JP5515943B2 - Granules containing branched chain amino acids and method for producing the same - Google Patents

Description

  The present invention relates to a granule for a pharmaceutical preparation containing three kinds of branched chain amino acids consisting of isoleucine, leucine and valine, and a method for producing the same.

A pharmaceutical granule preparation containing as an active ingredient three kinds of branched chain amino acids consisting of isoleucine, leucine and valine is an effective therapeutic agent for liver diseases.
These branched chain amino acids have a bitter taste and a characteristic amino acid odor, and since the dose per dose when taking the branched chain amino acid orally is large, at the time of formulation, the bitterness or odor is reduced, or Various attempts have been made to reduce the volume of granule preparations.

  In the Japanese Patent Application Laid-Open No. 2002-173423, the present applicant has only three kinds of branched chain amino acid particles composed of isoleucine particles and leucine particles having a particle size of 20 μm to 700 μm and valine particles having a particle size of 1 mm or less as active ingredients, The mixing ratio is isoleucine: leucine: valine = 1: 1.9 to 2.2: 1.1 to 1.3 by weight, and the sour agent is selected from citric acid, malic acid, acetic acid, tartaric acid and ascorbic acid A medicinal granule preparation characterized in that it contains at least one kind of organic acid, can improve bitterness and bad taste peculiar to branched-chain amino acids, and can provide a medicinal granule preparation with less discomfort when taken (Patent Document 1).

  In JP-A-2002-145769, the blending ratio is isoleucine: leucine: valine = 1: 1.9 to 2.2: 1.1 to 1.3 by weight ratio, and the particle size is 0.5 mm or less. The active ingredient contains only three kinds of branched chain amino acids consisting of isoleucine, leucine and valine consisting of 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%. Disclosed is a granule preparation, 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 feeling of foreign matter is weak and easy to take is obtained. It was shown that the granule preparation having a distribution is easy to package (Patent Document 2).

  Furthermore, in Japanese Patent Application Laid-Open No. 2003-221768, an isoleucine 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 μm to 1000 μm. Discloses a method for producing granules containing three kinds of branched chain amino acids, leucine and valine, as an active ingredient, thereby making it possible to reduce the dose per dose and to have a great effect on improving the dose (Patent Document 3).

  In the case of producing a granular preparation, in general, the active ingredient is often pulverized to 50 μm or less in order to satisfy the requirements such as ensuring uniformity of content and improving solubility. Granules 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 the above-mentioned three types of branched chain amino acid particles, since a single dose of the branched chain amino acid is about 4 to 5 g, a granule preparation is produced by pulverizing, granulating and sizing in the usual manner Then, the volume is about 8 mL to 10 mL, and it is bulky in the mouth and extremely difficult to squeeze. As noted above, the Applicant has shown that adding acid increases bulk density and reduces the volume of granules per dose, but uses as little additional ingredients as possible. In addition, it is desirable to reduce the specific volume of the granule preparation.

JP 2002-173423 A JP 2002-145769 A JP 2003-221768 A

  The present invention provides a granule preparation containing three kinds of branched chain amino acids consisting of isoleucine, leucine and valine, which are effective therapeutic agents for liver diseases, with a reduced specific volume and less discomfort when taken. The purpose is to obtain granules.

  As a result of intensive studies to solve the above problems, the present inventors granulated a mixture containing branched-chain amino acid particles, and then sized the particles for 2 minutes to 10 hours, compared to the normal sized time. It has been found that the above-mentioned problems can be solved without adding an acid or the like by implementing for a long time, and the present invention has been completed. That is, the present invention relates to the following [1] to [18].

