JP2008162955A - Valine-containing high density granular agent - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a valine-containing granules enabling to make a low volume of one time taking dosage for producing an oral preparation containing only valine as a main medicine, useful as a medicine of a liver regeneration-treating agent, hepatic disease-treating agent, etc. <P>SOLUTION: The granules obtained by performing a wet-granulation of a mixture containing the valine having 30 to 90 μm mean particle size, an acidic additive and a binder, or the granules obtained by the wet granulation of a mixture containing the valine and succinic acid, adipic acid or their mixture and the binder are provided. <P>COPYRIGHT: (C)2008,JPO&INPIT

Description

  The present invention relates to granules containing valine as an active ingredient. More specifically, the present invention relates to a granule containing valine as a main drug having liver regeneration action, liver function improvement action, lipid metabolism improvement action and the like, and more particularly to a valine-containing oral granule which is easy for patients to take. The present invention also relates to a method for producing granules containing valine as the active ingredient.

  It is known that a pharmaceutical granule formulation containing as an active ingredient a branched-chain amino acid composed of three types of isoleucine, leucine and valine is effective in improving liver function. Since these branched chain amino acids have a bitter taste and a characteristic amino acid odor, and there are many single doses, the reduction of the bitterness and odor and the reduction of the single dose are issues in the formulation. Various ideas have been taken so far.

  For example, Japanese Patent No. 3259931 (Patent Document 1) contains only three kinds of branched chain amino acid particles composed of isoleucine particles having a particle size of 20 to 700 μm and leucine particles and valine particles having a particle size of 1 mm or less as a main ingredient. The ratio is at least one selected from citric acid, malic acid, acetic acid, tartaric acid and ascorbic acid as a sour agent, with a ratio by weight of isoleucine 1 / leucine 1.9-2.2 / valine 1.1-1.3. It is disclosed that a pharmaceutical granule preparation containing an organic acid can be provided, and the bitterness and unpleasant taste peculiar to branched-chain amino acids can be improved to provide a pharmaceutical granule preparation with less discomfort when taken. Has been.

  In Japanese Patent No. 3233155 (Patent Document 2), the blending ratio is isoleucine 1 / leucine 1.9 to 2.2 / valine 1.1 to 1.3 by weight, and the particle size is 0.5 mm or less. Granules for pharmaceutical use comprising only three kinds of branched chain amino acids consisting of isoleucine, leucine and valine, comprising granulated particles having a particle size of 80% or more and particles having a particle size of less than 0.18 mm and less than 20% The preparation has been described, and by adjusting the particle size distribution of the granulated particles, the bitterness inherent to the amino acid component is reduced, and the effect that the foreign body feeling is weak and easy to take is obtained. It is disclosed that the formulation is easy to package.

  Furthermore, Japanese Patent No. 3368898 (Patent Document 3) is characterized by adding an acid to a particle mixture of three kinds of branched chain amino acids of isoleucine, leucine and valine having a particle size of 10 to 1000 μm and granulating. A method for producing granules containing three kinds of branched chain amino acids, isoleucine, leucine and valine, as active ingredients is described. This makes it possible to reduce the dose per dose and greatly improve the dose. It is disclosed that an effect can be brought about. In addition, in the same publication, “in the case of granules, in general, the active ingredient is often pulverized to 50 μm or less in order to satisfy the requirements for ensuring uniformity of content, improving solubility, etc. The granules thus produced usually have a specific volume of 2.0 mL / g or more, although there are some differences depending on the type of granulation method and granulation conditions. In the case of branched chain amino acid particles, since the single dose of the branched chain amino acid is about 4 to 5 g, when a granule preparation is produced by grinding to 50 μm or less, the volume becomes about 8 to 10 mL, and in the mouth It is described as “bulky and extremely difficult to squeeze in”, and as a solution to this problem, the bulk density can be increased by adding an acid. It is disclosed that the effect can be further enhanced by using, as a raw material, a particle mixture of three kinds of branched chain amino acids of isoleucine, leucine and valine, particularly 100 to 800 μm, preferably 150 to 500 μm.

