WO2003063856A1 - Jelly preparation containing branched amino acids - Google Patents

Jelly preparation containing branched amino acids Download PDF

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Publication number
WO2003063856A1
WO2003063856A1 PCT/JP2003/000581 JP0300581W WO03063856A1 WO 2003063856 A1 WO2003063856 A1 WO 2003063856A1 JP 0300581 W JP0300581 W JP 0300581W WO 03063856 A1 WO03063856 A1 WO 03063856A1
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WIPO (PCT)
Prior art keywords
acid
leucine
isoleucine
jelly
agent
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PCT/JP2003/000581
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French (fr)
Japanese (ja)
Inventor
Hiroyuki Higuchi
Hirokazu Hagio
Chisato Makino
Tomoaki Kawano
Mitsuyasu Ida
Akira Yabuki
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Ajinomoto Co., Inc.
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Publication of WO2003063856A1 publication Critical patent/WO2003063856A1/en

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    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
    • 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 jelly agent containing, as an active ingredient, three kinds of branched-chain amino acids consisting of isoleucine, leucine and parin.
  • the jelly agent referred to in the present invention refers to a solution or suspension which is made into a semi-solid state by using a gelling agent such as agar or gelatin.
  • compositions containing three types of branched-chain amino acids of isoleucine, leucine and valine as active ingredients are effective therapeutic agents for liver diseases, and currently marketed preparations are mainly granules.
  • granules containing the above three kinds of branched-chain amino acids as active ingredients have a drawback of-about 5 g, which is remarkably large compared to general preparations, and are difficult to take.
  • granules were generally problematic from the viewpoint of ingestibility, especially for the elderly, because they were caught between teeth in the mouth when taken and could not be swallowed well.
  • jellies are the preferred dosage form for formulations containing about 4 g of leucine, isoleucine and palin as active ingredients.
  • the active ingredient is 4 g, which is much larger than that of a conventional preparation, if a jelly preparation is prepared by a usual method, a single dose will be as large as about 10 OmL, and
  • the conventional technology must meet all of the above requirements. There was no effective way to do it. Disclosure of the invention
  • the present inventors have conducted intensive studies and found that The present inventors have found that the above-mentioned problems can be solved by allowing a suspending agent to coexist in addition to the gelling agent in syn, leucine, and palin, and have completed the present invention.
  • the present invention includes the following inventions.
  • a pharmaceutical jelly preparation comprising only three types of branched-chain amino acids consisting of isoleucine, leucine and palin as an active ingredient, and further comprising a suspending agent and a gelling agent.
  • the suspending agent is hydroxypropylmethylcellulose, methylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, hydroxyethylmethylcellulose, carmellose, carmellose sodium, carmellose calcium, crystalline cellulose and crystalline cellulose.
  • the pharmaceutical jelly preparation according to item (1) which is at least one selected from carmellose sodium.
  • the gelling agent is one selected from agar, agar powder, carrageenan, xanthan gum, guar gum, pectin, dielan gum, locust bean gum, arabic gum, arabic gum powder, tragacanth, tragacanth powder and gelatin.
  • the amount of the suspending agent is 0.0005 to 0.25 part by mass, preferably 0.2 part by mass, per 1 part by mass of the total of three types of branched-chain amino acids consisting of isoleucine, leucine and parin.
  • the concentration of three types of branched-chain amino acids consisting of isoleucine, leucine and parin is 11 to 70% (WZV), preferably 15 to 60% (W / V), more preferably 15 to 45% (W / V).
  • WZV concentration of three types of branched-chain amino acids consisting of isoleucine, leucine and parin
  • Average particle size (median size) of mixed particles of isoleucine, leucine and parin M is 1 to 200 m, preferably 5 to 120 m.
  • the organic acid is selected from citric anhydride, cunic acid, malic acid, tartaric acid, D-tartaric acid, ascorbic acid, succinic acid, maleic acid, malonic acid, L-glutamate hydrochloride, acetic acid, lactic acid and aspartic acid.
  • the pharmaceutical jelly agent according to item (8) which is at least one of the following:
  • the jelly agent of the present invention uses isoleucine, leucine and parin particles of the above-mentioned particle size in the above-mentioned mixing ratio, and is mixed with water together with a suspending agent. It is prepared by mixing with a solution in which a gelling agent is dispersed or dissolved.
  • a gelling agent is dispersed or dissolved.
  • the mixing means for preparing the jelly agent there is no particular limitation on the mixing means for preparing the jelly agent, and any mixing or pulverizing mechanism and model can be used as long as a uniform suspension can be obtained.
  • High-pressure emulsifiers such as various homogenizers and microfluidizers, colloid mills, and the like are preferably used, but universal mixers such as kneaders—pot mills, mortars, and the like can also be used.