[1] A granule containing three kinds of branched chain amino acids of isoleucine, leucine and valine obtained by granulating a mixture containing isoleucine, leucine and valine particles and then sizing for 2 minutes to 10 hours.
[2] The granule according to the above [1], obtained by sizing for 5 minutes to 5 hours.
[3] The granule according to the above [1], obtained by sizing for 15 minutes to 3 hours.
[4] The granule according to the above [1], obtained by sizing for 30 minutes to 1 hour.
[5] A mixture containing isoleucine, leucine and valine particles having a weight ratio of isoleucine: leucine: valine = 1: 1.9 to 2.2: 1.1 to 1.3 is granulated and adjusted. The granule according to any one of the above [1] to [4], obtained by granulation.
[6] The granule according to any one of [1] to [5], wherein the granulation is wet granulation.
[7] The granule according to the above [6], wherein the wet granulation is extrusion granulation.
[8] The granule according to any one of [1] to [7], wherein the sized particles are spherical sized particles.
[9] The granule according to any one of [1] to [8], wherein the specific volume is less than 2.0 mL / g.
[10] The granule according to any one of [1] to [8], wherein the specific volume is 1.94 mL / g or less.
[11] The granule according to any one of [1] to [8], wherein the specific volume is 1.93 mL / g or less.
[12] A method for producing a granule containing three kinds of branched chain amino acids of isoleucine, leucine and valine, wherein a mixture containing particles of isoleucine, leucine and valine is granulated and then sized for 2 minutes to 10 hours.
[13] The production method according to [12], wherein the sizing is performed for 5 minutes to 5 hours.
[14] The production method according to [12], wherein the sizing is performed for 15 minutes to 3 hours.
[15] The production method according to [12], wherein the sizing is performed for 30 minutes to 1 hour.
[16] The production method according to any one of [12] to [15], wherein the granulation is wet granulation. [17] The production method according to [16], wherein the wet granulation is extrusion granulation.
[18] The production method according to any one of [12] to [17], wherein the sizing is spherical sizing.

  According to the present invention, in a granule containing three kinds of branched chain amino acids consisting of isoleucine, leucine and valine, a specific volume can be reduced and a granule preparation with less discomfort when taken orally can be provided.

  The granule according to the present invention is produced by granulating a mixture containing particles of three kinds of branched chain amino acids composed of isoleucine, leucine and valine, and sizing for a longer time than the normal sizing time.

  In the present invention, “granule” is meant to include granules and powders described in the 15th revised Japanese Pharmacopoeia, and the particle size distribution of the granules is, for example, 80 wt. % Or more and less than 20% by weight of particles less than 0.18 mm. Here, “particle size” refers to the above-mentioned granule particles, using a No. 30 (opening 0.5 mm) and No. 83 (opening 0.18 mm) sieve prescribed by the 15th revised Japanese Pharmacopoeia. It is the particle size obtained by shaking with a type sieve shaker.

  In the granule of the present invention, among the three types of branched chain amino acids that are active ingredients, any of D-form, L-form, and DL-form can be used as isoleucine. In general, particles having a particle size of 1 mm or less produced by a fermentation method and satisfying the standards described in the 15th revised Japanese Pharmacopoeia Pharmaceuticals are used, but not limited thereto.

  As the leucine, any of D-form, L-form and DL-form can be used. In general, particles having a particle size of 1 mm or less manufactured by a fermentation method or an extraction method and satisfying the standards described in each article of the 15th revised Japanese Pharmacopoeia are used, but are not limited thereto.

  Furthermore, as the valine, any of D-form, L-form, and DL-form can be used. In general, particles having a particle size of 1 mm or less produced by a fermentation method or a synthesis method and satisfying the standards described in the 15th revised Japanese Pharmacopoeia Pharmaceuticals are used, but not limited thereto.

  In the present invention, the specific volume can be reduced regardless of the particle sizes of the isoleucine, leucine and valine. However, in consideration of handling of the granular material at the time of granule production, it is preferable to use particles having a particle size of 10 μm to 1000 μm, more preferably particles having a particle size of 100 μm to 800 μm, particularly particles having a particle size of 150 μm to 500 μm. Preferably used. The method for adjusting the particle size of the isoleucine, leucine and valine particles is not particularly limited, and a normal pulverization method is employed. Examples of pulverizers that can be used for pulverization include impact type (high-speed rotation type) pulverizers such as hammer mills, tumbler type (medium type) pulverizers such as ball mills, and fluid type (airflow type) pulverizers such as jet mills. It is done.

  The particle size of the branched chain amino acid is a value obtained by measurement by the following method. That is, using a laser diffraction / scattering type particle size distribution measuring apparatus (LA-910, manufactured by HORIBA, Ltd.), 200 mL of 2-propanol was placed in a circulation tank and circulated for 5 minutes while stirring and irradiating with ultrasonic waves. Next, 200 mL of 2-propanol was put into a circulation tank, and a sample of amino acid to be measured so that the transmittance was about 85% was added. Circulate for 4 minutes while sonicating, and measure the particle size 5 minutes after stopping the ultrasound. The average particle diameter obtained is shown using the median diameter based on volume.

