JP5582033B2 - Oral preparation containing branched chain amino acids - Google Patents
Oral preparation containing branched chain amino acids Download PDFInfo
- Publication number
- JP5582033B2 JP5582033B2 JP2010528740A JP2010528740A JP5582033B2 JP 5582033 B2 JP5582033 B2 JP 5582033B2 JP 2010528740 A JP2010528740 A JP 2010528740A JP 2010528740 A JP2010528740 A JP 2010528740A JP 5582033 B2 JP5582033 B2 JP 5582033B2
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- Prior art keywords
- chain amino
- glycine
- amino acid
- branched
- branched chain
- Prior art date
- Legal status (The legal status 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 status listed.)
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Classifications
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- 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
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- 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
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- A61K9/145—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic compounds
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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]
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- 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
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/12—Carboxylic acids; Salts or anhydrides thereof
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- 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
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
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- 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
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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Description
本発明は、嚥下し易い分岐鎖アミノ酸含有経口製剤、分岐鎖アミノ酸含有経口製剤の嚥下促進剤及び分岐鎖アミノ酸の嚥下促進方法に関する。 The present invention relates to a branched-chain amino acid-containing oral preparation that is easy to swallow, a swallowing promoter for a branched-chain amino acid-containing oral preparation, and a method for promoting swallowing of a branched-chain amino acid.
従来より、バリン、ロイシン、イソロイシンの３種のアミノ酸からなる分岐鎖アミノ酸（以下において、単に「ＢＣＡＡ」と略記する場合がある）は、蛋白質を増やす働きや、運動時のエネルギー源として重要な役割を果たすことが知られ、種々の分岐鎖アミノ酸を含有する医薬品、食品及びサプリメント等が開発され上市されている。 Traditionally, branched-chain amino acids consisting of three amino acids, valine, leucine, and isoleucine (hereinafter sometimes simply abbreviated as “BCAA”) play an important role in increasing protein and as an energy source during exercise. And pharmaceuticals, foods and supplements containing various branched chain amino acids have been developed and marketed.
しかし、一般に、分岐鎖アミノ酸を含有する医薬品、食品及びサプリメント等は、分岐鎖アミノ酸に由来する特有の苦味・臭いを有し、また、一回の服用量が、他の医薬品、食品及びサプリメント等に比べ、多量であることから、その服用感は、必ずしも良好とは言い難いものであった。
また、分岐鎖アミノ酸は、疎水性ないし撥水性であるため、例えば、分岐鎖アミノ酸を含有する顆粒製剤は、水に馴染みにくく、水無しで嚥下した場合又は水とともに服用した場合に、嚥下しきれなかった顆粒が口中に多量に残存する等の問題があった。このことは、入れ歯を装着した高齢者等においては、残存した顆粒製剤が入れ歯と歯茎の間に入り込むと、不快感や痛みの原因となるため、一層深刻な問題であった。However, in general, pharmaceuticals, foods and supplements containing branched-chain amino acids have specific bitterness and smell derived from branched-chain amino acids, and a single dose can be used for other pharmaceuticals, foods and supplements, etc. Compared to the above, since the amount was large, the feeling of taking was not necessarily good.
In addition, since branched-chain amino acids are hydrophobic or water-repellent, for example, granule preparations containing branched-chain amino acids are difficult to adapt to water and can be swallowed when swallowed without water or taken with water. There was a problem that a large amount of granules remained in the mouth. This is a more serious problem in elderly people wearing dentures because the remaining granule preparation enters between the dentures and gums, causing discomfort and pain.
一方、既存の技術として、アミノ酸をトレハロースと共に溶解させた水溶液を噴霧乾燥して、溶解性や口溶け性に優れた服用しやすい粉末製剤を製造する方法が提案されている（例えば、特許文献１）。しかし、この手法は、水への溶解度が低い分岐鎖アミノ酸では水溶液の濃度が低く、大量の水溶液を高温で噴霧乾燥する操作が必要であり、多大なコストがかかるため、製造方法としては、現実的ではない。 On the other hand, as an existing technique, there has been proposed a method for producing an easy-to-use powder preparation excellent in solubility and mouth solubility by spray drying an aqueous solution in which an amino acid is dissolved together with trehalose (for example, Patent Document 1). . However, this method requires a procedure of spraying and drying a large amount of aqueous solution at a high temperature for branched chain amino acids having low solubility in water, and requires a large amount of cost. Not right.
本発明が解決しようとする課題は、服用感が改善され、水無しで服用する際にも嚥下しやすい分岐鎖アミノ酸含有経口製剤、分岐鎖アミノ酸含有経口製剤の嚥下促進剤及び分岐鎖アミノ酸経口製剤の嚥下促進方法を提供することである。 Problems to be solved by the present invention include branched-chain amino acid-containing oral preparations with improved feeling of taking and easy to swallow even when taken without water, swallowing promoters and branched-chain amino acid oral preparations of branched-chain amino acid-containing oral preparations It is to provide a method for promoting swallowing.
本発明者らは、上記課題を解決すべく鋭意検討した結果、経口製剤が分岐鎖アミノ酸とグリシンとを組合せてなり、かつ、態様（１）（分岐鎖アミノ酸及びグリシン以外のアミノ酸を含有しない）又は態様（２）（バリン、ロイシン、イソロイシンの配合割合（質量比）が、バリン／ロイシン／イソロイシン＝１．０〜１．３／１．９〜２．２／１．０である）を満たすことにより、服用感が改善され、嚥下し易くなることを見出した。また、本発明者らは、分岐鎖アミノ酸及びグリシンに、更に有機酸を組み合わせることにより、服用感の改善効果に加え、嚥下に要する時間を短縮し得ることを見出した。また、本発明者らは、特に、分岐鎖アミノ酸、グリシン及びクエン酸を同時に含有する単一の製剤とすることにより、より一層、服用感の改善がより顕著となり、嚥下に要する時間も短縮し得ること、更には、製剤が水に馴染み易くなることを見出した。本発明者らは、これらの知見より、本発明を完成するに至った。 As a result of intensive studies to solve the above-mentioned problems, the present inventors have found that the oral preparation is a combination of a branched chain amino acid and glycine, and the embodiment (1) (containing no amino acids other than the branched chain amino acid and glycine) Or aspect (2) (the blending ratio (mass ratio) of valine, leucine, and isoleucine is valine / leucine / isoleucine = 1.0 to 1.3 / 1.9 to 2.2 / 1.0) is satisfied. It has been found that the feeling of taking is improved and it is easy to swallow. Further, the present inventors have found that the time required for swallowing can be shortened in addition to the effect of improving the feeling of dosing by further combining an organic acid with the branched chain amino acid and glycine. In addition, the inventors of the present invention, in particular, by making a single preparation containing a branched chain amino acid, glycine and citric acid at the same time, the improvement in dosing becomes even more remarkable and the time required for swallowing is shortened. In addition, it has been found that the preparation can be easily adapted to water. The present inventors have completed the present invention based on these findings.
