HRP20000884A2 - Pharmaceutical preparation on the basis of erythromycin-fatty acid salts with 12 to 22 carbon atoms in fatty acid residue and application of such erythromycin-fatty acid salts for topical treatment of skin diseases - Google Patents

Description

The presented invention relates to pharmaceutical preparations based on salts of fatty acids with from 12 to 22 carbon atoms and erythromycin and the use of these salts of fatty acids and erythromycin in the local treatment of skin diseases.

Acne is one of the most common skin diseases, especially among young people. Acne is recognized by a purulent skin rash, which mainly appears on the face, neck and chest. Infection of enlarged sebaceous glands is caused by Propionibacterium acnes, which are found on the surface of the skin. Because of this, pus bubbles form in the area of the sebaceous glands of the skin (Herder, Lexion der Biologie, Spektrum Akademische Verlag, Heidelberg, 1994, S. 87). An important aspect for the formation and maintenance of acne is the formation of fatty acids in the follicle of the sebaceous gland, which is caused by the lipase of Propionibacterium acnes. The reason for the formation of acne is multiple. For example, in the case of the most common acne vulgaris, the androgenic glands stimulate the secretion of sebum and in this way promote their formation. At the same time, the skin of acne sufferers often undergoes a multiple transformation of testosterone into effective dihydrotestosterone. Furthermore, bacterial secondary infections, hereditary and physiological factors, as well as poor nutrition play an important role in the formation of acne (Pschyrembel Klinisches Wörterbuch, Walter de Gruyter, Berlin, 1986, S. 13).

Given that bacteria play an important role in the release of irritable fatty acids, and are therefore significantly involved in the formation of acne, it has been suggested that antibiotics be used in the treatment. The role of erythromycin is particularly well known. With low toxicity, erythromycin has a broad action against a large number of gram-positive bacteria, such as Streptococcus and Staphylococcus, as well as gram-negative bacteria, such as neisseria and haemophilus, and against mycoplasmas (Römpp Cmemie-Lexiokon, Goerg Thieme Verlag , Stuttgart, 1997, p. 1210). The main indication of erythromycin is acne-papulo-pustulosis (Niedne, Ziegenmayer, Dermatika, Wissenschaftliche Verlagsgesellschaft, 1992, p. 94). Under the influence of erythromycin, the amount of formed fatty acids decreases. On the one hand, the number of bacteria is reduced based on the antibacterial effect of erythromycin, and on the other hand, a direct effect on lipase can be demonstrated, whereby erythromycin concentrations below the minimum heme concentration (MHK) are required. In addition, leukocyte chemotaxis decreases, which leads to relief of inflammation.

Treatment with antibiotics can be divided into oral administration and external administration. Erythromycin and erythromycin stearate for oral use are on the market in approved medicines for the treatment of acne and skin infections. Although oral application achieves a good effect on acne control, systematic application has a disadvantage because it burdens the entire organism. Furthermore, with this application, the active substance is forcibly diluted in the body.

Given that with external therapy, which means local application of erythromycin, the antibiotic is applied locally, the aforementioned disadvantages of oral administration can be avoided. After external application of erythromycin, there is a different penetration into the sebaceous gland, whereby lipophilic bases penetrate better than water-soluble salts. The problem so far in treatment with erythromycin appeared in maintaining the stability of the preparation with good simultaneous penetration of the product. The stability of topical preparations with erythromycin has been the subject of many studies so far. Thus, GB-A-1 152 644 describes a stable preparation with erythromycin in oil, where the oil has from 6 to 18 carbon atoms, and its iodine number is below 42. With these compounds on a lipophilic base, erythromycin is relatively stable, although the application fatty vehicles in the therapeutic treatment of acne is not particularly desirable, because they do not allow the appropriate release of antibiotics from the preparations. The latter do not allow immediate penetration of the preparation into the skin. Given that the skin of patients suffering from acne is oily by itself, oily ingredients are not suitable foundations. Low-fat preparations are much more suitable for the skin of patients with acne.

A suitable vehicle for the active substances used in the treatment of acne are U/V (oil in water) creams or emulsions that have only a small proportion of fat and a large proportion of water. Considering the good properties of these preparations, it is possible to absorb antibiotics well into the skin, and they are particularly effective in the treatment of acne. However, tests showed that the efficacy of erythromycin in emulsions with a high water content, when stored at 25 °C for 1 month, dropped to 60% of the initial value (International Journal of Pharmaceuticals, 67 (1991) 195-199). Due to the instability of aqueous preparations based on erythromycin, and as a result the limited durability of the products, industrial production and placing on the market of U/V creams and emulsions based on erythromycin is not possible.

