JP3341768B1 - Chewable preparation containing branched-chain amino acids - Google Patents

Abstract

Abstract: PROBLEM TO BE SOLVED: To provide a method for producing a chewable agent which does not generate sticking at the time of tableting, and to suppress the odor and bitterness peculiar to a branched-chain amino acid and to have excellent stability during handling and storage. Provided is a chewable agent containing three kinds of branched-chain amino acids as active ingredients. SOLUTION: The isoleucine, leucine and valine 3
Granulating a particle mixture containing various kinds of branched-chain amino acid particles as an active ingredient to produce granules, coating the granules with a coating solution containing a binder component to produce coated granules, and the coating A method for producing a chewable preparation comprising three types of branched-chain amino acids of isoleucine, leucine and valine as active ingredients, comprising a step of tableting granules to produce a chewable preparation.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a chewable pharmaceutical preparation containing three kinds of branched-chain amino acids of isoleucine, leucine and valine as active ingredients.

[0002]

2. Description of the Related Art Pharmaceutical preparations containing, as an active ingredient, three kinds of branched-chain amino acids consisting of isoleucine, leucine and valine are effective therapeutic agents for liver diseases, and currently commercially available preparations are mainly granules. . However, in the case of a granule containing the above-mentioned three kinds of branched chain amino acid particles as an active ingredient, 1
The remedy dose is about 5 g, which is significantly higher than general preparations,
There was a drawback that it was difficult to take.

[0003] In general, a chewable preparation which is chewed or dissolved in the mouth and taken when taking a preparation with a large dose is preferably used. Since the amount of the branched-chain amino acid mixture to be taken at one time is too large as compared with the case of other drugs, the binding between powders is low, and sticking is likely to occur as a tableting trouble at the time of tableting. For this reason, strong binding substances such as cellulosic compounds are added to prevent tableting disorders.However, formulations produced by such a method suffer from bitterness specific to branched-chain amino acids in the oral cavity. However, it was difficult to take the medicine.

[0004]

SUMMARY OF THE INVENTION An object of the present invention is to produce a chewable agent which does not cause sticking during tableting in a process for producing a chewable agent containing three kinds of branched chain amino acids of isoleucine, leucine and valine as active ingredients. It is to provide a method. Further, an object of the present invention is to use, as an active ingredient, the three kinds of branched-chain amino acids in which odor and bitterness peculiar to the branched-chain amino acids are suppressed, and excellent in stability during handling and storage. It is to provide a chewable agent.

[0005]

Means for Solving the Problems In order to solve the above problems, the present inventors have made intensive studies and as a result, have found that a chewable preparation containing only three kinds of branched chain amino acids of isoleucine, leucine and valine as an active ingredient is provided. In the tableting step in a series of manufacturing steps, sticking is prevented by applying a coating containing a binder component to a granule containing isoleucine, leucine and valine, which is a raw material for tableting, and then compressing the granule. As well as
The present inventors have found that the odor and bitterness peculiar to the three kinds of branched-chain amino acids can be reduced, and have completed the present invention. The present invention includes the following items.

(1) A step of granulating a particle mixture containing three kinds of branched chain amino acid particles of isoleucine, leucine and valine as an active ingredient to produce granules, and the granules are coated with a coating solution containing a binder component. It comprises a step of coating to produce coated granules, and a step of tableting the coated granules to produce a chewable preparation, comprising three types of branched-chain amino acids of isoleucine, leucine and valine as active ingredients. Of producing a chewable agent.

(2) The binder component in the coating solution is mannitol, erythritol, sorbitol, xylitol, trehalose, ethyl cellulose,
The chewable preparation according to (1), which is at least one selected from methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylethylcellulose, polyvinylpyrrolidone, carboxyvinyl polymer, polyvinyl alcohol, gum arabic and sodium alginate. Manufacturing method.

(3) The method according to (1) or (2), wherein the coating liquid contains a sweetener component.

(4) Aspartame, saccharin, sodium saccharin, glycyrrhizic acid, monoammonium glycyrrhizinate, diammonium glycyrrhizinate, dipotassium glycyrrhizinate, disodium glycyrrhizinate, trisodium glycyrrhizinate, The method for producing a chewable agent according to any one of (1) to (3), which is at least one selected from acesulfame K, mannitol, erythritol, sorbitol, xylitol, and trehalose.

