SK18652000A3 - PHARMACEUTICAL COMPOSITION ON THE BASIS OF ERYTHROMYCIN FATTYì (54) ACID SALTS FOR THE TOPICAL TREATMENT OF SKIN DISEASES - Google Patents

Abstract

The invention relates to a pharmaceutical composition which contains at least one erythromycin fatty acid salt with between 12 and 22 carbon atoms in the fatty acid rest and a liquid or viscous excipient. The invention also relates to the use of said erythromycin fatty acid salts for the topical treatment of skin diseases, in particular acne. The above pharmaceutical composition is characterized by good stability even when stored for an extended period, good penetration into the skin and high skin tolerance.

Description

Technical field

The invention relates to a pharmaceutical composition based on erythromycin fatty acid salts of 12 to 22 carbon atoms in the fatty acid residue, as well as the use of these erythromycin fatty acid salts for the topical treatment of skin diseases.

BACKGROUND OF THE INVENTION

Skin diseases, especially in adolescents, include acne. Acne is characterized by purulent skin rashes that appear predominantly on the face, neck, and chest. It is caused by infection of the enlarged sebaceous glands of the skin with Propionibacterium acnes, which are present on the skin surface. This leads to the formation of pus-filled blisters in the area of the sebaceous glands of the skin (Herder, Lexicon of Biology, Spektrum Akademischer Verlag, Heidelberg 1994, p. 87). An essential aspect of the formation and maintenance of acne is the formation of free fatty acids in the sebaceous gland follicle, which is induced by Propionibacterium acnes lipase. The causes of acne are many. In the case of the frequently occurring Acne vulgaris, for example, androgens stimulate sebum secretion and thereby promote the production of sebum. In the skin of acne patients, there appears to be an increased conversion of testosterone to actually effective dihydrotestosterone. Furthermore, bacterial secondary infections, hereditary and psychogenic diseases, as well as poor nutrition play a role in the development of acne. (Pschyrembel Klinisches Worterbuch, Walter de Gruyter, Berlin 1986, p. 13).

Since bacteria play an essential role in the release of irritating fatty acids and thus contribute substantially to the formation of acne, it has been suggested to be used in the treatment of antibiotics. In particular, the use of erythromycin is known. Eiytromycin, in addition to its low toxicity, is broadly effective against many Gram positive bacteria such as Streptococcus and Staphylococcus, as well as some Gram negative bacteria such as Neisseria and Haemophilus as well as against mycoplasmas (Rômpp Chemie-Lexikon, Georg Thieme) ·· ·· ·· ·· ··· ·························

-2Verlag, Stuttgart 1997, p. 1210). The main indication of erythromycin is papulopustular acne (Niedner, Ziegenmayer, Dermatika, Wissenschaftliche Verlagsgesellschaft 1992, p. 94). Under the influence of erythromycin, the amount of free fatty acids formed is reduced. Firstly, due to the antibacterial activity of erythromycin, the amount of bacteria is reduced, but secondly, a direct effect on lipase can also be demonstrated, with concentrations of erythromycin below the minimum inhibitory concentration (MHK) being inevitable. In addition, there is a reduction in leukocyte chemotaxis leading to a reduction in inflammation.

Treatment with antibiotics and especially erythromycin can be divided first into oral and second into external administration. Both erythromycin and erythromycin stearate are marketed in authorized oral formulations for the treatment of acne and skin infections. Although oral efficacy has good efficacy in combating acne, systemic administration has the disadvantage that the entire organism is burdened. Furthermore, in this use, the active ingredient is necessarily diluted throughout the body.

Because in external therapy, i. j. in the topical use of erythromycin, the antibiotic is administered topically, the above mentioned disadvantages of oral administration can be avoided. After external application of erythromycin, different penetration into the sebaceous gland occurs, with the iipophilic base penetrating better than the water-soluble salts. The problem with the treatment of erythromycin has so far been to maintain the stability of the formulation while at the same time penetrating the product well. The stability of topical erythromycin formulations has been the subject of various investigations. Thus GB-A-1 152 644 proposes a stable composition of erythromycin in oil, wherein the oil has 6 to 18 carbon atoms and an iodine number. In these lipophilic-based compositions, erythromycin is relatively stable, but the use of fatty carriers in the therapeutic treatment of acne is not particularly desirable as these compositions do not allow adequate antibiotic release. In addition, the composition does not enter the skin immediately. Because the skin of patients with acne is naturally oily, oil-containing ingredients do not constitute adequate carriers. Rather, the skin of an acne patient requires low fat preparations.