  • the method for preparing the three types of branched-chain amino acid particles is not particularly limited, and a usual pulverization method can be employed.
  • a shock type (high-speed rotation type) pulverizer such as a hammer mill, a tumbler set (medium type) such as a pole mill, and a fluid type (air flow type) pulverizer such as a jet mill can be used.
  • the three types of branched-chain amino acid particles used in the jelly agent particles whose particle size is adjusted to 1 to 200 from particles generally produced by a fermentation method are used. If the particle size of the branched-chain amino acid particles exceeds 200, a foreign-body sensation will remain when taken, and if the particle size is smaller than 1 ⁇ , the bitterness will increase, and in any case, it will be difficult to take.
  • the particle size is preferably 1 to 200 m, more preferably 5 to 120 zm.
  • the measurement of the particle size of the branched-chain amino acid particles used in the jelly agent can be performed as follows.
  • Laser diffraction scattering particle size distribution analyzer [Horiba Seisakusho Co., Ltd. LA-920] Put about 20 OmL of 2-propanol in the circulating layer, circulate for 2 minutes while stirring and irradiating with ultrasonic wave, and then perform blank measurement (no ultrasonic irradiation during measurement). Subsequently, introduce the amino acid sample to be measured so that the transmittance is within the range of 85 ⁇ 5%. Circulate for 2 minutes while stirring and irradiating ultrasonic waves, and measure after stopping ultrasonic irradiation. The average particle diameter is a volume-based median diameter.
  • suspending agent In the jelly preparation of the present invention, a suspending agent and a gelling agent are used in combination. Substances that can be used as suspending agents and gelling agents are selected from those that are acceptable as pharmaceutical excipients. Considering the maximum usage record, it is decided whether to use it alone or multiple times.
  • the suspending agent include hydroxypropylmethylcellulose, methylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, hydroxymethylmethylcellulose, carmellose, carmellose sodium, carmellose calcium, crystalline cellulose and crystalline cellulose. At least one selected from the group consisting of loin sodium and popidone is used. Particularly preferred suspending agents are hydroxypropylmethylcellulose and crystalline cellulose 'carmel sodium'.
  • the amount of the suspending agent added to the jelly preparation is from 0.01 to 5.0% (W / V), preferably from 0.02 to 3.0% (W / V). .
  • gelling agent used in the jelly agent of the present invention examples include agar, agar powder, carrageenan, xanthan gum, guar gum, pectin, dielan gum, stoving gum, arabic gum, arabic gum, tragacanth, tragacanth and gelatin. And the like.
  • Particularly preferred gelling agents are agar and agar powder.
  • the amount of the gelling agent to be added to the jelly agent is from 0.01 to 5.0% (W / V), preferably from 0.02 to 3.0% (W / V).
  • an organic acid, a sweetener, a fragrance and the like can be further added in addition to the above three kinds of branched-chain amino acids, a suspending agent and a gelling agent.
  • Organic acids include citric anhydride, cunic acid, malic acid, tartaric acid, D-tartaric acid, ascorbic acid, succinic acid, maleic acid, malonic acid, L-glutamate, Examples include acids such as acetic acid, lactic acid, and aspartic acid, but there is no particular limitation as long as the acid is acceptable as a pharmaceutical additive.
  • Preferred acids include citric anhydride, cunic acid, malic acid, tartaric acid, D-tartaric acid, ascorbic acid and the like.
  • As a sweetener that can be added to the jelly preparation of the present invention aspartame, saccharin, saccharin sodium, erythritol, xylitol, mannitol, stevia and the like are used.
  • fragrance imparting agents such as menthol, lemon flavor, sugarless, sweet flavor, strawberry oil and the like can be optionally used.
  • Example 2 After adding 20.0 g of N-sodium hydroxide solution to adjust the pH, the mixture was uniformly suspended with Nanomizer-1 (LEN03-12B from Nanomizer-1 Co., Ltd.) and suspended. A suspension was prepared. Also, 3.9 Og of agar powder was dispersed in 190.0 Og of purified water, heated and dissolved, and 630.0 g of this suspension and 3.9 g of lemon flavor were added. In addition, the mixture mixed with the stirrer was ice-cooled to prepare a pharmaceutical jelly.
  • Nanomizer-1 LN03-12B from Nanomizer-1 Co., Ltd.
  • Example 1 Was dissolved with a stirrer. To this solution, 476.0 g of isoleucine, 952.0 g of leucine, and 572.0 of palin having the same particle size as those used in Example 1 were added, and the mixture was suspended with the above stirrer. After adjusting the pH by adding 200.0 g of a solution, the mixture was uniformly suspended with a nanomizer. To 630.0 g of this suspension, 7.8 g of xanthan gum and 3.9 g of lemon flavor were added and dispersed with a stirrer to prepare a pharmaceutical jelly. Comparative Example 1
  • Flavor ⁇ not concerned, ⁇ not very concerned, ⁇ slightly concerned, X bad Easy to take: ⁇ easy to drink, ⁇ slightly concerned, X quite concerned ⁇ table 1 ⁇
  • the jelly agent containing only isoleucine, leucine and valin as an active ingredient provided by the present invention has a small volume per volume, and can have a good taste and throat passing over. It makes it possible to supply a jelly preparation that is easy for patients to take and greatly contributes to the improvement of compliance, and is clearly useful as a pharmaceutical preparation.

