DE3248328A1 - Aminoglycoside salts of low solubility, and formulations containing these with delayed release of active substance - Google Patents

Abstract

Salts, which are of low solubility in water, of aminoglycosides which are, where appropriate, derivatised on the hydroxyl and/or amino groups, and non-antibiotic organic carboxylic acids or sulphonic acids or hemiesters of polybasic inorganic acids with aliphatic alcohols.

Description

Slightly soluble salts of aminoglycosides as well as these

Formulations containing delayed release of active ingredient antibiotics The aminoglycoside series has long been used in human and veterinary medicine used to fight bacterial infections. Especially in veterinary medicine In the case of diseases of this type, there is a desire after just a single injection of the active ingredient to achieve a healing success. This is for example with penicillins quite possible if the animals are given a suspension of poorly soluble penicillin salts is injected, the active ingredient of which is only gradually released.

This ensures an effective penicillin blood level over a longer period of time Period of time and multiple repetitions of the injection become unnecessary.

In aminoglycosides, which are usually injected as an aqueous solution ~ the biological half-life is relatively short (approx. 1 h), so that with a If the infection is weak, an injection must be made several times a day.

So it would be desirable and for the pet owner and the veterinarian a great relief when the number of injections during the illness of the animal could be reduced.

Injection formulations of aminoglycosides with these properties are not yet known. Dosage forms are described in a different context been taking aminoglycosides continuously over an extended period of time be released. For example, U.S. Patents 4,188,373 and 4 115 544 eye drops that release gentamicin in a delayed manner. Are known also plastic or ceramic dosage forms that are implanted in infected bones and continuously release the aminoglycoside there (see e.g. DE-OS 2 815 934, DE-OS 3 005 350, DL 139 942 or DE-OS 2 807 132).

The creation of sparingly soluble salts has already been made for aminoglycosides described. However, these are also only intended for external use, but not for injection formulations. Thus, in DE-OS 2 301 633, water-insoluble Antibiotic salts, in which gentamicin or polymyxin as bases and penicillin or cephalosporins as acids the salt is produced. These salts have the disadvantage that the ratio of aminoglycoside / penicillin derivative by the Molar ratio is fixed and not adapted to the bacteriologically meaningful optimum can be.

With a slow release aminoglycoside formulation a combination preparation with ß-lactam antibiotics would also be possible, which is free from the disadvantages of the penicilin / gentamicin salt described above: Off From a microbiological point of view, a combination product made from penicillin derivative and Aminogllycoside is extremely desirable, since then almost all of the grannegative as well as gramositive Bacteria spectrum would be recorded. Unfortunately, both active ingredients are currently only able to To be injected separately at different parts of the body in order to receive from both active substances to get optimal effectiveness. The two injection solutions are also allowed because of the formation of the sparingly soluble salt in a syringe before use applied: see the application recommendations of the aminoglycoside solution manufacturer or e.g. I. Carrizosa and D. Rate, Antimicrobial Agents and Chemotherapy, 13 (3), S. 505-508 (1978) or M. Scheer, Therapy Week 27, 5. 8904-8913 (1977) or G.I. van Wingerden et al, J. Bone Joint Surg. 56 pp. 1452-1458 (1974).

It is already known from DE-OS 2 756 079, a combination preparation from aminoglycoside and penicillin derivatives by adding the penicillin with Polyvinylpyrrolidone and lecithin is coated. The dried powder is in Sterile glass bottles are filled and can be filled before use by adding an aqueous The aminoglycoside solution can be shaken together with the combination preparation. never manufacture however, this preparation is complex and expensive and a "ready-to-use" suspension cannot be produced like this.

It has been found that aminoglycoside formulations with the desired properties (delayed, uniform release of active ingredients, via a longer period; Combination possibility with ß-lactam antibiotics). manufactured if one of the new types of salts of aminoglycoside antibiotics, which are sparingly soluble in water goes out and this is preferably suspended in an oily carrier liquid.

The invention relates to salts of sparingly soluble in water Aminoglycoside antibiotics and non-antibiotic organic carbon or Sulphonic acids or half-esters of polybasic inorganic acids with aliphatic ones Alcohols. The invention also relates to injectable antibiotic formulations with sustained release, which is characterized by; are that they the salts according to the invention, preferably in the form of a suspension in a oily carrier liquid.

Hunter "sparingly soluble" in the sense of the present invention is too understand that at 200C 1 to 1000 mg of the salt dissolve in 1000 ml of water, preferably 1 to 500, particularly preferably 5 to 200 mg.

