JP3341771B1 - Granulation method of granules - Google Patents

Abstract

The present invention provides an extrusion granulation method capable of producing pharmaceutical granules containing the following three kinds of branched chain amino acids as active ingredients with stable granulation efficiency. SOLUTION: The isoleucine, leucine and valine 3
Kneading water is added to a particle mixture containing various kinds of branched-chain amino acids, and the mixture is kneaded. The temperature of the kneaded product is adjusted to 30 ° C to 0 ° C, and extrusion granulation is performed by an extrusion granulator. A method for producing pharmaceutical granules comprising only three types of branched chain amino acids of isoleucine, leucine and valine as active ingredients.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

[0001] The present invention relates to a method for producing a pharmaceutical granule comprising three kinds of branched chain amino acids of leucine, isoleucine and valine as active ingredients.

[0002]

BACKGROUND OF THE INVENTION Isoleucine, leucine and valine
The production of pharmaceutical granules containing various kinds of branched-chain amino acids as active ingredients is usually carried out by an extrusion granulation method. The reason why the extrusion granulation method is adopted for the production of the pharmaceutical granules is as follows:
It is a general and highly versatile wet granulation method, capable of continuous granulation, changing the particle size of the granulated material obtained by simply changing the pore size of the screen, and uniforming the particle size Is easy.

However, when granules are produced by extrusion granulation of a mixture of particles or powders of three kinds of branched chain amino acids of isoleucine, leucine and valine, the particle size of the raw materials, the particle size of the powder, the type of binder used, etc. Depending on the kneading conditions, the kneaded material may not come out of the screen, causing a slippery state, or the adhesion of granules due to stickiness due to stickiness, agglomeration, insufficient strength of the granules, etc. At present, it is difficult to set the optimum extrusion granulation conditions according to the change in the particle size of the charged raw materials due to instability.

[0004]

SUMMARY OF THE INVENTION The present invention provides a stable granulation efficiency which is independent of the particle size change of particles of three kinds of branched chain amino acids of isoleucine, leucine and valine as raw materials. An object of the present invention is to establish an extrusion granulation method capable of producing pharmaceutical granules containing a branched-chain amino acid as an active ingredient.

[0005]

Means for Solving the Problems In order to solve the above-mentioned problems, the present inventors have conducted intensive studies. As a result, in order to improve the instability of the above-mentioned granulation efficiency, the temperature of the kneaded material at the time of granulation was improved. Has been found to be important, and the present invention has been completed. The present invention includes the following inventions.

(1) Kneading water is added to a particle mixture containing three kinds of branched-chain amino acids of isoleucine, leucine and valine, and the mixture is extruded by an extrusion granulator.
The temperature of the kneaded product supplied to the extrusion granulator is 30 ° C to 0 ° C, preferably 25 ° C to 10 ° C, more preferably 25 ° C to 20 ° C.
A method for producing pharmaceutical granules comprising only three kinds of branched-chain amino acids of isoleucine, leucine and valine as an active ingredient, wherein the temperature is adjusted to ° C.

(2) Kneading water is added to a particle mixture containing three types of branched-chain amino acids of isoleucine, leucine and valine, and the mixture is extruded by an extrusion granulator.
In the extrusion granulator, the temperature of the kneaded product is 30 ° C to 0 ° C, preferably 25 ° C to 10 ° C, more preferably 25 ° C to 20 ° C.
A method for producing pharmaceutical granules comprising only three kinds of branched-chain amino acids of isoleucine, leucine and valine as an active ingredient, wherein the temperature is adjusted to ° C.

(3) The isoleucine and leucine described in (1), wherein the temperature of the kneaded material is adjusted to the temperature range by adjusting the temperature of kneading water used for kneading. And a method for producing pharmaceutical granules comprising only three kinds of branched-chain amino acids of valine as an active ingredient.

(4) In the extrusion granulator, the temperature of the kneaded product is further reduced to 30 ° C to 0 ° C, preferably 25 ° C to
The active ingredient is only three kinds of branched-chain amino acids of isoleucine, leucine, and valine according to the above item (1) or (3), which are controlled and maintained at 10 ° C, more preferably 25 ° C to 20 ° C. For producing pharmaceutical granules.

(5) The particle mixture and / or kneading water contains a granulating binder (1).
A method for producing a pharmaceutical granule, comprising as active ingredients only three kinds of branched-chain amino acids of isoleucine, leucine and valine according to any one of items to (4).