  In the granule of the present invention, isoleucine, leucine and valine are preferably contained in a weight ratio of isoleucine: leucine: valine = 1: 1.9 to 2.2: 1.1 to 1.3. The content of the three branched chain amino acids consisting of isoleucine, leucine and valine is 80% to 100% by weight, preferably 90% to 100% by weight, more preferably 94% to 97% by weight, based on the total amount of granules. Is appropriate.

  In order to obtain the granule of the present invention, a mixture containing the branched chain amino acid particles is granulated. A binder can be used for granulation. Examples of binders include cellulose derivatives such as methylcellulose, hydroxypropylcellulose, hypromellose and hypromellose phthalate; starches such as corn starch and wheat starch; synthetic polymers such as polyvinylpyrrolidone and acrylic acid polymers; As long as it is a general pharmaceutical binder such as natural polymers such as gelatin and satisfies standards such as the Japanese Pharmacopoeia or pharmaceutical additive standards, it can be used without particular limitation. Moreover, it can be used within the range in which normal granulation is possible.

  The branched amino acid powder can be mixed with other granular materials or additive components by a general mixing method used for formulation, horizontal cylindrical mixer, V-type mixer, double cone type. A mixer, a rocking rotary mixer, a single-shaft ribbon mixer, a double-shaft paddle mixer, a rotary mixer, a conical screw mixer, or the like is used.

  In the present invention, a mixture containing branched-chain amino acid particles can be granulated by a general granulation method, and both dry granulation and wet granulation can be used. Further, wet granulation such as spray drying granulation, fluidized bed granulation, tumbling granulation, tumbling fluidized bed granulation, and extrusion granulation is preferable, and extrusion granulation is particularly preferable. Here, the stirring and mixing granulation adds a binding liquid to the particles being stirred, gives shearing, rolling, compaction action, etc. by rotation of blades of various shapes, and promotes cross-linking of the particles and particles, This is a granulation method in which granulated particles are formed by repeating the generation, bonding (association) and crushing (dissociation) of fine particles to cause particle growth. Spray drying granulation is a granulation method in which a liquid is dispersed in a hot air stream and dried. Fluidized bed granulation is usually performed by spraying the binding liquid in a fluidized bed such as a fluidized bed, circulating fluidized bed, forced circulating fluidized bed, or spouted bed while keeping the powder bed in a fluidized state. Is a granulation method for agglomerating and granulating. In rolling granulation, raw material powder of particles is rolled in various containers by the action of stirring blades, and sprayed with a binding solution, while forming fine particles by forming cross-links between the particles. A granulation method that promotes grain growth by imparting rotational motion to particles, and is performed using a dish-type (van-type) granulator, drum-type granulator, vibration-type granulator or the like. Rolling fluidized bed granulation is a mechanism that combines the characteristics of agitation granulation and fluidized bed granulation, and sprays the binding liquid while rolling, flowing, and stirring the particles to promote cross-linking between the particles. It is a granulation method for forming granulated particles. Extrusion granulation refers to granulation by adding water or a binder solution and kneading and extruding the plasticized powder from a screen or die with many holes with a screw, roller, etc. This is performed using a machine, a disk pelleter granulator, a ring die granulator, a basket granulator, an oscillating granulator, a cylinder granulator, and the like.

  Next, in the present invention, the granulated powder is sized. The sizing is performed for 2 minutes to 10 hours, which is performed for a long time as compared with a normal sizing time (several tens of seconds). The sizing means that the shape and size of the granulated granules are set to a certain shape and size, grinding sizing, pulverization sizing with classification function, crushing sizing, wet continuous sizing, Examples thereof include rotary centrifugal crush sizing, high-speed or low-speed sizing, and spherical sizing. The sizing time is preferably 5 minutes to 5 hours, more preferably 10 minutes to 4 hours, further preferably 15 minutes to 3 hours, and 20 minutes to 2 hours. Is particularly preferable, and in consideration of an actual manufacturing process and the like, the time is most preferably set to 30 minutes to 1 hour.

  In the present invention, spherical sizing is preferably used among the above sizing methods. “Spherical sizing” refers to sizing powder into a spherical shape, preferably using a spherical sizing machine (“Malmerizer”, manufactured by Dalton Co., Ltd.).

  The granulator and the granulator used in the present invention, the disk and stirring blades, crushing blades, sieves, etc. constituting these devices are all shapes as long as they can be attached to the devices, Various types can be used.

  In the present invention, the granulated powder to be sized can be either a wet granulated powder or a dry granulated powder, but a wet granulated powder is preferred. A wet granulated powder is a powder in a wet state without being dried after granulation. The dried granulated powder is a powder that has been dried after granulation, and may be a fluidized bed dryer, a shelf dryer, or the like, or may be naturally dried.

