QUINOLINE CARBOXYLIC ACID TABLET AND FORMULATION

Abstract: A direct compression tablet formulation containing a non-­ hydrated quinoline carboxylic acid type antibacterial agent.

Description: BACKGROUND OF THE INVENTION The invention is concerned with a direct compression quinoline carboxylic acid tablet which utilizes non-hydrated quinoline carboxylic acid. From E.A. Gorman et al., Drug development and industrial Pharmacy, vol.8, no.3, 1982, pages 397-410, it is known that croscarmellose promotes a rapid dissolution of tablets. Hydrated and anhydrated 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-1,8- naphthyridine-3-carboxylic acid (EP-A-0058614) as well as certain quinoline carboxylic acids (see e.g. U.S. 4,146,719; U.S. 3,590,036; U.S. 4,292,317) are known orally active antibacterial agents. Norfloxacin is a particularly effective agent of this class and has the formula Its formulation into a tablet oral dosage form is disclosed in Italian patent application 20764A/79; this formulation requires that it contain about 2% to about 15% water to permit preparation of a tablet containing the minimal amount of inert ingredients carriers etc. and having suitable dissolution, disintegration and bioavailability characteristics. This water is added to the formulation ingredients prior to compression into a tablet. A tablet formulation has been discovered which requires no hydration, i.e. no addition of water prior to compression and which contains lesser amounts of inert ingredients than the prior art formulation, while maintaining equivalent dissolution disintegration, bioavailability and strength properties of the tablet prepared therefrom. The tablet formulation may be equally useful for other quinoline carboxylic acid type agents. SUMMARY OF THE INVENTION A direct compression tablet and a formulation containing less than 2% water for its preparation containing quinoline carboxylic acid antibacterial. DESCRIPTION OF THE INVENTION An embodiment of the invention is a direct compression tablet formulation containing quinoline carboxylic acid antibacterial agent. Examples of useful quinoline carboxylic acids are norfloxacin, ciprofloxacin, ofloxacin, rosoxacin, oxolinic acid, amifloxacin or pefloxacin. A preferred quinoline carboxylic acid is norfloxacin. The present formulation comprises a blend of said antibacterial agent and minimal amounts of other processing aids with no water added. More specifically, the processing aids are a disintegrant, a filler/binder and a lubricant, with a colorant being optionally added and the antibacterial agent is norfloxacin. This formulation is directly compressed into a tablet which is generally film coated, preferably using a conventional aqueous coating system. The film former is typically modified cellulose e.g. hydroxypropylcellulose and/or hydroxypropylmethylcellulose. Following are the compositions of illustrative tablet formulations containing 200 and 400 mg of an antibacterial agent (norfloxacin). The tablet is prepared by mixing the formulation ingredients with no hydration i.e. no water is added, prior to direct compression. This mixture of ingredients thus contains less than 2% or preferably less than 1% water. The tablet may be optionally film coated preferably using a water based system. The prior art formulation described in the above-cited Italian patent application requires addition of at least about 2% up to about 15% water to the tablet formulation prior to compression. The specific formulations disclosed in the examples of the Italian application show that tablet ingredients (norfloxacin is the active ingredient) are first subjected to a granulation followed by addition of water (6% in Example 7 , 8.2% - Example 2, 8% - Example 3, and 4) prior to compression. The present formulation also provides a processing advantage since it requires only blending of the ingredients without granulation or addition of water prior to compression. The elimination of the granulation operation also eliminates the use of a solvent (e.g., ethanol), and its attendant evaporation which could present environmental concerns. The dissolution rate, disintegration times and breaking resistance (tablet strength) and active ingredient bioavailability of tablets of the A and B formulations and of tablets formulated according to the Italian patent directions were found to be substantially equivalent. In each instance the tablets (A and B or Italian) were additionally film coated using conventional tablet film coating systems (aqueous for A and B and solvent for Italian both utilizing a modified cellulose film former). Each tablet formulation also contained less than 0.04% by weight of a colorant. The strength and dissolution data are tabulated below: The data show that the physical properties of the Italian application and present formulations are substantially equivalent. While only tablets containing 200 and 400 mg of the active ingredient (antibacterial agent) are shown, tablets containing more or less of the active ingredient can be prepared as needed.

Claims: A composition, for preparing a tablet by direct compression, comprising a mixture of quinoline carboxylic acid antibacterial agent and inert diluents, which mixture contains less than 2% water. The composition of claim 1 wherein the mixture contains less than 1% water. The composition of claim 1 or 2 wherein the quinoline carboxylic acid is norfloxacin. The composition of claims 1 to 3 wherein the diluents are a disintegrant, a filler/binder and a lubricant. The composition of Claim 4 wherein the composition contains at least about 80% by weight of norfloxacin. The composition of Claim 5 containing, by weight, about 80-85% norfloxacin, about 13.5-18.5% filler/binder, about 0.5-2% lubricant and about 1-4.5% disintegrant. The composition of Claim 6 containing less than 0.04% by weight of colorant. The composition of Claim 6 wherein the disintegrant is croscarmellose sodium, the filler/binder is a microcrystalline cellulose and the lubricant is magnesium stearate. A tablet prepared from the composition of claims 1 or 8. A tablet of Claim 9 which has a conventional film coating. A method of preparing a tablet comprising blending a composition according to any one of Claims 1 to 8 without addition of water and directly compressing the blend. The method of claim 11 wherein the blend contains less than 1% by weight water. A tablet prepared by the method of Claims 11 or 12.

Inventors: KATDARE, ASHOK V.
Applicants: MERCK & CO. INC.
Application year: 1986
Main classification: A61K31
IPC codes: A61K9, A61K31