On the other hand, it is not a mixed preparation of branched chain amino acids consisting of three types of isoleucine, leucine and valine, but valine alone, a liver regeneration treatment (Patent Document 4), a liver disease treatment or a composition for improving liver function (Patent Document 5). ), A composition for improving lipid metabolism (Patent Document 6), and an oral pharmaceutical composition for treating or improving hepatic encephalopathy (Patent Document 7). However, these patent documents do not describe that a single dose can be reduced by using the particle size of valine or the use of additives.
Japanese Patent No. 3259931 Japanese Patent No. 3233155 Japanese Patent No. 3368898 Japanese Patent No. 3696297 International Publication No. 99/016433 Pamphlet International Publication No. 02/030418 Pamphlet JP 2004-99610 A

  When a preparation containing only valine as the main drug is used as a drug for liver regeneration treatment, liver disease treatment, etc., the dose per administration is as high as 2 to 4 g (6 to 12 g / day). In addition, there is a concern about the badness of valine, and it is also necessary to devise a technique for reducing the bitterness and odor of valine itself, and there has been a demand for a valine-containing oral preparation that improves these points. However, in preparations containing only valine as the active ingredient, an acid is used, and the preparation is prepared using only valine at a particle size described as preferred as a particle mixture of three types of branched chain amino acids in Japanese Patent No. 3368898. However, the expected effect was not obtained.

  An object of the present invention is to provide a valine-containing oral preparation containing only valine as a main drug, which enables a single dose to be reduced in volume. More specifically, an object of the present invention is to provide a valine-containing granule for producing an oral preparation containing only valine, which is useful as a pharmaceutical agent such as a therapeutic agent for liver regeneration and a therapeutic agent for liver disease. In particular, it is to provide a high-density granule containing valine and a method for producing such a granule, which enables a single dose to be reduced in volume. Another object of the present invention is to provide valine-containing high-density granules in which the bitterness and smell of valine itself are reduced.

  As a result of intensive research in developing a valine-containing oral preparation containing valine alone as the main ingredient, the present inventors have wet-granulated valine having an average particle size of 30 to 90 μm, an acidic additive and a binder, Or it discovered that the high density granule obtained by carrying out wet granulation of valine, a succinic acid, adipic acid, or its mixture, and a binder solved these subjects, and came to this invention.

That is, according to the present invention,
(1) Granules containing valine as an active ingredient, obtained by wet granulating a mixture containing valine having an average particle size of 30 to 90 μm, an acidic additive and a binder, and the content of valine is 83 of the granules. The granule, the content of which is not less than wt% and the content of the acidic additive is 0.1 to 1.0 wt% of the granule,
(2) The granule according to (1), wherein the average particle size of valine is 50 to 70 μm,
(3) The granule according to (1), wherein the acidic additive is at least one acid selected from the group consisting of tartaric acid, citric acid, succinic acid, ascorbic acid, adipic acid, malic acid, fumaric acid and lactic acid. ,
(4) Granules containing valine as an active ingredient, obtained by wet granulation of a mixture containing valine, an acidic additive and a binder, the content of valine being 83% by weight or more of the granules, and acidic The granule, wherein the content of the additive is 0.1 to 1.0% by weight of the granule, and the acidic additive is succinic acid or adipic acid or a mixture thereof;
(5) The granule according to (1) or (4), wherein the content of valine is 96% by weight or more of the granule,
(6) The granule according to (1) or (4), wherein the valine is L-valine,
(7) The granule according to (1) or (4), wherein the bulk density is 0.54 g / mL or more,
(8) The granule according to (1) or (4), wherein the wet granulation is performed by a high-speed stirring granulation method,
(9) Granules containing the granule according to (1) or (4),
(10) By wet granulating a mixture containing valine having an average particle size of 30 to 90 μm, an acidic additive and a binder, the content of valine is 83% by weight or more of the granule, and the content of the acidic additive is A method for producing a granule which is 0.1 to 1.0% by weight of the granule,
(11) By wet granulating a mixture containing valine, succinic acid or adipic acid or a mixture thereof, and a binder, the content of valine is 83% by weight or more, and succinic acid or adipic acid or a mixture thereof The manufacturing method of the granule whose content is 0.1 to 1.0 weight%, and the manufacturing method as described in said (10) or (11) whose bulk density of the granule is 0.54 g / mL or more (12) ,
Is provided.