These tests further showed that W/O (water-in-oil) emulsions retain more than 90% of their initial efficacy when stored for 12 weeks. Alcoholic solutions and alcohol gels were slightly less durable, where when stored at 25 °C the alcohol solution had a loss of 10% during the first three weeks, while the alcohol gels showed a loss of 20% after two months. Furthermore, erythromycin was found to be particularly effective in an alcoholic environment, although adjusting the pH value to 8.5 has a detrimental effect on the action of the active substance. Accordingly, erythromycin-based drugs for local use almost exclusively have an alcohol vehicle.

US-A-4 000 263 describes an erythromycin-based solution with good storage stability, wherein the erythromycin is dissolved in a carrier consisting of propylene glycol, ethanol, and polyoxylene-lauryl alcohol.

US-A-4 469 684 proposes a storage-stable composition in which erythromycin appears as a zinc salt in t-butanol.

DE-A-37 12 758 describes stable anti-acne preparations based on erythromycin, in which erythromycin is contained in a pharmaceutically acceptable base containing from 20 to 99.5% by weight of monomethylether propylene glycol or dipropylene glycol.

Further preparations are described in FR-A-7707785, FR-A-7732761, as well as in EP-A8020929, in which also erythromycin is contained in a polyol, fatty alcohol or fatty acid base.

For these reasons, all these industrially prepared local preparations of erythromycin consist mainly of alcohol or alcohol mixtures, and anhydrous fatty bases. In this way, these preparations have a satisfactory stability, but they do not possess the desired skin-friendly properties that creams with a low fat content or emulsions have, and which are particularly suitable for the treatment of acne.

Therefore, the task of this invention is to prepare such a pharmaceutical preparation for the treatment of skin diseases, especially acne, whereby the preparation remains stable even in a long period of storage, and has a high effect, good penetration into the skin, as well as being well tolerated by the skin. In order to avoid the aforementioned disadvantages of oral administration, it is necessary to apply the preparation locally, if possible.

This task according to the present invention is solved using a pharmaceutical mixture containing at least one salt of erythromycin and a fatty acid with from 12 to 22 carbon atoms in the part related to the fatty acid, and a liquid, viscous carrier.

Furthermore, this invention relates to the use of salts of fatty acids and erythromycin with from 12 to 22 carbon atoms in the part related to the fatty acid in the treatment of skin diseases.

Quite surprisingly, it has been found that the C12-22-salt of fatty acid and erythromycin of this invention can be used for local application instead of the previously common erythromycin in the form of the free base.

The erythromycin derivative, which according to this invention is administered in the form of a C12-22 fatty acid salt, can contain saturated and unsaturated, as well as branched and unbranched fatty acids and their mixtures. Suitable examples of fatty acids used are myristic acid, palmitic acid, lauric acid and stearic acid. A particularly suitable active substance is erythromycin stearate, which is included in the pharmaceutical preparation of this invention.

The C12-22-salts of fatty acid and erythromycin can be produced according to usual procedures in a manner peculiar to itself. For example, erythromycin base, isolated from a culture solution of Streptomyces erythreus, can be dissolved in an organic solvent such as acetone. After that, a fatty acid or mixture of fatty acids is added to the resulting solution. In doing so, a practically pure salt of fatty acid and erythromycin is obtained.

The pharmaceutical preparation contains C12-22 fatty acid salt and erythromycin in a pharmaceutically effective amount. It is particularly suitable for the C12-22-salt of fatty acid and erythromycin to be applied in the range of 0.5 to 10% by weight, or even more preferably from 1 to 5% by weight, based on the total amount of the pharmaceutical preparation. Quite surprisingly, it was found that the action of the C12-22-salt of fatty acid and erythromycin, with an increased amount of fatty acid, is the same as with erythromycin in the form of a free base, with the same carrier. Therefore, the use of this derivative does not lead to a reduction in the effectiveness of acne treatment.

