WO2002038147A1 - Granular drug preparations containing branched amino acids and process for producing the same - Google Patents

Abstract

Granular drug preparations containing three branched amino acids, i.e., isoleucine, leucine and valine as the principal agents which are composed of 80% or more of grains having a grain size 0.5 mm or less and less than 20% of grains having a grain size less than 0.18 mm. Thus, the bitterness of drug preparations containing the three branched amino acids, i.e., isoleucine, leucine and valine can be effectively relieved and the flavor can be improved.

Description

 Specification

 TECHNICAL FIELD The present invention relates to a granular pharmaceutical preparation containing branched-chain amino acids and a method for producing the same.

 The present invention relates to a pharmaceutical granule preparation containing three kinds of branched-chain amino acids consisting of isoleucine, leucine and palin as a main drug and a method for producing the same. Background technology ''

 Pharmaceutical granules containing three types of branched-chain amino acids consisting of isoleucine, leucine and valine as the main drug are effective therapeutic agents for liver diseases. Granular preparations containing these three amino acids have the disadvantages that they are bitter as they are, have a poor flavor, and are very difficult to take.

 Pharmaceutical granules containing three amino acids, isoleucine, leucine, and valine, as the main drug, usually use sweeteners such as sucrose, glucose, and fructose, which are often used to form a flavoring coating layer. When it comes into contact with isoleucine, leucine and parin, which are so-called Maillard reactions, a brown compound is produced, which also has the disadvantage that the granule preparation is colored and storage stability is deteriorated.

 In addition, providing a coating layer to mask bitterness and bad flavor can increase costs.

It is known that nutrient pellets containing the above three types of branched-chain amino acids can reduce bitterness and unpleasant odor by adjusting the average diameter to 0.5 to 8.0 mm. 480 publication). However, the three types of branched-chain amino acids consisting of isoleucine, leucine and valin vary greatly in the bitterness and flavor of the granule preparation depending on the blending ratio. In addition, if the particle size of the granulated particles in the preparation is large, it is not only bulky and difficult to swallow in the mouth, but also it is easy to get caught in the teeth and there is a feeling of foreign matter. Not only is the degree of bitterness felt strong, but it is also difficult to pack the product because it becomes bitter and difficult to swallow, and it becomes bulky and less slippery on packaging materials. Disclosure of the invention

 Based on the above, it is an important issue to design a flavorful granule formulation that contains three types of branched-chain amino acids and that effectively suppresses bitterness to meet the specific purpose. Therefore, the present invention minimizes the bitterness and unpleasant taste peculiar to the three kinds of branched chain amino acids consisting of isoleucine, leucine and palin which are effective therapeutic agents for liver diseases, An object of the present invention is to provide a granule preparation which is less uncomfortable to take even if it is not coated, particularly a pharmaceutical granule preparation containing three kinds of branched-chain amino acids consisting of isoleucine, leucine and palin.

 The present inventors have conducted intensive studies in order to solve the above-mentioned problems, and as a result, they have been prepared by mixing three types of branched-chain amino acids consisting of isoleucine, leucine and palin with the main drug and blending them in a specific ratio. The present inventors have found that the above problem can be solved by strictly adjusting the particle size distribution of certain granulated particles to a specific range, and completed the present invention. The present invention includes the following inventions.

(1) Isoleucine, leucine and balin consisting of granulated particles in which 80% or more of particles having a particle size of 0.5 mm or less and particles having a particle size of less than 0.18 mm are less than 20%. Pharmaceutical granules containing three types of branched-chain amino acids as main drugs.

(2) The compounding ratio of isoleucine, leucine and parin is by weight, and isoisin Zin / leucine / valine = 11.9 to 2.2 / 1.1 to 1.3. 'A pharmaceutical granule preparation mainly comprising three kinds of branched-chain amino acids comprising isoleucine, leucine and valine as described in the above (1).

 The pharmaceutical granule of the present invention is a pharmaceutical granule produced by granulating particles of three kinds of branched-chain amino acids consisting of isoleucine, leucine and palin.

 In the pharmaceutical granule preparation of the present invention, the mixing ratio of isoleucine, leucine and palin is preferably isoleucine-norleucine Z valine = 1 / 1.9 to 2.2 / 1.1 to 1.3 by weight. .

The pharmaceutical granule preparation of the present invention means granules and powders described in the Japanese Pharmacopoeia or the European Pharmacopoeia, and the particle size distribution of the particles in the granule preparation is 0.5 mm or less. Is 80% or more and 20% of particles with a particle size of less than 0.18 mm It is a pharmaceutical granule preparation containing less than three amino acids of isoleucine, leucine and palin as main agents.

 The term “granularity” as used herein refers to particles obtained by granulating three types of branched-chain amino acids consisting of isoleucine, leucine, and palin as the main drug No. 30 (0.5 mm in size) specified by the Japanese Pharmacopoeia. This is the particle size obtained by using a sieve of No. 83 and No. 33 (0.18 mm opening) with a one-tap sieve shaker.

