JP3228288B1 - Method for producing pharmaceutical granule preparation containing branched chain amino acids - Google Patents

Abstract

Abstract: PROBLEM TO BE SOLVED: To reduce the risk of dust explosion at the time of pulverizing solid isoleucine, and to make it possible to safely produce a pharmaceutical granule preparation containing three amino acids of isoleucine, leucine and valine as main agents . SOLUTION: In the method for producing a pharmaceutical granule preparation mainly comprising isoleucine, leucine and valine, the method comprises the steps of:
A method for producing a pharmaceutical granule preparation, wherein the solid raw material isoleucine is pulverized with the solid raw material leucine and / or the solid raw material valine in the step of pulverizing a kind of solid raw material amino acid to adjust the particle size.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a method for producing a pharmaceutical granule containing three kinds of branched-chain amino acids consisting of isoleucine, leucine and valine as a main drug (active ingredient), and in particular, to a granulating raw material for the granule. The present invention relates to a pulverization method for avoiding the danger of dust explosion in a step of pulverizing and adjusting particles of three kinds of branched-chain amino acids from respective solid raw materials.

[0002]

2. Description of the Related Art Pharmaceutical granule preparations containing three kinds of branched-chain amino acids consisting of isoleucine, leucine and valine as a main drug are effective therapeutic agents for liver diseases. The granule preparation containing these three amino acids is subjected to a pulverization treatment in order to adjust the particle size to a predetermined particle size in order to guarantee the uniformity of the contents of the three amino acids constituting the granule preparation and to improve the granulation property in the granulation step. Have been. However, not only the solids of these three kinds of branched-chain amino acids but also the risk of dust explosion is always present in the pulverization process, and a great deal of equipment investment has been made for measures to prevent the explosion. The above three types of branched chain amino acids are no exception,
In particular, since there is a risk of dust explosion during the isoleucine crushing process, safety measures such as crushing under a nitrogen atmosphere, crushing by remote control, and installation of an explosion vent are currently being taken.

[0003]

DISCLOSURE OF THE INVENTION The present invention relates to a method for producing a granular pharmaceutical preparation containing three kinds of branched-chain amino acids consisting of isoleucine, leucine and valine, which are effective therapeutic agents for liver diseases. It is possible to avoid the danger of dust explosion in the pulverization step of the solid raw material of the amino acid performed to prepare the raw material particles of the seed amino acid,
It is an object of the present invention to provide a safe and inexpensive means that does not require a large-scale device.

[0004]

SUMMARY OF THE INVENTION In order to solve the above-mentioned problems, the present invention provides a method for producing a solid isoleucine, which has a high risk of explosion, using at least two solid amino acids consisting of other solid leucine and / or solid valine. This invention is characterized by mixing and grinding one kind, and further includes the following inventions.

(1) A method for pulverizing solid isoleucine, comprising mixing and pulverizing solid isoleucine with solid leucine and / or solid valine.

(2) A method for producing a granulated raw material particle mixture for producing a pharmaceutical granule preparation containing isoleucine, leucine and valine as a main component, comprising mixing and grinding solid isoleucine with solid leucine and / or solid valine. .

(3) A step of pulverizing a solid raw material of three kinds of branched-chain amino acids of isoleucine, leucine and valine to adjust the particle size, and then granulating a raw material containing each of the amino acid particles whose particle size has been adjusted. In the method for producing a pharmaceutical granule preparation mainly comprising isoleucine, leucine and valine, the step of pulverizing a solid raw material of the three kinds of branched-chain amino acids to adjust the particle size is performed by converting the solid raw material isoleucine into a solid raw material. during crushing of the solid raw materials isoleucine by <br/> grinding leucine and / or solid raw materials valine and mixed-
A method for producing a pharmaceutical granule preparation comprising only isoleucine, leucine and valine as a principal agent, which is intended to prevent dust explosion from occurring .

(4) A step of mixing and pulverizing solid raw materials of three kinds of branched-chain amino acids of isoleucine, leucine and valine to prepare a granulation particle mixture, and then granulating the granulation particle mixture. The method for producing a pharmaceutical granular preparation comprising isoleucine, leucine and valine as a main ingredient according to item (3), which is characterized in that:

(5) The mixing and pulverization of the solid raw material isoleucine with the solid raw material leucine and / or the solid raw material valine is such that the weight ratio of leucine 0 to 4.4 and valine 0 to 2.6 with respect to isoleucine 1; Production of a pharmaceutical granule preparation comprising isoleucine, leucine and valine as the main ingredient as described in the above (3) or (4), which is carried out in the presence of leucine and / or valine, preferably leucine. Method.