(5) The step of producing the granules is carried out according to the step (3).
(1) to (4) characterized in that it is a step of producing granules by adding an aqueous acid solution to a particle mixture containing various kinds of branched chain amino acid particles as an active ingredient and granulating the mixture.
Item 14. The method for producing a chewable agent according to any one of the above items.

(6) The step of tableting the coated granules to produce a chewable preparation is a step performed by mixing a magnesium compound with the coated granules. The method for producing a chewable agent according to any one of the above.

(7) The step of producing a chewable preparation by tableting the coated granules is a step of producing a chewable preparation having a hardness of 20 to 150 N. A method for producing the chewable agent according to any one of the preceding claims.

(8) The particle mixture containing the above-mentioned three kinds of branched chain amino acid particles of isoleucine, leucine and valine as an active ingredient has a mass ratio of isoleucine / leucine / valine = 1/1.
9 to 2.2 / 1.1 to 1.3.
The method for producing a chewable agent according to any one of (1) to (6).

(9) Any one of the above items (1) to (8)
A chewable agent having a hardness of 20 to 150 N, which is produced by the method for producing a chewable agent described in the paragraph.

(10) A chewable agent having a hardness of 30 to 120 N, which is produced by the method for producing a chewable agent according to any one of the above (1) to (8).

(11) A chewable agent having a hardness of 40 to 100 N, which is produced by the method for producing a chewable agent according to any one of the above (1) to (8).

(12) A pharmaceutical preparation for healing liver disease, comprising the chewable preparation according to any one of the above (9) to (11).

[0018]

BEST MODE FOR CARRYING OUT THE INVENTION The chewable preparation of the present invention is a pharmaceutical chewable preparation produced using three kinds of branched-chain amino acids consisting of isoleucine, leucine and valine as active ingredients.

The chewable agent of the present invention comprises isoleucine,
The mixing ratio of leucine and valine is mass ratio, and isoleucine / leucine / valine = 1 / 1.9 to 2.2 / 1.1 to
It is preferably 1.3.

In the chewable preparation of the present invention, the one used as isoleucine as one of the active ingredients is generally a particle having a particle size of 1 mm or less produced by a fermentation method. As long as
There is no particular limitation on the particle size of the particles.

There is no particular limitation on the particle size of leucine as long as it is generally produced by fermentation or extraction and has a particle size of 1 mm or less, or as long as it meets the specifications of the Japanese Pharmacopoeia. .

As valine, particles having a particle size of 1 mm or less, which are generally produced by a fermentation method or a synthesis method, are used. There are no particular restrictions.

In the manufacturing process of the chewable preparation of the present invention, the binder component used in the coating solution of the granules before tableting satisfies the standards such as the Japanese Pharmacopoeia or the Pharmaceutical Excipient Standards. One or more are selected and used. Binder components: mannitol, erythritol, sorbitol, xylitol, trehalose, ethylcellulose, methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylethylcellulose, polyvinylpyrrolidone, carboxyvinyl polymer, polyvinyl alcohol, gum arabic, sodium alginate and the like.

The sweetener which can be used in the coating solution together with the binder is selected from, for example, those exemplified below and used. Sweetener ingredients: aspartame, saccharin, saccharin sodium, glycyrrhizic acid, monoammonium glycyrrhizinate, diammonium glycyrrhizinate, dipotassium glycyrrhizinate,
Disodium glycyrrhizinate, trisodium glycyrrhizinate, Acesulfame K and the like. In addition, as the sweetener component, it is desirable to avoid using a reducing sugar or the like that causes a Maillard reaction with the three kinds of branched-chain amino acids.

The chewable preparation of the present invention can generally contain a flavoring agent used in pharmaceutical preparations, foods and the like. Various flavors can be used as such a flavoring agent, and examples thereof include a lemon flavor, an orange flavor, a grapefruit flavor, a chocolate flavor, dl-menthol, and l-menthol.
Menthol and the like.

As the granulation method for producing the granules in the production process of the chewable preparation of the present invention, a usual production method such as a wet method or a dry method can be applied. Granulator, planetary mixer, dry pressing granulator, crushing granulator, extrusion granulator, rolling granulator,
Equipment such as a spray drying granulator and a coating granulator is used. In the production of granules, it is preferable to add an acid solution to the raw material branched-chain amino acid particles and granulate the granules, because the specific volume of the granules can be reduced.