  According to the present invention, it is possible to provide a high-density granule containing valine as an active ingredient, particularly a granule having a bulk density of 0.54 g / mL or more. In addition, according to the present invention, the volume of a single dose has been reduced. As a result, handling at the time of packaging and filling is improved, and by combining with compact packaging technology, it is possible to reduce the burden on the patient at the time of long-term prescription. As the final purpose, an oral granule containing valine which is easy to take as a main drug can be provided to patients.

  The valine used in the present invention can be used regardless of a commercial product, a synthetic product, or other production methods. Any of D-form, L-form and DL-form can be used, but L-form is most preferred. In general, it is preferable to use particles having a particle size of 1 mm or less, which are produced by a fermentation method or a synthesis method, and satisfy the provisions of the Japanese Pharmacopoeia, but are not limited thereto.

  In this specification, the average particle size means a 50% average particle size, that is, a particle size having an integrated value of 50%, and means a value obtained by averaging the particle sizes of particle groups measured by a laser diffraction / scattering method.

  Granules containing the valine of the present invention as a main agent can be obtained by wet granulating a mixture containing valine, an acidic additive and a binder having an average particle size of 30 to 90 μm, preferably 50 to 70 μm. Here, valine is used so as to constitute 83% by weight or more, or 90% by weight or more, and preferably 96% by weight or more by weight with respect to the weight of the whole granule. For example, valine is used to constitute 95-98.5%, or 96-97.5% by weight of the granules.

Although there is no restriction | limiting in particular as a method of adjusting the average particle size of valine, Preferably it can adjust using an impact grinding method.
As the acidic additive used in the present invention, any acid that can be added as a pharmaceutical can be used. Specific examples include compounds such as tartaric acid, citric acid, succinic acid, ascorbic acid, adipic acid, malic acid, fumaric acid, and lactic acid. One kind of acidic additive may be used, or two or more kinds may be used in combination. Preferred is succinic acid, adipic acid or a mixture thereof.

  In the present invention, the acidic additive is 0.1 to 1.0% by weight based on the weight of the whole granule based on the weight of one kind of acidic additive alone or the total weight of two or more kinds of acidic additives. %, Preferably 0.3 to 0.8% by weight, more preferably 0.5 to 0.7% by weight.

These acidic additives can improve the wettability of the binder to valine when producing the high density granules of the present invention.
Moreover, the granule containing the valine of the present invention as a main agent can be obtained by wet granulating a mixture containing valine, succinic acid or adipic acid as an acidic additive or a mixture thereof, and a binder. Here, valine is used so as to constitute 83% by weight or more, or 90% by weight or more, and preferably 96% by weight or more by weight with respect to the weight of the whole granule. For example, valine is used to constitute 95-98.5%, or 96-97.5% by weight of the granules. Succinic acid or adipic acid or a mixture thereof is 0.1 to 1.0% by weight, preferably 0.3 to 0.8% by weight, more preferably 0.5 to 0.5% by weight based on the weight of the whole granule. It is added in the range of 0.7% by weight.

When succinic acid or adipic acid or a mixture thereof is used as the acidic additive, the average particle size of valine is not particularly limited, but is, for example, 30 to 90 μm.
The granule of the present invention is, for example, a high-speed agitation granulation method while adding water (purified water) to the valine whose average particle size is adjusted in advance by adding an acidic additive and a binder, and optional components as necessary And it can granulate and manufacture by wet granulation methods, such as an extrusion granulation method. The acidic additive and binder and optional components used as necessary may be granulated by dissolving them in water (purified water) or adding them to valine as an aqueous solution. For example, water can be used in a proportion of 25 to 40 parts by weight, preferably 30 to 39 parts by weight, with respect to 100 parts by weight of valine.

  As the binder in the present invention, for example, cellulose derivatives such as methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, synthetic polymers such as polyvinylpyrrolidone, polyethylene glycol, etc. satisfy the standards such as the Japanese Pharmacopoeia or pharmaceutical additive standards. If it is, it can be used without particular limitation. Further, the amount used may be within a range where normal granulation is possible, but it is preferably in the range of 1 to 4% by weight, more preferably in the range of 2 to 3% by weight with respect to the weight of the whole granule. Used in.

