Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Implant or insert
Reexamination Certificate
2002-02-05
2003-04-15
Azpuru, Carlos (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Implant or insert
Reexamination Certificate
active
06548079
ABSTRACT:
This application is a 371 continuation of PCT/EP00/07098 filed Jul. 25, 2000.
FIELD OF THE INVENTION
The present invention relates to an aqueous formulation comprising moxifloxacin hydrochloride and sodium chloride, to the formulation for use as a medicament and to the use of the formulation for preparing a medicament for preventing or treating bacterial infections in humans or animals.
BACKGROUND
Moxifloxacin (INN—International Nonproprietary Name) is an antibiotic from the class of the quinolonecarboxylic acids of the following formula:
1-cyclopropyl-7-([S,S]-2,8-diazabicyclo[4.3.0]non-8-yl)-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolonecarboxylic acid
It is a highly effective anti-infective agent and was described for the first time in EP-A-0 350 733. However, EP-A-0 350 733 does not describe any pharmaceutical preparations which are suitable for parenteral administration. Such solutions for infusion, which can be administered parenterally, are, however, needed for treating patients in intensive care units which cannot be treated orally.
For formulating solutions for infusion which are acceptable, it is necessary to adjust the osmolality to the physiological conditions of the organism (Sucker/Fuchs/Speiser; Pharmazeutische Technologie). Relatively pronounced hypo- or hyperosmotic variations can result in erythrocyte damage and/or tissue irritation. The i.v. administration of relatively strong hypoosmotic solutions leads to haemolysis, and administration of relatively large amounts of hyperosmotic solutions leads to plasmolysis. Hypoosmotic solutions contain fewer dissolved molecules or ions than are present in the blood or the tissue fluid. In this case, isotonization has to be carried out by addition of isotonizing agents (Bauer/Frömming/Führer, Pharmazeutische Technologie). A range from 270 to 350 mOsmol/kg is considered to be isotonically suitable.
Commercial isotonic solutions are, for example, a 5% strength glucose solution or a 0.9% strength sodium chloride solution.
EP-A-0534860 describes formulations of the quinolonecarboxylic acid antibiotic sparfloxacin with monocarboxyl-polyhydroxy acids or lactones thereof, such as, for example, ascorbic acid, and with glucose or glycerol as isotonizing additive. The invention is based on improving the solubility of sparfloxacin by means of monocarboxyl-polyhydroxy acids to obtain acceptable, isotonic or hypertonic formulations of suitable concentrations.
U.S. Pat. No. 5,563,149 describes the formulation of aqueous solutions of pyridonecarboxylic acids and esters and salts thereof as antibiotics as ready-to-use solutions for injection or infusion or concentrates for injection or infusion. Details about isotonization additives or about the tonicity of the formulations are not given. The object of said invention is to improve the solubility of the pyridonecarboxylic acids described.
EP-A-0507851 describes formulations comprising quinolonecarboxylic acid/metal ion acid complexes. It has been found that the solubility of the active compound is increased when polyvalent metal ions in the form of magnesium, calcium, manganese, zinc, cadmium, aluminium, cerium or iron ions are added, as a consequence of complex formation at neutral pH. Such formulations are described as being chemically and physically stable, even in the presence of glucose for isotonization, and are better tolerated, owing to a neutral pH.
U.S. Pat. No. 5,811,130 describes metal ion complexes with danofloxacin where in particular magnesium and zinc ions are used for complex formation and with which the solubility of danofloxacin is increased considerably. Formulations with high active compound concentration for subcutaneous injection are described which can only be achieved by the improved solubility of the metal ion/active compound complexes in water.
Furthermore, U.S. Pat. No. 5,084,276 teaches the use of quinolonecarboxylic acid/metal ion complexes, for example with magnesium, calcium, manganese, zinc, cadmium, iron-(II) and iron-(III) or cerium-(IV) ions for complexing the active compounds temafloxacin, toxyfloxacin or pefloxacin, where the active compound complexes are used together with excipients for reducing irritation of the veins. The formulations for parenteral infusion described are isotonized with glucose.
SUMMARY OF THE INVENTION
During the development work on moxifloxacin, it was surprisingly found that isotonization by addition of 5% commercial glucose or other sugars or sugar alcohols, such as 2.5% glycerol, gives unstable solutions in the case of moxifloxacin. This instability manifests itself by the occurrence of subvisual particles in the solution, the number of which exceeds the range permissible by the pharmacopoeias (USP XXIII, BP93). During storage, brown amorphous particles are formed, which frequently only occur after 4-8 weeks of storage at 40° C., and the number of which increases further during storage. At room temperature or on storage in the refrigerator, the formation of these particles is slower. We found that the particle formation is caused by a three-fold interaction between moxifloxacin and/or its salts, iron and sugar or sugar alcohols, such as glycerol. This was surprising, since similar phenomena in the formulation of parenteral formulations of quinolonecarboxylic acid have hitherto not been known, and in particular EP 0507851, U.S. Pat. No. 5,811,130 and U.S. Pat. No. 5,084,276 utilize the interaction of polyvalent metal ions with quinolonecarboxylic acids for stabilization and increasing solubility. The antibiotic ciprofloxacin, for example, tolerates considerably higher concentrations of iron.
Since the element iron is ubiquitous and is present in particular in the feedstock glucose, in which it may be bound in complex form, such a formulation can be prepared only at a great expense, both analytically and for quality assurance. In addition, the use of steel in the production plants is problematic, and only selected steels and controlled materials are allowed to come into contact with the solution. Furthermore, such a formulation requires, in principle, extremely iron-deficient active compound qualities which can only be prepared at great expense. In the case of moxifloxacin, solutions having an iron content above 20 ppb exhibit a particle content which increases considerably over time, so that, after the preparation, the required pharmaceutical quality of the formulations cannot be maintained for the stability period required. Moreover, glucose-isotonized formulations are considered to be very disadvantageous in various fields of clinical application, since they may represent additional stress for the energy balance of the patient and require special attention, in particular in the treatment of diabetics.
For parenteral aqueous formulations of hydrochlorides of quinolonecarboxylic acids there is, owing to their poor solubility properties in the presence of NaCl, the general problem of administering the composition with an acceptable infusion volume. In addition to the above-described possibility of increasing the solubility by metal complex formation, various possibilities of salt formation have also been explored.
Thus, EP-A-0219784 describes solutions for infusion of ciprofloxacin with physiologically acceptable acids. Also described is a formulation of 75 mg of ciprofloxacin/500 ml (0.015% w/v), 0.203 ml of 1 M hydrochloric acid/500 ml (corresponding to a molar ratio of ciprofloxacin/hydrochloric acid of 1.0 to 0.9) and 4.5 g of sodium chloride/500 ml (0.9%) as isotonization additive. This active compound concentration corresponds approximately to the saturation solubility of the active compound in the stated formulation at room temperature. Higher concentrations of ciprofloxacin in the presence of hydrochloric acid and isotonic amounts of NaCl cannot be realized, owing to the poor solubility of ciprofloxacin and its hydrochloride. At a customary dosage of ciprofloxacin of 100 to 400 mg per dose, 2 to 3 times per day, this results in unacceptable infusion volumes of about 1.31 to 81 per day. Because
Eisele Michael
Kühn Bernd
Mahler Hans-Friedrich
Azpuru Carlos
Bayer Aktiengesellschaft
Chiu Jerrie L.
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