すなわち、本発明は以下の各発明を包含するものである。
［１］分岐鎖アミノ酸及びグリシンを組み合わせてなる経口製剤であって、下記態様（１）又は態様（２）を満たす経口製剤。
態様（１）：分岐鎖アミノ酸及びグリシン以外のアミノ酸を含有しない、経口製剤。
態様（２）：バリン、ロイシン、イソロイシンの配合割合（質量比）が、バリン／ロイシン／イソロイシン＝１．０〜１．３／１．９〜２．２／１．０である、経口製剤。
［２］態様（１）において、分岐鎖アミノ酸が、バリン、ロイシン及びイソロイシンからなる群より選ばれる少なくとも１種である、上記［１］記載の経口製剤。
［３］バリン、ロイシン、イソロイシンの配合割合（質量比）が、バリン／ロイシン／イソロイシン＝１．１〜１．３／１．９〜２．２／１．０である、上記［１］又は［２］記載の経口製剤。
［４］グリシンの量が、分岐鎖アミノ酸の量の２．５重量％以上である、上記［１］〜［３］のいずれかに記載の経口製剤。
［５］有機酸を含有する、上記［１］〜［４］のいずれかに記載の経口製剤。
［６］有機酸が、クエン酸、リンゴ酸及び酒石酸からなる群より選ばれる少なくとも１種である、上記［５］記載の経口製剤。
［７］有機酸が、クエン酸である、上記［６］記載の経口製剤。
［８］分岐鎖アミノ酸、グリシン及び有機酸を、同時に含有する単一の製剤である、上記［５］〜［７］のいずれかに記載の経口製剤。
［９］剤型が、粉末製剤である、上記［１］〜［８］のいずれかに記載の経口製剤。
［１０］グリシンの量及びクエン酸の量の合計が、分岐鎖アミノ酸の量の５重量％以上である、上記［７］〜［９］のいずれかに記載の経口製剤。
［１１］グリシンの量及びクエン酸の量の合計が、分岐鎖アミノ酸の量の１０重量％以上である、上記［７］〜［１０］のいずれかに記載の経口製剤。
［１２］１回の服用量が、２ｇ以上である、上記［１］〜［１１］のいずれかに記載の経口製剤。
［１３］水落下試験の水落下時間が、１２０秒未満の粉末製剤である、上記［７］〜［１２］のいずれかに記載の経口製剤。
［１４］粒度が１７００μｍ以上である粉末の量が１重量％以下であり、かつ、粒度が１５０μｍ以下の粉末の量が１５重量％以下の粉末製剤である、上記［１］〜［１３］のいずれかに記載の経口製剤。
［１５］粒度が１５０μｍ以下の粉末の量が１０重量％以下である、上記［１４］記載の経口製剤。
［１６］分岐鎖アミノ酸とグリシンとクエン酸とを組み合わせてなる、分岐鎖アミノ酸含有粉末製剤を水に馴染みやすくする方法。
［１７］グリシンを組み合わせてなる、分岐鎖アミノ酸含有経口製剤の嚥下促進剤。
［１８］グリシンの口中存在下に分岐鎖アミノ酸を服用することを含む、分岐鎖アミノ酸含有経口製剤の嚥下促進方法。
［１９］分岐鎖アミノ酸とグリシンとを組み合わせてなる経口製剤を、上記［１８］記載の方法に関する事項を記載した記載物とともに包装した商業的パッケージ。That is, the present invention includes the following inventions.
[1] An oral preparation comprising a combination of a branched chain amino acid and glycine, which satisfies the following aspect (1) or aspect (2).
Aspect (1): An oral preparation containing no amino acids other than branched chain amino acids and glycine.
Aspect (2): An oral preparation in which the blending ratio (mass ratio) of valine, leucine and isoleucine is valine / leucine / isoleucine = 1.0 to 1.3 / 1.9 to 2.2 / 1.0.
[2] The oral preparation according to the above [1], wherein the branched chain amino acid is at least one selected from the group consisting of valine, leucine and isoleucine in the embodiment (1).
[3] The above [1], wherein the blending ratio (mass ratio) of valine, leucine, and isoleucine is valine / leucine / isoleucine = 1.1 to 1.3 / 1.9 to 2.2 / 1.0 [2] The oral preparation of the description.
[4] The oral preparation according to any one of [1] to [3] above, wherein the amount of glycine is 2.5% by weight or more of the amount of the branched chain amino acid.
[5] The oral preparation according to any one of [1] to [4] above, which contains an organic acid.
[6] The oral preparation of the above-mentioned [5], wherein the organic acid is at least one selected from the group consisting of citric acid, malic acid and tartaric acid.
[7] The oral preparation of the above-mentioned [6], wherein the organic acid is citric acid.
[8] The oral preparation according to any one of [5] to [7], which is a single preparation containing a branched chain amino acid, glycine and an organic acid at the same time.
[9] The oral preparation according to any one of [1] to [8] above, wherein the dosage form is a powder preparation.
[10] The oral preparation according to any one of [7] to [9] above, wherein the total amount of glycine and citric acid is 5% by weight or more of the amount of branched chain amino acids.
[11] The oral preparation according to any one of [7] to [10] above, wherein the total amount of glycine and citric acid is 10% by weight or more of the amount of branched chain amino acids.
[12] The oral preparation according to any one of [1] to [11] above, wherein a single dose is 2 g or more.
[13] The oral preparation according to any one of [7] to [12], which is a powder preparation having a water drop time of less than 120 seconds in a water drop test.
[14] The above-mentioned [1] to [13], wherein the amount of the powder having a particle size of 1700 μm or more is 1% by weight or less and the amount of the powder having a particle size of 150 μm or less is 15% by weight or less. An oral preparation according to any one of the above.
[15] The oral preparation of the above-mentioned [14], wherein the amount of powder having a particle size of 150 μm or less is 10% by weight or less.
[16] A method for making a branched-chain amino acid-containing powder preparation, which is a combination of a branched-chain amino acid, glycine, and citric acid, easily compatible with water.
[17] A swallowing promoter for a branched-chain amino acid-containing oral preparation comprising a combination of glycine.
[18] A method for promoting swallowing of a branched-chain amino acid-containing oral preparation, comprising taking the branched-chain amino acid in the presence of glycine in the mouth.
[19] A commercial package in which an oral preparation comprising a combination of a branched-chain amino acid and glycine is packaged together with a description describing matters relating to the method described in [18] above.
本発明の分岐鎖アミノ酸含有経口製剤は、水無しで服用した場合又は水とともに服用した場合であっても、服用感に優れ、嚥下し易い。また、本発明の分岐鎖アミノ酸含有経口製剤は、服用に要する時間が短い。また、本発明の分岐鎖アミノ酸含有経口製剤は、口溶けが良く、味・後味についても良好である。また、本発明の経口製剤は、親水性に優れ、よく水に馴染むものである。 Even when the branched-chain amino acid-containing oral preparation of the present invention is taken without water or taken with water, it is excellent in taking feeling and easy to swallow. The branched chain amino acid-containing oral preparation of the present invention takes a short time to be taken. In addition, the branched-chain amino acid-containing oral preparation of the present invention has good solubility in the mouth and good taste and aftertaste. In addition, the oral preparation of the present invention is excellent in hydrophilicity and is well adapted to water.
分岐鎖アミノ酸含有経口製剤が、グリシンの口中存在下で服用することにより、服用感が改善され、嚥下し易くなる理由としては、下記の理由等が考えられる。 The reason why the branched chain amino acid-containing oral preparation is taken in the presence of glycine in the mouth improves the feeling of dosing and facilitates swallowing.
例えば、分岐鎖アミノ酸含有顆粒のみを水無しで服用する場合、該顆粒は水馴染みが悪い為、水無しで顆粒を服用したことで唾液に触れた顆粒の内側にある乾燥した顆粒は、いつまでも唾液が浸透していかず凝集したままの状態となる（図１Ａ〜Ｃ）。即ち、図１Ａに示すとおり、分岐鎖アミノ酸含有顆粒は、通常、疎水性であるため、口内においては凝集状態となる。また、口内に含んだ直後は、分岐鎖アミノ酸含有顆粒は、唾液によって濡れていない。服用直後〜約１５秒においては、図１Ｂに示すとおり、唾液により、表面の分岐鎖アミノ酸含有顆粒は濡れるが、分岐鎖アミノ酸含有顆粒は水馴染みが良くないため、唾液が中心部に浸透しない。さらに、服用後約３０秒以降においても、図１Ｃに示すとおり、分岐鎖アミノ酸含有顆粒は、表面から徐々にしか湿潤せず、凝集状態が継続する。 For example, when taking only a branched chain amino acid-containing granule without water, the granule is unfamiliar with water. Does not permeate and remains agglomerated (FIGS. 1A to 1C). That is, as shown in FIG. 1A, the branched-chain amino acid-containing granule is usually hydrophobic, and thus becomes agglomerated in the mouth. Moreover, immediately after containing in a mouth, the branched chain amino acid containing granule is not wet with saliva. Immediately after taking, as shown in FIG. 1B, the branched chain amino acid-containing granules on the surface are wetted by saliva as shown in FIG. 1B, but the branched chain amino acid-containing granules are not well-adapted to water, so saliva does not penetrate into the center. Furthermore, even after about 30 seconds after taking, as shown in FIG. 1C, the branched chain amino acid-containing granules are only gradually wetted from the surface, and the aggregation state continues.