O / V (oil-in-water) creams or emulsions having a low fat content but a high water content are preferred vehicles for acne therapy. Due to the

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the skin of the appropriate properties of these formulations can be well absorbed by the skin of the antibiotic and are therefore particularly effective in the treatment of acne. However, investigations revealed that the efficacy of erythromycin in high water emulsions decreased by up to 60% of the baseline value at 25 ° C for one month (International Journal of Pharmaceutics 67, 195-199, 1991). Due to this instability of the aqueous erythromycin-based formulations and the reduced product shelf life, the industrial manufacture and sale of O / W-cream or erythromycin-based emulsions is not possible.

These investigations further show that the V / O (water-in-oil) emulsions retain an efficacy of greater than 90% of the initial value when stored for 12 weeks. Alcoholic solutions and alcoholic gels showed a slightly reduced shelf life, with a 10% loss in alcoholic solution for the first three weeks and a 20% loss in alcoholic gel after two months when stored at 25 ° C each. Furthermore, erythromycin was found to be particularly active in the alkaline region, but adjusting the pH to 0.5 had a detrimental effect on the activity of the active ingredient. Therefore, erythromycin-based drugs are offered for topical use almost exclusively in alcoholic carriers.

US-A-4 000 263 discloses an erythromycin-based solution with good storage stability, wherein the erythromycin is dissolved in a carrier consisting of propylene glycol, ethyl alcohol and polyoxyethylene-lauyl alcohol.

US-A-4 469 684 proposes a storage-stable composition in which erythromycin is in the form of its zinc salt in t-butanol.

DE-A-37 12 758 discloses a stable erythromycin-based anti-acne composition in which erythromycin is present in a pharmaceutically acceptable carrier comprising 20 to 99.5 wt. % of propylene glycol monoethylether or dipropylene glycol.

Other compositions are described in FR-A-7707785, FR-A-7732761 as well as in EP-A8020929, in which eiytromycin is also present in a carrier of a polyol, a higher aliphatic alcohol or a fatty acid ester.

All of these industrially manufactured topical erythromycin formulations therefore consist mainly of alcohol, respectively. alcoholic mixtures or anhydrous ointment bases. Thus, although these preparations are sufficiently stable, they have no desirable skin

-4 ···························································· The appropriate property of low-fat creams or emulsions, which are particularly suitable for the treatment of acne.

It is therefore an object of the present invention to provide a pharmaceutical composition for the treatment of skin diseases, in particular acne, which composition remains stable even after prolonged storage and exhibits high efficacy, good skin penetration as well as high skin tolerance. In order to avoid the known known disadvantages of oral administration of antibiotics, this composition should preferably be used topically.

SUMMARY OF THE INVENTION

This object is solved according to the invention by a pharmaceutical composition comprising at least one erythromycin salt of a C 12 -C 22 fatty acid in the fatty acid residue and a liquid or viscous carrier.

The present invention further relates to the use of erythromycin salts of C 12 -C 22 fatty acids in the fatty acid residue for the topical treatment of skin diseases.

Surprisingly, it has been found that the erythromycin salt of C1222 fatty acid used according to the invention can be used instead of the commonly used erythromycin as a free base for topical treatment.

Clarithromycin salt C ₂ -22 fatty acid, which is used according to the invention may comprise a saturated or unsaturated, and branched or unbranched fatty acids, and mixtures thereof. Preferred examples of useful fatty acids are myristic acid, palmitic acid, lauric acid and stearic acid. Especially preferably, erythromycin stearate is used as the active ingredient in the pharmaceutical composition of the invention.

Erythromycin salts of C 12-22 fatty acids can be prepared by conventional procedures in a manner known per se. For example, the erythromycin base isolated from Streptomyces erythreus culture can be dissolved in an organic solvent such as acetone. Subsequently, the solution obtained is mixed with a fatty acid or a mixture of fatty acids. A virtually pure fatty acid erythromycin salt precipitates.

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The pharmaceutical composition comprises a erythromycin salt of a C 12-22 fatty acid in a pharmaceutically effective amount. In particular, the erythromycin salt of the C 12-22 fatty acid is preferably used in an amount of from 0.5 to 10 wt. %, even more preferably from 1 to 5 wt. %, based on the total amount of the pharmaceutical composition. As was surprisingly found, the effectiveness of the erythromycin salt of a C ₂ -22 fatty acid in an amount, increased the proportion of a fatty acid, such that exactly one of erythromycin free base in the same vehicle. Therefore, the use of this derivative does not lead to a loss of efficacy in the treatment of acne.