 In the pharmaceutical granule preparation of the present invention, isoleucine, which is one of the main drugs, is generally a particle having a particle size of 1 mm or less, which is produced by a fermentation method. It meets any of the standards of the United States Pharmacopeia, but is not so limited. Those which are adjusted to a particle size of 10 to 500 m are used.

 Leucine is generally produced by fermentation or extraction and has a particle size of 1 mm or less and satisfies either the Japanese Pharmacopoeia, the European Pharmacopoeia, or the United States Pharmacopeia. It is not limited. Those which are adjusted to a particle size of 10 to 500 / m are used.

 In addition, palin, which is generally produced by fermentation or synthesis and has a particle size of lmm or less and meets any of the standards of the Japanese Pharmacopoeia, European Pharmacopoeia, and US Pharmacopoeia, is used. But not limited to. There is no particular restriction on the particle size of palin as long as it meets the pharmacopeia specifications.

 There is no particular limitation on the method of adjusting the particle size of the particles of the three amino acids consisting of isoleucine, leucine and palin used for granulation, and a usual pulverization method is employed. Pulverizers that can be used for pulverization include impact-type (high-speed rotary) pulverizers such as a hammer mill, and tumbler-type (medium-type) pulverizers and other fluid-type (air-flow) pulverizers such as jet mills. And the like.

A binder can be used for granulating the particles constituting the granular preparation of the present invention. Examples of the binder include cellulose derivatives such as methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose and hydroxypropylmethylcellulose, starches such as corn starch and wheat starch, synthetic polymers such as polyvinylpyrrolidone and acrylic acid polymer. A Any material can be used without particular limitation as long as it can be used as a medicinal product that meets the standards for natural polymers such as rubia rubber and gelatin. Also, the amount used is within the range in which normal granulation is possible.

 The granule preparation containing the three amino acids in the pharmaceutical granule preparation of the present invention may be a high-speed stirring granulator, a fluidized bed granulator, a planetary mixer, a dry press granulator, a crush granulator, an extrusion granulator. Granulation can also be performed using granulators, tumbling granulators, spray drying granulators, coating granulators, etc., but high-speed stirring granulators and extrusion granulators are preferred.

 Extrusion granulation is a method of granulating plasticized powder by extruding it through a screen with many holes.Pre-extrusion granulator, disk pellets, Yuichi granulator, ring die granulator Granulator, basket granulator, oscillating granulator, cylinder cylinder granulator, etc. are used.

 The high-speed stirring granulation method is a method of adding or spraying water or a pinda solution to powder, and performing shearing, rolling, and compaction by rotating stirring blades. Machine is used.

 The fluidized-bed granulation method is a granulation method performed by spraying water or a binder liquid while flowing the powder to agglomerate the powder. The fluidized-bed granulator, the stirred fluidized-bed granulator, A tumbling fluidized bed type granulator and a stirring tumbling fluidized bed type granulator are used.

 Dry press granulation is a method of compressing and molding powder without using water or a binder solution. Roll presses, pre-ketting machines, single-shot tablet presses, and one-stop tablet presses are used. used.

 The tumbling granulation method is a method of rolling and granulating powder, and a drum-type granulator, a dish-type granulator, a vibrating granulator, and a disk-type granulator are used.

 The granule preparation of the present invention produced by granulation with the above granulator can be prepared by adding a small amount of a sweet component or adding a small amount of coating in the granulation. It goes without saying that bitterness can be further reduced. BEST MODE FOR CARRYING OUT THE INVENTION

Next, the present invention will be described more specifically with reference to examples. It is not limited by the examples. Example 1

 Three types of branched-chain amino acids [leucine: isoloucine: valine = 2: 1: 1.2 by weight ratio] 2 kg, hydroxypropylcellulose 0.026 kg, aspartame 0.001 kg, menthol 0.005 kg The mixture was placed in a granulator (High Speed Mixer FS-10, manufactured by Fukae Patetech Co., Ltd.), and 0.7 kg of distilled water was added. The mixture was kneaded at 300 rpm for Agitate and 3600 rpm for Chiyopper for 3 minutes. Thereafter, the obtained kneaded product was granulated by using an extruder EXD S-60 (0.4 mm screen, shaft rotation speed 22 rpm, manufactured by Fuji Padal Co., Ltd.). The wet granules obtained were dried at 70 ° C with an air supply temperature of 70 ° C using FLOCO Ichiichi FLO-5 (Freund Sangyo Co., Ltd.), and sized to obtain granules.