しかし、グリシンと共に服用することで、全ての分岐鎖アミノ酸含有顆粒が唾液に湿潤するように通路を作り出し、分岐鎖アミノ酸含有顆粒が分散しやすい状態を作り出していることが予想される(図２Ａ〜Ｄ)。即ち、口内に含んだ直後においては、図２Ａに示すとおり、分岐鎖アミノ酸含有顆粒及びグリシン粉末は、唾液によって濡れていない。服用直後〜約１０秒においては、図２Ｂに示すとおり、唾液により、表面の分岐鎖アミノ酸含有顆粒及びグリシン粉末が濡れ、更に濡れたグリシン粉末が溶解する。服用後約１０秒〜約２０秒においては、図２Ｃに示すとおり、グリシン粉末が唾液により溶解して生じた隙間から、唾液が浸透し、中心の分岐鎖アミノ酸含有顆粒及びグリシン粉末が濡れ始める。服用後約２０秒以降においては、図２Ｄに示すとおり、唾液が浸透するにつれて、分岐鎖アミノ酸含有顆粒は、表面から順に、分散状態となる。 However, by taking with glycine, it is expected that all branched-chain amino acid-containing granules create a passage so that they are moistened in saliva, and the branched-chain amino acid-containing granules are easily dispersed (FIGS. 2A to 2). D). That is, immediately after being included in the mouth, as shown in FIG. 2A, the branched chain amino acid-containing granules and glycine powder are not wetted by saliva. From immediately after taking to about 10 seconds, as shown in FIG. 2B, the surface branched chain amino acid-containing granules and glycine powder are wetted by saliva, and the wet glycine powder is further dissolved. About 10 seconds to about 20 seconds after taking, as shown in FIG. 2C, saliva penetrates through the gap formed by dissolution of glycine powder with saliva, and the central branched chain amino acid-containing granules and glycine powder begin to get wet. After about 20 seconds after taking, as shown in FIG. 2D, as saliva penetrates, the branched chain amino acid-containing granules are sequentially dispersed from the surface.
また、グリシンの口中存在下で服用することで、分岐鎖アミノ酸含有顆粒のみの場合よりも、唾液の分泌量が増え、その増加した唾液により、口中が水を飲んだ状態に近づいたことで、嚥下が容易になった可能性も考えられる。 Also, by taking in the presence of glycine in the mouth, the amount of saliva increased compared to the case of only branched chain amino acid-containing granules, and the increased saliva caused the mouth to approach the state of drinking water, It is possible that swallowing has become easier.
つまり、グリシンを添加することで、分岐鎖アミノ酸含有製剤自体の溶解性に大きな変化はないものの、口中において分岐鎖アミノ酸含有製剤が分散し、口溶けが良くなったように感じることが、口溶け、服用感及び味等の改善、ひいては嚥下の促進につながったと考えられる。 In other words, by adding glycine, there is no significant change in the solubility of the branched-chain amino acid-containing preparation itself, but the branched-chain amino acid-containing preparation is dispersed in the mouth, and it feels like the mouth melted better. It is thought that it led to improvement of feeling and taste, and consequently promotion of swallowing.
本発明の経口製剤は、分岐鎖アミノ酸とグリシンとを組み合わせてなるものである。なお、本発明において、「分岐鎖アミノ酸」とは、例えば、バリン、ロイシン及びイソロイシンの３種のアミノ酸をいう。本発明において、「分岐鎖アミノ酸とグリシンとを組み合わせてなる経口製剤」とは、分岐鎖アミノ酸とグリシンとを同時に含有する単一の製剤、又は、分岐鎖アミノ酸とグリシンとが別々に製剤化された２種以上の製剤を組み合わせてなるものをいう。 The oral preparation of the present invention is a combination of a branched chain amino acid and glycine. In the present invention, “branched chain amino acid” refers to, for example, three types of amino acids: valine, leucine and isoleucine. In the present invention, the “oral preparation comprising a combination of a branched chain amino acid and glycine” is a single preparation containing the branched chain amino acid and glycine at the same time, or the branched chain amino acid and glycine are separately formulated. In addition, a combination of two or more types of preparations.
本発明の分岐鎖アミノ酸の1種であるバリンは、通常、発酵法又は合成法で製造され、日本薬局方の規格を満たすものであることが望ましいが、それに限定されない。 Although it is desirable that valine, which is one of the branched chain amino acids of the present invention, is usually produced by a fermentation method or a synthesis method and meets the standards of the Japanese Pharmacopoeia, it is not limited thereto.
本発明の分岐鎖アミノ酸の1種であるロイシンは、通常、発酵法又は合成法で製造され、日本薬局方の規格を満たすものであることが望ましいが、それに限定されない。 Although leucine, which is one of the branched-chain amino acids of the present invention, is preferably produced by a fermentation method or a synthesis method and meets the standards of the Japanese Pharmacopoeia, it is not limited thereto.
本発明の分岐鎖アミノ酸の1種であるイソロイシンは、通常、発酵法又は合成法で製造され、日本薬局方の規格を満たすものであることが望ましいが、それに限定されない。 Although it is desirable that isoleucine, which is one of the branched chain amino acids of the present invention, is usually produced by a fermentation method or a synthesis method and satisfies the standards of the Japanese Pharmacopoeia, it is not limited thereto.
本発明の経口製剤は、下記態様（１）又は態様（２）を満たす。
態様（１）：分岐鎖アミノ酸及びグリシン以外のアミノ酸を含有しない、経口製剤。
態様（２）：バリン、ロイシン、イソロイシンの配合割合（質量比）が、バリン／ロイシン／イソロイシン＝１．０〜１．３／１．９〜２．２／１．０である、経口製剤。The oral preparation of the present invention satisfies the following aspect (1) or aspect (2).
Aspect (1): An oral preparation containing no amino acids other than branched chain amino acids and glycine.
Aspect (2): An oral preparation in which the blending ratio (mass ratio) of valine, leucine and isoleucine is valine / leucine / isoleucine = 1.0 to 1.3 / 1.9 to 2.2 / 1.0.
本発明の経口製剤は、態様（１）において、分岐鎖アミノ酸及びグリシン以外のアミノ酸を実質的に含有しない。分岐鎖アミノ酸は、肝疾患等の患者に有用なアミノ酸であることが知られており、その効果に対する影響を考慮するとさらに追加する成分は必要最小限であることが好ましい。本発明は、分岐鎖アミノ酸及びグリシン以外のアミノ酸を実質的に含有しないと、製剤量を抑えて、コストの上昇を防ぎ得るという有利な効果、及び、分岐鎖アミノ酸及びグリシン以外のアミノ酸による分岐鎖アミノ酸の効果の予期せぬ減少を防ぎ得るという有利な効果を奏する点で、好ましい。なお、本発明において、「実質的に含有しない」とは、上述の有利な効果を奏しない量であれば含有していてもよいことを、意味する。 The oral preparation of the present invention contains substantially no amino acids other than the branched chain amino acid and glycine in the aspect (1). Branched chain amino acids are known to be useful amino acids for patients with liver diseases and the like, and it is preferable that the additional components be the minimum necessary in consideration of the effect on the effects. INDUSTRIAL APPLICABILITY The present invention has the advantageous effect that the amount of the preparation can be suppressed and the increase in cost can be prevented if it contains substantially no amino acids other than branched chain amino acids and glycine, and branched chains by amino acids other than branched chain amino acids and glycine. This is preferable in that it has an advantageous effect of preventing an unexpected decrease in the effect of amino acids. In the present invention, “substantially does not contain” means that it may be contained in an amount that does not exhibit the advantageous effects described above.
本発明の分岐鎖アミノ酸は、態様（１）において、バリン、ロイシン、イソロイシンからなる群より選ばれる少なくとも１種であることが好ましい。 In the aspect (1), the branched chain amino acid of the present invention is preferably at least one selected from the group consisting of valine, leucine and isoleucine.
本発明の経口製剤は、態様（２）において、バリン、ロイシン、イソロイシンの配合割合（質量比）が、通常、バリン／ロイシン／イソロイシン＝１．０〜１．３／１．９〜２．２／１であり、好ましくは、１．１〜１．３／１．９〜２．２／１であり、特に好ましくは、１．１〜１．３／１．９〜２．１／１である。かかる配合割合が、バリン／ロイシン／イソロイシン＝１．０〜１．３／１．９〜２．２／１の範囲内であると、肝疾患への有効性の点、タンパク質を豊富に含む卵・牛乳等の食品や理想的なアミノ酸組成を持つと広く知られる母乳と組成がほぼ等しい点、及び、成人が一日に必要とする必須アミノ酸の摂取量における分岐鎖アミノ酸の質量比（バリン／ロイシン／イソロイシン＝２６／３９／２０（ｍｇ／ｋｇ／ｄａｙ））とほぼ等しい点で、好ましい。 In the oral preparation of the present invention, in the aspect (2), the blending ratio (mass ratio) of valine, leucine and isoleucine is usually valine / leucine / isoleucine = 1.0 to 1.3 / 1.9 to 2.2. / 1, preferably 1.1 to 1.3 / 1.9 to 2.2 / 1, particularly preferably 1.1 to 1.3 / 1.9 to 2.1 / 1. is there. When the blending ratio is in the range of valine / leucine / isoleucine = 1.0 to 1.3 / 1.9 to 2.2 / 1, the effectiveness for liver disease and the egg rich in protein・ Mass ratio of branched chain amino acids in the intake of essential amino acids that adults need in one day (valin / Leucine / isoleucine = 26/39/20 (mg / kg / day)) is preferable in that it is almost equal.
