WO2002049638A1

WO2002049638A1 - Medicinal granular preparation containing branched amino acids

Info

Publication number: WO2002049638A1
Application number: PCT/JP2001/010527
Authority: WO
Inventors: Mitsuyasu Ida; Chisato Makino; Haruo Orita; Akira Yabuki
Original assignee: Ajinomoto Co., Inc.
Priority date: 2000-12-06
Filing date: 2001-12-03
Publication date: 2002-06-27
Also published as: JP2002173423A; JP3259731B1

Abstract

A medicinal granular preparation characterized by containing as the active ingredients three branched amino acids, i.e., isoleucine, leucine, and valine, and further containing at least one organic acid as an acidulating agent. Since the bitterness attributable to the branched amino acids is mitigated, the granular preparation is easy to take.

Description

Specification

Pharmaceutical granules containing branched-chain amino acids

TECHNICAL FIELD The present invention relates to a granular pharmaceutical preparation containing three kinds of branched-chain amino acids consisting of isoleucine, leucine and valine as active ingredients. The pharmaceutical granule preparation of the present invention refers to granules and powders described in the Japanese Pharmacopoeia and European Pharmacopoeia, and pills described in the Japanese Pharmacopoeia, and pharmaceutical granules and powders The particle size range of is defined by the Japanese Pharmacopoeia. In particular, the present invention relates to a pharmaceutical granule containing three types of branched-chain amino acids consisting of isoleucine, leucine, and valine, which has a strong bitterness, as an active ingredient, wherein the pharmaceutical composition eases the bitterness and is easy to take. It is. Background art

Pharmaceutical granules containing three types of branched chain amino acids consisting of isoleucine, leucine and palin as active ingredients are effective therapeutic agents for liver diseases. Pharmaceutical granules containing these three types of amino acids have the drawbacks that they are bitter as they are, have poor flavor, and are very difficult to take.

Japanese Patent No. 29711855 discloses that in foods containing amino acids, acidity is controlled in order to suppress the generation of flavors (generally animal odor) peculiar to amino acids generated by heat sterilization and long-term storage. A method has been proposed in which the pH is adjusted to an acidic range with a sweetener and the flavor is further adjusted with a sweetener. In addition, Japanese Patent Application Laid-Open Publication No. Hei 10-2875751 discloses a method for improving the unpleasant taste of an oral solution containing an amino acid having an unpleasant taste, which has an unpleasant flavor. It has been proposed to incorporate a thiamine derivative, and isoleucine, leucine, valine, etc. are exemplified as amino acids having an unpleasant flavor.However, this method may be effective particularly when methionine is contained as an amino acid. Has been described.

However, there is no example of adding or using a sour agent for the purpose of suppressing the bitterness of a pharmaceutical granule formulation containing the highly bitter branched amino acids isoleucine, leucine and palin as active ingredients. In addition, sucrose, glucose, fructose, etc., which are conventionally used as sweeteners, are blended in the granules, or a flavoring coating layer is provided with these sugars to mask the poor flavor inherent in amino acids. However, in the case of a granular pharmaceutical preparation containing an amino acid such as isoleucine, oral isine, and valine as an active ingredient, sucrose, glucose, fructose, and other sugar components are isoleucine, leucine, Contact with valine causes the so-called Maillard reaction, which causes the coloration of the pharmaceutical granule formulation and impairs the storage stability, and must be avoided. Disclosure of the invention

The present invention relates to a pharmaceutical granule preparation containing three types of branched-chain amino acids consisting of isoleucine, leucine and valine, which are effective therapeutic agents for liver disease, as an active ingredient, by adding an organic acid as an acidulant, Pharmaceutical granules with less discomfort in taking by improving the bitterness and unpleasant taste peculiar to branched-chain amino acids by further adding flavoring agents and flavoring agents that do not cause coloring due to the Maillard reaction etc. It is intended to provide a formulation.

The present invention for solving the above-mentioned problem is to provide a pharmaceutical granule manufactured using three kinds of branched-chain amino acids consisting of isoleucine, leucine, and valine as an active ingredient, so as to contain a sour agent as an organic acid. The basic means is to add a flavoring agent that does not cause coloring or the like due to the Maillard reaction or the like as necessary, and includes the following inventions.