The method for coating the granules in the production process of the chewable preparation of the present invention includes fluidized bed coating usually used for coating granules,
Various methods such as rolling layer coating can be applied.

In the tableting process for producing a chewable tablet from the coating granules in the chewable tablet preparation process of the present invention, tableting is usually carried out at a tableting pressure of 0.3 to 1.2 tons. But not limited to this. By compressing with such a compression pressure, a hardness of 30N is obtained.
A chewable preparation of 150 N or less can be tableted, and the chewability in the oral cavity can be improved when the chewable preparation is taken. When tableting the coated granules, it is preferable to add and mix a magnesium compound such as magnesium stearate or talc to the coated granules and tablet the tablets so that coloring during storage of the chewable preparation can be prevented.

[0029]

EXAMPLES Specific examples of the present invention are shown below as examples, but the present invention is not limited by these examples.

Example 1 Leucine 285.6 g, valine 171.6 g, isoleucine 142.9 g, hydroxypropylcellulose 1
After weighing 5.1 g, 19.6 g of cocoa powder and 285.0 g of distilled water, the mixture was extruded with a screen diameter of 0.5 mm and kneaded with a granulator (DG-L1 manufactured by Dalton), granulated, and fluidized bed granulated. It was dried with a machine (SFC-MIN manufactured by Freund Corporation). 888.3 g of granules obtained by repeating the same operation
It was weighed and separately coated as a coating solution in which 315.1 g of erythritol and 2.1 g of saccharin sodium were dissolved in 880 g of distilled water. 344.5 g of the coated granules thus obtained, 6.0 g of crospopidone, 0.3 g of chocolate flavor, and 10.8 g of magnesium stearate were mixed to produce raw material granules for chewable preparation. The raw material granules were tableted with a tableting machine (Hata Iron Works, HT-AP6SS-II) at 1.02 tons to produce chewable tablets.

Example 2 Leucine 285.6 g, valine 171.60 g, isoleucine 142.80 g, hydroxypropylcellulose 15.0 g, cocoa powder 19.5 g, distilled water 285.0 g
After weighing, the mixture was kneaded with an extrusion granulator (DG-L1 manufactured by Dalton) with a screen diameter of 0.5 mm. This was dried with a fluid bed granulator (SFC-MIN manufactured by Freund Corporation), and the same operation was repeated. This is 888.30
g of the solution, and 315.0 g of mannitol and 2.10 g of saccharin sodium were separately dissolved in 880 g of distilled water to form a coating solution, which was coated. 345.5 g of the coated granules, 18.0 g of crospopidone, 6.0 g of croscarmellose sodium, 0.3 g of chocolate flavor, 11.4 g of magnesium stearate
g were mixed to produce granules for chewable preparation. The granules were taken in a tableting machine (HT-AP6SS-II, manufactured by Hata Iron Works Co., Ltd.) to a pH of 0.1.
The tablets were compressed at 86 tons to produce chewable tablets.

Example 3 285.6 g of leucine, 171.60 g of valine, 142.8 g of isoleucine, 7.5 g of Kollidon K90 and 280.0 g of distilled water were weighed, and then extruded with a screen diameter of 0.5 mm using a granulator (manufactured by Dalton). DG-L1).
This is supplied to a fluid bed granulator (SFC-M manufactured by Freund Corporation).
The same operation, dried in IN), was repeated. 510.0 g of this was weighed, and 315.0 g of mannitol was separately added.
1.2 g of saccharin sodium was added to 1063.0 g of distilled water.
And coated by spraying. 345.5 g of the coated granules, 18.0 g of crospopidone, 6.0 g of croscarmellose sodium, 0.3 g of lemon oil, and 11.4 g of magnesium stearate were mixed to produce chewable granules. A tableting machine (HT-AP6S manufactured by Hata Iron Works Co., Ltd.)
The tablets were compressed at 0.71 ton with S-II) to produce chewable tablets.

