WO2002030416A1 - Suspensions medicamenteuses contenant des acides amines ramifies - Google Patents

Suspensions medicamenteuses contenant des acides amines ramifies Download PDF

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Publication number
WO2002030416A1
WO2002030416A1 PCT/JP2001/008781 JP0108781W WO0230416A1 WO 2002030416 A1 WO2002030416 A1 WO 2002030416A1 JP 0108781 W JP0108781 W JP 0108781W WO 0230416 A1 WO0230416 A1 WO 0230416A1
Authority
WO
WIPO (PCT)
Prior art keywords
suspension
leucine
isoleucine
branched
pharmaceutical
Prior art date
Application number
PCT/JP2001/008781
Other languages
English (en)
Japanese (ja)
Inventor
Hiroyuki Higuchi
Mitsuyasu Ida
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 WO2002030416A1 publication Critical patent/WO2002030416A1/fr

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Classifications

    • 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
    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
    • 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
    • A61K9/10—Dispersions; Emulsions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics

Definitions

  • the present invention relates to a highly stable pharmaceutical suspension containing, as an active ingredient, three kinds of branched-chain amino acid particles composed of isoleucine, leucine and palin.
  • the present invention relates to a highly stable pharmaceutical suspension containing, as an active ingredient, three types of branched-chain amino acid particles composed of highly bitter isoleucine, leucine and palin as an active ingredient.
  • compositions containing three types of branched-chain amino acids consisting of isoleucine, leucine and valine are effective remedies for cirrhosis, and currently marketed preparations are mainly granules.
  • the dose per dose is about 5 g, which is significantly larger than that of general preparations, and is taken due to the strong bitterness.
  • a drug that is taken in a large dose is a suspension that passes through the throat and does not require water when taken.
  • the concentration of the active ingredient is set to about 10% or less due to technical problems, except for enteral nutritional supplements containing some proteolytic products. (Eg, sucralf art, aluminum hydroxide / magnesium hydroxide, etc.).
  • An object of the present invention is to make it possible to increase the concentration of a suspension formulation in order to make a single dose of a highly bitter branched-chain amino acid drug an appropriate amount as a medicinal product, and to achieve a stable long-term treatment.
  • An object of the present invention is to provide a pharmaceutical suspension containing, as an active ingredient, three kinds of strongly bitter branched amino acid particles consisting of isoleucine, leucine and valine capable of maintaining a suspension state.
  • the present invention that can achieve the above object includes the following inventions.
  • It contains three kinds of branched-chain amino acid particles consisting of isoleucine, leucine and palin as an active ingredient, has a viscosity of 3 to 1500 OmPas, and has a hydrophilic-hydrophobic balance (HLB) of 3
  • a pharmaceutical suspending agent which comprises a suspending agent of from 40 to 40.
  • the said suspending agent is characterized in that it is at least one selected from the group consisting of cellulose derivatives, polypinyl alcohol, gelatin, agar, and tragacanth powder (1) or (2).
  • the cellulose derivative as the suspending agent is hydroxypropyl methylcell At least one selected from the group consisting of roose, methylcellulose, hydroxypropylcellulose, carmellose sodium, crystalline cellulose and crystalline cellulose 'carmellose sodium, and in particular at least one selected from hydroxypropylmethylcellulose and hydroxypropylcellulose.
  • the suspension concentration of the branched-chain amino acid particles comprising isoleucine, leucine and palin is 15 to 60% (W / V), wherein the suspension concentration is 15 to 60% (W / V). 2.
  • the suspension preparation for treating cirrhosis of the present invention refers to a suspension and a syrup described in the Japanese Pharmacopoeia or the European Pharmacopoeia, and the concentration thereof is also described in the Japanese Pharmacopoeia or the Japanese Pharmacopoeia. It is within the specified range.
  • the active ingredients in the suspension preparation of the present invention are three kinds of branched-chain amino acids consisting of isoleucine, leucine and valine.
  • Isoleucine is not particularly limited as long as it meets the standards of the Japanese Pharmacopoeia, the European Pharmacopoeia, or the United States Pharmacopeia, but usually it is manufactured by fermentation to a size of about 1 mm or less. Those having a particle size of pulverized and having a D50 of 3 to 100 are used.
  • leucine is not particularly limited as long as it meets any of the standards of the Japanese Pharmacopoeia, the European Pharmacopoeia, and the United States Pharmacopeia, but is usually manufactured by fermentation or extraction.
  • a powder having a particle size of about or less and having a D50 force of 3 to 100 / im is used.
  • palin is not particularly limited as long as it satisfies either the Japanese Pharmacopoeia, the European Pharmacopoeia, or the United States Pharmacopoeia, but it is usually produced by fermentation or synthesis. Those having a particle size of about mm or less are pulverized, and those having a D50 of 3 to 100 m are used.
  • the mixing ratio of isoloisin / peripheral blood mononuclear / valine is in the range of zirconium, leucine (1.9-2.2), and norin (1.1-1.3), with isoloicin as 1.
  • the mixing ratio is not limited to the above, and the mixing amounts can be appropriately increased or decreased.
  • the particle size of isoleucine, leucine, and palin is desirably D50 of 3 to 100 m, but any particle size up to about 500 m can be used. .