(6) The kneading water is a solution in which a binder is dissolved, and is a mixture of isoleucine, leucine and valine according to any one of (1) to (5).
A method for producing a pharmaceutical granule comprising only one kind of branched-chain amino acid as an active ingredient.

(7) The isoleucine, leucine and valine described in (5) or (6), wherein the binder is at least one selected from polyvinylpyrrolidone, polyvinyl alcohol and cellulose derivatives. A method for producing pharmaceutical granules comprising only three types of branched-chain amino acids as active ingredients.

(8) The above-mentioned binder is hydroxypropylcellulose, wherein the three branched-chain amino acids of isoleucine, leucine and valine according to any one of the above items (5) to (7). A method for producing a pharmaceutical granule containing only an active ingredient.

(9) Kneading water is added to a particle mixture containing three kinds of branched chain amino acids of isoleucine, leucine and valine, and the mixture is kneaded.
° C, preferably 25 ° C to 5 ° C, more preferably 25 ° C to
In the method of adjusting the temperature to 20 ° C. and supplying the same to an extrusion granulator, and extruding and granulating to produce a pharmaceutical granule, the method includes the steps of: a numerical change in power consumption of the power in the extrusion granulator; Controlling the temperature of the kneaded material entering the extrusion granulator based on the relationship with the temperature change of the material, and maintaining the temperature of the kneaded material during extrusion granulation within the above numerical range ( Item 1), (3)
A method for producing a pharmaceutical granule comprising only three types of branched-chain amino acids of isoleucine, leucine and valine according to any one of the above-mentioned items to (7).

(10) The temperature of the kneaded material entering the extrusion granulator is selected from the temperature of the particle mixture containing the three kinds of branched-chain amino acids, the temperature of the kneading water and the temperature in the kneading machine. (9) The method for producing pharmaceutical granules comprising only three kinds of branched-chain amino acids of isoleucine, leucine and valine as an active ingredient according to (9), wherein the temperature is controlled by controlling the temperature of at least one kind.

(11) The temperature of the kneaded material entering the extrusion granulator is further controlled and maintained by a temperature control means of an extrusion shaft in the extrusion granulator (9).
Or a method for producing a pharmaceutical granule comprising only the three kinds of branched-chain amino acids of isoleucine, leucine and valine according to item (10) as active ingredients.

(12) Kneading water is added to a particle mixture containing three kinds of branched-chain amino acids of isoleucine, leucine and valine and kneaded, and the obtained kneaded product is supplied to an extrusion granulator and extruded. In a method for producing pharmaceutical granules by granulating,
The temperature of the kneaded material in the extrusion granulator is set to 30 ° C. to 0 based on the relationship between the numerical change of the power consumption current of the power in the extrusion granulator and the temperature change of the kneaded material in the extrusion granulator.
° C, preferably 25 ° C to 5 ° C, more preferably 25 ° C to
A method for producing pharmaceutical granules comprising only three types of branched-chain amino acids of isoleucine, leucine and valine, which is controlled at 20 ° C.

(13) The mixing ratio of the three kinds of branched-chain amino acids is isoleucine / leucine / valine = 1 by mass ratio.
/1.9 to 2.2 / 1.1 to 1.3, wherein the three branches of isoleucine, leucine and valine according to any one of the above items (1) to (12) are provided. A method for producing a pharmaceutical granule comprising only an active-chain amino acid as an active ingredient.

[0019]

BEST MODE FOR CARRYING OUT THE INVENTION Pharmaceutical granules produced by the method of the present invention are granule preparations containing only three types of branched chain amino acids of isoleucine, leucine and valine as active ingredients, and are effective treatments for liver diseases. It is a drug, and the compounding ratio of isoleucine, leucine and valine is isoleucine / leucine / valine = 1 / 1.9 to 2.2 / 1.1- by mass ratio.
1.3 is a granule preparation.

The particles of isoleucine, leucine and valine are generally produced by fermentation or extraction and have a particle size of 1 mm or less, preferably 20 to 700 μm, more preferably 50 to 500 μm, and It meets the standards of the Japanese Pharmacopoeia.

Examples of the binder used in the production of the pharmaceutical granules of the present invention include cellulose derivatives such as methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose phthalate, starches such as corn starch, wheat starch and polyvinyl. Synthetic polymers such as pyrrolidone and polyvinyl alcohol acrylic acid polymer, agar, gelatin, xanthan gum, arbia gum and the like are not particularly limited as long as they can be used for medicine. The amount used is not particularly limited as long as normal granulation is possible. The binder may be mixed with the three kinds of branched-chain amino acid particles in powder form and added to the kneading raw material, or may be added in the state of being dissolved in kneading water.