本発明の経口製剤における分岐鎖アミノ酸の量は、通常、５０重量％〜９５重量％である。通常、分岐鎖アミノ酸について矯味付けや造粒操作などを行うことから添加剤を加える必要があるが、製剤全量が多すぎると服用しづらくなるため、本発明の経口製剤における分岐鎖アミノ酸の量は、７０重量％〜９０重量％が特に好ましい。 The amount of the branched chain amino acid in the oral preparation of the present invention is usually 50% to 95% by weight. Usually, it is necessary to add an additive for performing branching amino acid flavoring or granulation operation, but since it is difficult to take if the total amount of the preparation is too much, the amount of the branched chain amino acid in the oral preparation of the present invention is 70% by weight to 90% by weight is particularly preferable.
本発明の経口製剤において、分岐鎖アミノ酸とグリシンとが単一の製剤として、製剤化される場合のグリシンの量は、分岐鎖アミノ酸の量に対して２．５重量％以上であり、造粒性や酸味の調節の観点から、好ましくは、２．５重量％〜４９重量％であり、特に好ましくは、５重量％〜１５重量％である。かかる量が、２．５重量％に満たないと、水馴染みの良い粉末製剤の調製が困難となる。 In the oral preparation of the present invention, when the branched chain amino acid and glycine are formulated as a single preparation, the amount of glycine is 2.5% by weight or more based on the amount of the branched chain amino acid, and granulated. From the viewpoint of adjusting the properties and sourness, it is preferably 2.5% by weight to 49% by weight, and particularly preferably 5% by weight to 15% by weight. If the amount is less than 2.5% by weight, it is difficult to prepare a powder formulation that is well-familiar with water.
分岐鎖アミノ酸とグリシンとが別々に製剤化される場合、本発明の経口製剤におけるグリシンの量が、分岐鎖アミノ酸の量に対して、１２．５重量％以上であると、経口製剤の服用感、水の必要性、口溶け、味及び後味が良好となり、また、服用に要する時間が短くなることから、特に好ましく、２５重量％〜５０重量％が、最も好ましい。 When the branched-chain amino acid and glycine are formulated separately, if the amount of glycine in the oral preparation of the present invention is 12.5% by weight or more with respect to the amount of the branched-chain amino acid, the feeling of taking the oral preparation In particular, the necessity of water, dissolution in the mouth, taste and aftertaste are improved, and the time required for taking is shortened, so that the content is particularly preferably 25 to 50% by weight.
本発明の経口製剤は、さらに有機酸を組み合わせてもよい。本発明の経口製剤は、有機酸を組み合わせることにより、服用に要する時間がより短時間となる。但し、有機酸を組み合わせる場合、有機酸由来の酸味、分岐鎖アミノ酸由来の苦味及びグリシン由来の甘味のバランスによって、経口製剤の味及び後味等が低下することがあり、その結果、服用感の改善効果が阻害されることがあることに留意する。
該有機酸としては、例えば、クエン酸、リンゴ酸、酒石酸、コハク酸、乳酸、フマル酸、アジピン酸、酢酸、グルコン酸、マレイン酸、マロン酸、アスコルビン酸、イタコン酸、フィチン酸等及びそれらの塩等が挙げられ、中でも、分岐鎖アミノ酸との苦味のバランスや服用感を改善させる為の添加量の点において、クエン酸、リンゴ酸、酒石酸が好ましい。The oral preparation of the present invention may further be combined with an organic acid. The oral preparation of the present invention takes a shorter time for taking by combining an organic acid. However, when combining organic acids, the taste and aftertaste of oral preparations may be reduced due to the balance of sourness derived from organic acids, bitterness derived from branched chain amino acids, and sweetness derived from glycine, resulting in an improved feeling of taking. Note that the effect may be inhibited.
Examples of the organic acid include citric acid, malic acid, tartaric acid, succinic acid, lactic acid, fumaric acid, adipic acid, acetic acid, gluconic acid, maleic acid, malonic acid, ascorbic acid, itaconic acid, phytic acid, and the like. Among them, citric acid, malic acid, and tartaric acid are preferable in terms of the addition amount for improving the balance of bitterness with branched chain amino acids and the feeling of taking.
本発明の経口製剤における有機酸の量は、分岐鎖アミノ酸の量に対して通常、０．５重量％〜４７．５重量％であり、酸味の調節の観点から、好ましくは、０．５重量％〜１０重量％である。かかる量が、０．５重量％に満たないと、有機酸由来の酸味が感じられなくなり、味や後味の服用感改善効果が認められなくなる。逆に、有機酸の量が、４７．５重量％を超えると、酸味が強くなりすぎるため服用しづらい経口製剤となる。 The amount of the organic acid in the oral preparation of the present invention is usually 0.5% by weight to 47.5% by weight with respect to the amount of the branched chain amino acid, and preferably 0.5% by weight from the viewpoint of adjusting the sourness. % To 10% by weight. If the amount is less than 0.5% by weight, the sourness derived from the organic acid is not felt, and the effect of improving the feeling of taking the taste and aftertaste is not recognized. On the other hand, when the amount of the organic acid exceeds 47.5% by weight, the sour taste becomes too strong, resulting in an oral preparation that is difficult to take.
上記有機酸がクエン酸であって、本発明の経口製剤が分岐鎖アミノ酸、グリシン及びクエン酸が単一製剤として製剤化される場合、本発明の経口製剤におけるクエン酸の含有量は、分岐鎖アミノ酸含有量に対して通常１重量％〜４７．５重量％であり、造粒性や酸味の調節の観点から、好ましくは、３重量％〜１０重量％である。かかる含有量が、１重量％に満たないと、水馴染みの良い粉末製剤の調製が困難となり、逆に４７．５重量％を超えると、酸味が強すぎる。 When the organic acid is citric acid and the oral preparation of the present invention is formulated as a single preparation of branched chain amino acids, glycine and citric acid, the content of citric acid in the oral preparation of the present invention is It is usually 1% by weight to 47.5% by weight with respect to the amino acid content, and preferably 3% by weight to 10% by weight from the viewpoint of adjusting granulation properties and acidity. If the content is less than 1% by weight, it is difficult to prepare a powder formulation that is well-familiar with water. Conversely, if the content exceeds 47.5% by weight, the acidity is too strong.
上記有機酸がクエン酸である場合、グリシンの含有量とクエン酸の含有量との合計は、通常、分岐鎖アミノ酸の含有量の５重量％以上であり、粉末製剤の水馴染みとクエン酸の酸味とグリシンの甘みを確保しつつ、粉末製剤の全量を多すぎないようするという観点から、好ましくは、１０重量％〜２０重量％であり、最も好ましくは、１４重量％〜１６重量％である。かかる合計が、５重量％に満たないと、水馴染みの良さを確保できず、又酸味や甘みが弱いので服用しづらい粉末製剤となる。 When the organic acid is citric acid, the sum of the content of glycine and the content of citric acid is usually 5% by weight or more of the content of branched chain amino acids. From the standpoint of ensuring that the sourness and sweetness of glycine are ensured and that the total amount of the powder preparation is not too large, it is preferably 10% by weight to 20% by weight, and most preferably 14% by weight to 16% by weight. . If the total is less than 5% by weight, good water familiarity cannot be ensured, and since the acidity and sweetness are weak, the powder preparation is difficult to take.
本発明の経口製剤は、分岐鎖アミノ酸、グリシン及びクエン酸が同時に製剤化された単一の製剤であってもよく、又は、別々に製剤化された２種以上の製剤を含むものであってもよいが、経口製剤が分岐鎖アミノ酸、グリシン及びクエン酸を含むものである場合は、同時に製剤化された単一の製剤であることにより、服用感、水の必要性、口溶け、味及び後味が改善し、また、服用に要する時間も短縮するので、特に好ましい。 The oral preparation of the present invention may be a single preparation in which a branched chain amino acid, glycine and citric acid are formulated simultaneously, or include two or more preparations formulated separately. However, if the oral preparation contains branched chain amino acids, glycine and citric acid, it is a single preparation formulated at the same time, which improves the feeling of taking, the need for water, dissolution in the mouth, taste and aftertaste. In addition, the time required for taking is shortened, which is particularly preferable.