Comparative Example 1 Leucine 285.6 g, valine 171.6 g, isoleucine 142.8 g, hydroxypropylcellulose 1
After weighing 5.0 g, 19.5 g of cocoa powder and 285.0 g of distilled water, they were kneaded with an extruder (DG-L1 manufactured by Dalton) with a screen diameter of 0.5 mm. This was dried with a fluid bed granulator (SFC-MIN manufactured by Freund Corporation). 253.8 g of the obtained granules, crospovidone 6.0
g, chocolate flavor, 0.3 g, and magnesium stearate, 10.8 g, were mixed to prepare raw material granules for producing a chewable agent. The raw material granules were directly tableted at 1.10 tons using a tableting machine (Hata Iron Works, HT-AP6SS-II) to produce chewable tablets.

Test Example The tabletability of the raw material granules of the above Examples and Comparative Examples and the hardness of the obtained chewable tablets were measured using a hardness tester (TS-5 manufactured by Okada Seiko Co., Ltd.).
0N).

[0035]

[Table 1]

[0036]

Industrial Applicability According to the present invention, sticking is prevented in the tableting step in the manufacture of a pharmaceutical chewable preparation containing isoleucine, leucine and valine as active ingredients, and therefore, the production efficiency is greatly improved, and the effect is apparent. It is. The chewable pharmaceutical preparation produced by the present invention is a preparation that can be rapidly chewed in the mouth and that is highly ingestible.

──────────────────────────────────────────────────続 き Continued on the front page (58) Field surveyed (Int. Cl. ⁷ , DB name) A61K 31/198 A61K 9/20 WPIDS (STN)

Claims (12)

(57) [Claims] The present invention relates to isoleucine, leucine and valine.
Granulating a particle mixture containing various kinds of branched-chain amino acid particles as an active ingredient to produce granules, coating the granules with a coating solution containing a binder component to produce coated granules, and the coating A method for producing a chewable preparation comprising three types of branched-chain amino acids of isoleucine, leucine and valine as active ingredients, comprising a step of tableting granules to produce a chewable preparation. 2. The binder component in the coating solution includes mannitol, erythritol, sorbitol, xylitol, trehalose, ethyl cellulose, methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl ethyl cellulose, polyvinylpyrrolidone, carboxyvinyl polymer, polyvinyl alcohol, 2. The method for producing a chewable agent according to claim 1, wherein the method is at least one selected from gum arabic and sodium alginate. 3. The method according to claim 1, wherein the coating liquid contains a sweetener component. 4. The sweetener component in the coating liquid,
Aspartame, saccharin, saccharin sodium,
Glycyrrhizic acid, monoammonium glycyrrhizinate, diammonium glycyrrhizinate, dipotassium glycyrrhizinate, disodium glycyrrhizinate, trisodium glycyrrhizinate, acesulfame K, mannitol, erythritol, sorbitol, xylitol and trehalose. The method for producing a chewable agent according to any one of claims 1 to 3, which is characterized in that: 5. The method according to claim 1, wherein the step of producing the granules is a step of producing a granule by adding an aqueous acid solution to a particle mixture containing the three kinds of branched-chain amino acid particles as an active ingredient and granulating the mixture. A method for producing the chewable agent according to any one of claims 1 to 4, characterized in that: 6. The method according to claim 1, wherein the step of tableting the coated granules to produce a chewable preparation is a step of mixing a magnesium compound with the coated granules. Item 15. The method for producing a chewable agent according to item 4. 7. The method according to claim 1, wherein the step of tableting the coated granules to produce a chewable preparation is a step of producing a chewable preparation having a hardness of 20 to 150 N. 3. The method for producing a chewable agent according to item 1. 8. The particle mixture containing the three kinds of branched-chain amino acid particles of isoleucine, leucine and valine as an active ingredient has a mass ratio of isoleucine / leucine / valine = 1 / 1.9 to isoleucine / leucine / valine.
The method for producing a chewable agent according to any one of claims 1 to 7, wherein the ratio is 2.2 / 1.1 to 1.3. 9. A chewable agent having a hardness of 20 to 150 N, which is manufactured by the method for manufacturing a chewable agent according to any one of claims 1 to 8. 10. A chewable agent having a hardness of 30 to 120N, which is manufactured by the method for manufacturing a chewable agent according to any one of claims 1 to 8. 11. A chewable agent having a hardness of 40 to 100 N, which is manufactured by the method for manufacturing a chewable agent according to any one of claims 1 to 8. 12. A pharmaceutical preparation for treating liver disease, comprising the chewable preparation according to any one of claims 9 to 11.