GB845454A — Preparation of improved tetracycline antibiotic compositions

USPTO Abstract

A tetracycline antibiotic is solubilised in aqueous solution by the addition of a soluble non-toxic source of alkaline earth ions and a pyridine derivative having the formula: <FORM:0845454/IV(b)/1> wherein R is hydrogen or a N-alkylcarbamyl, N-alkanolcarbamyl, hydrazinocarbonyl, hydroxyl, hydroxyalkyl, alkoxycarbonyl or carboxyl radical or a salt of a carboxyl group with a soluble non-toxic metal; R1 is hydrogen or a methyl group and R11 and R111 are each hydrogen or a hydroxymethyl group. The tetracycline antibiotic is tetracycline, chlortetracycline, oxytetracycline, bromtetracycline or soluble salts thereof such as the hydrochloride and sulphate. Sources of alkaline earth ions are the chloride, sulphate, citrate, ascorbate, pantotherate, gluconate and lactate of calcium or magnesium. The alkaline earth ion and the pyridine derivative may be combined, e.g. magnesium nicotinate. One or more pyridine derivatives may be present. Examples are nicotinamide, isonicotinamide, N-ethanol nicotinamide, N-methyl nicotinamide, picolinamide, nicotinic acid hydrazide, isonicotinic acid hydrazide, methyl nicotinate, methyl isonicotinate, sodium nicotinate, pyridoxine hydrochloride, 4-propanol pyridine and 2-propanol pyridine. The molecular ratio of tetracycline antibiotic : alkaline earth ions : pyridine compound is at least 1:1:4 or 1: 1/2 :40 and is preferably 1:2.5:8. Specification 793,558 is referred to.ALSO:A tetracycline antibiotic composition of enhanced solubility and stability which is, or is adapted on addition of water to provide, a clear aqueous solution and comprises a tetracycline antibiotic, a soluble non-toxic source of alkaline earth ions, and a pyridine derivative having the formula: <FORM:0845454/VI/1> wherein R is hydrogen or a N-alkylcarbamyl, N-alkanolcarbamyl, hydrazinocarbonyl, hydroxyl, hydroxyalkyl, alkoxycarbonyl, or carboxyl radical or a salt of a carboxyl group with a soluble non-toxic metal; R1 is hydrogen or a methyl group and R11 and R111 are each hydrogen or a hydroxy-methyl group. The tetracycline antibiotic is tetracycline, chlortetracycline, oxytetracycline, bromtetracycline or soluble salts thereof such as the hydrochloride and sulphate. sources of alkaline earth ions are the chloride, sulphate, citrate, ascorbate, pantothenate, gluconate and lactate of calcium or magnesium. The alkaline earth ion and the pyridine derivative may be combined e.g. magnesium nicotinate. One or more pyridene derivatives may be present. Examples thereof are nicotinamide, isonicotinamide, N-ethanol nicotinamide, N-methyl nicotinamide, picolinamide, nicotinic acid hydrazide, isonicotinic acid hydrazide, methyl nicotinate, methyl isonicotinate, sodium nicotinate, pyridoxine hydrochloride, 4-propanol pyridine and 2-propanol pyridine. The molecular ratio of tetracycline: alkaline earth ions: pyridine compound is at least 1:1:4 or 1: 1/2 :40 and is preferably 1:2,5:8. For parenteral administration there may be present a soluble, non-toxic alpha hydroxy acid or a salt thereof. Other additions are (a) anaesthetic e.g. procaine (b) analgesic e.g. antipyrine (c) stabiliser e.g. sodium sulphite. Specification 793,558 is referred to.