(6) The mixing and pulverization of the solid raw material isoleucine with the solid raw material leucine and / or the solid raw material valine is carried out by an impact type (high-speed rotation) pulverizer such as a hammer mill or a tumbler type (medium type) pulverizer such as a ball mill. The method according to any one of items (1) to (5), wherein the mixing and pulverization is performed by a fluid (air flow) pulverizer such as a mill or a jet mill.

(7) The mixed and pulverized product has a particle size of isoleucine particles of 5 to 700 μm, preferably 10 to 500 μm.
The method for producing a pharmaceutical granule preparation comprising isoleucine, leucine and valine as the main drug according to any one of the above-mentioned items (3) to (6), characterized in that:

(8) In the granulation particle mixture, isoleucine / leucine / valine = 1 / 1.9 to 2.2 / 1.
Item 1. The method for producing a pharmaceutical granule preparation comprising isoleucine, leucine and valine as the main drug as described in any one of the above items (3) to (7), which is characterized by being 1 to 1.3.

[0013]

BEST MODE FOR CARRYING OUT THE INVENTION The solid raw material isoleucine, solid raw material leucine and solid raw material valine in each method of the present invention are produced by granulating particles of the three kinds of branched-chain amino acids which are effective therapeutic agents for liver diseases. It is an amino acid useful as a raw material for pharmaceutical granules.

In the pharmaceutical granule preparation of the present invention, isoleucine, which is one of the main drugs, is a particle generally produced by a fermentation method and having a particle size of 1 mm or less, which meets the specifications of the Japanese Pharmacopoeia. However, it is not limited to this. They are 5 to 700 μm, preferably 10 to 500
What is adjusted to a particle size of μm is used. Leucine is generally a particle having a particle size of 1 mm or less produced by a fermentation method or an extraction method and satisfies the standards of the Japanese Pharmacopoeia, but is not limited thereto. 5 to them
Particles adjusted to a particle size of 700 μm, preferably 10 to 500 μm are used. In addition, valine generally has a particle size of 1 m produced by a fermentation method or a synthesis method.
Particles having a particle size of m or less and satisfying the standards of the Japanese Pharmacopoeia are used, but not limited thereto. There is no particular limitation on the particle size of valine as long as it meets the specifications of the Pharmacopoeia.

[0015] The mixed pulverization here means isoleucine,
A method in which leucine and valine are premixed and then crushed,
Alternatively, any method of pulverizing while mixing isoleucine, leucine and valine may be used.

The term "mixing" as used herein means a container rotary mixer such as a container mixer, an air stirring mixer such as a fluidized bed mixer, a stirring mixer by rotating stirring blades and a stirring ribbon, and a powder transport line. Mixing by a feeder type mixer installed at a raw material supply port such as a line mixer or a pulverizer for mixing in the inside is preferable, but not particularly limited.

The term "pulverization" as used herein refers to pulverization using an impact (high-speed rotation) pulverizer such as a hammer mill, a tumbler (medium type) pulverizer such as a ball mill, or a fluid (pneumatic) pulverizer such as a jet mill. Is preferred, but is not particularly limited.

Isoleucine in the granular preparation of the present invention,
The mixing ratio of leucine and valine is isoleucine / leucine / valine = 1 / 1.9 to 2.2 / 1.1.
1.3.

In producing the granular preparation of the present invention, a binder can be used. As the binder, methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, cellulose derivatives such as hydroxypropylmethylcellulose phthalate, corn starch, starches such as wheat starch, polyvinylpyrrolidone, synthetic polymers such as acrylic acid polymer, gum arabic, Any polymer can be used without particular limitation as long as it can be used as a medicinal product satisfying the standards such as the Japanese Pharmacopoeia or excipient standards such as natural polymers such as gelatin. Also, the amount used is within the range in which normal granulation is possible.