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Abstract

A jelly preparation which contains three branched amino acids consisting of isoleucine, leucine, and valine as the only active ingredients and which can be administered in a reduced amount in each dose, has a satisfactory taste, and smoothly passes the throat. The medicinal jelly preparation is characterized by containing three branched amino acids consisting of isoleucine, leucine, and valine as the only active ingredients and containing a suspending agent and a gellant.

Description

明 細 書  Specification
分岐鎖ァミノ酸を含有するゼリ一剤 技術分野  Jelly preparations containing branched-chain amino acids
本発明は、 イソロイシン、 ロイシン及びパリンからなる 3種の分岐鎖アミノ酸 を有効成分として含有するゼリー剤に関する。 本発明でいうゼリー剤とは、 溶液 状又は懸濁状のものを寒天やゼラチンなどのゲル化剤を用いて半固体状にしたも のをいう。 背景技術  The present invention relates to a jelly agent containing, as an active ingredient, three kinds of branched-chain amino acids consisting of isoleucine, leucine and parin. The jelly agent referred to in the present invention refers to a solution or suspension which is made into a semi-solid state by using a gelling agent such as agar or gelatin. Background art
イソロイシン、 ロイシン及びバリンの 3種の分岐鎖アミノ酸を有効成分として 含む医薬用製剤は肝疾患に有効な治療薬であり、 現在市販されている製剤は顆粒 剤が主体である。しかし、上記 3種の分岐鎖アミノ酸を有効成分とする顆粒剤は、 —服用量が約 5 gと一般の製剤と比較して著しく多く、 服用し難いという難点が あった。 また、 顆粒剤は一般的に服用時に口内で歯間にはさまったり、 上手く飲 み込めなかったりと、特に高齢者には服用性の観点から問題のある製剤であった。 上述の点を考慮すると、 約 4 gのロイシン、 イソロイシン及びパリンを有効成 分とする製剤にはゼリー剤が好適な剤型である。 しかしながら、 有効成分が 4 g と通常の製剤と比較して非常に多いため通常の方法でゼリー剤を調製すると、 一 回服用量は、 約 1 0 O m Lと多量になってしまうし、 また、 水分制限されている 患者が多いため、 できるだけ水分量を少なくする必要があることから、 服用性の 更なる改善が必要とされるが、 従来技術では、 以上のような要求に全て応えるこ とができる有効な手段はなかった。 発明の開示  Pharmaceutical preparations containing three types of branched-chain amino acids of isoleucine, leucine and valine as active ingredients are effective therapeutic agents for liver diseases, and currently marketed preparations are mainly granules. However, granules containing the above three kinds of branched-chain amino acids as active ingredients have a drawback of-about 5 g, which is remarkably large compared to general preparations, and are difficult to take. In addition, granules were generally problematic from the viewpoint of ingestibility, especially for the elderly, because they were caught between teeth in the mouth when taken and could not be swallowed well. In view of the above, jellies are the preferred dosage form for formulations containing about 4 g of leucine, isoleucine and palin as active ingredients. However, since the active ingredient is 4 g, which is much larger than that of a conventional preparation, if a jelly preparation is prepared by a usual method, a single dose will be as large as about 10 OmL, and However, since there are many patients whose fluids are restricted, it is necessary to minimize the amount of fluid as much as possible.Therefore, it is necessary to further improve the ingestibility.However, the conventional technology must meet all of the above requirements. There was no effective way to do it. Disclosure of the invention
本発明の課題は、 一服用量が少量化され、 風味や喉越しが良好である、 イソ口 イシン、 ロイシン及びバリンからなる 3種の分岐鎖アミノ酸のみを有効成分とす 'るゼリー剤を提供することにある。  It is an object of the present invention to provide a jelly preparation which has only a small amount of three kinds of branched-chain amino acids consisting of isocyanate, leucine and valine, which has a small dose, good flavor and good throat passing over, and an active ingredient. Is to do.
上記課題を解決するために本発明者らは鋭意検討し、 有効成分であるイソロイ シン、 ロイシン及びパリンに、 ゲル化剤の外に懸濁化剤を共存せしめることによ り、 上記課題を解決できることを見出し、 本発明を完成するに至った。 In order to solve the above-mentioned problems, the present inventors have conducted intensive studies and found that The present inventors have found that the above-mentioned problems can be solved by allowing a suspending agent to coexist in addition to the gelling agent in syn, leucine, and palin, and have completed the present invention.
本発明は、 以下の各発明を包含する。  The present invention includes the following inventions.