In addition to the active ingredient, the erythromycin salt of the C12.22 fatty acid, the pharmaceutical composition comprises a liquid or viscous carrier which can be selected from conventional pharmaceutical carriers. Preferably, the carrier is selected such that the composition obtained is suitable for topical application. It is particularly preferred that the carrier exists in the form of an emulsion, suspension, cream or gel to allow problem-free application of the composition to the skin. It is particularly preferred that the carrier has a very low fat content and a high water content. Particularly preferred are low fat creams or emulsions, such as O / W-creams or emulsions, but also dosage forms with extremely high water content, such as gels. The proportion of water is usually at least about 40%, but for pure aqueous carriers a proportion of water of almost 100% is possible. Particularly preferred is a water content of from 60 to almost 100%, since the composition in this way particularly absorbs the skin.

Fats such as oils and waxes as well as alcohols may be present as further carrier components in the composition of the invention. When an O / V cream or emulsion is used, the lipid component may be selected from cetearyl octanoate, decyl oleate, medium chain triglycerides, glyceryl monostearate, stearic acid, cetyl alcohol, liquid wax esters, isopropyl myristate and cetyl palmitate. Particular preference is given to using cetearyl octanoate, glycyl monostearate, cetyl alcohol and medium chain triglycerides.

The pharmaceutical composition may, on the one hand, be creamy and / or creamy. paste-like character, but may also have a liquid, gel-like consistency. It preferably allows rapid penetration into the skin and sebaceous glands.

In addition to the ingredients, the formulation may contain other pharmaceutically acceptable ingredients such as preservatives, flavoring agents, antioxidants,

-6 ···································· Blowing agents, dyes and / or pigments. However, both the carrier and the other ingredients are not particularly limited as long as they do not affect the effect of the erythromycin salt of the C 12-22 fatty acid.

The pharmaceutical composition may contain, in addition to the erythromycin salt of the C 12,22 fatty acid, other active substances which are suitable for the treatment of skin diseases. Examples of these active ingredients are not particularly limited insofar as they do not affect the effect of the erythromycin salt of a C 12-22 fatty acid. As further active ingredients, the composition according to the invention may contain, for example, adapalene, isotretinoin, tretinoin, metronidazole, benzoyl peroxide, triclosan, hexachlorophene, estradiol, clotrimazole, ketoconazole, miconazole, croconazole, azelaic acid, spironolactone, cyproterone acetate, chlormadoketol acetate.

The pharmaceutical composition of the invention may be prepared in a conventional manner. Depending on the type of preparation (e.g. liquid emulsion, cream, gel), the individual components, in particular the liquid carrier and the active substance, are bonded to one another. If lipid components are used, these are usually added to the aqueous phase components. In order to improve the mixing of the two phases, the fat phase or the aqueous phase may be heated. Both phases are particularly preferably heated prior to coupling. The temperature depends on the ingredients, but is usually 30 ° C to 90 ° C, preferably 40 ° C to 80 ° C. It is further preferred that the fat phase is slowly added to the aqueous phase with stirring or homogenization. The erythromycin salt of C 12-22 fatty acid may be incorporated after the combination of the fatty and aqueous soybean. Before addition of the active ingredient, the mixture is typically cooled to a temperature of 20 DEG C. to 40 DEG C., preferably 25 DEG C. ^c Caž35.

Erythromycin salt of a C ₂ -22 fatty acids may be used according to the invention for topical treatment of skin disorders, in particular acne.

The invention is illustrated by the following examples. However, it should not be limited to them.

DETAILED DESCRIPTION OF THE INVENTION

Examples of compositions

Example 1:

Example 2:

Example 3:

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erytromycínstearát 6,12 g decyl 15,00 g glyceryl stearate 10,00 g stearic acid 4,00 g ceteareth-3 ?? 2,50 g tronietamin 0.50 g Cera Alba 0.50 g perfume 0.50 g preservative q.s.. ??

water to 100.0 g

Cream of nonerythromycin erytromycínstearát 3,0 g cetearyl octanoate 8,0 g cetomacrogol 300 3,0 g cetomacrogol 1200 1.5 g glyceryl 3,0 g cetyl alcohol 3,0 g dimethicone 100 0.5 g 1,2-propylene glycol 4.0 g preservative qs water ad 100.0 g Erythromycin cream erytromycínstearát 6,0 g glyceryl 8,0 g neutral oil 5.0 g stearic acid 2,0 g glyceryl 9,0 g preservative qs