Examples of optional components that can be used in the production of the granule of the present invention include excipients, flavoring agents, coloring agents, and fragrances.
Examples of the excipient include D-mannitol, lactose and corn starch. Considering the reactivity with valine, D-mannitol which is a non-reducing sugar is preferable. The amount of the excipient used is preferably not used or as small as possible for the purpose of reducing the dose.

  Examples of the corrigent include aspartame, sodium saccharin, glycyrrhizic acid, dipotassium glycyrrhizinate, stevia, sucralose, and acesulfame potassium. Preferably, saccharin sodium is used. The amount of the excipient used may be within the range where normal granulation is possible, but preferably 0.1 to 1% by weight, more preferably 0.4 to It can be used in the range of 0.5% by weight.

As a fragrance | flavor, vanillin, L-menthol, etc., Preferably L-menthol is mentioned, When using any, it can be used in a suitable quantity.
In addition, in this specification, the weight of the whole granule is the sum of the weight of each component other than water used for granulation of the granule.

In the present invention, the wet granulation can be performed, for example, by a high-speed stirring granulation method, an extrusion granulation method, a fluidized bed granulation method, a rolling fluidized bed granulation method, or the like.
It is preferable to carry out by a high speed stirring granulation method. The high-speed stirring granulation method is a method in which water or a binder liquid is charged or sprayed on a powder, and granulation is performed by shearing, dynamic rotation, and consolidation by rotation of a stirring blade. Vertical and horizontal stirring granulators can be used.

When granulation is performed by the high-speed stirring granulation method, the setting of the rotation speed is not particularly limited, but is performed at a rotation speed according to the blade screw 300 rpm and the cross screw 3000 rpm. Moreover, valine is premixed, and then a component other than valine dissolved in water (purified water) can be added and granulated for about 15 to 30 minutes. The granulated product obtained by wet granulation The granules of the present invention can be obtained by appropriately drying and sieving. Drying can be performed, for example, by shelf drying at a drying temperature and time of 70 ° C. for 2 hours. For example, sieving can be obtained by sieving the granulated product after drying through a 1400 μm sieve with a 250 μm sieve and collecting the sieved residue as granules.

  A granule of the present invention obtained by wet granulating a mixture containing valine having an average particle size of 30 to 90 μm, an acidic additive and a binder, and valine, succinic acid or adipic acid or a mixture thereof, and a binder The granules of the present invention obtained by wet granulating the mixture have a high density. That is, the granule of the present invention has a bulk density of 0.54 g / mL or more, preferably 0.54 to 0.64 g / mL, or 0.58 to 0.64 g / mL.

  Thus, since the granule of this invention is high-density, it is suitable for the granule for oral use for which the volume reduction of a single dose is required. It is particularly suitable for valine-containing oral granules that are easy for patients to take.

  The granule of the present invention can be used as it is as an oral granule. Moreover, a composite granule can be manufactured by mixing with the other component containing granule by a conventional method using the granule of this invention.

Furthermore, solid preparations such as powders, pills, tablets, and troches can be produced by using the granules of the present invention by conventional methods such as sizing, tableting, and coating.
As shown in the following examples, the granule of the present invention has a bulk density of 0.58 g / mL or more, particularly when the average particle size of valine is 50 μm to 70 μm. Regardless of the average particle size of valine, granules having a higher bulk density than other acidic additives can be produced, particularly when succinic acid and / or adipic acid is added as an acidic additive. It is included in the present invention.

  The contents of the present invention will be described in more detail in the following examples, but the present invention is not limited to the contents. In each example, the average particle size of valine used is a value measured by the following method. Using a laser diffraction / scattering type particle size distribution measuring device (Microtrac (registered trademark), Nikkiso Co., Ltd.), an appropriate amount of 2-propanol is circulated in a circulation tank, and blank measurement is performed. Subsequently, an appropriate amount of 2-propanol is added to the circulation tank and circulated. The valine was dispersed so that the device could be measured, and the measurement was performed. Here, the measurement of the average particle size by the laser diffraction / scattering method is obtained by calculating from the intensity pattern of the diffraction / scattered light emitted from a particle group irradiated with laser light. Moreover, in each Example, a bulk density is measured by the mass of the granulated material with respect to the same volume at the time of using 50 mL of measurement containers. Measurement was performed using a powder tester (registered trademark, manufactured by Hosokawa Micron Corporation).