本発明の経口製剤の剤型は、特に限定されるものでないが、例えば、顆粒剤、散剤、細粒剤、微粒剤、錠剤、丸剤、カプセル剤、経口液剤、シロップ剤、懸濁剤、乳剤、経口ゼリー剤等が挙げられ、服用性の観点から好ましくは、顆粒剤、散剤、細粒剤である。本発明においては、その効果の点で、粉末製剤であることが好ましい。 The dosage form of the oral preparation of the present invention is not particularly limited. For example, granules, powders, fine granules, fine granules, tablets, pills, capsules, oral solutions, syrups, suspensions, Emulsions, oral jelly preparations and the like can be mentioned. From the viewpoint of ingestion, granules, powders and fine granules are preferred. In the present invention, a powder preparation is preferable in view of the effect.
本発明の粉末製剤に関して、「粉末」とは、顆粒、細粒及び微粒等を含み、「粉末製剤」としては、日本薬局方に規定されている顆粒剤、散剤、細粒剤及び微粒剤等を含み、好適には顆粒剤である。具体的には、本発明の「粉末製剤」とは、粒度が２０００μｍ以下である粉状、粒状等の固形物状製剤が挙げられる。また、本発明において、「粒度」とは、粉末の粒子径をいい、日本薬局方記載の一般試験法３．０４「粒度測定法」第２法「ふるいわけ法」、又は、一般試験法６．０３「製剤の粒度の試験法」により測定される。
本発明の経口製剤の剤型が粉末製剤である場合、該粉末製剤は、通常、粒度が１７００μｍ以上（好ましくは、１４００μｍ以上）である粉末の含量が１％以下であり、好ましくは全く含まない。粒度が１７００μｍ以上である粉末を多く含むと、服用時の口触り感が悪くなる。また、本発明の粉末製剤は、通常、粒度が１５０μｍ以下（好ましくは、２５０μｍ以下）の粉末の含有量が１５重量％以下（好ましくは、１０重量％、特に好ましくは、５重量％以下）である。粒度が１５０μｍ以下の粉末の含有量が１５重量％を超えると、服用時に粉っぽく感じ、むせることもある。
かかる粒度の粉末製剤の粒度は、例えば、目開き１７００μｍの篩により篩分した粉末製剤について、音波振動形式の粒度分布測定装置（ロボットシフターＲＰＳ−９５Ｃ、セイシン企業社製）により、直径８ｃｍ、目開き１４００、８５０、５００、３５５、２５０、１８０、１５０、１０６、７５μｍの篩を用いて測定する。該粒度分布測定装置に造粒物約５ｇを投入し、５分間振動を行い、篩分後の各篩上の顆粒重量より、粒度分布を計算し、対数正規分布に近似することにより、幾何平均粒子径を求めることによって確認することができる。Regarding the powder preparation of the present invention, “powder” includes granules, fine granules, fine granules, etc., and “powder preparation” includes granules, powders, fine granules, fine granules, etc. prescribed by the Japanese Pharmacopoeia. And preferably a granule. Specifically, the “powder preparation” of the present invention includes solid preparations such as powder and granules having a particle size of 2000 μm or less. In the present invention, “particle size” refers to the particle size of the powder. General test method 3.04 “particle size measurement method”, second method “sieving method” or general test method 6 described in the Japanese Pharmacopoeia 0.03 “Testing method for formulation particle size”.
When the dosage form of the oral preparation of the present invention is a powder preparation, the powder preparation usually has a powder content with a particle size of 1700 μm or more (preferably 1400 μm or more) of 1% or less, preferably not contained at all. . When many powders having a particle size of 1700 μm or more are included, the feeling of touch at the time of taking becomes worse. In addition, the powder preparation of the present invention usually has a particle size of 150 μm or less (preferably 250 μm or less) and a powder content of 15 wt% or less (preferably 10 wt%, particularly preferably 5 wt% or less). is there. When the content of the powder having a particle size of 150 μm or less exceeds 15% by weight, it may feel like powder when taken and may be peeled off.
The particle size of the powder formulation having such a particle size is, for example, about 8 cm in diameter with a particle size distribution measuring apparatus (Robot Shifter RPS-95C, manufactured by Seishin Enterprise Co., Ltd.) in a sonic vibration format for a powder formulation sieved with a sieve having an opening of 1700 μm. Measurement is performed using a sieve having openings 1400, 850, 500, 355, 250, 180, 150, 106, and 75 μm. About 5 g of the granulated product is put into the particle size distribution measuring apparatus, shaken for 5 minutes, the particle size distribution is calculated from the weight of the granules on each sieve after sieving, and approximated to the lognormal distribution, thereby obtaining a geometric mean This can be confirmed by determining the particle size.
本発明の経口製剤が、別々に製剤化された２種以上の製剤を組み合わせてなるものである場合、２種以上の製剤の剤型は、同一であっても、それぞれ異なるものであってもよい。別々に製剤化された製剤の剤型の具体的な組合せとしては、例えば、下記の組合せが挙げられるが、これらに限定されない。
（１）分岐鎖アミノ酸を含有する顆粒とグリシンを含有する顆粒との組合せ
（２）分岐鎖アミノ酸を含有する顆粒とグリシンを含有する細粒との組合せ
（３）分岐鎖アミノ酸を含有する細粒とグリシンを含有する顆粒との組合せ
（４）分岐鎖アミノ酸を含有する細粒とグリシンを含有する細粒との組合せWhen the oral preparation of the present invention is a combination of two or more preparations formulated separately, the dosage forms of the two or more preparations may be the same or different. Good. Specific combinations of dosage forms of preparations formulated separately include, but are not limited to, the following combinations.
(1) Combination of granules containing branched chain amino acids and granules containing glycine (2) Combination of granules containing branched chain amino acids and fine granules containing glycine (3) Fine granules containing branched chain amino acids (4) Combination of fine granules containing branched chain amino acids and fine granules containing glycine
本発明の経口製剤が別々に製剤化された２種以上の製剤を組み合わせてなるものである場合、かかる２種以上の製剤を組み合わせる方法としては、２種以上の製剤を略均一に混合せしめ得る方法であれば特に制限されないが、例えば、一般的な容器回転型混合機（例、V型、二重円錐型、回転揺動型等）、容器固定型混合機（例、リボン型、円錐スクリュー型等）、気流攪拌型混合機等の混合機を用いた方法が挙げられる。また、混合均一性に問題がある場合であれば、分包機等により各々の製剤の規定量を定められた容器に投入し混合する方法等が挙げられる。 When the oral preparation of the present invention is a combination of two or more preparations formulated separately, as a method of combining the two or more preparations, the two or more preparations can be mixed substantially uniformly. The method is not particularly limited, but, for example, a general container rotation type mixer (eg, V type, double cone type, rotary swing type, etc.), a container fixed type mixer (eg, ribbon type, conical screw) Type), and a method using a mixer such as an airflow stirring type mixer. If there is a problem with mixing uniformity, there may be mentioned a method in which a prescribed amount of each preparation is put into a predetermined container and mixed by a packaging machine or the like.
本発明の製剤は、結合剤を含有してもよい。かかる結合剤としては、日本薬局方又は医薬品添加物規格等の規格を満たしているものが好ましく、例えば、メチルセルロース、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース、ヒドロキシプロピルメチルセルロースフタレート等のセルロース誘導体：トウモロコシデンプン、コムギデンプン等のデンプン類：ポリビニルピロリドン、ポリビニルアルコール、アクリル酸ポリマーなどの合成高分子類：寒天、キサンタンガム、アラビアゴム、ゼラチン等の天然高分子類等が挙げられる。また、その含有量は、通常の造粒が可能な範囲内であればよい。 The preparation of the present invention may contain a binder. As such a binder, those satisfying standards such as Japanese Pharmacopoeia or pharmaceutical additive standards are preferable. For example, cellulose derivatives such as methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose phthalate: corn starch, wheat Starches such as starch: synthetic polymers such as polyvinylpyrrolidone, polyvinyl alcohol, and acrylic acid polymers: natural polymers such as agar, xanthan gum, gum arabic, and gelatin. Moreover, the content should just be in the range in which normal granulation is possible.