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· · · · · · • · · • • • • • • • • · • · • • · · · • • • · • · • • • • · • · • ··· · • · · • • · · · · · · • · · • · ·

glycerin water

3.0 g and 100.0 g

Example 4: Liquid emulsion erytromycinstearát 4.0 g cetomacrogol 300 1.5 g cetomacrogol 1200 1.5 g cetearyl octanoate 4.0 g glyceryl 2.5 g cetyl alcohol 1.5 g 1,2-propylene glycol 3,0 g preservative qs

water to 100.0 g

Example 5: Erythromycin / triclosan cream erythromycinstearate

4.0 g triclosan

0.5 g

glycerol monostearate 10,0 g neutral oil 8,0 g emulsifying cetyl stearyl alcohol 1 5.0 g 1,2-propylene glycol 3,0 g preservative qs Water ad 100.0 g

Example 6: Erythromycin / miconazole cream

erytromycinstearát 6,0 g mikonazolnitrát 2,0 g glycerol monostearate 8,0 g neutral oil 5.0 g stearic acid 2,0 g

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glyceryl monoricin oleate preservative glycerin water 9.0 g q.s. 3,0 g ad 100.0 g Example 7: Erythromycin / adapalene cream erytromycinstearát 6,0 g adapalene 0.1 g cetearyl octanoate 8,0 g cetomacrogol 300 3,0 g cetomacrogol 1200 1.5 g glycerol 3,0 g cetyl alcohol 3,0 g dimeticon 100 0.5 g BHT ?? 0,04 g 1,2-propylene glycol 4.0 g preservative qs Water ad 100.0 g

Example 8: Erythromycin / isotretinoin cream

erytromycinstearát 6,0 g izotretionin 0.05 g cetearyl octanoate 8,0 g cetomacrogol 300 3,0 g cetomacrogol 1200 1.5 g glycerol 3,0 g cetyl alcohol 3,0 g dimethicone 100 0.5 g BHT 0,04 g 1,2-propylene glycol 4.0 g

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- 10 Preservative q. with.

water to 100.0 g

Example 9: Erythromycin / tretinoin cream

erytromycinstearát 6,0 g tretionin 0.05 g cetearyl octanoate 8,0 g cetomacrogol 300 3,0 g cetomacrogol 1200 1.5 g glycerol 3,0 g cetyl alcohol 3,0 g dimethicone 100 - 0.5 g BHT 0,04 g 1,2-propylene glycol 4.0 g

preservative

qs

water to 100.0 g

2, Preparation of the preparation

A formulation containing the ingredients of Example 3 (erythromycin cream) was prepared as follows.

Fat phase substances, e.g. j. glycerol monostearate, neutral oil, stearic acid, giyceryl monoricin oleate and glycerin were weighed together and heated to 75 ° C. The components of the aqueous phase, i. j. water and preservative were also heated to 75 ° C. When both phases reached this temperature, the fat phase was slowly added to the aqueous phase with stirring or homogenization. The resulting emulsion was cooled with stirring. At about 30 ° C, erythromycin stearate was incorporated to obtain an erythromycin cream.

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99

999 ··

99

99

999

3. Stability tests

A formulation of 6.12 wt. % of erythromycin stearate (corresponding to 4.0 wt% erythromycin base) in the O / W-cream was stored at 25 ° C for 6 months. As can be seen from Table 1, there was no significant decrease in content and thus efficiency.

Table 1 (calculated as erythromycin base)

Default ¹ value  2 weeks 1 month 2 months 6 months 4,01% 3.86% 3.86% 3.89% 3.91% 100.00% 96,30% '96,30% 97.00% 97.50%

Claims (8)

PATENT CLAIMS A pharmaceutical composition comprising at least one erythromycin salt of a C 12 -C 22 fatty acid in a fatty acid residue and a liquid or viscous carrier. Pharmaceutical composition according to claim 1, characterized in that the erythromycin fatty acid salt is erythromycin stearate. Pharmaceutical composition according to any one of claims 1 or 2, characterized in that the carrier is in the form of an emulsion, suspension, cream or gel. Pharmaceutical composition according to any one of claims 1 to 3, characterized in that the carrier comprises water. Pharmaceutical composition according to any one of claims 1 to 4, characterized in that the composition comprises 0.5 to 10 wt. % erythromycin fatty acid salt. Pharmaceutical composition according to claim 5, characterized in that the composition contains 1 to 5 wt. % erythromycin fatty acid salt. Use of erythromycin salts of C 12 -C 22 fatty acids in the fatty acid residue for topical treatment of skin diseases. Use according to claim 7 for the treatment of acne.