  • the suspending agent used in the suspension preparation of the present invention is at least one selected from the group consisting of cellulose derivatives, polyvinyl alcohol, gelatin, agar, and tragacanth powder.
  • cellulose derivative examples include hydroxypropylmethylcellulose, methylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, hydroxyxethylmethylcellulose, carmellose, carmellose sodium, carmellose calcium, crystalline cellulose, crystalline cellulose, and carmellose sodium.
  • the range of the amount of the suspending agent used is 0.1 to 5.0% (WZV), preferably 0.3 to 3.0% (W / V), based on the total volume of the suspension formulation.
  • the ratio is 0.5 to 25.0% (W / V), preferably 1.5 to 15.0% (W / V) for amino acid pairs.
  • synthetic polymers such as carboxylvinyl polymer, partially or completely saponified polyvinyl alcohol used as a suspending agent in ordinary pharmaceutical suspensions, polyvinylalcohols, and sodium alginate, alginic acid Natural polymers such as propylene glycol ester can also be used.
  • surfactants such as polysorbate 80, polyoxyethylene hydrogenated castor oil 60, polyoxyl stearate 40, inorganic substances such as magnesium metasilicate aluminate and light caffeic anhydride can also be used. .
  • preservatives used in ordinary suspensions can be used in consideration of safety, compatibility with the branched-chain amino acid as the main drug, and the like.
  • preservatives that can be used include sorbic acid and its salts, benzoic acid and its salts, paraoxybenzoic acid and its esters, and the like.
  • the suspension preparation of the present invention is prepared by using isoleucine, leucine, and palin particles having the above-mentioned particle diameters in the above-mentioned mixing ratio, and mixing with water together with the suspending agent.
  • the mixing means for preparing the suspension formulation and the mixing mechanism and model are not limited as long as a uniform suspension can be obtained.
  • homogenizers such as microfluidizers, colloid mills, etc.
  • high-pressure emulsifiers such as microfluidizers, colloid mills, etc.
  • universal mixers such as kneaders, pot mills, mortars, etc. can also be used.
  • the measurement of the particle size of the branched-chain amino acid particles used in the suspension preparation can be performed as follows.
  • a laser diffraction / scattering type particle size distribution analyzer (LA-920, manufactured by HORIBA, Ltd.), put about 20 Om 1 of 2-propanol into the circulation layer, and carry out stirring and ultrasonic irradiation for 2 minutes. After circulating, perform blanking (no ultrasonic irradiation during measurement). Subsequently, the amino acid sample to be measured is introduced so that the transmittance is within the range of 85% and 5%. Stir and circulate for 2 minutes while irradiating ultrasonic waves, and measure 1 minute after stopping ultrasonic irradiation. The average particle diameter is a volume-based median diameter.
  • the HLB of the suspending agent used in the suspension formulation of the present invention is based on the chemical structure of the components or main components in the suspending agent. ) p158 ”, and can be calculated from the Davies formula based on the radix of Davies.
  • the viscosity of the suspending agent used in the suspension preparation of the present invention is determined by using a 2% aqueous solution or dispersion as a cone-plate rotary viscometer described in the Japanese Pharmacopoeia 13th Edition, General Test Method, Viscosity Measurement Method. device used (Toki Sangyo TV- 3 0 form), those liquid at room temperature which has been gelled 2 5 ° C, at room temperature to implement the c invention obtained as measured value measured at a temperature of sol Best form for
  • HPMC hydroxypropylmethylcellulose
  • HLB HLB 15.7
  • disperser IKA-Labortcchnik URTRA- TURRAX25
  • HPC hydroxypropylcellulose
  • HLB 17.3 hydroxypropylcellulose
  • disperser as in Example 1 was added. Melted in one. To this solution were added 1.25 g of citrate anhydride, 0.25 g of saccharin sodium, 37.50 g of erythritol, and 0.13 g of dimethylpolysiloxane, and dissolved with a disperser. To this solution, the same isoleucine 23.80 g, leucine 47.60 g, and phosphorine 28.60 g as used in Example 1 were added, and suspended with a disperser. Was added to make the total volume 62.5 ml. To this solution, a very small amount of Beguchi Essence was added, and the suspension was uniformly suspended using the same Mic-mouth Fluidizer as used in Example 1 to prepare a pharmaceutical suspension.
  • HPC hydroxypropylcellulose
  • Examplementation ⁇ Row 4 Purified water in 250 ml with a viscosity of 55 mPa's, HLB 15.9 HPMC 2.80 g and viscosity 1195 mPa a's, HLB 33.0 crystal cell opening '0.2 g of carmellose sodium was added and dispersed with the same disperser as in Example 1. To this dispersion, 0.80 g of tartaric acid, 0.16 g of saccharin sodium and 0.80 g of dimethylpolysiloxane were added and dissolved with the same disperser.
  • Example 2 To this solution, add 19.04 g of isoleucine, 38.08 g of leucine, and 2.2.8 g of valine as used in Example 1, suspend with a disperser, and add purified water. The total volume was adjusted to 376 ml. Strobery essence was added to this liquid, and the liquid was uniformly suspended with the same microfluidizer as used in Example 1 to prepare a pharmaceutical suspension.
  • the pharmaceutical suspension of the present invention comprising three types of branched-chain amino acids consisting of isoleucine, leucine and parin has excellent storage stability at a high concentration, has improved This contributes to improving compliance.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Dispersion Chemistry (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Preparation (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