In addition to the active substance, the C12-22 fatty acid salt and erythromycin, the pharmaceutical preparation also contains a liquid or viscous carrier. First of all, the carrier is selected so that the resulting preparation is suitable for local application. It is particularly suitable for the carrier to be in the form of an emulsion, suspension, cream or gel, in order to enable problem-free application of the preparation to the skin. It is particularly suitable for the carrier to have a low proportion of fat and a high proportion of water. Creams or emulsions with a low fat content, such as U/W creams and emulsions, as well as products with an extremely high water content, such as gels, are particularly suitable. It is usual for the proportion of water to be at least around 40%, although with pure water carriers a proportion of almost 100% water is also possible. Preparations with a water content of 60 to 100% are particularly advantageous, as they are then absorbed particularly well into the skin.

Other components of the vehicles of the preparations of this invention are fats, for example oils, waxes, and alcohols. If a U/W-cream or emulsion is used, then the lipid component is selected from the group consisting of cetearyl octanoate, decyloctanoate, medium-long triglycerides, glyceryl monostearate, stearic acid, cetyl alcohol, liquid waxes, isopropyl myristate and cetyl palmitate. Particularly suitable are cetearyl octanoate, glyceryl monostearate, cetyl alcohol and medium-long triglycerides.

A pharmaceutical preparation can have the characteristics of a cream or paste on the one hand, or a liquid consistency or a gel consistency. It enables convenient, quick penetration into the skin and into the sebaceous glands.

In addition to the listed ingredients, the pharmaceutical preparation may contain further pharmaceutically acceptable substances, such as preservatives, fragrances, antioxidants, buffers, dyes, and/or pigments. Neither the carrier nor further additives are particularly limited, as long as they do not affect the action of the C12-22 fatty acid salt and erythromycin.

In addition to the C12-22 fatty acid salt and erythromycin, the pharmaceutical preparation may contain further active substances that are suitable for the treatment of skin diseases. Examples of these active substances are not particularly limited, as long as they do not affect the action of C12-22 fatty acid salts and erythromycin. Further active substances that the preparation of this invention may contain are adapalene, isotretinoin, tretinoin, metronidazole, benzoyl peroxide, triclosan, hexachlorophene, estradiol, clotrimazole, miconazole, croconazole, azelaic acid, spironolactone, cyproterone acetate, chlormadinoacetate, cioctol, and their mixtures.

The pharmaceutical composition of the present invention can be prepared in conventional ways. Depending on the type of preparation (e.g. liquid emulsion, cream, gel), individual ingredients, especially the liquid carrier and the active substance, are connected to each other. When lipid ingredients are used, they are then usually added to the aqueous phase. In order to improve the mixing of both phases, the fat or water phase can be heated. It is particularly convenient to heat both phases before bringing them into contact. The temperature depends on the ingredients, and is usually from 30 °C to 90 °C, or more suitable from 40 °C to 80 °C. Furthermore, it is convenient if the fatty phase is added to the aqueous phase, with slow mixing or homogenization. The C12-22-salt of the fatty acid and erythromycin can be added after contacting the fatty and aqueous phases. Before adding the active substance, the resulting mixture is usually cooled to a temperature of 20 °C to 40 °C, or more conveniently from 25 °C to 35 °C.

The C12-22 fatty acid and erythromycin salts of the present invention can be used for topical treatment of skin diseases, especially acne.

The following examples illuminate the invention in more detail. The invention should not be limited only to them.

