it contains allylamine of formula (I) in an amount of 0.1 to 5% by weight, based on the total weight of the composition.