本発明の製剤は、矯味物質や矯臭物質を含有してもよい。かかる矯味物質としては、例えば、サッカリン、サッカリンナトリウム、アスパルテーム、グリチルリチン酸、グリチルリチン酸モノアンモニウム、グリチルリチン酸二アンモニウム、グリチルリチン酸二カリウム、グリチルリチン酸二ナトリウム、グリチルリチン酸三ナトリウム、アセスルファムＫ、マンニトール、エリストール、ソルビトール、キシリトール、トレハロース、カカオ末等が挙げられ、矯臭物質としては、例えば、レモンフレーバーなどの各種フレーバーやメントール等が挙げられる。 The preparation of the present invention may contain a taste-masking substance and a taste-masking substance. Examples of such taste-masking substances include saccharin, saccharin sodium, aspartame, glycyrrhizic acid, monoammonium glycyrrhizinate, diammonium glycyrrhizinate, dipotassium glycyrrhizinate, disodium glycyrrhizinate, trisodium glycyrrhizinate, acesulfame K, mannitol, erystole, Examples include sorbitol, xylitol, trehalose, cacao powder, and examples of flavoring substances include various flavors such as lemon flavor and menthol.
粉末製剤が顆粒である場合、その造粒法は、特に制限はなく、自体公知の造粒法が採用される。使用できる造粒機としては、例えば、高速混練造粒機、攪拌造粒機、押出し造粒機、流動層型造粒機、転動造粒機等が挙げられ、中でも、高速混練造粒機が好ましい。 When the powder preparation is a granule, the granulation method is not particularly limited, and a granulation method known per se is adopted. Examples of the granulator that can be used include a high-speed kneading granulator, a stirring granulator, an extrusion granulator, a fluidized bed granulator, a rolling granulator, and the like. Is preferred.
高速混練造粒機は、混練およびせん断を行う混練部材（アジテーター）とせん断および破砕を行う解砕部材（チョッパー）を備えており、両部材は公転速度と自転速度を独立に調節して駆動させることが可能であり、両部材が複合的に作用して、粉体と結合剤の練り込み、せん断および解砕が進行し、短時間で効率的に粉体の混練および造粒が可能な装置である。
攪拌造粒法とは、粉末に水又はバインダー液を、投入又は噴霧し、攪拌羽根の回転によりせん断・転動・圧密化を行い造粒する方法であり、縦型・横型の攪拌造粒機等が使用される。
押出し造粒法とは、可塑性を付与された粉末を、多数の穴のあいたスクリーンから押し出すことにより造粒する方法であり、押出し式造粒機、ディスクペレッター式造粒機、リングダイ式造粒機、バスケット式造粒機、オシレーティング式造粒機、シリンダー式造粒機等が使用される。
流動層造粒法とは、粉末を流動しながら水又はバインダー液を噴霧し、粉末を凝集させることにより行われる造粒法であり、流動層型造粒機、攪拌流動層型造粒機、転動流動層型造粒機、攪拌転動流動層型造粒機等が使用される。
転動造粒法とは、粉末を転がして造粒する方法のことであり、ドラム型造粒機、皿型造粒機、振動造粒機、円盤回転式造粒機等が使用される。The high-speed kneading granulator is equipped with a kneading member (agitator) for kneading and shearing and a crushing member (chopper) for shearing and crushing, and both members are driven by adjusting the revolution speed and the rotation speed independently. This is an apparatus capable of kneading and granulating the powder efficiently in a short period of time, with both members acting in a complex manner and kneading, shearing and crushing of the powder and binder. It is.
The agitation granulation method is a method in which water or a binder liquid is charged or sprayed into a powder and granulated by shearing, rolling, or compacting by rotating a stirring blade, and a vertical or horizontal agitation granulator. Etc. are used.
The extrusion granulation method is a method of granulating a powder imparted with plasticity by extruding it from a screen with a large number of holes. It is an extrusion granulator, a disk pelleter granulator, a ring die granulator. A granulator, a basket granulator, an oscillating granulator, a cylinder granulator, etc. are used.
The fluidized bed granulation method is a granulation method performed by spraying water or a binder liquid while flowing a powder, and aggregating the powder. A fluidized bed granulator, a stirred fluidized bed granulator, A rolling fluidized bed granulator, a stirring rolling fluidized bed granulator, or the like is used.
The rolling granulation method is a method of rolling and granulating a powder, and a drum granulator, a dish granulator, a vibration granulator, a disk rotary granulator, or the like is used.
本発明の経口製剤の１回の服用量は、分岐鎖アミノ酸として、通常、１５００ｍｇ〜５０００ｍｇ、好ましくは、２５００ｍｇ〜４５００ｍｇであり、剤型が粉末製剤である場合は、粉末製剤として、通常、２〜６ｇである。 The single dose of the oral preparation of the present invention is usually 1500 mg to 5000 mg, preferably 2500 mg to 4500 mg as a branched chain amino acid. When the dosage form is a powder preparation, it is usually 2 ~ 6g.
本発明において、「水に馴染み易くなる」とは、親水性に優れていることをいい、例えば、粉末等を水面上に撒布した場合に、攪拌・振盪などの操作をすることなく、該粉末の大部分が、直ちに、水面から落下することをいい、具体的には、下記にて説明する水落下試験にて測定した水落下時間が１２０秒未満、好ましくは、６０秒未満であることをいう。なお、混入する際に、該粉末等が水に溶解又は懸濁することまで要するものではない。また、逆に「水に馴染まない」とは、例えば、粉末等を水面上に撒布した場合に、該粉末等が水面から落下することなく、一定時間経過後も水面上に浮き、水面上に粉が積もった状態であることをいい、具体的には、下記にて説明する水落下試験にて測定した水落下時間が１２０秒を超えることをいう。 In the present invention, “easy to become familiar with water” means excellent hydrophilicity. For example, when the powder is spread on the surface of the water, the powder is not subjected to operations such as stirring and shaking. Is that the water drop time measured by the water drop test described below is less than 120 seconds, preferably less than 60 seconds. Say. In addition, when mixing, it is not required until the powder or the like is dissolved or suspended in water. On the other hand, “unsuitable to water” means that, for example, when powder is distributed on the surface of the water, the powder does not fall off the surface of the water and floats on the surface of the water after a certain period of time. It means that the powder is piled up. Specifically, it means that the water drop time measured in the water drop test described below exceeds 120 seconds.
本発明の製剤は、分岐鎖アミノ酸及びグリシンを同時に含有する場合、水落下試験の水落下時間が１２０秒未満、好ましくは、６０秒未満である。かかる水落下時間が１２０秒以上であると、親水性が十分ではなく、水に馴染みにくいので、製剤を水と共に服用しても口腔内への残存粉末が多く、飲み心地が悪くなる。 When the preparation of the present invention contains a branched chain amino acid and glycine at the same time, the water drop time of the water drop test is less than 120 seconds, preferably less than 60 seconds. When the water dropping time is 120 seconds or more, the hydrophilicity is not sufficient and it is difficult to be familiar with water. Therefore, even if the preparation is taken together with water, there are many residual powders in the oral cavity and the drinking comfort is deteriorated.
本発明における「水落下試験」とは、粉末製剤の水への馴染みやすさの指標となる「水落下時間」を測定する試験であり、具体的には、以下の方法による。
直径約４ｃｍ、高さ約５ｃｍの３０ｍＬ容量ビーカーに、３０ｍＬの常温の水を入れる。時間の測定を開始し、その５秒後から７秒後までに、２ｇの粉末製剤を、５ｃｍ〜１０ｃｍの高さから該ビーカーの水面に瞬時に落下させる。測定開始から水面上から積みあがった粉末製剤が水中に落下し、水面から積みあがっている粉末製剤の高さが２ｍｍ以下になる時間を、水落下時間とする。The “water drop test” in the present invention is a test for measuring the “water drop time” which is an index of the ease with which the powder preparation is familiar with water, and specifically, by the following method.
A 30 mL beaker having a diameter of about 4 cm and a height of about 5 cm is charged with 30 mL of room temperature water. Time measurement is started, and from 5 seconds to 7 seconds later, 2 g of the powder preparation is instantaneously dropped from the height of 5 cm to 10 cm onto the water surface of the beaker. The time when the powder preparation piled up from the water surface from the start of measurement falls into the water and the height of the powder preparation piled up from the water surface becomes 2 mm or less is defined as the water drop time.