1. Examples of preparations

Example 1: erythromycin stearate 6.12 g

children loleat 15.00 g

glyceryl stearate 10.00 g

stearic acid 4.00 g

ceteareth-3 2.50 g

tromethamine 0.50 g

cera alba 0.50

fragrance 0.50 g

sufficient amount of preservative

water up to 100.0 g

Example 2: Cream containing erythromycin

erythromycin stearate 3.0 g

cetearyl octonate 8.0 g

cetomacrogol 300 3.0 g

cetomacrogol 1200 1.5 g

glycerol monostearate 3.0 g

dimethicone 100 0.5 g

1,2-propylene glycol 4.0 g

sufficient amount of preservative

water up to 100.0 g

Example 3: Erythromycin cream

erythromycin stearate 6.0 g

glycerol monostearate 8.0 g

neutral oil 5.0 g

stearic acid 2.0 g

glyceryl monoricinoleate 9.0 g

sufficient amount of preservative

glycerin 3.0 g

water up to 100.0 g

Example 4: Liquid emulsion

erythromycin nstearate 4.0 g

cetomacrogol 300 1.5 g

cetomacrogol 1200 1.5 g

cetearyl octonate 4.0 g

glycerol monostearate 2.5 g

cetyl alcohol 1.5 g

1,2-propylene glycol 3.0 g

sufficient amount of preservative

water up to 100.0 g

Example 5: Erythromycin/triclosan cream

erythromycin stearate 4.0 g

triclosan 0.5 g

glycerol monostearate 10.0 g

neutral oil 8.0 g

emulsifying cetylstearyl alcohol 5.0 g

1,2-propylene glycol 4.0 g

sufficient amount of preservative

water up to 100.0 g

Example 6: Erythromycin/miconazole cream

erythromycin stearate 4.0 g

miconazole nitrate 2.0 g

glycetol monostearate 8.0 g

neutral oil 5.0 g

stearic acid 2.0 g

glyceryl monoricinoleate 9.0 g

sufficient amount of preservative

glycerin 3.0 g

water up to 100.0 g

Example 7: Erythromycin/adapalene cream

erythromycin stearate 6.0 g

adapalene 0.1 g

cetearyl octonate 8.0 g

cetomacrogol 300 3.0 g

cetomacrogol 1200 1.5 g

glycerol monostearate 3.0 g

cetyl alcohol 3.0 g

dimethicone 100 0.5 g

BHT 0.04 g

1,2-propylene glycol 4.0 g

sufficient amount of preservative

water up to 100.0 g

Example 8: Erythromycin/isotretinoin cream

erythromycin stearate 6.0 g

isotretinoin 0.05 g

cetearyl octonate 8.0 g

cetomacrogol 300 3.0 g

cetomacrogol 1200 1.5 g

glycerol monostearate 3.0 g

cetyl alcohol 3.0 g

dimethicone 100 0.5 g

BHT 0.04 g

1,2-propylene glycol 4.0 g

sufficient amount of preservative

water up to 100.0 g

Example 9: Erythromycin/tretionine cream

erythromycin stearate 6.0 g

trethionine 0.05 g

ceteari loktonate 8.0 g

cetomacrogol 300 3.0 g

cetomacrogol 1200 1.5 g

glycerol monostearate 3.0 g

cetyl alcohol 3.0 g

dimethicone 100 0.5 g

BHT 0.04 g

1,2-propylene glycol 4.0 g

sufficient amount of preservative

water up to 100.0 g

2. Production of the preparation

The preparation containing the ingredients from Example 3 (Erythromycin cream) is prepared in the following way.

The fatty phase substances, namely glycerol monosarttearate, neutral oil, stearic acid, glyceryl monoricinoleate and glycerin, are weighed together and heated to 75 °C. The ingredients of the aqueous phase, namely water and preservative, are also heated to 75 °C. When both phases reach that temperature, the fat phase is slowly added to the water phase, with mixing or homogenization. The resulting emulsion is cooled with stirring. At a temperature of about 30 °C, erythromycin stearate is added to form erythromycin cream.

3. Stability tests

The preparation prepared according to Example 1 with a 6.12% mass fraction of erythromycin stearate (corresponding to a 4.0% mass fraction of erythromycin base) in the U/V cream is stored for 6 months at a temperature of 25 °C. As can be seen from Table 1, there was no significant loss of content, and thus no loss of action.

Table 1 (converted to erythromycin base)

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Claims (8)

1. Pharmaceutical preparation, characterized in that it contains at least one salt of fatty acid and erythromycin with from 12 to 22 carbon atoms in the part related to the fatty acid, and one liquid or viscous carrier. 2. Pharmaceutical preparation according to claim 1, characterized in that it is a salt of fatty acid and erythromycin - erythromycin stearate. 3. Pharmaceutical preparation according to claim 1 or 2, characterized in that the carrier is in the form of an emulsion, suspension, cream or gel. 4. Pharmaceutical preparation according to claim 1 to 3, characterized in that the carrier contains water. 5. Pharmaceutical preparation according to claims 1 to 4, characterized in that the preparation contains from 0.5 to 10% of the total mass of fatty acid salts and erythromycin. 6. Pharmaceutical preparation according to claim 5, characterized in that the preparation contains from 1 to 5% of the total mass of fatty acid salts and erythromycin. 7. Application of salts of fatty acids and erythromycin with from 12 to 22 carbon atoms, indicated to be used for local treatment of skin diseases. 8. Application according to claim 7, characterized in that it is for the treatment of acne.