<Granularity>
Example 1
The pulverized L-valine 230.88 g (average particle size 52 μm) was put into a high-speed stirring granulator (FM-VG-01 Powerex) and mixed for 1 minute under the conditions of blade 300 rpm and cross screw 3000 rpm. After mixing, an aqueous solution obtained by dissolving all components other than valine shown in Table 1 in 70 mL of purified water was added, followed by stirring and granulation for 30 minutes under the same conditions. The obtained granulated product was dried at 70 ° C. for 2 hours with a shelf dryer, then sieved with a 1400 μm sieve and sieved with a 250 μm sieve, and the sieved product of 250 μm sieve was collected to obtain granules. It was 0.61 g / mL when the bulk density of the obtained granule was measured.

Example 2
The pulverized L-valine (average particle size 54 μm) was put into a high-speed stirring granulator (FM-VG-01 Powerex) and mixed for 1 minute under the conditions of blade 300 rpm and cross screw 3000 rpm. After mixing, an aqueous solution obtained by dissolving all components other than valine shown in Table 1 in 70 mL of purified water was added, followed by stirring and granulation for 30 minutes under the same conditions. The obtained granulated product was dried at 70 ° C. for 2 hours with a shelf dryer, then sieved with a 1400 μm sieve and sieved with a 250 μm sieve, and the sieved product of 250 μm sieve was collected to obtain granules. It was 0.61 g / mL when the bulk density of the obtained granule was measured.

Example 3
The pulverized L-valine (average particle size 56 μm) was put into a high-speed stirring granulator (manufactured by FM-VG-01 Powerex) and mixed for 1 minute under the conditions of blade 300 rpm and cross screw 3000 rpm. After mixing, an aqueous solution obtained by dissolving all components other than valine shown in Table 1 in 70 mL of purified water was added, followed by stirring and granulation for 30 minutes under the same conditions. The obtained granulated product was dried at 70 ° C. for 2 hours with a shelf dryer, then sieved with a 1400 μm sieve and sieved with a 250 μm sieve, and the sieved product of 250 μm sieve was collected to obtain granules. It was 0.61 g / mL when the bulk density of the obtained granule was measured.

Example 4
The pulverized L-valine (average particle size 63 μm) was put into a high-speed stirring granulator (manufactured by FM-VG-01 Powrex) and mixed for 1 minute under the conditions of blade 300 rpm and cross screw 3000 rpm. After mixing, an aqueous solution obtained by dissolving all components other than valine shown in Table 1 in 70 mL of purified water was added, followed by stirring and granulation for 15 minutes under the same conditions. The obtained granulated product was dried at 70 ° C. for 2 hours with a shelf dryer, then sieved with a 1400 μm sieve and sieved with a 250 μm sieve, and the sieved product of 250 μm sieve was collected to obtain granules. It was 0.62 g / mL when the bulk density of the obtained granule was measured.

Example 5
The pulverized L-valine (average particle size: 69 μm) was put into a high-speed stirring granulator (manufactured by FM-VG-01 Powerex), and mixed for 1 minute under the conditions of blade 300 rpm and cross screw 3000 rpm. After mixing, an aqueous solution obtained by dissolving all components other than valine shown in Table 1 in 70 mL of purified water was added, followed by stirring and granulation for 30 minutes under the same conditions. The obtained granulated product was dried at 70 ° C. for 2 hours with a shelf dryer, then sieved with a 1400 μm sieve and sieved with a 250 μm sieve, and the sieved product of 250 μm sieve was collected to obtain granules. It was 0.60 g / mL when the bulk density of the obtained granule was measured.