(1) It is characterized by containing three types of branched-chain amino acids consisting of isoleucine, leucine and palin as an active ingredient and containing one or more organic acids that are acceptable as pharmaceutical additives as sour agents. Pharmaceutical granules.

(2) The three types of branched-chain amino acids consisting of isoleucine, leucine, and palin are mixed at a weight ratio of isoleucine / leucine / valine = 11.9 to

2.2 / 1 .: The pharmaceutical granule preparation according to the above item (1), which is! -1.3.

(3) The three types of branched-chain amino acids consisting of isoleucine, leucine and pervaline have a particle size of 20 to 700 μπ, preferably 50 to 500 μm Isoloisin, leucine and The pharmaceutical granule preparation according to the above mode (1) or (2), which is produced using particles of three kinds of branched-chain amino acids consisting of valine as a granulation raw material.

The particle size of the branched-chain amino acid in the pharmaceutical granule is a numerical value measured by the following method.

Using a laser diffraction / scattering particle size distribution analyzer (LA-910, manufactured by HORIBA, Ltd.), 2-propanol 20 Om1 was placed in a circulation tank and stirred and circulated for 5 minutes while irradiating with ultrasonic waves. Then, perform blank measurement (ultrasonic wave is turned off during measurement). Subsequently, 200 ml of 2-propanol is put into the circulation tank, and the amino acid sample to be measured is introduced so that the transmittance becomes about 85%. Circulate for 4 minutes while stirring and irradiating with ultrasonic wave, and measure the particle size 5 minutes after stopping the ultrasonic wave. The median diameter based on volume was used as the average particle diameter.

(4) The method according to any one of items (1) to (3), wherein the sour agent is at least one selected from cunic acid, malic acid, acetic acid, tartaric acid, and ascorbic acid. Pharmaceutical granule preparation.

(5) In addition to the acidulant, aspartame, saccharin, sodium saccharin, glycyrrhizic acid and salts thereof, acesulfame K, mannitol, erythritol, sorbitol, xylitol, trehalose, cocoa powder and menthol The pharmaceutical granule preparation according to any one of (1) to (4), further comprising at least one flavoring agent selected from the group consisting of:

(6) The pharmaceutical granule preparation according to any one of (1) to (5), further comprising a flavoring agent.

The pharmaceutical granule of the present invention is a pharmaceutical granule produced by granulating particles of three types of branched-chain amino acids consisting of isoleucine, leucine and paparin. In the pharmaceutical granule preparation of the present invention, the mixing ratio of isoleucine, leucine and palin is by weight, and isoleucine / mouthrin / valine = 1 / 1.9 to 2.2 / 2 / 1.1 to 1.3. preferable.

The sour agent used in the pharmaceutical granule preparation of the present invention is citric anhydride, cunic acid, cU-malic acid, tartaric acid, d-tartaric acid, ascorbic acid, acetic acid, lactic acid, succinic acid, maleic acid, malonic acid, L -Organic acids such as glutamate hydrochloride. Particularly preferred are citric anhydride, citric acid, dl-malic acid, tartaric acid, d-tartaric acid, ascorbic acid, and acetic acid. And the like.

Flavoring agents used in the pharmaceutical granule preparation of the present invention include aspartame, saccharin, saccharin sodium, glycyrrhizic acid, monoammonium glycyrrhizinate, diammonium glycyrrhizinate, dipotassium glycyrrhizinate, disodium glycyrrhizinate, trisodium glycyrrhizinate, Acesulfame K, mannitol, erythritol, sorbitol, xylitol, Torehachirose, cocoa powder, etc. .

Various flavors can be used as the flavoring agent used in the pharmaceutical granule preparation of the present invention, and examples thereof include lemon flavor, orange flavor, grapefruit flavor, chocolate flavor, and (、-). Menthol, menthol and the like.

In the pharmaceutical granule preparation of the present invention, isoleucine, one of the active ingredients, generally has a particle size produced by a fermentation method of 1 mm or less, preferably 20 to 700 m, more preferably These particles are 50 to 500 particles and meet any of the standards of the Japanese Pharmacopoeia, the European Pharmacopoeia, and the United States Pharmacopeia.

