Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
  • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
  • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
  • A61P17/10—Anti-acne agents

Definitions

• the present invention relates to a pharmaceutical composition based on erythromycin fatty acid salts with 12 to 22 carbon atoms in the fatty acid residue and the use of these erythromycin fatty acid salts for the topical treatment of skin diseases.
• Acne is a skin disease that is particularly common in adolescents. Acne is characterized by a purulent rash, which mainly occurs on the face, neck and chest. It is caused by the infection of enlarged sebaceous glands of the skin with Propionibacterium acnes, which are present on the surface of the skin. This leads to the formation of pus-filled vesicles in the area of the sebaceous glands of the skin (Herder, Lexicon of Biology, Spektrum Akademischer Verlag, Heidelberg, 1994, p. 87). An essential aspect for the development and maintenance of acne is the formation of free fatty acids in the sebaceous gland follicle, which are caused by the lipase of Propionibacterium acnes. The causes of acne are numerous.
• Erythromycin is broadly effective against one with low toxicity Numerous Gram-positive bacteria, e.g. Streptococcus and Staphylococcus as well as some Gram-negative bacteria, e.g. Neisse a and Haemophilus, as well as against mycoplasmas (Römpp Chemie-Lexikon, Georg Thieme Verlag, Stuttgart, 1997, p. 1210).
• erythromycin The main indication of erythromycin is acne-papulo-pustulosa (Niedner, Ziegenmayer, Dermatika,ticianliche Veriagsgesellschaft, 1992, p. 94). Under the influence of erythromycin, the free fatty acids formed are reduced. On the one hand, bacteria are reduced due to the antibacterial effectiveness of erythromycin, on the other hand, a direct effect on the lipase can also be demonstrated, whereby erythromycin concentrations are necessary which are below the minimum inhibitory concentration (MIC). In addition, there is a decrease in leukocyte chemotaxis, which leads to a decrease in inflammation.
• MIC minimum inhibitory concentration
• Treatment with antibiotics and erythromycin in particular can be divided into oral administration and external administration.
• Both erythromycin and erythromycin stearate are on the market for oral use in approved drugs for the treatment of acne and skin infections.
• oral administration gives good effectiveness in combating acne, systematic administration has the disadvantage that the entire organism is strained. Furthermore, the active ingredient is inevitably diluted in the body in this application.
• GB-A-1 152 644 proposes a stable composition of erythromycin in an oil, the oil having 6 to 18 carbon atoms and an iodine number below 42.
• erythromycin is relatively stable, however, the use of fatty carriers in the therapeutic treatment of acne is not particularly desirable because the compositions do not allow adequate release of the antibiotic. Furthermore, the composition does not immediately penetrate the skin. Since the skin of acne patients is naturally oily, oil-containing constituents are not adequate carriers. Rather, the skin of the acne patient requires low-fat preparations.
• a preferred vehicle for the active ingredients in acne therapy are O / W (oil-in-water) creams or emulsions which contain only a low fat content but a high water content. Due to the skin-adequate properties of these formulations, the antibiotics can be easily absorbed by the skin and are therefore particularly effective in acne therapy. However, it has been found in studies that the effectiveness of erythromycin in emulsions with a high water content decreased by up to 60% of the initial value when stored for one month at 25 ° C. (International Journal of Pharmaceutics, 67 (1991) 195-199) . Due to this instability of the aqueous preparations based on erythromycin and the resulting reduced shelf life of the product, industrial production and marketing of o / w creams or emulsions based on erythromycin is not possible.
• W / ⁇ (water-in-oil) emulsions retained an activity of more than 90% of the initial value after storage for 12 weeks.
• Alcoholic solutions and alcoholic gels had a slightly reduced shelf life, with storage at 25 ° C for the alcoholic solution, a loss of 10% during the first three weeks and for the alcoholic gel, a loss of 20% after two months .
• erythromycin is particularly active in the alkaline range, but adjusting the pH to 8.5 had a deleterious effect on the activity of the active ingredient.
• drugs based on erythromycin for topical use are offered almost exclusively in alcoholic vehicles.