本発明の経口製剤は、グリシンの口中存在下に分岐鎖アミノ酸を服用することを含む分岐鎖アミノ酸含有経口製剤の嚥下促進方法に関する事項を記載した記載物とともに包装した商業パッケージとすることができる。また、分岐鎖アミノ酸含有経口製剤とグリシンとを組み合わせてなる製剤、食品又はサプリメントも、同様に、グリシンの口中存在下に分岐鎖アミノ酸を服用することを含む分岐鎖アミノ酸含有経口製剤の嚥下促進方法に関する事項を記載した記載物とともに包装した商業パッケージとすることができる。
なお、本発明において、グリシンの口中存在下に分岐鎖アミノ酸を服用する方法としては、分岐鎖アミノ酸とグリシンとを口中に同時に存在せしめ得るものであれば特に制限されないが、例えば、本発明が、分岐鎖アミノ酸とグリシンとが別々に製剤化された２種以上の製剤を組み合わせてなるものである場合、２種以上の製剤を略均一に混合したものを服用する方法等が挙げられる。The oral preparation of the present invention can be a commercial package packaged with a description describing matters relating to a method for promoting swallowing of a branched-chain amino acid-containing oral preparation including taking a branched-chain amino acid in the presence of glycine in the mouth. Similarly, a preparation, food or supplement comprising a combination of a branched-chain amino acid-containing oral preparation and glycine, similarly, taking a branched-chain amino acid in the presence of glycine in the mouth, and a method for promoting swallowing of a branched-chain amino acid-containing oral preparation It can be a commercial package that is packaged with a description that describes the matter.
In the present invention, the method of taking a branched chain amino acid in the presence of glycine in the mouth is not particularly limited as long as it can cause the branched chain amino acid and glycine to exist in the mouth at the same time. In the case where two or more kinds of preparations in which a branched chain amino acid and glycine are separately formulated are combined, a method of taking a mixture of two or more kinds of preparations in a substantially uniform manner can be mentioned.
以下に実施例、及び比較例を示して本発明をより具体的に説明するが、本発明はこれらの実施例等によって限定されるものではない。 Hereinafter, the present invention will be described more specifically with reference to examples and comparative examples, but the present invention is not limited to these examples and the like.
（分岐鎖アミノ酸含有粉末製剤の製造）
＜実施例１及び２、比較例１〜４＞
予めバリン、ロイシン及びイソロイシンを、バリン：ロイシン：イソロイシン＝１．２：２：１の質量比で混合し、奈良式自由粉砕機を用いて粗粉砕した。粗粉砕した分岐鎖アミノ酸混合物の平均粒子径は、２５０μｍであった。該分岐鎖アミノ酸混合物８００ｇに、下記表１記載の組成の副原料と水１１２ｇとを加えて、高速混練造粒機（トリプルマスターＴＭＧ−５、株式会社品川工業所製）に投入し、公転２６ｒｐｍ、アジテーター自転５００ｒｐｍ、チョッパー自転３９１４ｒｐｍで１０分間造粒した。得られたウェットな造粒物を、流動層乾燥機（フローコーター ＦＬＯ−１ フロイント産業株式会社製）を用いて、給気温度約８０℃で乾燥し、目開き１７００μｍの篩により篩分して、大粒子を除去し目的とする粉末製剤をそれぞれ得た。なお、この手法で得た粉末製剤はすべて１５０μｍ以下の粒子の量が１０重量％以下であった。(Production of branched chain amino acid-containing powder formulations)
<Examples 1 and 2, Comparative Examples 1-4>
In advance, valine, leucine and isoleucine were mixed at a mass ratio of valine: leucine: isoleucine = 1.2: 2: 1, and coarsely pulverized using a Nara free grinder. The average particle diameter of the coarsely pulverized branched chain amino acid mixture was 250 μm. To 800 g of the branched chain amino acid mixture, an auxiliary raw material having the composition shown in Table 1 below and 112 g of water are added and charged into a high-speed kneading granulator (Triple Master TMG-5, manufactured by Shinagawa Kogyo Co., Ltd.). The mixture was granulated at 500 rpm for agitator rotation and 3914 rpm for chopper rotation for 10 minutes. The obtained wet granulated product is dried at a supply air temperature of about 80 ° C. using a fluidized bed dryer (Flow coater FLO-1 manufactured by Freund Sangyo Co., Ltd.), and sieved with a sieve having an opening of 1700 μm. The large particles were removed to obtain the desired powder formulations. In addition, all powder preparations obtained by this method had an amount of particles of 150 μm or less of 10% by weight or less.
＜実施例３、比較例５＞
分岐鎖アミノ酸８００ｇに代えて、平均粒子径２７０μｍのイソロイシン８００ｇを用いた以外は、実施例１と同様の操作を行い、目的とする粉末製剤をそれぞれ得た。なお、この手法で得た粉末製剤はすべて１５０μｍ以下の粒子の量が１０重量％以下であった。<Example 3, Comparative Example 5>
The target powder formulation was obtained in the same manner as in Example 1 except that 800 g of isoleucine having an average particle size of 270 μm was used instead of 800 g of the branched chain amino acid. In addition, all powder preparations obtained by this method had an amount of particles of 150 μm or less of 10% by weight or less.
（水落下試験）
実施例１〜３、比較例１〜５において得られた粉末製剤について、それぞれ水落下時間を測定した。なお、かかる水落下時間の測定は、上述の水落下試験により行った。結果を下記表１に示す。評価については、水落下時間が、１２０秒未満であったものは「良」とし、１２０秒以上であったものは「不可」とした。また、表中の単位は、全てｇとする。(Water drop test)
About the powder formulation obtained in Examples 1-3 and Comparative Examples 1-5, the water fall time was measured, respectively. The water drop time was measured by the water drop test described above. The results are shown in Table 1 below. Regarding the evaluation, the case where the water falling time was less than 120 seconds was determined as “good”, and the case where the water falling time was longer than 120 seconds was determined as “impossible”. The unit in the table is all g.
表１の結果から明らかなように、分岐鎖アミノ酸にグリシン及びクエン酸を添加して造粒することにより、該分岐鎖アミノ酸含有粉末製剤は水に馴染みやすくなった（実施例１〜３）。これに対し、グリシンを用いなかった場合（比較例４、５）や、グリシンに代えてグリシンと同等の溶解性を有する糖アルコール（マンニトール）を用いた場合（比較例１）は、その粉末製剤は水に馴染まなかった。また、グリシンを用いた粉末製剤であっても、クエン酸に代えて同量の酒石酸又はリンゴ酸を用いた場合（比較例２、３）には、その粉末製剤は水に馴染まなかった。 As is apparent from the results in Table 1, the branched-chain amino acid-containing powder preparation was easily adapted to water by adding glycine and citric acid to the branched-chain amino acid and granulating (Examples 1 to 3). On the other hand, when glycine was not used (Comparative Examples 4 and 5) or when sugar alcohol (mannitol) having solubility equivalent to glycine was used instead of glycine (Comparative Example 1), the powder formulation Didn't get used to water. Even in the case of a powder preparation using glycine, when the same amount of tartaric acid or malic acid was used instead of citric acid (Comparative Examples 2 and 3), the powder preparation was not compatible with water.
（官能試験）
５名の被験者により、表２記載の各サンプルの服用感、口溶け、水の必要性、味、後味について、５段階に評価し、該評価の平均を算出した。(Sensory test)
Five subjects evaluated each sample listed in Table 2 on the feeling of ingestion, melting in the mouth, necessity of water, taste, and aftertaste in five stages, and the average of the evaluation was calculated.
サンプルＡ〜Ｒとしては、別々に製剤化された分岐鎖アミノ酸を含有する顆粒とグリシン及び有機酸を含有する細粒とを、混合したものを使用した。該分岐鎖アミノ酸を含有する顆粒としては味の素株式会社製のリーバクト（商品名）（２０７５ｍｇ中、Ｌ−イソロイシン４７６ｍｇ、Ｌ−ロイシン９５２ｍｇ、Ｌ−バリン５７２ｍｇ含有）を使用し、混合はそれぞれ一包分ずつ規定量秤量したものをアルミスティックに投入し、投入口をヒートシールしたサンプルを１サンプルにつき１分程度手振りにて行った。
サンプルＳ及びＴとしては、上記実施例１又は２において製造した粉末製剤を、サンプルＵ及びＶとしては、クエン酸を加えなかった以外は上記実施例１又は２と同様に製造した粉末製剤を、それぞれ用いた。Samples A to R were prepared by mixing granules containing branched-chain amino acids formulated separately and fine granules containing glycine and an organic acid. As a granule containing the branched chain amino acid, React (trade name) manufactured by Ajinomoto Co., Inc. (in 2075 mg, containing 476 mg of L-isoleucine, 952 mg of L-leucine, and 572 mg of L-valine) was used, and mixing was performed in one package. Each sample weighed a specified amount was put into an aluminum stick, and a sample with the inlet sealed in a heat seal was shaken for about 1 minute per sample.