La présente invention concerne des suspensions médicamenteuses contenant une concentration élevée de particules d'acides aminés ramifiés en tant que substances actives, ont une stabilité élevée et peuvent être facilement administrées. Des études intensives ont permis de mettre au point des suspensions médicamenteuses se caractérisant en ce qu'elles contiennent des acides aminés ramifiés comprenant l'isoleucine, la leucine et la valine en tant que substances actives, en ce qu'elles ont une viscosité de 3 à 15000 mPa . sec, et en ce qu'elles ont un rapport hydrophile-lipophile (HLB) de 3 à 40. Ces préparations ont une excellente stabilité au stockage à des concentrations élevées, et contribuent à l'amélioration des propriétés d'administration et de la conformité du traitement.
PCT/JP2001/008781 2000-10-10 2001-10-05 Suspensions medicamenteuses contenant des acides amines ramifies WO2002030416A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
JP2000309086 2000-10-10
JP2000-309086 2000-10-10
JP2001-296990 2001-09-27
JP2001296990A JP3341766B2 (ja) 2000-10-10 2001-09-27 分岐鎖アミノ酸を含有する医薬用懸濁剤

Publications (1)

Publication Number Publication Date
WO2002030416A1 true WO2002030416A1 (fr) 2002-04-18

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WO (1) WO2002030416A1 (fr)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR101458670B1 (ko) * 2012-03-30 2014-11-06 주식회사 서울제약 분지쇄아미노산을 함유하는 약제학적 조성물 및 그 제조방법

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS6049751A (ja) * 1983-08-29 1985-03-19 Ajinomoto Co Inc 食品組成物
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
JPH11116485A (ja) * 1997-10-09 1999-04-27 Taiyo Yakuhin Kogyo Kk スクラルファート懸濁液製剤

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS6049751A (ja) * 1983-08-29 1985-03-19 Ajinomoto Co Inc 食品組成物
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
JPH11116485A (ja) * 1997-10-09 1999-04-27 Taiyo Yakuhin Kogyo Kk スクラルファート懸濁液製剤

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Publication number Publication date
JP3341766B2 (ja) 2002-11-05
JP2002187840A (ja) 2002-07-05

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