Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Tablets – lozenges – or pills
Reexamination Certificate
2000-02-17
2002-09-17
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Tablets, lozenges, or pills
C424S468000, C424S469000, C424S489000, C424S490000, C424S493000, C424S494000, C424S495000, C424S497000, C424S501000
Reexamination Certificate
active
06451345
ABSTRACT:
TECHNICAL FIELD
The present invention relates to effective taste masking while achieving rapid release of Linezolid as a burst in the upper intestinal tract using a combination of microencapsulation and functional coating.
More particularly, it relates to taste masked antibiotic particles which are composed of 1) a primary ethylcellulose coating of Linezolid needle-like crystals with a median particle size of 20 microns by solvent coacervation (producing Microcaps ®Linezolid), 2) an optional seal coat of shellac, and 3) an enteric coating.
BACKGROUND
Linezolid is one of the oxazolidinone antibiotics with a chemical name (S)-N-{{3-fluors4-(4-morpholinyl)phenyl}-2-oxo-5-oxazolidinyl)methyl}-acetimide; it is orally effective and fairly soluble in water. It is believed to be effective against bacteria resistant to other antibiotics. The present invention is directed to effective taste-masking of oxazolidinone antibiotics as well as other broad spectrum antibiotics such as macrolides.
A number of processes are widely used for masking the unpleasant, often bitter, taste of pharmacologically effective candidates. An overview by Roy, “Taste masking in oral pharmaceuticals”,
Pharmaceutical Technology
, April 1994, pages 84-99 addresses a number of processes and formulations for achieving taste masking of bitter drugs. The techniques described herein and other documents such as U.S. Pat. No. 5,075,114 assigned to Roche, U.S. Pat. No. 5,082,669 to Shirai et al. and U.S. Pat. No. 5,084,278 to Mehta, use polymeric materials (single or in combination), such as cellulosic polymers and Eudragit L and E type.
SUMMARY OF THE INVENTION
In accordance with the present invention, taste masked granules of Linezolid, or other oxazolidinone or macrolide antibiotics, are obtained by a combination of microencapsulation (i.e., by coacervation of ethylcellulose in cyclohexane) and application of functional coating on said microcapsules, the latter including an optional seal coat and an enteric coat. By providing uniform, impervious high coating levels on bitter Linezolid crystals, the present invention not only provides extremely effective taste masking, but also rapid release of the drug in the upper intestine. While the discussion which follows references the use of Linezolid, it will be apparent that it also pertains to other orally effective oxazolidinone or macrolide antibiotics.
The taste-masked granules obtained as described above are optionally blended with other pharmaceutically acceptable excipients such as flavors, sweeteners, suspending agents and/or preservatives and filled into unit dose containers or compressed into fast disintegrating, effervescent or chewable tablets. Stable aqueous suspensions can be constituted from the contents of unit doses for oral administration up to 21 days of pediatric and geriatric patients who are unwilling and/or find it difficult to swallow tablets. Fast disintegrating tablets rapidly disintegrate in the mouth and are therefore suitable for oral administration to patients who find it difficult to swallow tablets. Such dosage forms on oral administration should release not more than 5%, most preferably not more than 3%, at pHs of the saliva but rapidly release at least 70% within an hour or so at pHs of the upper intestinal tract.
DETAILED DESCRIPTION
The present invention provides taste-masked microcapsules of Linezolid or the like (any member of the orally effective oxazolidinone or macrolide antibiotics), suitable for oral administration as a suspension, a fast-disintegrating, effervescent or chewable tablet, and more specifically relates to such oral dosage forms in which the bitter taste of Linezolid contained therein is masked by a combination of microencapsulation by solvent coacervation and subsequent functional membrane coating on said microcapsules. A taste-masked microcapsule composition for taste masking an orally effective oxazolidinone or macrolide antibiotic in accordance with the present invention comprises microcapsules of the drug in a polymeric coating matrix prepared by solvent coacervation of a microencapsulation polymer. The resulting microcapsules may be provided with an optional seal coat and then are coated with a plasticized enteric polymer. In the resulting taste masked microcapsule composition the coating materials account for approximately 30 to 60% of the composition by weight. The taste-masked granules thus obtained release less than 5%, more preferably less than 3%, at a pH of 4.0 to 6.0 (pH of the saliva) but rapidly release (as a burst) at pHs of the upper intestinal tract. Accordingly, the Linezolid or other orally effective oxazolidinone or macrolide antibiotic can be orally administered without producing an unpleasant taste of the drug because of the minimal release at the pH of the saliva and yet the drug is rapidly released in the upper intestinal tract.
In one embodiment of the invention, Linezolid crystals are microencapsulated by suspending in ethylcellulose solution in cyclohexane at 80° C. and cooling gradually. The process for the preparation of individual taste masked bitter tasting pharmaceuticals by microencapsulation of the pharmaceutical in a coacervation medium containing cyclohexane, an encapsulating polymer and a phase inducing agent is well known in the art. A typical process is described in U.S. Pat. No. 3,860,733 to Lewis D. Morse et al which discloses microencapsulation of vitamin mixes by polymer/polymer incompatibility coacervation. A disclosed coating polymer is ethylcellulose, a disclosed phase inducing polymer is polyethylene and a disclosed solvent for the polymers is cyclohexane. Because of its detailed description of the coacervation process, U.S. Pat. No. 3,860,733 is incorporated herein by reference in its entirety. Another description of the preparation of ethylcellulose microcapsules by the liquid-liquid phase separation of ethylcellulose in cyclohexane is given in U.S. Pat. No. 4,411,933, which patent disclosure is also incorporated herein by reference in its entirety.
A microencapsulation polymer is used to encapsulate the antibiotic in a polymeric coating matrix prepared by solvent coacervation. Microencapsulation polymers suitable for use in the present invention include ethylcellulose, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate, anionic methacrylic acid-acrylate copolymers, neutral methacrylic acid esters and polyvinyl acetate. Preferably, the microencapsulation polymer is cellulosic and, in particular, ethylcellulose. Ethylcellulose used in the microencapsulation typically has an ethoxy content of about 45 to 50% and a viscosity in the range of 14 to 100 cps at 25° C. The amount of ethylcellulose employed can vary but for taste masking purposes, the ethylcellulose typically comprises about 10% to 40% by weight of the coated granules. One useful ethylcellulose is Ethylcellulose, NF manufactured by Dow Chemical Company having a 49.4% ethoxy content and a 103 cps viscosity at 25° C.
Any pharmaceutically acceptable organic solvent in which the active ingredient is not soluble but the polymer is soluble is suitable for microencapsulation, though the solvent of choice is cyclohexane. A coacervation inducer such as polyethylene, polyisobutylene, and the like, may be dissolved in the coacervation solution in which Linezolid is suspended. The polymers suitable for use as the coacervation inducer can have a molecular weight of between 5,000 and 10,000 and can be any of the commercial types customarily used for encapsulating purposes. One example of a useful polyethylene is Epolene C-10 manufactured by Eastman Kodak Company. The concentration of ethylcellulose and polyethylene and the wall thickness should be optimized for a particular formulation. The polyethylene is typically used in an amount of about 0.5 to 2% by volume.
After application of the ethylcellulose, a drying step should preferably be carried out for such a time period and at such temperatures so as to reduce residual solvent level below that recommended for human consumption.
These mi
Percel Phillip J.
Venkatesh Gopi M.
Vishnupad Krishna S.
Eurand Pharmaceuticals Ltd.
Fubara Blessing
Page Thurman K.
Thompson Hine LLP
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