As samples S and T, the powder formulation produced in Example 1 or 2 above, and as samples U and V, the powder formulation produced in the same manner as in Example 1 or 2 except that citric acid was not added, Each was used.
上記サンプルＡ、Ｄ、Ｅ、Ｆ、Ｇ、Ｈ、Ｓ、Ｔ、Ｕ及びＶにおける、粒度が１５０μｍ以下の顆粒及び１４００μｍ以上の顆粒のそれぞれ含有割合を、表３に示す。
粒度及び各粒度の顆粒の含有割合の測定は、日本薬局方記載の一般試験法６．０３「製剤の粒度の試験法」に従い、音波振動形式の粒度分布測定装置（ロボットシフターＲＰＳ−９５Ｃ、セイシン企業社製）を用いて行った。Table 3 shows the content ratios of granules having a particle size of 150 μm or less and granules of 1400 μm or more in the samples A, D, E, F, G, H, S, T, U, and V, respectively.
The particle size and the content ratio of the granule of each particle size were measured according to the general test method 6.03 “Test method for the particle size of the preparation” described in the Japanese Pharmacopoeia, with a particle size distribution measuring device (robot shifter RPS-95C, Seishin) (Made by company company).
５段階評価の詳細は、下記の通りである。
＜服用感、口溶け、味、後味＞
−４：非常に悪い、−２：悪い、０：同じ、＋２：良い、＋４：非常によい
＜水の必要性＞
０：必要、＋１：有るほうが良い、＋２：どちらでも良い、＋３：無くても良い、＋４：必要ないDetails of the five-step evaluation are as follows.
<Dosage, mouth melt, taste, aftertaste>
-4: Very bad, -2: Bad, 0: Same, +2: Good, +4: Very good <Necessity of water>
0: Necessary, +1: It should be, +2: Either, +3: Not required, +4: Not required
＜嚥下所要時間＞
被験者が各サンプルの全てを口中に含んでから、口中の全てのサンプルを飲み込むまでの所要時間を計測し、該所要時間の被験者５人の平均を算出して、嚥下所要時間とした。<Time required for swallowing>
The time required for the subject to swallow all the samples in the mouth after all the samples were contained in the mouth was measured, and the average of the five subjects for the required time was calculated as the time required for swallowing.
結果を、表４に示す。 The results are shown in Table 4.
表４の結果から明らかなとおり、分岐鎖アミノ酸とグリシンとを組み合わせたサンプルＢ〜Ｈは、分岐鎖アミノ酸のみを含有するサンプルＡと比較して、服用感が改善し、また、嚥下時の水の必要性についても改善した。特に、グリシンの量が２５０ｍｇ以上、即ち、分岐鎖アミノ酸の量に対して１２．５重量％以上であるサンプルＤ〜Ｈは、服用感、水の必要性のみならず、口溶け、味及び後味についても著しく改善した。グリシンと併せて有機酸を組み合わせたサンプルＩ〜Ｒでは、グリシンのみを組み合わせたＣ及びＤと比べ、服用感及び水の必要性が改善し、更に、嚥下所要時間が短縮した。なお、有機酸を組み合わせたサンプルの一部では、服用感の改善が確認できなかったが、その原因としては、有機酸由来の酸味、分岐鎖アミノ酸由来の苦味及びグリシン由来の甘味のバランスによって、味や後味が低下したこと等が考えられる。分岐鎖アミノ酸、グリシン及びクエン酸を同時に含有する単一の製剤としたサンプルＳ及びＴは、服用感、水の必要性が改善し、また、嚥下所要時間も短縮した。該サンプルＳ及びＴは、上述の水落下試験の結果に示されたとおり、水に対する親和性が改善され、水に馴染みやすくなったものであり、従って、これらの結果から、水に対する親和性の改善が実際に服用感の改善につながることが、示唆された。 As is clear from the results in Table 4, samples B to H, which are a combination of branched chain amino acids and glycine, have improved dosing sensation compared to sample A containing only branched chain amino acids, and water during swallowing. The need for improved. In particular, samples D to H in which the amount of glycine is 250 mg or more, that is, 12.5% by weight or more with respect to the amount of branched chain amino acids are not only about the feeling of taking and the need for water, but also about mouth melting, taste and aftertaste. Also improved significantly. Samples I to R combined with an organic acid in combination with glycine improved the feeling of taking and the need for water, and further shortened the swallowing time compared to C and D combined with glycine alone. In addition, in some of the samples combined with the organic acid, improvement in the feeling of taking could not be confirmed, but the cause is due to the balance between the acidity derived from the organic acid, the bitterness derived from the branched chain amino acid, and the sweetness derived from glycine, It can be considered that the taste and aftertaste are lowered. Samples S and T, which are single preparations containing a branched chain amino acid, glycine and citric acid at the same time, improved the feeling of taking, the need for water, and shortened the swallowing time. As shown in the results of the water drop test described above, the samples S and T had improved affinity for water and became easy to become familiar with water. Therefore, from these results, the affinity for water was improved. It was suggested that the improvement actually leads to an improvement in taking feeling.
本発明の経口製剤は、水無しで服用する場合であっても、服用感が良好であり、嚥下に要する時間が短いので、非常に服用し易い。 Even when the oral preparation of the present invention is taken without water, the feeling of taking is good and the time required for swallowing is short, so it is very easy to take.
本発明は、日本で出願された特願２００８−２３１２９６を基礎としており、その内容は本明細書に全て包含されるものである。 The present invention is based on Japanese Patent Application No. 2008-231296 filed in Japan, the contents of which are incorporated in full herein.
１ 乾燥状態の分岐鎖アミノ酸含有顆粒
２ 少し濡れた分岐鎖アミノ酸含有顆粒
３ 湿潤状態の分岐鎖アミノ酸含有顆粒
４ 乾燥状態のグリシン粉末
５ 少し濡れたグリシン粉末
６ 湿潤状態のグリシン粉末DESCRIPTION OF SYMBOLS 1 Branched chain amino acid containing granule in dry state 2 Slightly wet branched chain amino acid containing granule 3 Wet state branched chain amino acid containing granule 4 Dry glycine powder 5 Slightly wet glycine powder 6 Wet glycine powder
Claims (11)
態様（１）：分岐鎖アミノ酸及びグリシン以外のアミノ酸を実質的に含有せず、分岐鎖アミノ酸が、Ｌ−バリン、Ｌ−ロイシン及びＬ−イソロイシンからなる群より選ばれる少なくとも１種である、経口製剤。 A powdered oral preparation comprising a combination of a branched chain amino acid, glycine and citric acid, wherein the amount of glycine is 5% by weight to 15% by weight of the amount of the branched chain amino acid, and satisfies the following aspect (1 ) .
Aspect (1): Oral which contains substantially no amino acids other than branched-chain amino acids and glycine , and the branched-chain amino acids are at least one selected from the group consisting of L-valine, L-leucine and L-isoleucine Formulation .
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| JPS61186320A (en) * | 1985-02-12 | 1986-08-20 | Morishita Seiyaku Kk | Amino acid preparation |
| JPH01285157A (en) * | 1988-05-11 | 1989-11-16 | Sanwa Kagaku Kenkyusho Co Ltd | Raw material for amino acid food |
| JPH0725838A (en) * | 1993-05-13 | 1995-01-27 | Yotsuba Yuka Kk | Orally administering agent for preventing or recovering fatigue |
| JPH07118150A (en) * | 1993-08-31 | 1995-05-09 | Yoshiaki Akiyama | Oral medicine having adjusted taste comprising branched amino acid as active ingredient |
| WO2008105368A1 (en) * | 2007-02-28 | 2008-09-04 | Meiji Dairies Corporation | Amino acid composition |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS61186320A (en) * | 1985-02-12 | 1986-08-20 | Morishita Seiyaku Kk | Amino acid preparation |
| JPH01285157A (en) * | 1988-05-11 | 1989-11-16 | Sanwa Kagaku Kenkyusho Co Ltd | Raw material for amino acid food |
| JPH0725838A (en) * | 1993-05-13 | 1995-01-27 | Yotsuba Yuka Kk | Orally administering agent for preventing or recovering fatigue |
| JPH07118150A (en) * | 1993-08-31 | 1995-05-09 | Yoshiaki Akiyama | Oral medicine having adjusted taste comprising branched amino acid as active ingredient |
| WO2008105368A1 (en) * | 2007-02-28 | 2008-09-04 | Meiji Dairies Corporation | Amino acid composition |
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| JPN7013003981; 日本医薬品添加剤協会編 医薬品添加物事典２００７ （第１刷） , 20070725, 薬事日報社 * |
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