Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Particulate form
Patent
1997-06-26
1999-01-19
McKane, Joseph K.
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Particulate form
424489, 424501, 514242, A61K 3153
Patent
active
058611797
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/GB45/02865 filed Dec. 7, 1995.
The present invention relates to a pharmaceutical formulation of lamotrigine and pharmaceutically acceptable acid addition salts thereof. The invention also relates to the preparation of such a formulation.
Lamotrigine is 3,5-diamino-6-(2,3-dichlorophenyl)-1,2,4-triazine. It is disclosed in EP-A-0021121. Lamotrigine is useful for the treatment of epilepsy. No powder formulation of lamotrigine or one of its salts is currently available.
Pharmaceutical formulations in powder form can be prepared by a fluid bed granulating process or spray granulation. However, such processes represent a complex interaction of processing variables.
We have now prepared a number of powder formulations of lamotrigine. Only one type of formulation, however, proved to be entirely satisfactory. Accordingly, the present invention provides a pharmaceutical formulation which comprises:
(a) from 0.5 to 50% by weight of lamotrigine or a pharmaceutically acceptable acid addition salt thereof,
(b) from 15 to 50% by weight of lactose,
(c) from 15 to 50% by weight of starch,
(d) from 0.5 to 15% by weight of crystalline cellulose, and
(e) from 5 to 15% by weight of polyvinylpyrrolidone, following properties: to 850 .mu.m, Disintegration Test of The Pharmacopoeia of Japan, twelfth edition, 1991, and granules dissolves within 30 minutes when the granules are subjected to the Dissolution Test, method 2 (paddle method) of The Pharmacopoeia of Japan, twelfth edition, 1991.
The Disintegration Test of The Pharmacopoeia of Japan is a method to determine the resistance or disintegration of solid preparations for internal use in the test fluids. The test utilizes an apparatus consisting of a basket-rack assembly, a beaker, a suitable thermostatic arrangement for heating and a motor. The test liquid may be acidic, basic or water.
In the procedure, the basket-rack assembly is immersed in a liquid in the beaker and the apparatus is adjusted so as to raise and lower the basket smoothly at a constant frequency of 29-32 cycles per minute through a distance of 53-57 millimeters. At the lowest point of the downward stroke, the wire mesh must be 25 millimeters distant from the bottom of the beaker and the volume of the fluid in the beaker is such that at the lowest point of the downward stroke, the top of the basket is unlevel with the surface of the liquid. The temperature of the liquid is maintained at 37.degree. plus or minus 2 during the test.
The Dissolution Test is a method to test the dissolution of active ingredient from solid preparations for internal use. In the paddle method described, the testing assembly includes a rotary shaft with a blade. The blade and rotary shaft are inserted in a test solution and the sample is allowed to sink to the center of the vessel containing the test solution and the test performed.
The formulation of the invention is provided by a process which comprises spray-granulating:
(a) from 0.5 to 50% by weight of lamotrigine or a lamotrigine salt,
(b) from 15 to 50% by weight of lactose,
(c) from 15 to 50% by weight of starch, and
(d) from 0.5 to 15% by weight of crystalline cellulose,
(e) from 5 to 15% by weight of polyvinylpyrrolidone.
The granules of which the powder of the invention is composed are agglomerates. The lamotrigine or lamotrigine salt is provided on particles of lactose and starch which each act as an adsorbent bulking agent. A homogenous powder mixture comprising components (a) to (d) may be formed as a pre-blend prior to starting the spray granulation procedure. The presence of the lactose aids the formation of this pre-blend. The crystalline cellulose confers disintegrant and dissolution properties on the granules. The polyvinylpyrrolidone acts as a binder.
Any suitable lamotrigine salt which is a pharmaceutically acceptable acid addition salt can be used. Preferred salts are the methanesulphonate and isethionate salts. These salts can be made by reacting lamotrigine as the free base with the appropriate acid.
Preferably up to 98% by weight
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Hiskett Simon Philip
Taylor Susan Ann
McKane Joseph K.
The Wellcome Foundation Limited
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