Patent GB-779504-A (GB)
Title: Tetracycline antibiotic complexes
IPC: A61K31/65
Filed: 1955-02-08
Abstract: A tetracycline antibiotic complex useful for intramuscular injection consists of a tetracycline antibiotic, aluminium and an alpha hydroxy carboxylic acid.  The complexes may contain 1 to 8 moles. of aluminium and 1 to 24 moles. of acid per mole. of antibiotic.  The number of moles. of acid is preferably at least as great as the number of moles. of aluminium.  The complex is preferably formed in aqueous solution by mixing ionizable forms of the antibiotic, acid and aluminium and allowing to stand.  If desired, the pH is adjusted to 1 to 12 and preferably 3.5 to 7.0 by means of acid or alkali.  The complex may be used in the solution in which it is formed, or may be recovered therefrom by (a) the addition of a water-miscible solvent such as ethanol or isopropanol or (b) freeze drying.  The antibiotics are tetracycline, chlortetracycline, bromotetracycline and oxytetracycline.  Specified ionizable forms of the antibiotic are the free base, the hydrochloride, the hydrobromide, the nitrate, an amine salt, an alkali metal salt, e.g. the sodium salt and an alkaline earth metal salt, e.g. calcium salt.  The aluminium is in the form of the citrate, nitrate, tartrate, formate, chloride, sulphate, potassium aluminium sulphate, hydroxide, salts with polyhydric alcohols, aryloxides, ethoxide or isopropoxide; the two latter being preferred.  The alpha hydroxy acid is preferably a sugar acid such as gluconic acid and lactobionic acid, but it may be citric, lactic, glycollic, malic or tartaric acid.  The complexes form stable complexes with the polyvalent metals antimony, barium, cadmium, calcium, chromium, cobalt, copper, gold, iron, magnesium, manganese, nickel, selenium, silver, strontium, tin and zinc.  This second complex is produced by adding an ionizable form of the desired polyvalent metal to the reaction solution for the antibiotic-aluminium-acid complex.  A solubilizing agent is added to improve the stability of the less soluble complexes.  Specified are the surface active polyoxyethylene derivatives of fatty acid esters of polyhydric alcohols, e.g. sorbitan monolaurate and polyoxyethylene ethers of long-chain alcohols such as lauryl alcohol.  Examples describe the preparation of (1) chlortetracycline aluminium gluconate; (2) oxytetracycline aluminium gluconate; (3) chlortetracycline aluminium lactobionate; (4) chlortetracycline aluminium tartrate (6) tetracycline aluminium gluconate; (6) tetracycline aluminium citrate; (7) tetracycline aluminium glycollate; (8) tetracycline aluminium lactate; (9) tetracycline aluminium malate; (10) tetracycline aluminium gluconate complexes with (a) calcium, (b) antimony, (c) cadmium, (d) chromium, (e) cobalt, (f) copper, (g) gold, (h) iron, (i) manganese, (j) nickel, (k) selenium, (l) silver, (m) strontium, (n) tin and (o) zinc; and (11) chlortetracycline aluminium gluconate with (a) sorbitan monolaurate and (b) polyoxyethylene lauryl ether.  The reactants for the complex may be mixed dry and the powder so formed dissolved in water shortly before use.  The tetracycline antibiotic complexes are incorporated in therapeutic preparations for human and animal treatment (see Group VI).  Specifications 678,117 and 680,471 are referred to.ALSO:A tetracycline antibiotic complex consisting of a tetracycline antibiotic (namely tetracycline, oxytetracycline, chlortetracycline or bromotetracycline), aluminium and an alpha hydroxy carboxylic acid (see Group IV(b)) is put up in pharmaceutical forms suitable for administration to man and animals.  The comlex forms stable complexes with the polyvalent metals antimony, barium, cadmium, calcium, chromium, cobalt, copper, gold, iron, manganese, magnesium, nickel, selenium, silver, strontium, tin and zinc (see Group IV(b)) and such are also used pharmaceutically.  Intramuscular injections consist of aqueous solutions of the complex with or without a solubilizer which is a surface active polyoxyethylene derivative of a fatty acid ester of a polyhydric alcohol or a polyoxyethylene ether of a long chain alcohol e.g. lauryl alcohol. Suspensions in oil are used parenterally, as a burn dressing, and for gauze impregnation. Oral preparations consist of capsules, tablets, elixirs and aqueous solutions and suspension.  Topical applications are ophthalmic solutions and ointments aural and nasal solutions, mouth washes, ointments and suppositories.  Specifications 678,117 and 680,471 are referred to.