Further, leucine is a particle generally produced by a fermentation method or an extraction method and having a particle size of 1 mm or less, preferably 20 to 700 m, more preferably 50 to 500 im. There is no particular limitation as long as it can produce a pharmaceutical granule that meets any of the standards of the Japanese Pharmacopoeia, the European Pharmacopoeia, and the United States Pharmacopeia.

In addition, valine is generally a particle manufactured by fermentation or synthesis and having a particle size of 1 mm or less, and meets any of the standards of the Japanese Pharmacopoeia, European Pharmacopoeia, and the United States Pharmacopeia. There is no particular limitation as long as a granular preparation can be produced.

A binder can be used to granulate the particles constituting the pharmaceutical granule 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, polyvinylpyrrolidone, polypinyl alcohol, and acrylic acid. Po Synthetic polymers such as lima, agar, gelatin, xanthan gum, gum arabic and the like can be used without particular limitation as long as they can be used for medicine. Also, the amount used is arbitrary as long as normal granulation is possible.

The granule preparation containing the three types of branched-chain 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, or an extruder. It can also be produced using equipment such as a granulator, a tumbling granulator, a spray-drying granulator, and a coating granulator. However, a high-speed stirring granulator or an extrusion granulator is preferable. Extrusion granulation is a method in which plasticized powder is extruded from a screen with many holes to granulate it.Pre-extrusion granulator, disc pellet pelletizer, ring die granulator Granulator, basket granulator, oscillating granulator, cylinder granulator, etc. are used.

The high-speed stirring granulation method is a method in which water or a binder solution is charged or sprayed into powder, and the powder is subjected to shearing, rolling, and consolidation by rotation of a stirring blade, and granulation is performed. A granulator 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 compression granulation is a method of compacting powder without using water or a binder solution, and is used for roll pressing, pre-ketting machines, single-shot tablet presses, and single-table tablet presses. Machine is 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. BEST MODE FOR CARRYING OUT THE INVENTION

Hereinafter, the present invention will be described more specifically with reference to examples. However, the present invention is not limited to the following examples. Example 1

High-speed stirring granulator (High-speed mixer, Fukae Bautech) (Average particle size 28 urn) 47.60 g, leucine (average particle size 23 im) 95.2

0 g, 57.20 g of phosphorus (average particle size: 22 urn), 10.00 g of citric anhydride, and 5.00 g of hydroxypropyl cell mouth were weighed and uniformly mixed. A solution obtained by dissolving a trace amount of lemon flavor in 30.00 g of distilled water was used as a binding solution, and this was added to perform granulation. The granules were dried at 60 using a tray dryer for 2 hours to obtain granules.

After sieving with a 1400 / im sieve, the sieved product was forcibly sieved using a 1400 sieve and thoroughly mixed with the sieved product to obtain a pharmaceutical granule formulation. Example 2

To a high-speed stirring granulator (high-speed mixer, manufactured by Fukae Powertech Co., Ltd.), 47.60 g of isoguchiine (average particle size 28 m), 95.2 g of leucine (average particle size 23 / xm), norin ( (Average particle size 22 ^ m) 57.20 g, 10.00 g of citric anhydride, 75.00 g of mannitol, 0.38 g of sodium saccharin, and 5.00 g of hydroxypropylcellulose were weighed and mixed uniformly. A solution obtained by dissolving a small amount of lemon flavor in 40.00 g of distilled water was used as a binding solution, and this was added to perform granulation. The granulated product was dried at 60 ° C for 2 hours using a tray dryer to obtain granules. After sieving with a 1400 im sieve, the sieved product was forcibly sieved using a 1400 ιη sieve, and sufficiently mixed with the sieved product to obtain a pharmaceutical granule preparation. Example 3

High-speed agitation granulator (high-speed mixer, Fukae Patetech Co., Ltd.) 28.56 g of isoguchiin (average particle size 28 m), leucine (average particle size 23 m) 57.1

2 g, palin (average particle size: 22 μπι) 34.32 g, malic acid 2.25 g, torayachiguchi 13.0 g, aspartame 90 g, hydroxypropylcellulose 3.00 g, weigh and uniform Was mixed. A solution obtained by dissolving a small amount of grape fresh flavor in 20.00 g of distilled water was used as a binding solution, and this was added to perform granulation. The granulated product was dried at 60 ° C for 2 hours using a tray dryer to obtain granules. After sieving with a 1400-m sieve, the sieved product was forcibly sieved using a 1400 sieve, and thoroughly mixed with the sieved product to obtain a pharmaceutical granule formulation. Example 4