According to the invention, preferred aminoglycoside antibiotics are those suitable for the following: Gentamicin, Sisomicin, Etomicin, Amikacin, Streptomycin, Bluensomycin, Neomycin, $ paromomycin, lividomycin, kanamycin, dibekacin, nebramycin, ribostamycin, Butirosin, Kasugamycin, sagamycin, apramycin, verdamicin, xylostasin, Destomycin, Hygromycin, Seldomycin, Umtarnicin, Tobramycin, Sepctinomycin and Fortimicin.

Particularly preferred from this group are especially gentamicin, sisomicin, Etomicin, Amikacin, Streptomycin, Neomycin, Kanamycin, Tobramycin, and Fortimicin.

According to the invention, aminoglycosides also come into consideration, which at their Hydroxyl and / or amino groups are derivatized. These are, for example, Derivatives according to DE-OS 2 712 160 (aminoglycosides which have a carry an alkyl or acyl radical containing an ether or thioether group), DE-OS 2 924 659 (Aminoglycosides which contain an aminohydroxyalkyl radical on at least one nitrogen atom wear), DE-OS 2 753 769 (1-N-carbamoyl and 1-N-alkoxycarbonyl aminoglycosides), DE-OS 2,832,268 (aminoglycosides which have a polyhydroxyalkyl radical on at least one nitrogen atom carry), DE-OS 2 921 973 (1-N-Hydroxyalkylaminoalkyloxycarbonyl-sisomicin), DE-OS 2 928 183 (sisomicin, substituted on the 1-N atom with secondary alkyl), DE-OS 3 100 739 (sisomicin substituted on the 5-0 atom by a carbamoyl group) and DE-OS 3 101 376 (1-hydroxyalkyl urethane sisomicin) and the pseudodisaccharides according to DE-OS 2,730,372.

All of them come as the acid component of the salts according to the invention non-antibiotic organic carboxylic acids or sulfonic acids as well Half esters of inorganic acids with aliphatic alcohols in question, those with the respective aminoglycoside (derivative) form a salt that is sparingly soluble in water. Examples are: Emboxylic acid or Pamoa acid (= 4,4'-methylene-bis- [3-hydroxy-2-naphthalene carboxylic acid]), 1,5-naphthalene disulfonate or higher fatty acids, e.g. dodecanoic acid, tetradecanoic acid, Hexadecanoic acid, octadecanoic acid, cerotic acid, oleic acid, elaidic acid, linoleic acid or ß-hydroxymyristic acid.

Preferred among these acids are emboxylic acids and optionally unsaturated ones Fatty acids with s - 25 atoms, in particular 12-18 carbon atoms. Be considered also half esters from di- or polybasic inorganic or organic acids With aliphatic alcohols such as monocetyl sulfate or monocetyl malonate or else Ethyl succinate. Half-esters of long-chain (S - 25, preferably 12 - 18 carbon atoms) alcohols.

All oils suitable for injection are used as the carrier liquid Question, e.g. natural like sesame oil, peanut oil, rlandel oil, corn oil or olive oil or synthetic triglycerides such as a triglyceride mixture of saturated vegetable fatty acids medium chain length (C8-C12) or caprylic / capric acid triglyceride. Also fatty acid esters such as ethyl oleate are used in injection formulations.

Of course, other suspension formulations can also be used excipients known per se are added, e.g. wetting agents such as lecithin or Polyoxyethylene sorbitan monooleate, thickeners such as aluminum monostearate, preservatives such as phenols, benzyl alcohol or p-hydroxybenzoic acid esters. Preferred the salts according to the invention are used in combination with ß-lactam antibiotics, obi the latter can be in the form of the free acid as well as in salt form. According to the invention, all ß-lactam antibiotics known per se come in this context contemplated, e.g., penicillins, cephalosporins and oxacephems. Cited as an example be ampicillin, propicillin, oxacil lin, dicloxacil lin, carbenicillin, azidocillin, Mezlocillin, Azlocillin, Penicillin G, Procaine-Penicillin G, Pivampicillin, Amoxicillin, Flucloxacillin, Ticarcillin, Carindacillin, Cielacillin, Epicillin, Cefaloridin, Cefalothin, Cefazolin, Cefamandol, Gefoxitin, Cefuroxim, Cephalexin, Cefradin, Cefaclor, Cefadroxil, thienamycin and cefotaxime.

Preparation of the salts according to the invention: The poorly soluble salts The aminoglycoside antibiotics can be prepared by making aqueous solutions of free basic aminoglycosides or of their neutral salts with inorganic ones or reacting organic acids with aqueous solutions of salts e.g.

the higher fatty acids or the fatty acid. The reaction temperature is usually in the range between 5 ° and 95 ° C, preferably between 50 ° and 8000. The poorly soluble precipitate formed is then suctioned off with water washed well and dried according to the usual methods.