In the present invention, kneading means that the powder to which a binder is added if necessary is wetted with a liquid, or the powder is wetted and kneaded with a binding solution in which the binder is dissolved as necessary. Meaning, as a machine that can be used for kneading, a wheel-type kneading machine, a ball-type kneading machine, a blade-type kneading machine, a roll-type kneading machine, and the like. A mold kneading machine is preferred.

The extrusion granulator used for producing the pharmaceutical granules of the present invention maintains the temperature of the kneaded product containing three types of branched chain amino acid particles at 30 ° C. or lower, preferably 25 ° C. or lower. An apparatus capable of extrusion granulation is preferable. More preferably, the inside of the granulator is maintained at or below the above temperature by a suitable refrigerant, and particularly preferably, the kneaded product is obtained by cooling the shaft itself through a refrigerant in an extrusion shaft in an extrusion granulator. Extrusion granulator of the type capable of controlling the temperature of the extruder.

The extrusion granulator is preferably of a type which is directly connected to the kneading machine and which can directly extrude and granulate the kneaded material prepared at a predetermined temperature in the kneading machine. The extrusion granulator constantly detects a change in current flowing through a power supply for driving a power unit in the granulator, and based on the current value, the temperature of the kneading machine, the temperature of the kneading water, the raw material branched chain amino acid particles. The temperature of the kneaded material is controlled by the temperature of the kneaded material, or the temperature of the kneaded material supplied to the extrusion screen in the granulator is controlled by additionally controlling the temperature of the refrigerant in the extrusion shaft in the granulator. It is preferable to provide a temperature control mechanism that can maintain a predetermined value.

In the method of the present invention, the temperature of the kneaded product to be extruded and granulated is 30 ° C. or less, preferably 25 ° C. to 20 ° C.
It is important that they are maintained at all times. If the temperature of the kneaded material supplied to the extrusion granulator exceeds 30 ° C., the resistance when the kneaded material passes through the extrusion screen increases, and the current value of the power source for driving the extrusion shaft increases. If the extrusion operation is continued at such a high temperature, the kneaded material slips on the screen and cannot pass through the screen, and the granulator may be stopped or the screen may be broken.

The temperature control mechanism mounted on the extruder is:
For example, the current value of the drive power supply for the extrusion shaft of the extrusion granulator is constantly detected, and the temperature of the kneaded material supplied to the extrusion shaft is 30%.
At the same time as detecting the current value indicating that the temperature approached ° C., or controlling the temperature of the kneading machine, the temperature of the kneading water, the temperature of the raw material branched chain amino acid particles alone, or by controlling each at the same time A mechanism that can control the temperature of the kneaded material to a predetermined value can be employed. Further, at the same time, it has a mechanism capable of controlling the flow rate of the refrigerant flowing in the extrusion shaft and controlling the temperature of the extrusion shaft so that the temperature of the kneaded material is maintained at a predetermined value. Is also good.

[0027]

EXAMPLES Hereinafter, the method of the present invention will be specifically described based on examples, but the present invention is not limited to these examples.

Example 1 7 kg of isoleucine, 14 kg of leucine, 8.4 of valine
kg and 0.39 kg of hydroxypropylcellulose, 10 L of purified water at about 25 ° C. is added thereto, and the mixture is stirred at a high speed for 3 minutes at room temperature with a kneading machine (stirring granulator; Powrex: Vertical Granulator VG-200P). To obtain a kneaded product. The kneaded product was granulated through a 0.6 mm screen using an extrusion granulator (Fuji Paudal; Extruder EXDCS-100) capable of controlling the temperature by a refrigerant flowing in the extrusion shaft. The granulator has a temperature measurement recording device that continuously measures and records the temperature of the kneaded material supplied to the extrusion shaft, a recording device that continuously records the current consumption of the driving power supply of the granulator, An alarm device that detects when the current consumption value has reached a predetermined value and issues an alarm is provided.

FIG. 1 shows the relationship between the change in the temperature of the kneaded material supplied to the granulator and the change in the current value consumed by the granulator when granulating the kneaded material. From FIG. 1, the temperature of the kneaded material is 2
The current consumption increases as the temperature exceeds 5 ° C. and approaches 30 ° C. On the contrary, when the temperature of the kneaded material is lower than 25 ° C., the current consumption is low.

