WO2002040011A1 - Fabrication de medicaments en granules renfermant des acides amines ramifies - Google Patents

Fabrication de medicaments en granules renfermant des acides amines ramifies Download PDF

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Publication number
WO2002040011A1
WO2002040011A1 PCT/JP2001/009638 JP0109638W WO0240011A1 WO 2002040011 A1 WO2002040011 A1 WO 2002040011A1 JP 0109638 W JP0109638 W JP 0109638W WO 0240011 A1 WO0240011 A1 WO 0240011A1
Authority
WO
WIPO (PCT)
Prior art keywords
chain amino
particle size
amino acid
branched
kneading
Prior art date
Application number
PCT/JP2001/009638
Other languages
English (en)
Japanese (ja)
Inventor
Kazuhiro Takanosu
Hidetoshi Sakai
Akira Yabuki
Original Assignee
Ajinomoto Co., Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Ajinomoto Co., Inc. filed Critical Ajinomoto Co., Inc.
Publication of WO2002040011A1 publication Critical patent/WO2002040011A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1682—Processes

Definitions

  • the present invention relates to a method for producing pharmaceutical granules containing three kinds of branched-chain amino acids of isoleucine, leucine and palin as a main drug.
  • the extrusion granulation step for preparing the raw material granules requires a water amount of 30 to 50 to be added at the time of kneading the raw materials. %, And extrusion granulation is performed, but the yield of granules having an appropriate appropriate particle size range varies greatly.
  • the particle size of the granules to be produced is out of the appropriate particle size range, it will be a loss. If the yield of the granules in the appropriate particle size range in the extrusion granulation process is low, other factors such as the appearance of the granulated product may be considered.
  • the optimal amount of kneading water is estimated based on experience with the product, and it is changed and adjusted to an appropriate particle size range.However, the fluctuation range of the yield in the granulation process must always be kept small. Is an extremely difficult task requiring skill. Disclosure of the invention
  • An object of the present invention is to provide a process for granulating granules containing three kinds of branched-chain amino acids consisting of isoleucine, leucine and palin, in which granules having an appropriate particle size range can be produced stably and in high yield. It is to provide a grain method.
  • the present inventors have studied the operating conditions of the process of granulating 20 to 32 (mesh) granules for applying a coating containing three kinds of branched-chain amino acids consisting of isoleucine, leucine and palin. Thus, the present inventors have found that there is a correlation between the granulation yield and the amount of water added during kneading, the particle size of the raw material branched chain amino acid, and the amount of the binder, and completed the present invention. According to the present invention, the production of coarse granules due to excessive kneading is suppressed, and the granule yield is significantly improved and stabilized by optimizing the granule strength and suppressing the amount of fine powder.
  • the present invention includes the following inventions.
  • Amount of kneading water (% by weight of powder) (-0.25xD [50] + A) X (1.1-B / 13.1)
  • A a number from 48 to 53
  • D [50] Average particle size of raw material branched-chain amino acids measured by a laser diffraction particle size distribution analyzer, and a median diameter (m )
  • the isoleucine used as a raw material branched chain amino acid in the method of the present invention has a particle size of 1 mm or less produced by a fermentation method or the like, and is selected from the Japanese Pharmacopoeia, the Japanese Pharmacopoeia, the United States Pharmacopeia, and Satisfies, but is not limited to.
  • Leucine a raw material branched-chain amino acid, is manufactured by fermentation or extraction and has a particle size of lmm or less, and meets any of the standards of the Japanese Pharmacopoeia, European Pharmacopoeia, or the United States Pharmacopeia. It is not limited to that.
  • palin a raw material branched chain amino acid
  • the mixing ratio of isoleucine / leucine valine is leucine (1.9 to 2.2) and valine (1.:! To 1.3), where isoloicin is 1 by weight, and these are ground to 5 to 1 50 m, preferably 20 to 80 m.
  • the granules in the present invention are those obtained by adding kneading water to a powder in which the raw material branched chain amino acid is powdered, kneading the resultant, and drying the wet granules obtained by extrusion granulation.
  • the particle size of the powder obtained by pulverizing the amino acid is measured, and kneading is performed with the kneading water amount derived from the calculation formula described in paragraph [0000], whereby the excessive kneading is performed.
  • the formation of coarse granules due to the above is suppressed, and the granule strength is optimized and the generation of fine powder is also suppressed, so that the yield is significantly improved and stabilized as compared with the prior art.
  • Pulverization here refers to pulverization using a shock (high-speed rotation) pulverizer such as a hammer mill, a tumbler type (medium type) such as a ball mill, or a fluid (air flow) pulverizer such as a jet mill. Preferred, but not limited to.
  • the particle size of the powder containing the raw material amino acids was measured by placing 2-propanol 20 Om 1 in a circulation tank and stirring. After circulating for 5 minutes while irradiating ultrasonic waves, perform blank measurement (ultrasonic wave is OFF during measurement). Next, 200 ml of 2-propanol is put into the circulation tank, and the amino acid sample to be measured is introduced so that the transmittance becomes about 85%. Stir and circulate for 4 minutes while irradiating ultrasonic waves, and measure the particle size 5 minutes after stopping the ultrasonic waves. The median diameter based on volume was used as the average particle diameter.
  • Kneading is the operation of kneading the wet powder, which is performed before the extrusion granulation operation, and is performed by, but not limited to, Shinagawa-type kneading machines, vertical and horizontal stirring granulators, etc. It is not something.
  • Extrusion granulation is a method of granulating by extruding plasticized powder through a screen with many holes.
  • Pre-extrusion granulator, disk pelletizer complete granulator, ring die type Granulators, basket-type granulators, oscillating-type granulators, cylinder-type granulators, etc. are used, but are not limited thereto.
  • Yield is the percentage of the ratio of the amount of granules that can be sent to the next step and the charged amount, expressed as a percentage.
  • the amount that can be sent to the next step is preferable if the next step is a coating step 20 to 32 mesh granules, and when the next step is a packaging step, preferably 16 to 48 mesh granules.
  • FIG. 1 is a diagram showing the relationship between the particle size of branched-chain amino acids and the amount of kneading water.
  • Example 1 Example 1
  • the kneaded material was extruded eight times and granulated by an extruder EXD S-100 (0.6 mm screen, shaft rotation speed: 22 rpm).
  • the obtained wet granulated product is divided into two parts, each of which is dried with a flow drier (N FOD-120) (supply air temperature: 70 ° C), and then 20 to 32 M (mesh) using a sieve. ) was obtained.
  • the yield was 94.1%.
  • the kneaded product was extruded eight times and granulated by an extruder EXD S-100 (0.6 mm screen, shaft rotation speed: 22 rpm).
  • the obtained wet granulated product is divided into two parts, each of which is dried by a flow dryer (N FOD—120) (at an air supply temperature of 70), and then subjected to 20 to 32 M (mesh) using a sieve. ) Was obtained.
  • the yield was 94.0%.
  • the kneaded product was extruded eight times and granulated by an extruder EXD S-100 (0.6 mm screen, shaft rotation speed: 22 rpm).
  • the obtained wet granulated product is divided into two parts, each of which is dried with a flow drier (N FOD-120) (at an air supply temperature of 70) and then 20 to 32 M (mesh) using a sieve. This gave granules of The yield was 94.3%.
  • FIG. 1 shows the relationship between the particle size of the raw material branched-chain amino acid and the amount of kneading water prepared based on the results of the examples and comparative examples, and experimental results of the same type.
  • y indicates the amount of kneading water (% by weight of powder)
  • X indicates the particle size ( m ) of the raw material branched chain amino acid.
  • BCAA Branched chain amino acid