Preparation of the formulation: the aminoglycoside salts according to the invention can e.g.

in an amount from 0.5 to 30% by weight, preferably from 1 to 15% by weight (calculated in each case as aminoglycoside base), based on the entire formulation, be introduced into the carrier. The proportion of auxiliary substances can be between 0.05 and 10% by weight, preferably 0.2-5% by weight, vary. The proportion of ß-lactam antibiotics in the combination formulation, for example, between 1 and 40% by weight, preferably 10-30% by weight (in each case based on the entire formulation).

The ready-to-use suspensions are produced in and of themselves known way under aseptic conditions.

A) The desired salt becomes sterile to a certain grain size precipitated or the sterile salt is ground under aseptic conditions. the Grain size should preferably be between 2 and 60 μm, particularly preferably between 5 and 30 pm.

B) The ground substance is placed in the previously sterilized suspension medium introduced and homogenized. The homogeneous suspension is made under sterile conditions fell off.

The formulation examples listed below were used according to above regulation under a laminar flow tent.

example Input materials ABCDEFGH Etomicin Sulphate 1.6 g 1.6 g (# 1% base) Sodium sulfite 0.2 g Water per ad injection 100 ml 2% aluminum ad ad monostearate gel 100 ml 100 ml with sesame oil Etomicin Embonate 3.46 g 3.46 g (# 1.0 g base) Ethyl oleate ad 100 ml Etomicin Hexa- 4.15 g decanate (# 1.0 g base) Etomicin Dodecanate 3.49 g (# 1.0 g base) Sesame oil ad ad ad ad 100 ml 100 ml 100 ml 100 ml Penicillin G 6.30 g potassium Example (continued) Input materials ABCDEFGH Gentamicin - 3.48 g Embonate (# 1.0 g base) Sisomicin penta- 3.69 g embonate (# 1.0 g base) The blood levels of the aminoglycoside were determined from these formulations in the following manner: The formulations were administered intramuscularly in appropriate doses to beagle dogs. Blood samples were taken at various times after treatment and the serum was taken by centrifugation. The determination of the active substance content in the serum was carried out microbiologically with the help of the agar diffusion test (hole test).

The strain Bacillus subtilis ATCr 6633 was used as the detection germ, and DST agar as the test medium. The active ingredient content in the various serum samples was determined using a standard in buffer. The results (see table) show that after application of the sparingly soluble salts, therapeutically relevant blood levels were reached over a considerably longer period of time than, for example, with the corresponding water-soluble sulfates. As a result of the significant increase in the half-life, these formulations offer decisive advantages for therapy. Table 1 Canine / Intramuscular Serum Levels Formulation Etomicin Salt Dose Half-Life Serum Concentration (J / ml) examples mg / kg (h) 1h 8h 12h B sulfate 4 1 9.5 0.2 - C Embonate 4 1.8 5 0.7 - Sulfate + 4 2 7.5 0.46 - Embonate E dodecanate 4 2.5 8.8 1.3 0.36 4 2.3 7.8 0.7 0.1 1 2 1.4 0.15 - D hexadecanate 4 3.9 4.4 1.3 0.36 4 3.9 3.1 0.84 0.45 1 2.4 2 0.3 -

Claims (10)

Claims in salts of aminoglycosides that are sparingly soluble in water, which are optionally derivatized on the hydroxyl and / or amino groups, and non-antibiotic organic carboxylic acids or sulfonic acids or half-esters of polybasic inorganic acids with aliphatic alcohols. -2. Salts according to claim 1, characterized in that they are in water from 2000 have a solubility of 1 to 1000 mg / l. 3. Salts according to claim 1 or 2, characterized in that the Acid component from the croup embonic acid, also unsaturated fatty acids with 8 to 25 carbon atoms and monosulfates of alcohols with 8 to 25 carbon atoms selected is. 4. Antibiotic formulation, characterized in that it is a salt according to claim 1 to 3 contains. 5. Formulation according to claim 4, characterized in that-they has a shape suitable for injections. 6. Formulation according to claim 4 or 5, characterized in that the salt is suspended in an oily carrier liquid. 7. Formulation according to claim 4 to 6, characterized in that the grain size of the salt is between 1 and 70 p. 8. Formulation according to claim 4 to 7, characterized in that it also contains ß-lactam antibiotics, optionally in salt form. 9. Formulation according to claim 8, characterized in that it 0.5-30% by weight of the salt (calculated as aminoglycoside base) and 1-40% by weight of one Contains lactam antibiotic. 10 Use of salts according to claims 1 to 3 and formulations according to claim 4 to 9 in the fight against bacterial infections in the human or veterinary medicine.