Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Tablets – lozenges – or pills
Reexamination Certificate
2000-10-17
2003-05-06
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Tablets, lozenges, or pills
C424S400000, C424S464000, C424S468000, C424S470000, C424S472000, C424S474000
Reexamination Certificate
active
06558700
ABSTRACT:
TECHNICAL FIELD
This invention relates to a multiple-unit sustained release tablet comprising a granular part and a powdery part.
BACKGROUND ART
Pharmaceutical preparations for controlling a dissolution rate of an active ingredient may be classified into a single-unit pharmaceutical preparation and a multiple-unit pharmaceutical preparation. The single-unit pharmaceutical preparation is mainly in the form of tablets, while the multiple-unit one is mainly in the form of capsules or granules. The multiple-unit pharmaceutical preparation is superior to the single-unit one in the following characteristics: (1) less change in absorption of an active ingredient, (2) easier reproducibility of dissolution, and (3) being applicable to two or more active ingredients. Due to these excellent features, the multiple-unit pharmaceutical preparation is desirable as a sustained release preparation. The multiple-unit pharmaceutical preparation is desirably in the form of tablets rather than capsules or granules so that it may be taken more easily.
However, the conventional multiple-unit sustained release tablet is prepared by coating core particles with a drug layer, coating the surface of said coated particles with a release-controlling agent to form sustained release granules, blending said granules with a powdery part and then compressing to tablets. A sustained release film of the granules may often be broken during compression to tablets, resulting in difficulty in controlling dissolution of the drug. For coping with these problems, there have been proposed multiple-unit tablets, which comprises a granule of an indefinite form and a powdery part, said granule being composed of an uncoated granule containing low-melting fats and oils and an active ingredient, and a release-controlling film (JP-A-7-316042), or sustained release compression tablets prepared by compressing numerous microcapsules composed of fine particles of an active ingredient, said active ingredient being coated with a sustained release polymer composition, wherein said microcapsules have non-uniform particle diameters within the range of from about 5 &mgr; to about 400 &mgr; and can be immediately disintegrated in an aqueous solution to disperse into individual microcapsules (Japanese Patent No. 2601660). However, sustained release granules according to the prior art having an indefinite and unequal shape would make it difficult to apply a uniform coating film and to prepare sustained release tablets with a stable dissolution rate.
The object of the invention is to provide multiple-unit sustained release tablets with little change in dissolution rate caused by compression during tableting step.
DISCLOSURE OF THE INVENTION
We have found that the above problems can be dissolved by using a granule comprising a matrix composed of a water-insoluble polymer and an active ingredient (hereinafter referred to as a matrix granule) or said matrix granule further coated with a release-controlling film (hereinafter referred to as a coated granule), upon which the present invention has been completed.
More specifically, the present invention includes the following inventions:
(1) A multiple-unit sustained release tablet characterized by consisting of a granular part and a powdery part, each granule in the granular part comprising a matrix composed of a water-insoluble polymer and an active ingredient.
(2) The multiple-unit sustained release tablet as described in the item (1), wherein said granule comprises a core particle and a matrix layer composed of a water-insoluble polymer and an active ingredient for coating said core particle.
(3) The multiple-unit sustained release tablet as described in the item (1) or (2), wherein a weight ratio of said water-insoluble polymer to said active ingredient is 0.7:1-3:1.
(4) The multiple-unit sustained release tablet as described in any of the items (1)-(3), wherein said water-insoluble polymer is ethyl cellulose.
(5) The multiple-unit sustained release tablet as described in the item (4), wherein said ethyl cellulose has a viscosity of not less than 15 cps at 25° C. when dissolved at 5% by weight in a mixed solution of toluene and ethanol (8:2 w/w).
(6) The multiple-unit sustained release tablet as described in any of the items (1)-(5), wherein said granule is coated with a release-controlling film.
(7) The multiple-unit sustained release tablet as described in the item (6), wherein said release-controlling film is a water-insoluble polymer.
(8) The multiple-unit sustained release tablet as described in the item (6) or (7), wherein said water-insoluble polymer is ethyl cellulose.
(9) The multiple-unit sustained release tablet as described in any of the items (6)-(8), wherein said granule has a granule strength of not less than 3,000 g/mm
2
in the state not coated with said release-controlling film.
The water-insoluble polymer as used herein means a water-insoluble polymer used in the pharmaceutical field as a sustained release coating agent, an enteric coating agent, a gastric coating agent, etc., which may include, for example, ethyl cellulose, purified shellac, white shellac, aminoalkyl methacrylate copolymer RS, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, carboxymethylethyl-cellulose, cellulose acetate phthalate, methacrylic acid copolymer L, methacrylic acid copolymer LD, methacrylic acid copolymer S, aminoalkyl methacrylate copolymer E, polyvinyl acetal diethylaminoacetate, etc. Of these polymers, ethyl cellulose may be most preferable.
Preferably, the type, degree of substitution and molecular weight of the water-insoluble polymers should be chosen for their proper use, depending on solubility of the active ingredient in water or an alcohol, the desired sustained release level and the like. These water-insoluble polymers may be used either alone or in combination. There may be further incorporated a hydrogenated oil, stearic acid, cetanol, etc. as a coating auxiliary agent, and a middle-chain triglyceride, triacetin, triethyl citrate, cetanol, etc. as a plasticizer.
The ethyl cellulose used herein preferably has an ethoxyl content of 43-50% (substitution degree of 2.2-2.6). In order to carry out the invention, ethyl cellulose has a viscosity of not less than 15 cps, preferably not less than 20 cps, more preferably 20-50 cps, at 25° C. when dissolved at 5% by weight in a mixed solution of toluene and ethanol (8:2 w/w).
A solvent for the water-insoluble polymer may vary depending on the type of the polymer. In general, a mixture of water and a lower alcohol or a lower alcohol is preferable. In case of ethyl cellulose, a 60% or more aqueous ethanol solution is preferable. It is essential that the water-insoluble polymer be dissolved in such a solvent and that an active ingredient be dissolved or uniformly dispersed in the water-insoluble polymer solution. Where the active ingredient is of a dispersed form, it is effective to maintain an average particle diameter below 20 &mgr;m for improving adhesion to a core particle and securing uniformity, and to perform a sufficient stirring for establishing uniformity.
The present invention may be applied to various active ingredients including water-soluble drugs by varying the type of water-insoluble polymers or blending ratio thereof or by additional coating of the matrix granule with a release-controlling film. Accordingly, the kind of the active ingredient to be used in this invention is not particularly restricted. The active ingredients which may be used in this invention are exemplified as follows: Diprophylline, dextromethorphan hydrobromide, phenylpropanolamine hydrochloride, belladonna (total) alkaloids, acetaminophen, theophylline, sodium salicylate, aspirin, ibuprofen, noscapine, dl-methylephedrine hydrochloride, dihydrocodeine phosphate, ethenzamide, bromhexine hydrochloride, d-chloropheniramine maleate, aminophylline, proxyphylline, caffeine, etc. These active ingredients may be used in admixture with two or more thereof.
According to the invention, it is feasible to freely control dissolutio
Aoki Shinji
Tsuchida Kazutaka
Evans Charesse
Page Thurman K.
Sughrue & Mion, PLLC
Taisho Pharmaceutical Co. Ltd.
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