(1) イソロイシン、 ロイシン及びパリンからなる 3種の分岐鎖アミノ酸のみを 有効成分として含有し、 かつ懸濁化剤及びゲル化剤を含有することを特徴とする 医薬用ゼリー剤。  (1) A pharmaceutical jelly preparation comprising only three types of branched-chain amino acids consisting of isoleucine, leucine and palin as an active ingredient, and further comprising a suspending agent and a gelling agent.
(2) 前記懸濁化剤が、 ヒドロキシプロピルメチルセルロース、 メチルセル口一 ス、 ヒドロキシプロピルセルロース、 ヒドロキシェチルセルロース、 ヒドロキシ ェチルメチルセルロース、 カルメロース、 カルメロースナトリウム、 カルメロ一 スカルシウム、 結晶セルロース及び結晶セルロース 'カルメロースナトリウムの うちから選ばれる 1種類以上であることを特徴とする （1) 項に記載の医薬用ゼ リ—剤。  (2) The suspending agent is hydroxypropylmethylcellulose, methylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, hydroxyethylmethylcellulose, carmellose, carmellose sodium, carmellose calcium, crystalline cellulose and crystalline cellulose. The pharmaceutical jelly preparation according to item (1), which is at least one selected from carmellose sodium.
(3)前記ゲル化剤が、 カンテン、 カンテン末、 カラギーナン、 キサンタンガム、 グァ一ガム、 ぺクチン、 ジエランガム、 ローカス卜ビーンガム、 アラビアガム、 アラビアガム末、 トラガン卜、 トラガント末及びゼラチンから選ばれる 1種類以 上であることを特徴とする （1) 又は （2) 項に記載の医薬用ゼリー剤。  (3) The gelling agent is one selected from agar, agar powder, carrageenan, xanthan gum, guar gum, pectin, dielan gum, locust bean gum, arabic gum, arabic gum powder, tragacanth, tragacanth powder and gelatin. The pharmaceutical jelly according to (1) or (2), which is characterized in that:
(4) イソロイシン、 ロイシン及びパリンからなる 3種の分岐鎖アミノ酸の合計 1質量部に対し、 懸濁化剤量が 0. 0005〜0. 25質量部、 好ましくは 0. (4) The amount of the suspending agent is 0.0005 to 0.25 part by mass, preferably 0.2 part by mass, per 1 part by mass of the total of three types of branched-chain amino acids consisting of isoleucine, leucine and parin.
00 1〜0. 1 5質量部であり、 ゲル化剤量が 0. 0005〜0. 25質量部、 好ましくは 0. 001〜0. 1 5質量部である （1) 〜 （3) 項のいずれか 1項 に記載の医薬用ゼリー剤。 00 1 to 0.15 parts by mass, and the amount of the gelling agent is 0.0005 to 0.25 parts by mass, preferably 0.001 to 0.15 parts by mass (1) to (3). The pharmaceutical jelly according to any one of claims 1 to 7.
(5) イソロイシン、 ロイシン及びパリンの配合割合が質量比で、 イソロイシン /ロイシン/パリン = 1 / 1. 9〜2. 2/1. 1〜 1. 3であることを特徴と する （1) 〜 （4) 項のいずれか 1項に記載の医薬用ゼリー剤。  (5) The compounding ratio of isoleucine, leucine and parin is by mass ratio, and isoleucine / leucine / parin = 1/1 / 1.9 to 2.2 / 1.1 to 1.3. (1) to (4) The pharmaceutical jelly according to any one of the above (4).
(6) イソロイシン、 ロイシン及びパリンからなる 3種の分岐鎖アミノ酸の濃度 が 1 1〜 70 % (WZV)、 好ましくは 15〜60% (W/V)、 より好ましくは 1 5〜45 % (W/V) であることを特徴とする （ 1 ) 〜 （5) 項のいずれか 1 項に記載の医薬用ゼリー剤。  (6) The concentration of three types of branched-chain amino acids consisting of isoleucine, leucine and parin is 11 to 70% (WZV), preferably 15 to 60% (W / V), more preferably 15 to 45% (W / V). The pharmaceutical jelly according to any one of (1) to (5), wherein
(7) イソロイシン、 ロイシン及びパリンの混合粒子の平均粒径 （メジアン径） が 1〜2 0 0 m、 好ましくは 5〜 1 2 0 ； mであることを特徴とする （1 ) 〜 ( 6 ) 項のいずれか 1項に記載の医薬用ゼリー剤。 (7) Average particle size (median size) of mixed particles of isoleucine, leucine and parin M is 1 to 200 m, preferably 5 to 120 m. The pharmaceutical jelly agent according to any one of (1) to (6), wherein
( 8 ) 前記 3種の分岐鎖アミノ酸、 懸濁化剤及びゲル化剤に加えて、 さらに有機 酸を含有することを特徴とする （ 1 ) 〜 （7 ) 項のいずれか 1項に記載の医薬用 ゼリー剤。  (8) The method according to any one of (1) to (7), further comprising an organic acid in addition to the three kinds of branched-chain amino acids, a suspending agent and a gelling agent. Pharmaceutical jelly.
( 9 ) 前記有機酸が、 無水クェン酸、 クェン酸、 リンゴ酸、 酒石酸、 D—酒石酸、 ァスコルビン酸、 コハク酸、 マレイン酸、 マロン酸、 L—グルタミン酸塩酸塩、 酢酸、 乳酸及びァスパラギン酸から選ばれる 1種以上である （8 ) 項記載の医薬 用ゼリー剤。  (9) The organic acid is selected from citric anhydride, cunic acid, malic acid, tartaric acid, D-tartaric acid, ascorbic acid, succinic acid, maleic acid, malonic acid, L-glutamate hydrochloride, acetic acid, lactic acid and aspartic acid. The pharmaceutical jelly agent according to item (8), which is at least one of the following:
本発明のゼリー剤は、 前記粒径のイソロイシン、 ロイシン及びパリンの粒子を 前記配合割合で使用し、 懸濁化剤と共に水と混合し、 更にこの懸濁液に前記ゲル 化剤あるいは水に前記ゲル化剤を分散あるいは溶解させた溶液と共に混合して調 製される。 ゼリー剤を調製するための混合手段に特に制限はなく、 均一な懸濁液 が得られる限り、 混合又は粉碎のメカニズム、 機種を問わない。 各種のホモジナ ィザ一、 マイクロフルイダィザ一等の高圧乳化機、 コロイドミル等が好ましく使 用されるが、ニーダ一等の万能混合機ゃポットミル、乳鉢等でも使用可能である。  The jelly agent of the present invention uses isoleucine, leucine and parin particles of the above-mentioned particle size in the above-mentioned mixing ratio, and is mixed with water together with a suspending agent. It is prepared by mixing with a solution in which a gelling agent is dispersed or dissolved. There is no particular limitation on the mixing means for preparing the jelly agent, and any mixing or pulverizing mechanism and model can be used as long as a uniform suspension can be obtained. High-pressure emulsifiers such as various homogenizers and microfluidizers, colloid mills, and the like are preferably used, but universal mixers such as kneaders—pot mills, mortars, and the like can also be used.
3種の分岐鎖アミノ酸粒子の調整方法に特に制限はなく、 通常の粉砕法が採用 できる。 粉砕には、 ハンマーミル等の衝撃式 （高速回転式） 粉砕機、 ポールミル 等のタンブラ一式 （媒体式） 粉碎機及びジェットミル等の流体式 （気流式） 粉碎 機等が使用できる。  The method for preparing the three types of branched-chain amino acid particles is not particularly limited, and a usual pulverization method can be employed. For the pulverization, a shock type (high-speed rotation type) pulverizer such as a hammer mill, a tumbler set (medium type) such as a pole mill, and a fluid type (air flow type) pulverizer such as a jet mill can be used.
ゼリー剤中に用いられる 3種の分岐鎖アミノ酸粒子としては、 一般的に発酵法 で製造されている粒子から、 粒度が 1〜 2 0 0 に調整されているものが使用 される。 分岐鎖アミノ酸粒子の粒度が 2 0 0 を越えると、 服用時に異物感が 残るし、 1 μ πιより細かくなると苦味が強くなり、 いずれの場合も服用し難いも のとなる。 粒径は、 好ましくは 1〜 2 0 0 mであり、 より好ましくは 5 ~ 1 2 0 z mである。  As the three types of branched-chain amino acid particles used in the jelly agent, particles whose particle size is adjusted to 1 to 200 from particles generally produced by a fermentation method are used. If the particle size of the branched-chain amino acid particles exceeds 200, a foreign-body sensation will remain when taken, and if the particle size is smaller than 1 μπι, the bitterness will increase, and in any case, it will be difficult to take. The particle size is preferably 1 to 200 m, more preferably 5 to 120 zm.
ゼリー剤中に用いられる分岐鎖アミノ酸粒子の粒度の測定は、 次のように行う ことができる。  The measurement of the particle size of the branched-chain amino acid particles used in the jelly agent can be performed as follows.
レーザー回折 ·散乱式粒度分布測定装置 〔堀場製作所 （株） L A— 9 2 0〕 を 用い、 2—プロパノ一ル約 2 0 O m Lを循環層に入れ、 撹拌、 超音波照射を行い ながら、 2分間循環させた後、 ブランク測定（測定中は超音波照射なし） を行う。 引き続いて、 測定アミノ酸試料を透過率が 8 5 ± 5 %の範囲内になるように投入 する。 撹拌、 超音波照射しながら 2分間循環させ、 超音波照射を停止した後に測 定を行う。 平均粒径は体積基準のメジアン径とする。 Laser diffraction scattering particle size distribution analyzer [Horiba Seisakusho Co., Ltd. LA-920] Put about 20 OmL of 2-propanol in the circulating layer, circulate for 2 minutes while stirring and irradiating with ultrasonic wave, and then perform blank measurement (no ultrasonic irradiation during measurement). Subsequently, introduce the amino acid sample to be measured so that the transmittance is within the range of 85 ± 5%. Circulate for 2 minutes while stirring and irradiating ultrasonic waves, and measure after stopping ultrasonic irradiation. The average particle diameter is a volume-based median diameter.
本発明のゼリ一剤には、 懸濁化剤とゲル化剤とが併用される。 懸濁化剤及びゲ ル化剤として使用することができる物質としては、 医薬品添加物として許容され ているものから選択されるが、 本発明のゼリー剤に適用に際しては、 各物質につ いての最大使用実績を考慮して、 単独使用するか複数使用するかが決定される。 前記懸濁化剤としては、 ヒドロキシプロピルメチルセルロース、 メチルセル口 —ス、 ヒドロキシプロピルセルロース、 ヒドロキシェチルセルロース、 ヒドロキ シェチルメチルセルロース、 カルメロース、 カルメロ一スナトリウム、 カルメロ —スカルシウム、結晶セルロース及び結晶セルロース 'カルメロースナトリウム、 ポピドン等から選ばれる少なくとも 1種類が使用されるが、 特に好ましい懸濁化 剤は、 ヒドロキシプロピルメチルセルロース及び結晶セルロース 'カルメロ一ス ナトリゥムである。  In the jelly preparation of the present invention, a suspending agent and a gelling agent are used in combination. Substances that can be used as suspending agents and gelling agents are selected from those that are acceptable as pharmaceutical excipients. Considering the maximum usage record, it is decided whether to use it alone or multiple times. Examples of the suspending agent include hydroxypropylmethylcellulose, methylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, hydroxymethylmethylcellulose, carmellose, carmellose sodium, carmellose calcium, crystalline cellulose and crystalline cellulose. At least one selected from the group consisting of loin sodium and popidone is used. Particularly preferred suspending agents are hydroxypropylmethylcellulose and crystalline cellulose 'carmel sodium'.
