Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-05-09
2003-07-08
Bernhardt, Emily (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C544S363000
Reexamination Certificate
active
06589955
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to gatifloxacin suitably taste-masked so that it can be utilized in oral dosage forms, particularly for pediatric formulations.
BACKGROUND OF THE INVENTION
Gatifloxacin, chemically 1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(3-methyl-1-piperazinyl)-4-oxo-3-quinolinecarboxylic acid, is represented by the following structure:
Gatifloxacin is a broad-spectrum quinolone antibacterial that is disclosed and claimed in U.S. Pat. No. 4,980,470. U.S. Pat. No. 5,043,450 discloses gatifloxacin isolated as the hemihydrate. U.S. Pat. No. 5,880,283 discloses a sesquihydrate crystalline form of gatifloxacin that is advantageous over the hemihydrate in pharmaceutical manufacturing. Regardless of the particular form of gatifloxacin, typical of quinolone compounds, it has an extremely bitter taste.
It is recognized that quinolone antibacterials, such as gatifloxacin, have primary application in the treatment of infections in children. Those antibacterials that have a bitter taste are at a considerable disadvantage for pediatric use since many pediatric preparations are in liquid form for ease of administration. Such therapeutic agents can only be administered in liquid dosage forms, including those constituted from dry powder or granules, if the formulations made therefrom have at least an acceptable taste to pediatric patients. Typically, such liquid preparations are available in the form of powders or granules that are mixed with water by a pharmacist at the time of dispensing to form a suspension in a flavored vehicle. The fine particles or granules of active substance in such preparations must either remain suspended in the liquid vehicle or be readily re-dispersed therein simply by shaking the container.
One disadvantage to pediatric suspensions as described above is that, in order to be readily suspended in an aqueous vehicle, the particles/granules of therapeutic agent are very fine. The fineness of the particles exposes a very large surface area to the aqueous vehicle. As a result, leaching of the therapeutic agent can occur, particularly over time. This phenomenon can take place regardless of the mechanism of binding utilized to mask the taste of the therapeutic agent, for example micro-encapsulation. In addition to effectively masking the taste of the therapeutic agent, the binding or coating means employed must maintain the integrity of the granules or particles in the mouth because any appreciable solubilization or leaching of the therapeutic agent by the saliva in the mouth will potentially negate the acceptable flavor of the preparation. Further, although the means of masking the taste of the therapeutic agent must maintain its integrity in the vehicle over a normal course of treatment and in the mouth, it must readily release the therapeutic agent in the stomach for absorption in order for it to be efficacious.
Numerous techniques are known in the art for masking the taste of bitter therapeutic agents. For example, Romanian Patent No. 88836, published Mar. 31, 1986, discloses a process for masking the bitter taste of erythromycin comprising co-precipitation with stearic acid in a ratio of 1:10 utilizing acetone as the common solvent at a temperature not exceeding 40° C. Tablets prepared from the product may be chewed or suspended in a liquid, typically water, for administration. Various other representative techniques focus on the particular taste-masking substance that is mixed with, coated onto or otherwise combined with the bitter-tasting active medicament. Examples of such substances include: acidic phospholipid or lysophospholipid, EP 0 631 787 B1; tocopherol polyethyleneglycol succinate, U.S. Pat. No. 5,891,469; certain ion-exchange resins, WO 01/05431 A1; and embonic acid, a salt or derivative thereof, U.S. Pat. No. 5,808,076. U.S. Pat. No. 5,622,978 discloses amorphous co-precipitates of dihydropyridines and a polymer, such as polyvinyl pyrrolidone, that are administered by dispersing in water. It is stated that the co-precipitates are formed by techniques to minimize crystallinity as crystallinity has a negative effect on bioavailability.
There are also a number of teachings of techniques for coating a bitter-tasting medicament with a waxy substance and then forming a powder therefrom, typically by spray drying, heat-assisted solvent removal and the like. U.S. Pat. No. 5,405,617 discloses a method of taste-masking a bitter pharmaceutical by admixing it with stearyl stearate in the molten state and spray congealing to form a powder. European application EP 0 855 183 A2 discloses a similar process wherein a quinoline derivative and a fatty acid are combined in a blender at a temperature between 30° and 140° C. and blended until a granulation is formed that masks the bitter taste of the drug. In some instances, e.g. Canadian Patent Application 2,227,314, the molten mixture is cooled to solidify it and then granulated. In WO 98/35656, a solution of the bitter-tasting medicament, a lipid and conventional fillers is filled into suitable forms, the solvent is thereafter removed by freeze-drying or other means and the resulting solid mass removed from the molds to yield discrete dosage units. U.S. Pat. No. 4,865,851 discloses taste-masking formulations of cefuroxime axetil by an integral coating of a lipid or mixture of lipids.
Regardless of the numerous techniques and pharmaceutical adjuncts known in the art to mask the taste of bitter-tasting medicaments, there remains the need to find an effective technique, adjunct or combination thereof for specific agents. This has been the case with gatifloxacin, particularly with regard to preparations that would be suitable for pediatric administration. Such preparations are provided in accordance with the present invention. It will be appreciated that, while the usefulness of the taste-masked gatifloxacin formed in accordance with the present invention will be emphasized in regard to pediatric medicine, it is likewise useful for preparations intended for all patients who, as a result of physical challenge or preference, would prefer a liquid preparation. The taste-masked gatifloxacin of the invention is further advantageous in that constituted liquid preparations made therefrom are stable over the normal therapeutic dosage schedule, typically fourteen days.
SUMMARY OF THE INVENTION
In accordance with the present invention, there is provided a form of gatifloxacin having its natural sharply bitter taste sufficiently masked so that it can be effectively utilized in pediatric formulations. Gatifloxacin is formed as a co-precipitate with at least one of stearic acid and palmitic acid in a critical weight ratio. The weight ratio of the two constituents is essential to the advantageous properties of taste-masking and stability of formulations containing it. The present invention further pertains to a process for the preparation of taste-masked gatifloxacin, pharmaceutical formulations containing it and the use thereof in the treatment of a wide variety of infections.
DETAILED DESCRIPTION OF THE INVENTION
In accordance with the present invention, there is provided a taste-masked form of the broad spectrum antibacterial gatifloxacin, 1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(3-methyl-1-piperazinyl)-4-oxo-3-quinolinecarboxylic acid.
Gatifloxacin is approved for use as a broad spectrum antibacterial therapeutic agent. Gatifloxacin has been shown to be both safe and efficacious in the treatment of infections in hepatically impaired individuals. It has also been shown to be effective against a broad spectrum of microorganisms, including antibiotic-resistant strains of
Streptococcus pneumoniae
, and to possess excellent overall tolerability.
In accordance with the present invention, it has been found that the characteristic extremely bitter taste of gatifloxacin can be effectively masked by the formation of a crystalline co-precipitate of gatifloxacin and at least one of stearic acid and palmitic acid in a particular weight ratio. Crystalline forms of gatifloxacin reported in the lit
Bembenek Kenneth S.
Benkerrour Loutfy
Corrao Richard G.
Esposito Luigi
Raghavan Krishnaswamy S.
Bernhardt Emily
Bristol--Myers Squibb Company
Volles Warren K.
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