According to the specifications of the granulator used in the present embodiment, a load alarm is issued at a current consumption of 12 A, and a safety device for preventing damage is activated at 14 A to make an emergency stop. Kneaded material temperature is 2
When the temperature exceeds 5 ° C., the granulation can be continued, but an alarm is issued. It has been observed that the screen of the granulator is deformed when the alarm is frequently given. Further, when the temperature of the kneaded material was 30 ° C. or higher, a slipping state in which the kneaded material did not come out of the screen occurred, and it was also recognized that the granulator was shut down urgently and, in some cases, the screen was broken.

At the stage where the current consumption of the granulator is 12 A and the load alarm is issued, the temperature of the kneading water used in the kneading machine is lowered and the refrigerant flowing through the extrusion shaft of the granulator is simultaneously cooled. When the temperature of the kneaded material entering the extrusion screen was lowered by increasing the amount and the temperature of the shaft, the current consumption value was reduced, the alarm was stopped, and normal extrusion granulation could be continued.

Example 2 To a powder having the same composition as in Example 1, 10 L of purified water cooled to 18 ± 2 ° C. was added and kneaded to obtain a powder having a temperature of 2 ° C.
A kneaded product in the range of 5 ° C. to 22 ° C. was prepared and granulated by the same extrusion granulator as in Example 1. FIG. 2 shows the relationship between the current consumption of the granulator and the temperature of the kneaded material. The temperature of the kneaded mixture entering the extrusion granulator is constantly adjusted to 25 ° C. or less depending on the temperature of the purified water, and as a result, the current consumption does not reach 12 A at which an alarm is issued, resulting in extremely stable extrusion granulation. Can be implemented.

[0033]

According to FIGS. 1 and 2, according to the method of the present invention, it is possible to produce extruded pharmaceutical granules containing only three kinds of branched chain amino acids of isoleucine, leucine and valine as active ingredients. It is clear that the process is stable and the granulation efficiency is improved.

[Brief description of the drawings]

FIG. 1 is a diagram showing a relationship between a change in temperature of a kneaded material entering a granulator and a change in a consumed current value in the method of Example 1.

FIG. 2 is a diagram showing a relationship between a change in temperature of a kneaded material entering a granulator and a change in a consumed current value in the method of Example 2.

Continuing from the front page (72) Inventor Hirozumi Usuki 1730 Hinaga, Yokkaichi City, Mie Prefecture Inside Ajinomoto Co., Inc. (72) Inventor Tsutomu Mimura 1730 Niagara Yokkaichi, Yokkaichi City, Mie Prefecture Ajinomoto Co., Inc. Inside the Tokai Plant (72) Inventor Yuichi Hasegawa 1-1, Suzuki-cho, Kawasaki-ku, Kawasaki City, Kanagawa Prefecture Ajinomoto Co., Inc. Kawasaki Plant (58) Fields investigated (Int. Cl. ⁷ , DB name) A61K 31/198 A61K 9/16 WPIDS (STN)

Claims (5)

(57) [Claims] The present invention relates to isoleucine, leucine and valine.
When kneading water is added to a particle mixture containing various types of branched-chain amino acids and kneaded, and the mixture is extruded and granulated by an extrusion granulator, the temperature of the kneaded product supplied to the extrusion granulator is 30 ° C to 0 ° C. A method for producing pharmaceutical granules comprising only three kinds of branched-chain amino acids of isoleucine, leucine and valine as an active ingredient, wherein the temperature is adjusted to ° C. 2. The isoleucine according to claim 1, wherein the temperature of the kneaded material is adjusted to the temperature range by adjusting the temperature of kneading water used for kneading.
A method for producing pharmaceutical granules comprising only three types of branched chain amino acids, leucine and valine, as active ingredients. 3. The three kinds of isoleucine, leucine and valine according to claim 1 or 2, wherein the temperature of the kneaded product is further adjusted and maintained in the extrusion granulator at 30 ° C. to 0 ° C. A method for producing a pharmaceutical granule comprising only the branched-chain amino acid as an active ingredient. 4. The particle mixture and / or kneading water contains a binder for granulation.
A method for producing a pharmaceutical granule comprising only three types of branched chain amino acids of isoleucine, leucine and valine according to any one of the above. 5. The isoleucine, leucine and valine 3
Kneading water is added to a particle mixture containing a kind of branched-chain amino acid, and the mixture is kneaded. When the mixture is extruded by an extrusion granulator, the temperature of the kneaded product is reduced to 30 ° C to 0 ° C in the extrusion granulator. A method for producing pharmaceutical granules comprising only three types of branched-chain amino acids, isoleucine, leucine and valine, as an active ingredient.