懸濁化剤のゼリー剤への添加量は、 0 . 0 1 ~ 5 . 0 % (W/ V ) であり、 好 ましくは 0 . 0 2〜 3 . 0 % (W/ V ) である。  The amount of the suspending agent added to the jelly preparation is from 0.01 to 5.0% (W / V), preferably from 0.02 to 3.0% (W / V). .
本発明のゼリー剤に使用される前記ゲル化剤としてはカンテン、 カンテン末、 カラギーナン、 キサンタンガム、 グァーガム、 ぺクチン、 ジエランガム、 口一力 ストビーンガム、 アラビアガム、 アラビアガム末、 トラガント、 トラガント末及 びゼラチン等が挙げられるが、 特に好ましいゲル化剤は、 カンテン及びカンテン 末である。  Examples of the gelling agent used in the jelly agent of the present invention include agar, agar powder, carrageenan, xanthan gum, guar gum, pectin, dielan gum, stoving gum, arabic gum, arabic gum, tragacanth, tragacanth and gelatin. And the like. Particularly preferred gelling agents are agar and agar powder.
ゲル化剤のゼリー剤への添加量は、 0 . 0 1〜 5 . 0 % (W/ V ) であり、 好 ましくは 0 . 0 2〜 3 . 0 % (W/ V ) である。  The amount of the gelling agent to be added to the jelly agent is from 0.01 to 5.0% (W / V), preferably from 0.02 to 3.0% (W / V).
本発明のゼリー剤には、 前記 3種の分岐鎖アミノ酸、 懸濁化剤及びゲル化剤に 加えて、 さらに有機酸や甘味剤、 芳香剤等を添加することができる。  To the jelly agent of the present invention, an organic acid, a sweetener, a fragrance and the like can be further added in addition to the above three kinds of branched-chain amino acids, a suspending agent and a gelling agent.
有機酸としては、 無水クェン酸、 クェン酸、 リンゴ酸、 酒石酸、 D—酒石酸、 ァスコルビン酸、 コハク酸、 マレイン酸、 マロン酸、 L—グルタミン酸塩酸塩、 酢酸、 乳酸、 ァスパラギン酸のような酸が挙げられるが、 医薬品添加物として許 容される酸である限り、 特に制限はない。 好ましい酸としては、 無水クェン酸、 クェン酸、 リンゴ酸、 酒石酸、 D—酒石酸、 ァスコルビン酸等が挙げられる。 本発明のゼリ一剤に添加することができる甘味剤としては、 アスパルテーム、 サッカリン、 サッカリンナトリウム、 エリスリ トール、 キシリ トール、 マンニト —ル、 ステビア等が使用される。 Organic acids include citric anhydride, cunic acid, malic acid, tartaric acid, D-tartaric acid, ascorbic acid, succinic acid, maleic acid, malonic acid, L-glutamate, Examples include acids such as acetic acid, lactic acid, and aspartic acid, but there is no particular limitation as long as the acid is acceptable as a pharmaceutical additive. Preferred acids include citric anhydride, cunic acid, malic acid, tartaric acid, D-tartaric acid, ascorbic acid and the like. As a sweetener that can be added to the jelly preparation of the present invention, aspartame, saccharin, saccharin sodium, erythritol, xylitol, mannitol, stevia and the like are used.
また、 メントール、 レモンフレーバー、 シュガーレス、 スイートフレーバ一、 ストロベリーオイル等の芳香付与剤も、 任意に使用することができる。 発明を実施するための最良の形態  In addition, fragrance imparting agents such as menthol, lemon flavor, sugarless, sweet flavor, strawberry oil and the like can be optionally used. BEST MODE FOR CARRYING OUT THE INVENTION
本発明の具体例を以下に実施例として示すが、 本発明はこれらに限定されるも のではない。 実施例 1  EXAMPLES Specific examples of the present invention will be shown below as examples, but the present invention is not limited to these examples. Example 1
精製水 5 2 0 Om 1に、 防腐剤としてパラォキシ安息香酸プロピル 1. O g、 パラォキシ安息香酸メチル 2. 5 gを加え、 撹拌機 〔東京理化器械 （株） 製、 M AZ E LA Z— 2 1 1 0〕 で溶解させ、 この溶液にヒドロキシプロピルメチル セルロース 6 0. 0 g及び結晶セルロース ·カルメロースナトリウム 5. O gを 加え、 前記撹拌機で分散させた。 この分散液に酸味剤として酒石酸 4 7. 5 g、 甘味剤としてマンニトール 5 0 0. 0 g、 サッカリンナトリウム 5. O g及びス テビア 2. 5 g、 消泡剤としてジメチルポリシロキサン 2 0. O gを加え、 前記 撹拌機で溶解させた。この溶液に、粒径 D 5 0が 1 5 mのイソロイシン 4 7 6. 0 g、 ロイシン 9 5 2. 0 g、 ノ リン 5 7 2. 0を加え、 前記撹拌機で懸濁させ、 さらに 2 N—水酸化ナトリウム溶液 2 0 0. 0 gを加えて pHを調整後、 ナノマ ィザ一 〔ナノマイザ一 （株） 製、 L EN 0 3— 1 2 B〕 により均一に懸濁させて、 懸濁液を調製した。 また、 カンテン末 3. 9 O gを精製水 1 9 0. O gに分散し、 加温して溶解させたものに、 この懸濁液 6 3 0. 0 g、 レモンフレーバー 3. 9 gを加え、 前記撹拌機で混合したものを氷冷して、 医薬用ゼリー剤を調製した。 実施例 2 To purified water 520 Om 1, 1.O g of propyl paraoxybenzoate and 2.5 g of methyl paraoxybenzoate as preservatives were added, and a stirrer [MAZ E LAZ-2 manufactured by Tokyo Rikakiki Co., Ltd. 11.0], and 60.0 g of hydroxypropylmethylcellulose and 5.O g of crystalline cellulose-carmellose sodium were added to the solution, and the mixture was dispersed with the stirrer. In this dispersion, 47.5 g of tartaric acid as a sour agent, 50.0 g of mannitol as a sweetener, 5.O g of sodium saccharin and 2.5 g of stevia, and 2.0 g of dimethylpolysiloxane as a defoamer Was added, and the mixture was dissolved with the stirrer. To this solution was added 476.0 g of isoleucine having a particle size D50 of 15 m, 952.0 g of leucine, and 572.0 of phosphorus, and suspended with the above-mentioned stirrer. After adding 20.0 g of N-sodium hydroxide solution to adjust the pH, the mixture was uniformly suspended with Nanomizer-1 (LEN03-12B from Nanomizer-1 Co., Ltd.) and suspended. A suspension was prepared. Also, 3.9 Og of agar powder was dispersed in 190.0 Og of purified water, heated and dissolved, and 630.0 g of this suspension and 3.9 g of lemon flavor were added. In addition, the mixture mixed with the stirrer was ice-cooled to prepare a pharmaceutical jelly. Example 2
