Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – 3,10-dihydroxy-2-naphthacene carboxamide or derivative doai
Patent
1996-02-12
1998-05-19
Cintins, Marianne M.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
3,10-dihydroxy-2-naphthacene carboxamide or derivative doai
514153, A01N 3718, A61K 3165
Patent
active
057536368
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/EP94/01696 filed May 25, 1994.
FIELD OF THE INVENTION
The invention relates to an injection solution for subcutaneous or intramuscular administration to animals and a process for the production thereof.
BACKGROUND OF THE INVENTION
Tetracycline antibiotics are the agents of first choice in many countries for numerous therapeutic indications in the veterinary sector. Moreover, oxytetracycline (OTC) is the tetracycline used most for parenteral administrations.
Nevertheless, a number of serious problems is associated with the use of tetracyclines. Thus, parenteral use is restricted by their poor solubility and low stability in aqueous media. In addition, they lead to severe irritation at the injection site on intramuscular or subcutaneous injection.
Many attempts have been made to solve the problem of the low solubility of tetracyclines in water by using water-miscible solvents and cosolvents. Examples which may be mentioned are polyethylene glycol, 1,2-propanediol and N,N-dimethylacetalide, which in their turn are highly irritant and have haemolytic effects, NOUWS, Vet. Quart., 1984, 6, 2, 80-84; NOUWS, Vet. Quart., 1990, 12, 3, 129-138; RASMUSSEN et al., Res. vet. Sci., 1976, 20, 55-60; HAPKE et al., DTW, 1983, 90, 161-200 and 216-218.
Better pharmaceutical solutions are obtained by using water-miscible and better tolerated pyrrolidone derivatives which are employed as solubilizers, solvents or cosolvents in aqueous parenteral tetracycline compositions. Reference should be made in this connection to polyvinylpyrrolidone, 2-pyrrolidone, N-methylpyrrolidone and 2-hydroxyethylpyrrolidone. These derivatives permit oxytetracycline formulations of high concentration to be produced.
The advantage of highly concentrated oxytetracycline formulations with 20% OTC is that an antimicrobially effective serum level which persists for up to 72 hours after injection--so-called long-acting formulations (oxytetracycline LA)--can be produced with a single intramuscular injection of a dose of 20 mg per kg of body weight. LA formulations are very popular for administration in veterinary medicine for practical reasons.
Solutions, which are suitable for parenteral, oral and local administration, of oxytetracycline-magnesium complexes in up to 25% strength aqueous polyvinylpyrrolidone with an oxytetracycline content of up to 15% are disclosed in GB-A-1 131 007. The solutions described therein have a pH in the range from 8.0 to 9.5. The pH is adjusted with the aid of sodium hydroxide, ammonia, ethanolamine or ethylenediamine. Solutions of this type are relatively well tolerated but have the disadvantage that the OTC concentration cannot be adjusted to higher than 10% in formulations suitable for parenteral administration. The LA effect of other 20% strength formulations cannot be achieved thereby.
DE-A-26 15 140 discloses an active substance formulation for topical transdermal administration having a vehicle system composed of N-methylpyrrolidone and 2-pyrrolidone in a ratio of 1:4 to 4:1. The vehicle system in the composition described therein is intended to promote passage through the skin of the active substance applied to the skin. Administration of formulations of this type by injection is not intended.
DE-A-26 59 152 describes formulations, which are suitable for injection, of a tetracycline complex in aqueous 2-pyrrolidone, which may additionally contain polyvinylpyrrolidone. However, the solutions described therein have proved to be exceptionally irritant for tissues. The injections are frequently painful for the animals and lead to undesired necroses. The tissue irritation leads to high and long-lasting residue levels in the tissue and result in undesirably long withdrawal periods (Nouws; Rasmussen et al.).
EP-A-0 096 942 describes an oxytetracycline composition in which 10 to 30 parts by weight of oxytetracycline in the form of an alkaline earth metal complex and 2.5 to 10 parts by weight of polyvinylpyrrolidone are dissolved together with antioxidants and bases in aqueous N-methylpyr
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patent: 2644782 (1953-07-01), Harned et al.
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patent: 3557280 (1971-01-01), Weber et al.
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Dornhofer Winfried
Embrechts Erwin
Cintins Marianne M.
Jones Dwayne C.
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