Example 6
The pulverized L-valine (average particle size 38 μm) was put into a high-speed stirring granulator (manufactured by FM-VG-01 Powerex) and mixed for 1 minute under the conditions of blade 300 rpm and cross screw 3000 rpm. After mixing, an aqueous solution obtained by dissolving all components other than valine shown in Table 1 in 70 mL of purified water and 15 mL of purified water were added, followed by stirring and granulation for 15 minutes under the same conditions. The obtained granulated product was dried at 70 ° C. for 2 hours with a shelf dryer, then sieved with a 1400 μm sieve and sieved with a 250 μm sieve, and the sieved product of 250 μm sieve was collected to obtain granules. It was 0.54 g / mL when the bulk density of the obtained granule was measured.

<Acid>
Example 7
The pulverized L-valine (average particle size 25 μm) was put into a high-speed stirring granulator (manufactured by FM-VG-01 Powerex), and mixed for 1 minute under the conditions of blade 300 rpm and cross screw 3000 rpm. After mixing, all components other than valine shown in Table 2 (acidic additive used adipic acid) were dissolved in 70 mL of purified water, and 15 mL of purified water was added, followed by 15 minutes under the same conditions. Agitation granulation was performed. The obtained granulated product was dried at 70 ° C. for 2 hours with a shelf dryer, then sieved with a 1400 μm sieve and sieved with a 250 μm sieve, and the sieved product of 250 μm sieve was collected to obtain granules. It was 0.58 g / mL when the bulk density of the obtained granule was measured.

Example 8
The pulverized L-valine (average particle size 25 μm) was put into a high-speed stirring granulator (manufactured by FM-VG-01 Powerex), and mixed for 1 minute under the conditions of blade 300 rpm and cross screw 3000 rpm. After mixing, all components other than valine shown in Table 2 (acidic additive used succinic acid) was dissolved in 70 mL of purified water, and 15 mL of purified water was added, followed by 15 minutes under the same conditions. Agitation granulation was performed. The obtained granulated product was dried at 70 ° C. for 2 hours with a shelf dryer, then sieved with a 1400 μm sieve and sieved with a 250 μm sieve, and the sieved product of 250 μm sieve was collected to obtain granules. It was 0.54 g / mL when the bulk density of the obtained granule was measured.

Example 9
The pulverized L-valine (average particle size 56 μm) was put into a high-speed stirring granulator (manufactured by FM-VG-01 Powerex) and mixed for 1 minute under the conditions of blade 300 rpm and cross screw 3000 rpm. After mixing, all components other than valine shown in Table 2 (acidic additive used adipic acid) were dissolved in 70 mL of purified water, and 10 mL of purified water was added, followed by 30 minutes under the same conditions. Agitation granulation was performed. The obtained granulated product was dried at 70 ° C. for 2 hours with a shelf dryer, then sieved with a 1400 μm sieve and sieved with a 250 μm sieve, and the sieved product of 250 μm sieve was collected to obtain granules. It was 0.63 g / mL when the bulk density of the obtained granule was measured.
<Granularity>
Comparative Example 1
The pulverized L-valine (average particle size: 207 μm) was charged into a high-speed stirring granulator (manufactured by FM-VG-01 Powerex), and mixed for 1 minute under conditions of blade 300 rpm and cross screw 3000 rpm. After mixing, an aqueous solution obtained by dissolving all components other than valine shown in Table 1 in 70 mL of purified water was added, followed by stirring and granulation for 15 minutes under the same conditions. The obtained granulated product was dried at 70 ° C. for 2 hours with a shelf dryer, then sieved with a 1400 μm sieve and sieved with a 250 μm sieve, and the sieved product of 250 μm sieve was collected to obtain granules. It was 0.36 g / mL when the bulk density of the obtained granule was measured.

Comparative Example 2
L-leucine: L-isoleucine: L-valine = 2: 1: 1.2 (average particle size 111 μm) was charged into a high-speed stirring granulator (FM-VG-01 manufactured by Powrex), blade 300 rpm, cross screw 3000 rpm conditions Mix for 1 minute under. After mixing, an aqueous solution obtained by dissolving all the components other than the branched chain amino acids shown in Table 3 in 70 mL of purified water was added, followed by stirring and granulation for 7 minutes under the same conditions. The obtained granulated product was dried at 70 ° C. for 2 hours with a shelf dryer, then sieved with a 1400 μm sieve and sieved with a 250 μm sieve, and the sieved product of 250 μm sieve was collected to obtain granules. It was 0.39 g / mL when the bulk density of the obtained granule was measured.

