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Method for improving dissolvability of anticoagulant

A technology of additives and granules, applied in pill delivery, pharmaceutical formulations, medical preparations of non-active ingredients, etc., can solve problems such as solubility drop

Active Publication Date: 2012-11-21
DAIICHI SANKYO CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] Compound I is a basic compound with good solubility in strongly acidic aqueous solution, but decreased solubility in neutral aqueous solution (such as neutral buffer)

Method used

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  • Method for improving dissolvability of anticoagulant
  • Method for improving dissolvability of anticoagulant
  • Method for improving dissolvability of anticoagulant

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0154] (granulation)

[0155] Under each condition described in Table 1, 1010 g of compound Ia, 2480 g of sieved mannitol (Mannit P, manufactured by TOWA-KASEI Co., Ltd.), 1050 g of pregelatinized starch (PCS PC-10, manufactured by Asahi Kasei Chemicals Corp.) and 267.5 g of crospovidone (Polyplasdone INF-10, manufactured by ISP) with 7 w / v% hydroxypropyl cellulose (HPC-L, manufactured by Nippon Soda Co., Ltd. ) of 2179 mL aqueous solution for fluidized bed granulation. In the fluidized bed granulation, a fluidized bed granulator (FLO-5, manufactured by Freund Corp.) was used

[0156] [Table 1]

[0157]

[0158] (dry).

[0159] Next, the granules thus granulated under the respective conditions were dried so that the water content of the granules after drying was 4.0% or more (A-1 and B-1 in Table 2), 2.0% or more and less than 4.0% (A in Table 2). -2 and B-2), or less than 2.0% (A-3 and B-3 in Table 2)

[0160] [Table 2]

[0161]

[0162] (compression).

[0163] 1...

Embodiment 2

[0175] The dissolution profile of Compound I from each tablet in pH 6.8 phosphate buffer was tested varying the maximum water content of the granules during granulation.

[0176] 7.274 kg of compound Ia, 17.85 kg of sieved mannitol (Mannit P, manufactured by TOWA-KASEI Co., Ltd.), 7.56 kg of pregelatinized starch (PCS PC-10, manufactured by Asahi Kasei Chemicals Corp.) and 1.926 kg Crospovidone (Polyplasdone INF-10, manufactured by ISP) was fluidized with 15.5 L of an aqueous solution containing 7 w / v% hydroxypropylcellulose (HPC-L, manufactured by Nippon Soda Co., Ltd.) Granulate. In fluidized bed granulation, FLO-30 or FLO-30SJ (manufactured by Freund Corp.) is used. The air inlet temperature, liquid spraying speed and spraying air pressure were set to 90 °C, 250 mL / min and 0.25 MPa, respectively. As a result, granules with a maximum water content of 9.6% of the granules during granulation were successfully prepared. Moreover, keeping the granule preparation ratio unchang...

Embodiment 3

[0179] 20.2 kg of compound Ia, 49.6 kg of sieved mannitol (PEARITOL 50C, manufactured by Roquette Corp.), 21 kg of pregelatinized starch (PCS PC-10, manufactured by Asahi Kasei Chemicals Corp.) and 5.35 kg of crospovidone (Polyplasdone INF-10, manufactured by ISP) Fluidized bed granulation was performed with 43.57 kg of an aqueous solution containing 7 w / w% hydroxypropylcellulose (HPC-L, manufactured by Nippon Soda Co., Ltd.). In fluidized bed granulation, WSG-120 (manufactured by Powrex Corp.) was used. The inlet temperature, liquid spraying speed, and air injection volume were set at 90 °C, 700 g / min, and 750 NL / min, respectively, so that the maximum water content (%) of the granules during granulation was below 10%.

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Abstract

There have been demands for a pharmaceutical composition, which has good dissolvability and contains a compound represented by formula (I), a pharmaceutically acceptable salt thereof or a solvate of the compound or salt, and which has an inhibitory effect on activated blood coagulation factor X and is useful as a prophylactic and / or therapeutic agent for thrombotic diseases. Disclosed is a method for producing a pharmaceutical composition that contains a compound represented by formula (I), which comprises a step wherein a compound represented by formula (I), a pharmaceutically acceptable salt thereof or a solvate of the compound or salt, one or more excipients selected from the group consisting of sugar alcohols and water-swellable additives, a disintegrant and a binder are mixed under such conditions that the maximum water content in a granulated product is maintained at 10% or less during the granulation.

Description

technical field [0001] The present invention relates to a process for the preparation of pharmaceutical compositions which exhibit favorable dissolution properties, contain compounds which exhibit an inhibitory effect on activated coagulation factor X (FXa), and are useful for the prophylaxis and / or prophylaxis of thrombotic diseases or therapeutic drugs. Background technique [0002] N represented by the following formula (I) 1 -(5-Chloropyridin-2-yl)-N 2 -((1S,2R,4S)-4-[(dimethylamino)carbonyl]-2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c] Pyridin-2-yl)carbonyl]amino}cyclohexyl)oxalamide (in this specification, also referred to as compound I): [0003] [Formula 1] [0004] [0005] or a pharmaceutically acceptable salt thereof, or a solvate thereof (in this specification, compound I, a pharmaceutically acceptable salt thereof, and a solvate thereof are also collectively referred to as compound I, etc.) known to activate blood coagulation factor X Exhibits effecti...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/444A61K9/16A61K9/20A61K9/32A61K9/36A61K47/10A61K47/32A61K47/36A61K47/38A61P7/02
CPCA61K9/1652A61K9/1694A61K9/2077A61K31/444A61K9/1623A61K9/1635A61P7/02
Inventor 釜田信关口学木所资典
Owner DAIICHI SANKYO CO LTD
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