精製水 5200m lに、 防腐剤としてパラォキシ安息香酸プロピル 1. 0 g、 パラォキシ安息香酸メチル 2.5 gを加え、実施例 1と同様の撹拌機で溶解させ、 この溶液にヒドロキシプロピルメチルセルロース 60. 0 g及び結晶セルロー ス ·カルメロースナトリウム 5. 0 gを加え、 前記撹拌機で分散させた。 こ'の分 散液に酸味剤として酒石酸 47. 5 g、甘味剤としてマンニトール 500. 0 g、 サッカリンナトリウム 5. 0 g及びステビア 2. 5 g、 消泡剤としてジメチルポ リシロキサン 20. 0 gを加え、 撹拌機で溶解させた。 この溶液に、 実施例 1で 使用したものと同じ粒径のイソロイシン 476. 0 g、 ロイシン 952. 0 g、 パリン 572. 0を加え、 前記撹拌機で懸濁させ、 さらに 2 N—水酸化ナトリウ ム溶液 200. 0 gを加えて pHを調整後、 ナノマイザ一により均一に懸濁させ た。 この懸濁液 630. 0 gにキサンタンガム 7. 8 g、 レモンフレーバ一3. 9 gを加え、 撹拌機で分散させて、 医薬用ゼリー剤を調製した。 比較例 1  To 5200 ml of purified water, 1.0 g of propyl paraoxybenzoate and 2.5 g of methyl paraoxybenzoate were added as preservatives, and dissolved with the same stirrer as in Example 1.60.0 g of hydroxypropyl methylcellulose was added to this solution. 5.0 g of crystalline cellulose-carmellose sodium was added and dispersed with the above-mentioned stirrer. To this dispersion, add 47.5 g of tartaric acid as a sour agent, 500.0 g of mannitol as a sweetener, 5.0 g of sodium saccharin and 2.5 g of stevia, and 20.0 g of dimethylpolysiloxane as an antifoaming agent. Was dissolved with a stirrer. To this solution, 476.0 g of isoleucine, 952.0 g of leucine, and 572.0 of palin having the same particle size as those used in Example 1 were added, and the mixture was suspended with the above stirrer. After adjusting the pH by adding 200.0 g of a solution, the mixture was uniformly suspended with a nanomizer. To 630.0 g of this suspension, 7.8 g of xanthan gum and 3.9 g of lemon flavor were added and dispersed with a stirrer to prepare a pharmaceutical jelly. Comparative Example 1
精製水 1000 m 1に粒径 D 50が 15 mのイソロイシン 9. 52 g、 ロイ シン 19. 04 g、 ノ リン 1 1. 44 gを加え、 撹拌機 〔東京理化器械 （株） 製、 MAZELA Z— 21 10〕 で溶解させた。 またカンテン末 6. 24 gを精製 水 200 gに分散し、加温して溶解させた溶液に、この 3種アミノ酸溶液を加え、 撹拌機で混合したものを氷冷して、 医薬用ゼリー剤を調製した。 試験例  9.52 g of isoleucine having a particle size D50 of 15 m, 19.04 g of leucine, and 1.44 g of phosphorus were added to 1000 m1 of purified water, and a stirrer [MAZELA Z manufactured by Tokyo Rika Instruments Co., Ltd. — 21 10]. In addition, 6.24 g of agar powder was dispersed in 200 g of purified water, and the three amino acids solution was added to a solution obtained by heating and dissolving the mixture. Was prepared. Test example
前記の実施例及び比較例で得られた各種医薬用ゼリー剤をイソロイシン、 ロイ シン、バリンの合計の質量が 4. 0 gとなるように量りとつた。その時の服用量、 風味、 服用しやすさの官能評価結果を次表に示す。  The various pharmaceutical jelly preparations obtained in the above Examples and Comparative Examples were weighed so that the total mass of isoleucine, leucine and valine was 4.0 g. The following table shows the sensory evaluation results of the dose, flavor, and ease of taking at that time.
判断基準は次の通りである。  The criteria are as follows.
服用量： ©少ない、 〇多少多い、 △多い、 X非常に多い Dosage: © small, 〇 slightly more, △ more, X very much
風味 ：◎気にならない、 〇あまり気にならない、 △多少気になる、 X悪い 服用しやすさ ： ©飲みやすい、 △多少気になる、 Xかなり気になる 【表 1】 Flavor: ◎ not worried, 〇 not very worried, △ slightly worried, X bad Easy to take: © easy to drink, △ slightly worried, X quite worried 【table 1】
Figure imgf000009_0001
Figure imgf000009_0001
産業上の利用可能性 Industrial applicability
以上のことから、 本発明により提供される、 イソロイシン、 ロイシン及びバリ ンのみを有効成分として含有するゼリー剤は、 一容量当たりの容量が小さく、 風 味や喉越しが良好にすることができ、 患者が服用しやすくコンプライアンスの向 上に多大な貢献をするゼリー剤を供給することを可能としたもので、 医薬用製剤 として有用であることは明らかである。  From the above, the jelly agent containing only isoleucine, leucine and valin as an active ingredient provided by the present invention has a small volume per volume, and can have a good taste and throat passing over. It makes it possible to supply a jelly preparation that is easy for patients to take and greatly contributes to the improvement of compliance, and is clearly useful as a pharmaceutical preparation.