Comparative Example 3
L-leucine: L-isoleucine: L-valine = 2: 1: 1.2 (average particle size 52 μm) was put into a high-speed stirring granulator (FM-VG-01 Powerex), blade 300 rpm, cross screw 3000 rpm. Mix for 1 minute under conditions. After mixing, an aqueous solution obtained by dissolving all the components other than the branched chain amino acids shown in Table 3 in 70 mL of purified water was added, followed by stirring and granulation for 15 minutes under the same conditions. The obtained granulated product was dried at 70 ° C. for 2 hours with a shelf dryer, then sieved with a 1400 μm sieve and sieved with a 250 μm sieve, and the sieved product of 250 μm sieve was collected to obtain granules. It was 0.52 g / mL when the bulk density of the obtained granule was measured.

<Acid>
Comparative Example 4
The pulverized L-valine (average particle size 25 μm) was put into a high-speed stirring granulator (manufactured by FM-VG-01 Powerex), and mixed for 1 minute under the conditions of blade 300 rpm and cross screw 3000 rpm. After mixing, all components other than valine shown in Table 2 (the acidic additive used tartaric acid) was dissolved in 70 mL of purified water and 15 mL of purified water was added, followed by stirring for 15 minutes under the same conditions. Granulation was performed. The obtained granulated product was dried at 70 ° C. for 2 hours with a shelf dryer, then sieved with a 1400 μm sieve and sieved with a 250 μm sieve, and the sieved product of 250 μm sieve was collected to obtain granules. It was 0.53 g / mL when the bulk density of the obtained granule was measured.

  As is clear from Examples 1-9 and Comparative Examples 1-4, the granules obtained according to the present invention all showed a bulk density of 0.54 g / mL or more, whereas the average particle size of valine. Since the bulk density is small (Comparative Example 1), small one (Comparative Example 4), and a mixture of branched chain amino acids (Comparative Examples 2 and 3), not valine alone. Thus, it was found that a single dose can be further reduced in a pharmaceutical preparation containing valine as the main drug.

Claims (12)

  A granule containing valine as a main agent, which is obtained by wet granulating a mixture containing valine having an average particle size of 30 to 90 μm, an acidic additive and a binder, and the content of valine is 83% by weight or more of the granule Wherein the content of the acidic additive is 0.1 to 1.0% by weight of the granule.   The granule according to claim 1, wherein the average particle size of valine is 50 to 70 µm.   The granule according to claim 1, wherein the acidic additive is at least one acid selected from the group consisting of tartaric acid, citric acid, succinic acid, ascorbic acid, adipic acid, malic acid, fumaric acid and lactic acid.   A granule containing valine as a main agent, obtained by wet granulation of a mixture containing valine, an acidic additive and a binder, wherein the content of valine is 83% by weight or more of the granule, The granule, wherein the content is 0.1 to 1.0% by weight of the granule, and the acidic additive is succinic acid or adipic acid or a mixture thereof.   The granule according to claim 1 or 4, wherein the content of valine is 96% by weight or more of the granule.   The granule according to claim 1 or 4, wherein the valine is L-valine.   The granule of Claim 1 or 4 whose bulk density is 0.54 g / mL or more.   The granule according to claim 1 or 4, wherein the wet granulation is performed by a high-speed stirring granulation method.   The granule containing the granule of Claim 1 or 4.   By wet granulating a mixture containing valine having an average particle size of 30 to 90 μm, an acidic additive and a binder, the content of valine is 83% by weight or more of the granule, and the content of the acidic additive is 0% of the granule. A method for producing granules of 1 to 1.0% by weight.   By wet granulating a mixture containing valine, succinic acid or adipic acid or a mixture thereof, and a binder, the content of valine is 83% by weight or more, and the content of succinic acid or adipic acid or a mixture thereof is A method for producing granules of 0.1 to 1.0% by weight.   The production method according to claim 10 or 11, wherein the bulk density of the granules is 0.54 g / mL or more.