In a high-speed stirring granulator (high-speed mixer, Fukae Patetech Co., Ltd.), 38.08 g of isoguchiin (average particle diameter 28 m), leucine (average particle diameter 23 ^ m) 76.16 g, valine (average) Particle size 22 m) 45.76 g, tartaric acid 3.00 g, mannitol 60.00 g, saccharin sodium 0.30 g, hydroxypropylcellulose 4.00 g were weighed and mixed uniformly. A solution obtained by dissolving a trace amount of lemon flapper in 45.00 g of distilled water was used as a binding solution, and the solution was added to perform granulation. The granulated product was dried at 60 using a tray dryer for 2 hours to obtain granules. After sieving with a 1400 sieve, the sieved product was forcibly sieved using a 1400 m sieve, and thoroughly mixed with the sieved product to obtain a pharmaceutical granule preparation. Example 5 '

In a high-speed stirring granulator (high-speed mixer, Fukae Patetech Co., Ltd.), 38.08 g of isoguchiin (average particle diameter 51 ^ m), 76.16 g of leucine (average particle diameter 59 ^ m), palin ( Average particle size: 22 m) 45.76 g, acetic acid 80 g, mannitol 60.00 g, saccharin sodium 0.30 g, hydroxypropylcellulose 4.00 g were weighed out and mixed uniformly. A solution obtained by dissolving a small amount of orange flavor in 45.00 g of distilled water was used as a binding solution, and the solution was added to perform granulation. The granulated product was dried at 60 ° C for 2 hours using a tray dryer to obtain granules. After sieving with a 1400 sieve, the sieved product was forcibly sieved using a 1400 m sieve, and thoroughly mixed with the sieved product to obtain a pharmaceutical granule preparation. Comparative Example 1

High-speed agitation granulator (8-speed mixer, manufactured by Fukae Patetech Co., Ltd.), 38.08 g of isoguchiine (average particle size 28 m), leucine (average particle size 23 im) 76.16 g, valine (average (Particle size 22 / m) 45.76 g and hydroxypropyl cellulose 4.00 g were weighed out and mixed uniformly. A solution obtained by dissolving a trace amount of lemon flavor in 40.00 g of distilled water was used as a binding solution, and this was added to perform granulation. Shelves with granules The granules were dried at 60 ° C for 2 hours using a stage dryer. After sieving with a 1400 / xm sieve, the sieved product was forcibly sieved using a 1400 sieve, and thoroughly mixed with the sieved product to obtain a pharmaceutical granule preparation. Experimental example 1

In the pharmaceutical granule preparations obtained in Examples 1 to 5 and the pharmaceutical granule preparation obtained in Comparative Example 1, sensory evaluation was performed using 5 adult male panelists while ensuring blindness. We evaluated the bitterness and residual aftertaste of the medicinal granule preparation of the three types of branched-chain amino acids (BCAA) after taking it and taking it.

The criteria are as follows.

◎: Good or not at all.

〇: I don't care much.

△: slightly anxious or slightly bitter.

X: Difficult to drink or bitter. table 1

Industrial applicability

As described above, the pharmaceutical granule preparation containing isoleucine, leucine, and palin according to the present invention hides the bitterness peculiar to the branched-chain amino acid and is easy to take. Granule preparation,

Claims

The scope of the claims

1. It contains three types of branched-chain amino acids consisting of isoleucine, leucine and palin as an active ingredient, and contains at least one organic acid that is acceptable as a pharmaceutical additive as a sour agent. Pharmaceutical granules.

2. The pharmaceutical granule preparation according to claim 1, wherein the sour agent is at least one selected from cunic acid, malic acid, acetic acid, tartaric acid and ascorbic acid.

3. In addition to the above-mentioned acidulants, aspartame, saccharin, sodium saccharin, glycyrrhizic acid and salts thereof, acesulfame K, mannitol, erythritol, sorbitol, xylitol, torehaulose, cacao powder and menthol 3. The pharmaceutical granule preparation according to claim 1, which comprises at least one flavoring agent selected from the group consisting of:

4. The pharmaceutical granule preparation according to any one of claims 1 to 3, further comprising a flavoring agent in addition to the sour agent.