Claims

請 求 の 範 囲 The scope of the claims
1. イソロイシン、 ロイシン及びパリンからなる 3種の分岐鎖アミノ酸のみを有 効成分として含有し、 かつ懸濁化剤及びゲル化剤を含有することを特徴とする医 薬用ゼリ一剤。 1. A medicinal jelly preparation comprising only three types of branched-chain amino acids consisting of isoleucine, leucine and palin as an active ingredient, and further comprising a suspending agent and a gelling agent.
2. 前記懸濁剤が、 ヒドロキシプロピルメチルセルロース、 メチルセルロース、 ヒドロキシプロピルセルロース、 ヒドロキシェチルセルロース、 ヒドロキシェチ ルメチルセルロース、 カルメロース、 カルメロースナトリウム、 カルメロース力 ルシゥム、 結晶セルロース及び結晶セルロース ·カルメロ一スナ卜リゥムうちか ら選ばれる 1種類以上であることを特徴とする請求の範囲第 1項記載の医薬用ゼ リ—剤。  2. The suspending agent is hydroxypropylmethylcellulose, methylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, hydroxyethylmethylcellulose, carmellose, carmellose sodium, carmellose force lucidum, crystalline cellulose, and crystalline cellulose. 2. The pharmaceutical jelly preparation according to claim 1, which is at least one member selected from the group consisting of:
3. 前記ゲル化剤が、 カンテン、 カンテン末、 カラギーナン、 キサン夕ンガム、 グァ一ガム、 ぺクチン、 ジエランガム、 口一カストビーンガム、 アラビアガム、 アラビアガム末、 トラガント、 トラガント末及びゼラチンから選ばれる 1種類以 上である請求の範囲第 1項又は第 2項に記載の医薬用ゼリー剤。  3. The gelling agent is selected from agar, agar powder, carrageenan, xansu gum, guar gum, pectin, dielan gum, lipstick cast bean gum, arabic gum, arabic gum powder, tragacanth, tragacanth powder and gelatin. 3. The pharmaceutical jelly according to claim 1 or 2, which is one or more kinds.
4. イソロイシン、 ロイシン及びパリンからなる 3種の分岐鎖アミノ酸の合計 1 質量部に対し、懸濁化剤量が 0. 0 0 0 5~0. 2 5質量部で、 ゲル化剤量が 0. 0 0 0 5 - 0. 2 5質量部である請求の範囲第 1項〜第 3項のいずれか 1項に記 載の医薬用ゼリー剤。  4. The amount of the suspending agent is 0.005 to 0.25 parts by mass, and the amount of the gelling agent is 0 parts by mass per 1 part by mass of the three kinds of branched chain amino acids consisting of isoleucine, leucine and palin. 4. The pharmaceutical jelly according to any one of claims 1 to 3, which is 0.0005 to 0.25 parts by mass.
5. イソロイシン、 ロイシン及びパリンの配合割合が質量比で、 イソロイシン/ ロイシン/バリン = 1 / 1. 9〜2. 2/1. 1〜： 1. 3であることを特徴とす る請求の範囲第 1項〜第 4項のいずれか 1項に記載の医薬用ゼリ一剤。 5. Claims characterized in that the mixing ratio of isoleucine, leucine and palin is by mass ratio, and isoleucine / leucine / valine = 1/1 / 1.9 to 2.2 / 1. Item 5. The pharmaceutical jelly preparation according to any one of Items 1 to 4.
6. イソロイシン、 ロイシン及びパリンからなる 3種の分岐鎖アミノ酸の濃度が 1 1〜7 0 % (W/V) であることを特徴とする請求の範囲第 1項〜第 5項のい ずれか 1項に記載の医薬用ゼリー剤。  6. The method according to any one of claims 1 to 5, wherein the concentration of the three kinds of branched-chain amino acids consisting of isoleucine, leucine and palin is 11 to 70% (W / V). 2. The pharmaceutical jelly according to item 1.
7 ·イソロイシン、 ロイシン及びパリンの混合粒子の平均粒径 （メジアン径） が 2 0 0 m以下であることを特徴とする請求の範囲第 1項〜第 6項のいずれか 1 項に記載の医薬用ゼリー剤。  7. The medicament according to any one of claims 1 to 6, wherein an average particle diameter (median diameter) of a mixed particle of isoleucine, leucine and palin is 200 m or less. Jelly agent.
8. 前記 3種の分岐鎖アミノ酸、 懸濁化剤及びゲル化剤に加えて、 さらに有機酸 を含有することを特徴とする請求の範囲第 1項〜第 7項のいずれか 1項に記載の 医薬用ゼリー剤。 8. In addition to the three branched-chain amino acids, suspending agent and gelling agent, The pharmaceutical jelly agent according to any one of claims 1 to 7, which comprises:
9 . 前記有機酸が、 無水クェン酸、 クェン酸、 リンゴ酸、 酒石酸、 D—酒石酸、 ァスコルビン酸、 コハク酸、 マレイン酸、 マロン酸、 L一グルタミン酸塩酸塩、 酢酸、 乳酸及びァスパラギン酸から選ばれる 1種以上である、 請求の範囲第 8項 に記載の医薬用ゼリー剤。  9. The organic acid is selected from citric anhydride, cunic acid, malic acid, tartaric acid, D-tartaric acid, ascorbic acid, succinic acid, maleic acid, malonic acid, L-glutamate, acetic acid, lactic acid and aspartic acid. The pharmaceutical jelly according to claim 8, which is at least one kind.
PCT/JP2003/000581 2002-01-30 2003-01-23 Jelly preparation containing branched amino acids WO2003063856A1 (en)

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JP2004182696A (en) * 2002-12-05 2004-07-02 Shiseido Co Ltd External preparation composition
JP2004262857A (en) * 2003-03-03 2004-09-24 Shiseido Co Ltd External preparation composition
JP2004262859A (en) * 2003-03-03 2004-09-24 Shiseido Co Ltd External preparation composition
JP2004269459A (en) * 2003-03-11 2004-09-30 Nippon Unicar Co Ltd Oily cosmetic containing amino acid derivative-modified silicone
JPWO2007043363A1 (en) 2005-10-12 2009-04-16 株式会社大塚製薬工場 Composition for suppressing hypoglycemia symptoms
TWI397418B (en) 2006-10-10 2013-06-01 Otsuka Pharma Co Ltd Anti-depression drug
JP5837276B2 (en) * 2009-09-30 2015-12-24 味の素株式会社 Gel composition for oral consumption and method for producing the same
WO2012099082A1 (en) * 2011-01-17 2012-07-26 味の素株式会社 Branched-chain amino acid-containing jelly
JP5854077B2 (en) * 2014-04-14 2016-02-09 味の素株式会社 Gel composition for oral consumption and method for producing the same

Citations (1)

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Publication number Priority date Publication date Assignee Title
JPH0769877A (en) * 1993-08-31 1995-03-14 Yoshiaki Akiyama Oral medicine containing branched-chain amino acid

Patent Citations (1)

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Publication number Priority date Publication date Assignee Title
JPH0769877A (en) * 1993-08-31 1995-03-14 Yoshiaki Akiyama Oral medicine containing branched-chain amino acid

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