The granules containing the three kinds of branched-chain amino acid particles in the pharmaceutical granule of the present invention may be a high-speed stirring granulator, a fluidized bed granulator, a planetary mixer, a dry pressing granulator, a crushing granulator. Granulation machine, extrusion granulator, tumbling granulator, spray drying granulator, and coating granulator can be used, but high-speed stirring granulator and extrusion granulator are preferred. . Extrusion granulation is a method of granulating by extruding plasticized powder through a screen with many holes, pre-extrusion granulator, disk pelletizer granulator, ring die granulator. Machine, basket type granulator, oscillating type granulator, cylinder type granulator and the like are used.

The high-speed stirring granulation method is a method in which water or a binder liquid is charged or sprayed into powder, and the powder is subjected to shearing / rolling / consolidation by rotation of a stirring blade to perform granulation.
A horizontal stirring granulator is used. The fluidized bed granulation method is a granulation method performed by spraying water or a binder liquid while flowing the powder, and aggregating the powder.A fluidized bed granulator, a stirred fluidized bed granulator, A tumbling fluidized bed type granulator and a stirring tumbling fluidized bed type granulator are used.

The dry pressing granulation method is a method of compressing and molding a powder without using water or a binder liquid, and includes a roll press, a briquetting machine, a single-shot tableting machine, and a rotary tableting machine. used. The rolling granulation method is a method of rolling and granulating powder, and a drum-type granulator,
Dish-type granulators, vibratory granulators, and rotary disk granulators are used.

[0023]

EXAMPLES Next, the present invention will be described more specifically with reference to examples, but the present invention is not limited to the following examples.

Example 1 The dust explosive properties of three types of branched-chain amino acids (leucine, isoleucine, and valine), each of which was individually pulverized, mixed with three types of branched-chain amino acids, and then pulverized, were compared. . The explosion risk was as follows: In the case of single-piece grinding, leucine was class II, isoleucine was class I, and valine was class II, but the mixed and crushed product was class II. It was found that the risk of explosion was significantly reduced.

The explosion countermeasures for each class are as follows. Class I: Nitrogen purge required, Class I: Explosion-proof measures such as explosion vents required Class II: Ground installation Class III: No measures required Table 1 and Figure 1 summarize the dust explosion evaluation results for three types of branched-chain amino acids. Shown.

[0026]

[Table 1]

[0027]

As is evident from the above results, according to the method of the present invention for mixing and grinding three kinds of amino acids, dust explosion in the grinding step can be greatly reduced. Thus, it is possible to safely carry out the production of a pharmaceutical granule preparation which is a therapeutic agent for liver disease of the present invention and contains various amino acids.

[Brief description of the drawings]

FIG. 1 is a view showing the dust explosive properties of a ground product of three types of branched-chain amino acids (leucine, isoleucine, and valine).

────────────────────────────────────────────────── ─── Continuation of the front page (56) References JP-A-8-198748 (JP, A) (58) Fields investigated (Int. Cl. ⁷ , DB name) A61K 31/198

Claims (3)

(57) [Claims] The present invention relates to isoleucine, leucine and valine.
A process of adjusting the particle size by crushing the seed solid amino acid,
Next, a step of granulating a raw material containing each of the amino acid particles whose particle size has been adjusted is performed. The mixing ratio of isoleucine, leucine, and valine is isoleucine / leucine / valine = 1 / 1.9 to 2.2 / 1. In the method for producing a pharmaceutical granule preparation containing only isoleucine, leucine and valine as the main drug, the step of pulverizing the three solid amino acids to adjust the particle size, the method comprises the steps of:
Leucine as solid raw material leucine and / or solid raw material valine
Solid raw materials isoleucine by to mixed-to Milling
A method for producing a pharmaceutical granule, which is intended to prevent dust explosion during pulverization . 2. The mixing and grinding of the solid raw material isoleucine and the solid raw material leucine and / or the solid raw material valine is performed by mixing and grinding leucine 0 to 4.4 and valine 0 to 2.6 with respect to isoleucine 1 in a weight ratio. The method for producing a pharmaceutical granule preparation according to claim 1, wherein: 3. The mixing and grinding of the solid raw material isoleucine and the solid raw material leucine and / or the solid raw material valine is performed by a shock (high-speed rotation) pulverizer such as a hammer mill or a tumbler (medium type) pulverizer such as a ball mill. 3. The method for producing a pharmaceutical granule preparation according to claim 1, wherein the pulverization is performed by mixing and pulverization using a fluid (air flow) pulverizer such as a jet mill.