 15% of particles larger than 0.5 mm, 75% of particles 0.18 to 0.50 mm, and 10% of particles smaller than 0.18 mm as measured by the one-tap shaking method. A granular formulation having a degree distribution was produced. As a result of a sensory evaluation by five panelists, all of the five persons obtained an evaluation that the obtained granule preparation had reduced bitterness, had a weak foreign body sensation, and was easy to take. Example 2

 Three kinds of branched-chain amino acids (leucine: isoleucine: valine = 2: 1: 1.2 by weight) as in Example 1 2 kg, hydroxypropylcellulose 0.026 kg, saccharin sodium 0.001 kg, menthol 0 Put 005 kg into a high-speed agitation granulator (High Speed Mixer FS-10, manufactured by Fukae Powertech Co., Ltd.), add 0.7 kg of distilled water, and use an agitator at 300 rpm and a chopper at 3600 rpm for 3 minutes. Kneaded. Thereafter, the obtained kneaded product was granulated with an extruder EXD S-60 (0.4 mm screen, shaft rotation speed 22 rpm, manufactured by Fuji Padal Co., Ltd.). The obtained wet granulated product was dried at an air supply temperature of 70 ° C. using a Fouichi Coater FLO-5 (manufactured by Freund Corporation) and sized to obtain granules.

5% of particles larger than 0.5 mm were measured by the low tap sieve shaking method. A granule formulation was produced with a particle size distribution of 90% of 50 mm particles and 5% of particles less than 0.18 mm. As a result of a sensory evaluation by five panelists in the same manner as in Example 1, the obtained granule preparation was evaluated by all five persons as having a reduced bitterness, a weak foreign body sensation, and being easy to take.

 '

Comparative Example 1

 The same three branched-chain amino acids as in Example 1 (leucine: isoloicin: valine = 2: 1: 1.2 by weight) 2 kg, hydroxypropylcellulose 0.026 kg, aspartame 0.001 kg, menthol 0. Add 005 kg to a high-speed agitation granulator (Hi-Speed Mixer FS-10, manufactured by Fukae Bautech), add 0.7 kg of distilled water, and use an agitator at 300 rpm and a chopper at 3600 rpm. Kneaded for 3 minutes. Thereafter, the obtained kneaded product was granulated with an extruder EXD S-60 (0.7 mm screen, shaft rotation speed 22 rpm, manufactured by Fuji Padal Co., Ltd.). The obtained wet granules were dried at 70 ° C with an air supply temperature of Floco Ichiyo FLO-5 (Freund Sangyo Co., Ltd.), and sized to obtain granules.

 Particle size distribution of 70% of particles larger than 0.5 mm, 25% of particles 0.18 to 0.50 mm, and 5% of particles smaller than 0.18 mm as measured by the one-tap sieve shaking method Was prepared. As a result of the sensory evaluation performed by five panelists in the same manner as in Example 1, all five persons evaluated that the granule preparation had reduced bitterness but had a strong foreign body sensation and was difficult to take. Comparative Example 2

The same three kinds of branched-chain amino acids as in Example 1 (leucine: isoloicin: valine = 2: 1: 1.2 by weight ratio) 2 kg, hydroxypropylcellulose 0.005 kg, aspartame 0.001 kg, menthol 0. Add 005 kg to a high-speed stirring granulator (Hi-Speed Mixer FS-10, manufactured by Fukae Powertech Co., Ltd.), add 0.7 kg of distilled water, agitator 300 rpm, chopper 3600 rpm for 3 minutes Kneaded. Thereafter, the obtained kneaded product was granulated with an extrusion granulator EXD S-60 (0.4 mm screen, shaft rotation speed 22 rpm, manufactured by Fuji Padal Co., Ltd.). Obtained The wet granulated product was dried at a supply air temperature of 70 ° C. with FLO-5 (produced by Freund Corporation) to obtain granules.

 Manufacture a granulated product with a ratio of 0% of particles larger than 0.5 mm, 25% of particles 0.18 to 0.50 mm, and 75% of particles smaller than 0.18 mm as measured by a low tap sieve shaking method. did. As a result of the sensory evaluation by five panelists in the same manner as in Example 1, all the five persons were evaluated to be "bulky and hard to take due to being stuck in the mouth". The results are summarized in Table 1. table 1

Industrial applicability

 As described above, in a pharmaceutical granule preparation containing three kinds of amino acids consisting of isoleucine, leucine and palin, by adjusting the particle size distribution of granulated particles as in the present invention, bitterness inherent to the amino acid component is reduced. The effect was obtained that the particle size was reduced, the foreign-body sensation was weak, and it was easy to take, and the granule preparation having the particle size distribution was easy to pack.

Claims

The scope of the claims 1. Particles with a particle size of 0.5 mm or less are 80% or more, and particles with a particle size of less than 0.18mm are less than 20%, and are composed of granulated particles of isoleucine, leucine, and balin. Pharmaceutical granules containing three types of branched-chain amino acids as main drugs.  2. The compounding ratio of isoleucine, leucine and parin is by weight ratio, and isoisin / leucine Z valine = 1 / 1.9 to 2.2 / \. 1 to 1.3. 2. A pharmaceutical granule preparation comprising three kinds of branched-chain amino acids consisting of isoleucine, leucine and valine according to claim 1 as a main drug.