Particle and preparation containing the particle

A particle and average particle size technology, applied in the field of particles, can solve the problems of irritating dosage, difficult nasal administration, difficult micronization, etc., and achieve the effect of full effectiveness

Inactive Publication Date: 2008-04-30
ONO PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The bioavailability can be improved by making an amorphous preparation nasal administration (patent document 2), but because there are a lot of well-developed nerve tissues in the nasal mucosa, there is a transient irritation produced by Compound 1 during nasal administration, and the nasal Limited mucosal surface area makes nasal administration of high doses difficult
[0009] In addition, compound 1 has adhesion and agglomeration, and there is a problem that it is difficult to micronize
[0010] The average particle size of the crystals obtained after recrystallization of Compound 1 is about 120 μm. The bioavailability of the particle is very low when administered orally, and it is insoluble in water when administered intravenously. Although the absorption rate in the body is higher than that of oral administration, nasal administration On the one hand, when compound 1 is administered through the nasal cavity, it is irritating or the dosage is limited due to the small surface area. Due to these problems, it is not very effective to use this compound as a medicine by the above-mentioned route of administration.

Method used

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  • Particle and preparation containing the particle

Examples

Experimental program
Comparison scheme
Effect test

Embodiment

[0096] Hereinafter, the present invention will be more specifically described by way of formulation examples, comparative examples, absorption test examples, and test examples, but the present invention is not limited thereto. In the following inhalation experiments, the cascade collision classifier is the particle size evaluation device for inhalation preparations described in the 28th revision of the US Pharmacopoeia, and the basic operation method is carried out in accordance with the 28th revision of the US Pharmacopoeia. When predicting the absorption of a compound from the lungs, the lung delivery of inhaled formulations can be assessed in vitro using a cascade impactor.

[0097] In addition, a hexane solution (20 mM) of the aerosol OT was used as a dispersion medium in the measurement of the particle size. The measurement particles were put into the test tube, and 1 mL of the dispersion medium was added to make a suspension. The suspension was sonicated for 1 minute, a...

preparation example 1

[0098] Preparation Example 1: Preparation of Suspension

[0099] After dissolving HPC (hydroxypropylcellulose)-SL (150 g) and sodium dodecyl sulfate (SDS) (1.5 g) in purified water (2548.5 g), Compound 1 (300 g) was suspended therein. Then, the suspension was pulverized in water with a pulverizer to obtain a suspension for pulmonary administration (3000 g) (theoretical concentration 10% w / w, measured concentration 8.37% w / w). The average particle size of Compound 1 in the resulting suspension was 201 nm.

preparation example 2

[0100] Formulation Example 2: Preparation of Suspension

[0101] After dissolving HPC-SL (100 g) and sodium lauryl sulfate (1 g) in purified water (1699 g), compound 1 (200 g) was suspended therein. Then, the suspension was pulverized in water by a pulverizer to obtain a suspension (2000 g) of Compound 1 (theoretical concentration 10% w / w, measured concentration 9.69% w / w). The suspension (5g) was diluted with a solution (57.5g) of HPC-SL (5.556w / w%) and sodium lauryl sulfate (0.056w / w%) in purified water (94.389w / w%), A suspension for pulmonary administration is obtained. The average particle size of Compound 1 in the resulting suspension was 395 nm.

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Abstract

Particles of 0.01 to 20 [mu]m average diameter comprising tert-butyl (4R)-4-{[((1R)-2-[(1-benzylpiperidin-4-yl)amino]-1-{[(cyclohexylmethyl)thio]methyl}-2-oxoethyl)amino]carbonyl}-1,3-thiazolidine-3-carboxylate. Preparations comprising the particles excel in transition into the lungs by inhalation and excel in dispersibility as particles, so that handling thereof is easy to thereby enable use of the compound as transpulmonary preparations.

Description

technical field [0001] The present invention relates to a compound containing (4R)-4-{[((1R)-2-[(1-benzylpiperidin-4-yl)amino]-1-{[(cyclohexylmethyl)thio] Methyl}-2-oxoethyl)amino]carbonyl}-1,3-thiazolidine-3-carboxylic acid tert-butyl ester, particles with a certain particle size. [0002] In detail, the present invention relates to [0003] 1) A compound containing (4R)-4-{[((1R)-2-[(1-benzylpiperidin-4-yl)amino]-1-{[(cyclohexylmethyl)thio]methyl Base}-2-oxoethyl)amino]carbonyl}-1,3-thiazolidine-3-carboxylic acid tert-butyl ester particles, the average particle size is 0.01-20μm, [0004] 2) its preparation method and [0005] 3) Formulations using the above particles. Background technique [0006] Since (4R)-4-{[((1R)-2-[(1-benzylpiperidin-4-yl)amino]-1-{[(cyclohexylmethyl)sulfanyl]methyl}-2 -Oxoethyl)amino]carbonyl}-1,3-thiazolidine-3-carboxylic acid tert-butyl ester (hereinafter referred to as compound 1.) and its salt have N-type calcium channel blocking effect, a...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K38/00A61K9/72A61K47/24A61K47/26A61K47/38A61P29/00
CPCA61K9/1652A61K9/0075A61K9/1623Y10T428/13Y10T428/2982A61P25/04A61P29/00C07D417/12A61K38/00A61K9/00
Inventor 增田英雄杉原光西浦昭雄林和行
Owner ONO PHARMA CO LTD
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