• US-A-4 000 263 describes a solution based on erythromycin with good storage stability, the erythromycin being dissolved in a carrier consisting of propylene glycol, ethyl alcohol and polyoxyethylene-lauric alcohol.
• a storage-stable composition is proposed in US Pat. No. 4,469,684 in which the erythromycin is present in the form of its zinc salt in t-butanol.
• DE-A-37 12 758 describes a stable anti-acne composition based on erythromycin, in which the erythromycin is present in a pharmaceutically acceptable carrier which contains 20 to 99.5% by weight of methyl ether of propylene glycol or of di- contains propylene glycol.
• compositions are described in FR-A-7707785, FR-A-7732761 and in EP-A-8020929, in which the erythromycin is also present in a carrier made of a polyol, a fatty alcohol or a fatty acid ester.
• the object of the present invention to provide a pharmaceutical composition for the treatment of skin diseases, in particular acne, the composition remaining stable even when stored over a longer period of time, high effectiveness, good penetration into the skin and a high level Has skin tolerance.
• the composition should preferably be applied topically.
• This object is achieved according to the invention by a pharmaceutical composition which contains at least one erythromycin fatty acid salt with 12 to 22 carbon atoms in the fatty acid residue and a liquid or viscous carrier.
• the present invention further relates to the use of erythromycin fatty acid salts with 12 to 22 carbon atoms in the fatty acid residue for the topical treatment of skin diseases.
• the erythromycin-C 2-22 fatty acid salt used according to the invention can be used as a free base for topical treatment instead of conventionally used erythromycin.
• the erythromycin derivative in the form of a C 2-22 fatty acid salt which is used according to the invention, can contain saturated or unsaturated, as well as branched or unbranched fatty acids and mixtures thereof.
• Preferred examples of usable fatty acids are myristic acid, palmitic acid, lauric acid and stearic acid.
• Erythromycin stearate is particularly preferably used as an active ingredient in the pharmaceutical composition according to the invention.
• the erythromycin C ⁇ 2-22 fatty acid salts can be prepared in a manner known per se by conventional methods.
• the erythromycin base isolated from culture solutions of Streptomyces erythreus can be dissolved in an organic solvent such as acetone. Then the solution obtained is mixed with the fatty acid or fatty acid mixture.
• the practically pure erythromycin fatty acid salt fails.
• the pharmaceutical composition containing erythromycin C ⁇ 2-22 fatty acid salt in a pharmaceutically effective amount preferably used in an amount of 0.5 to 10% by weight, more preferably 1 to 5% by weight, based on the total amount of the pharmaceutical composition.
• the effectiveness of the erythromycin C ⁇ 2-22 fatty acid salt in one around the fatty acid content increased amount as high as the activity of erythromycin as the free base in the same vehicle. The use of this derivative does not lead to a loss of effectiveness in acne therapy.
• the pharmaceutical composition also contains a liquid or viscous carrier which can be chosen from conventional pharmaceutical carriers.
• the carrier is preferably selected so that the composition obtained is suitable for topical application. It is particularly preferred that this carrier is in the form of an emulsion, suspension, cream or gel in order to allow the composition to be applied to the skin without problems. It is particularly preferred that the carrier has a low fat content and a high water content. In particular, low-fat creams or emulsions, such as O / W creams or emulsions, but also dosage forms with an extremely high water content, such as gels, are preferred. The water content is usually at least approx. 40%, but a water content of almost 100% is possible for purely aqueous carriers. In particular, a water content of 60 to almost 100% is particularly advantageous since the preparation is particularly well absorbed by the skin in this way.
• fats e.g. Oils and waxes, as well as alcohols
• the lipid component can be selected from cetearyl octanoate, decyl oleate, medium-chain triglycerides, glyceryl monostearate, stearic acid, cetyl alcohol, liquid wax esters, isopropyl myristate and cetyl palmitate. Cetearyl octanoate, glyceryl monostearate, cetyl alcohol and medium-chain triglycerides are particularly preferably used.
• the pharmaceutical composition can have a creamy or pasty character, on the one hand, or a liquid, gel-like consistency. It preferably enables rapid penetration into the skin and sebaceous glands.