  The granule of the present invention produced through the granulation and sizing described above may be further reduced in bitterness by adding a slight taste-masking agent or applying a slight coating during the granulation. Needless to say, you can. Examples of the corrigent include aspartame, saccharin sodium hydrate, glycyrrhizic acid, dipotassium glycyrrhizinate, stevia, sucrose, and acesulfame potassium. Examples of the coating agent include sugar coating agents such as sucrose; cellulose polymers such as hydroxypropyl cellulose, hypromellose, hydroxyethyl cellulose, and methylhydroxyethyl cellulose; synthetic polymers such as polyvinyl acetal diethylaminoacetate, aminoalkyl methacrylate copolymer, and polyvinylpyrrolidone; Water-soluble film coating agents such as polysaccharides such as pullulan, cellulosic polymers such as hypromellose phthalate ester, hypromellose acetate succinate, carboxymethyl ethyl cellulose, cellulose acetate phthalate; acrylic acid such as methacrylic acid copolymer -Based polymers; enteric film coating agents such as natural polymers such as shellac.

  Furthermore, in producing the granules of the present invention, excipients, disintegrants, flavoring agents, coloring agents, lubricants, lubricants, fluidizers, brighteners, stabilizers, surfactants, plasticizers Agent, capsule film, solubilizer, reducing agent, buffer, sweetener, base, volatilization aid, synergist, suspending agent, curing agent, antioxidant, absorption enhancer, adsorbent, fragrance, efficacy Enhancer, skin, support, sustaining agent, wetting agent, wetting conditioner, filler, antifoaming agent, cooling agent, feeding accelerator, adhesive, enhancing agent, chewing agent, antistatic agent, etc. Tonicizer, softener, emulsifier, combustion agent, adhesive, adhesion enhancer, thickener, flame retardant, fever, foaming agent, pH adjuster, skin protectant, flotation agent, dispersant, jetting Agents, disintegration aids, fragrances, rust preventives, moisture-proofing agents, controlled release films, antiseptics, scavengers, preservatives, soothing agents, attractants, solubilizers, solubilizers, solvents, mold release agents, etc. Through It can be used common additives used during formulation.

  The granule containing the branched chain amino acid of the present invention has a reduced specific volume and is suitable for oral administration. The specific volume of the granule of the present invention is preferably less than 2.0 mL / g, more preferably 1.94 mL / g or less, and particularly preferably 1.93 mL / g or less. When the specific volume is 2.0 mL / g or more, when a granule containing about 4 g of branched chain amino acid, which is a normal dose per one time, is prepared, the specific volume of the granule becomes as high as 8 mL or more. This is because it becomes difficult to take orally. In consideration of industrial production conditions and the like, the specific volume of the granule containing the branched chain amino acid of the present invention is usually 1.5 mL / g or more. In the present invention, the specific volume is measured by pouring granules into a measuring cylinder, measuring the volume and weight, and calculating the specific volume from the obtained values.

  EXAMPLES Next, although an Example is given and this invention is demonstrated more concretely, this invention is not limited by a following example.

[Example 1] When the sizing time is 1 hour (1) L-isoleucine 476 g, L-leucine 952 g, L-valine 572 g (weight ratio of L-isoleucine, L-leucine and L-valine = 1: 2: 1.2), 40.5 g of polyvinyl pyrrolidone K90 and 16.5 g of polyvinyl alcohol (partially saponified product) were mixed for 5 minutes in a high speed mixer (FS-10JD, manufactured by Fukae Powtech Co., Ltd.) (agitator rotation speed: 300 rpm, Chopper rotation speed: 1500 rpm).
(2) 8.5 g of saccharin sodium hydrate was dissolved in 455 g of water to obtain a binding solution.
(3) The binding solution of (2) was added to the mixture obtained in (1) and mixed for 5 minutes (agitator rotation speed: 300 rpm, chopper rotation speed: 1500 rpm).
(4) The mixture obtained in (3) is processed by an extrusion granulator ("Petterter Double", manufactured by Dalton Co., Ltd., screen hole diameter: 1.0 mm), and further a granulator ("Malmerizer"), The resulting granulated product was dried with a fluidized bed dryer (FLO-1 type, manufactured by Freund Sangyo Co., Ltd.).

[Example 2] When the sizing time was 30 minutes.

[Example 3] When the sizing time was 45 minutes.

[Example 4] When the sizing time was 70 minutes.