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Epidemiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Inorganic Chemistry (AREA)
  • Medicinal Preparation (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

Cette invention concerne un procédé de granulation selon lequel des granules d'une taille appropriée peuvent être produites de manière homogène et avec une efficacité élevée. Ces granules renferment comme agents principaux trois acides aminés : l'isoleucine, la leucine et la valine. Ce procédé se caractérise en ce que le volume d'eau à utiliser pour le pétrissage au cours du processus de formation des granules par extrusion est calculée d'après la formule suivante : volume d'eau pour le pétrissage (en pourcentage de poids de la poudre) = (-0,25 x D[50] +A) x (1,1 B/13,1) dans laquelle A est une valeur numérique comprise entre 48 et 53 ; D[50] correspond à la taille moyenne des grains des matières d'acides aminés exprimée par le diamètre médian (νm) représentant les 50 % cumulés en distribution logarithmique normale de la taille des grains par rapport au volume ; et B représente la teneur en hydroxyrpopylcellulose (en % d'acides aminés ramifiés), 0,5≤ b≤ 5.
PCT/JP2001/009638 2000-11-16 2001-11-02 Fabrication de medicaments en granules renfermant des acides amines ramifies WO2002040011A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2000349983A JP3228289B1 (ja) 2000-11-16 2000-11-16 分岐鎖アミノ酸を含有する医薬用顆粒の製造方法
JP2000-349983 2000-11-16

Publications (1)

Publication Number Publication Date
WO2002040011A1 true WO2002040011A1 (fr) 2002-05-23

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Family Applications (1)

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PCT/JP2001/009638 WO2002040011A1 (fr) 2000-11-16 2001-11-02 Fabrication de medicaments en granules renfermant des acides amines ramifies

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JP (1) JP3228289B1 (fr)
WO (1) WO2002040011A1 (fr)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
TWI503128B (zh) * 2007-07-31 2015-10-11 Ajinomoto Kk A granule preparation containing an amino acid with excellent taste

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0184999A2 (fr) * 1984-12-12 1986-06-18 Boehringer Mannheim Italia S.P.A. Produits diététiques granulaires à base d'amino-acides et méthode pour leur préparation
JPH03204814A (ja) * 1989-10-09 1991-09-06 Otsuka Pharmaceut Factory Inc 腎不全用経口アミノ酸製剤
JPH0920689A (ja) * 1995-07-10 1997-01-21 Asahi Chem Ind Co Ltd 粒剤及びその製法

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0184999A2 (fr) * 1984-12-12 1986-06-18 Boehringer Mannheim Italia S.P.A. Produits diététiques granulaires à base d'amino-acides et méthode pour leur préparation
JPH03204814A (ja) * 1989-10-09 1991-09-06 Otsuka Pharmaceut Factory Inc 腎不全用経口アミノ酸製剤
JPH0920689A (ja) * 1995-07-10 1997-01-21 Asahi Chem Ind Co Ltd 粒剤及びその製法

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JP3228289B1 (ja) 2001-11-12
JP2002154958A (ja) 2002-05-28

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