• the preparation can contain further pharmaceutically acceptable additives, such as preservatives, fragrances, antioxidants, buffer substances, dyes and / or pigments.
• preservatives such as preservatives, fragrances, antioxidants, buffer substances, dyes and / or pigments.
• both the carrier and the other additives are not particularly limited as long as they do not impair the action of the erythromycin C 2-22 fatty acid salt.
• the pharmaceutical composition can in addition to the Erythromycin-C ⁇ 2 . 22 - Fatty acid salt contains other active substances that are suitable for the treatment of skin diseases. Examples of these active substances are not particularly limited as long as they have the effect of the erythromycin-C ⁇ 2 . 22 Do not interfere with the fatty acid salt.
• composition according to the invention can contain, for example, adapalene, isotretinoin, tretinoin, metronidazole, benzoyl peroxide, triclosan, hexachlorophene, estradiol, clotrimazole, ketoconazole, miconazole, croconazole, azelaic acid, spironolactone, cyproteradine acetate and mixtures, chloromotone acetate, mixtures, chloromethane.
• the pharmaceutical composition according to the invention can be produced in a conventional manner.
• the individual components in particular the liquid carrier and the active ingredient, are combined with one another.
• these are usually added to the components of the water phase.
• the fat phase or the water phase can be heated. Both phases are particularly preferably heated before merging.
• the temperature depends on the respective constituents, but is usually 30 ° C. to 90 ° C., preferably 40 ° C. to 80 ° C. It is also advantageous if the fat phase is slowly added to the water phase with stirring or homogenization.
• the Erythromycin-C ⁇ 2-22 fatty acid salt can be incorporated after combining the fat and water phase. Prior to the addition of the active ingredient and the resulting mixture is usually cooled to a temperature of 20 to 40 ° C, preferably 25 to 35 C ⁇ .
• Erythromycin C ⁇ 2-22 fatty acid salts can be used according to the invention for the topical treatment of skin diseases, especially acne.
• the invention is illustrated by the following examples. However, it is not to be limited to these.
• Example 2 Cream containing erythromvcin
• Example 4 Liquid emulsion
• Example 9 En thromvcin / tretinoin cream
• a preparation containing the ingredients according to Example 3 was prepared in the following way.
• the substances of the fat phase ie glycerol monostearate, neutral oil, stearic acid, glyceryl monoricinoleate and glycerin, were weighed together and heated to 75 ° C.
• the components of the water phase ie water and preservatives, were also heated to 75 ° C. When both phases had reached this temperature, the fat phase was slowly added to the water phase with stirring or homogenization. The emulsion obtained was cooled with stirring.
• the erythromycin stearate was incorporated at a temperature of approximately 30 ° C. in order to obtain an erythromycin cream. 3. Stability studies
• a preparation prepared according to Example 1 with 6.12% by weight erythromycin stearate (corresponding to 4.0% by weight erythromycin base) in an O / W cream was stored at 25 ° C. for 6 months. As can be seen from Table 1, there was no significant drop in the content and thus in the effectiveness.

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• Health & Medical Sciences (AREA)
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• Pharmacology & Pharmacy (AREA)
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• 1999
  • 1999-04-19 DE DE19917548A patent/DE19917548A1/de not_active Ceased
• 2000
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  • 2000-04-03 EP EP00920654A patent/EP1085883A1/de not_active Withdrawn
  • 2000-04-03 WO PCT/EP2000/002950 patent/WO2000062784A1/de not_active Application Discontinuation
  • 2000-04-03 SK SK1865-2000A patent/SK18652000A3/sk unknown
  • 2000-04-03 PL PL00344988A patent/PL344988A1/xx not_active Application Discontinuation
  • 2000-04-03 HU HU0102702A patent/HUP0102702A3/hu unknown
  • 2000-04-03 AU AU41151/00A patent/AU4115100A/en not_active Abandoned
  • 2000-12-08 NO NO20006260A patent/NO20006260L/no not_active Application Discontinuation
  • 2000-12-19 HR HR20000884A patent/HRP20000884A2/hr not_active Application Discontinuation
  • 2000-12-27 BG BG105093A patent/BG105093A/bg unknown

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