  Table 1 shows the composition of the granules obtained in Examples 1 to 4 above.

[Comparative Example 1] When the sizing time is 1 minute (1) In the same manner as in Example 1 above, 476 g of L-isoleucine, 952 g of L-leucine, 572 g of L-valine, 40.5 g of polyvinylpyrrolidone K90, polyvinyl 16.5 g of alcohol (partially saponified product) was mixed, and an aqueous solution in which 8.5 g of sodium saccharin hydrate was dissolved in 455 g of water was added and mixed as a binding solution.
(2) The mixture obtained in (1) above is processed by an extrusion granulator ("Petterter Double", manufactured by Dalton Co., Ltd., screen hole diameter: 1.0 mm), and further a granulator ("Malmerizer"). , Manufactured by Dalton Co., Ltd. for 1 minute, and the resulting granulated product was dried with a fluidized bed dryer (FLO-1 type, manufactured by Freund Corporation).

[Comparative Example 2] When the sizing time was 10 seconds It was prepared in the same manner as Comparative Example 1 except that the processing time by the sizing machine was 10 seconds.

[Comparative Example 3] When the sizing time was 0 seconds.

  The composition of the granules obtained in Comparative Examples 1 to 3 is the same as the composition shown in Table 1.

[Measurement of specific volume]
The specific volumes of the granules obtained in Examples 1 to 4 and Comparative Examples 1 to 3 were measured as follows. That is, the granules obtained in each Example and Comparative Example were each poured into a graduated cylinder, the volume and weight were measured, and calculated from the obtained measured values. The measurement results are shown in Table 2.

  As is clear from Table 2, the specific volume of the granules obtained in Examples 1 to 4 of the present invention was 1.88 mL / g to 1.93 mL / g, both of which were less than 2.0 mL / g. . On the other hand, the specific volume of the granules obtained in Comparative Examples 1 to 3 was 2.18 mL / g to 2.63 mL / g, and all were 2.0 mL / g or more.

  As described above, the present invention provides a granule preparation containing three kinds of branched chain amino acids consisting of isoleucine, leucine and valine, having a reduced specific volume and less discomfort when taken orally. .

  This application is based on a patent application No. 2009-230602 filed in Japan, the contents of which are incorporated in full herein.

Claims (14)

Isoleucine, granulated extruded mixture containing particles of leucine and valine, obtained by subsequent 2 minutes to 10 hours spheronization, specific volume Ru der less than 2.0 mL / g, isoleucine, leucine and valine Granules containing three kinds of branched chain amino acids in an amount of 80% by weight to 100% by weight based on the total amount of the granules. The granule of Claim 1 which contains 90 weight%-100 weight% of 3 types of branched chain amino acids, isoleucine, leucine, and valine with respect to the granule whole quantity. The granule of Claim 1 which contains 94 weight%-97 weight% of 3 types of branched chain amino acids, isoleucine, leucine, and valine with respect to a granule whole quantity. The granule according to any one of claims 1 to 3 , obtained by spherical sizing for 5 minutes to 5 hours. The granule according to any one of claims 1 to 3 , obtained by spherical sizing for 15 minutes to 3 hours. The granule according to any one of claims 1 to 3 , obtained by spherical sizing for 30 minutes to 1 hour. Furthermore, the granule of Claim 3 obtained by extruding and granulating the mixture containing polyvinylpyrrolidone and polyvinyl alcohol as an additive, and carrying out spherical sizing after that. Isoleucine in the mixture, the weight ratio of leucine and valine, isoleucine: leucine: valine = 1: 1.9 to 2.2: a 1.1 to 1.3, any one of 請 Motomeko 1-7 Granules according to 1.   The granule according to any one of claims 1 to 8, wherein the specific volume is 1.94 mL / g or less.   The granule according to any one of claims 1 to 8, wherein the specific volume is 1.93 mL / g or less. A mixture containing particles of isoleucine, leucine and valine is extruded and granulated, and then spherically sized for 2 minutes to 10 hours. The three branched chains of isoleucine, leucine and valine with a specific volume of less than 2.0 mL / g The manufacturing method of the granule which contains an amino acid 80weight%-100weight% with respect to the granule whole quantity . The production method according to claim 11 , wherein spherical sizing is performed for 5 minutes to 5 hours. The production method according to claim 11 , wherein spherical sizing is performed for 15 minutes to 3 hours. The production method according to claim 11 , wherein spherical sizing is performed for 30 minutes to 1 hour.