WO2002034256A1 - Process for producing granular drug preparation containing branched amino acids - Google Patents
Process for producing granular drug preparation containing branched amino acids Download PDFInfo
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- WO2002034256A1 WO2002034256A1 PCT/JP2001/009333 JP0109333W WO0234256A1 WO 2002034256 A1 WO2002034256 A1 WO 2002034256A1 JP 0109333 W JP0109333 W JP 0109333W WO 0234256 A1 WO0234256 A1 WO 0234256A1
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- isoleucine
- leucine
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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
- A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid
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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
- 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
- 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 method for producing a pharmaceutical granule preparation containing three kinds of branched-chain amino acids consisting of isoleucine, leucine and valine as a main drug (active ingredient), and in particular, to three kinds of branching materials which are granulation raw materials for the granule preparation.
- the present invention relates to a pulverizing method for avoiding a risk of dust explosion in a step of pulverizing particles of a chain amino acid from each solid raw material to prepare the same.
- compositions containing three types of branched-chain amino acids consisting of isoleucine, leucine and valine as the main drug are effective therapeutic agents for liver diseases.
- the granule formulation containing these three amino acids is ground to adjust the particle size to the specified size to ensure uniformity of the content of the three amino acids that make up the granule formulation and to improve granulation in the granulation process. Is being processed.
- the present invention provides raw particles of three amino acids used in the manufacture of a pharmaceutical granule formulation containing three types of branched-chain amino acids consisting of isoleucine, leucine and valine, which are effective therapeutic agents for liver diseases. It is an object of the present invention to provide a safe and inexpensive means that can avoid the danger of dust explosion in the pulverization process of a solid raw material of amino acid that is carried out, does not require a large-scale device.
- the present invention for solving the above-mentioned problems is particularly advantageous for solid-state And pulverizing at least one of two kinds of solid amino acids consisting of other solid leucine and / or solid valine at the time of pulverizing the powder, and further includes the following inventions.
- a method for pulverizing solid isoleucine comprising mixing and pulverizing solid isoleucine with solid leucine and / or solid palin.
- a method for producing a granulated raw material particle mixture for producing a pharmaceutical granule preparation comprising isoleucine, leucine and palin as a main ingredient, comprising mixing and grinding solid isoleucine with solid leucine and / or solid parin.
- the solid raw material isoloisin in the step of pulverizing the solid raw material of the three kinds of branched-chain amino acids to adjust the particle size is obtained by solid raw material mouth and
- the mixing and pulverization of the solid raw material isoleucine and the solid raw material leucine and the solid raw material palin is performed by a shock type (high-speed rotation type) pulverizer such as a hammer mill, a tumbler type (medium type) pulverizer such as a pole mill or the like.
- a shock type (high-speed rotation type) pulverizer such as a hammer mill
- a tumbler type (medium type) pulverizer such as a pole mill or the like.
- the mixed ground material has a particle size of 5 to 7006 ⁇ , preferably in a range of 10 to 500, and any one of the above items (3) to (6). 4.
- the method for producing a pharmaceutical granular preparation comprising isoleucine, leucine and valine as
- the solid raw material isoleucine, the solid raw material leucine and the solid raw material valine in each method of the present invention are pharmaceutical granules produced by granulating particles of the three kinds of branched-chain amino acids, which are effective therapeutic agents for liver diseases. It is an amino acid useful as a raw material for pharmaceuticals.
- isoleucine which is one of the main drugs, is generally a particle having a particle size of 1 mm or less produced by a fermentation method, and is a Japanese Pharmacopoeia; It meets any of the standards of the United States Pharmacopeia, but is not so limited.
- Leucine is generally manufactured by fermentation or extraction and has a particle size of lmm or less and meets the standards of the Japanese Pharmacopoeia, European Pharmacopoeia or the United States Pharmacopeia. It is not limited.
- palin which is generally produced by fermentation or synthesis and has a particle size of lmm or less and meets any of the standards of the Japanese Pharmacopoeia, European Pharmacopoeia, and US Pharmacopoeia, is used. But not limited to.
- mixed grinding refers to a method in which isoleucine, leucine and palin are mixed in advance and then crushed, or a method in which isoleucine, leucine and parin are mixed and ground while being mixed.
- mixing refers to a container rotary mixer such as a container mixer, an air stirring mixer such as a fluidized bed mixer, a stirring mixer by rotating stirring blades and stirring lipons, and mixing in a powder transport line.
- a feeder type mixer installed at a raw material supply port such as a line mixer or a pulverizer is not particularly limited.
- Pulverization here means an impact type such as a hammer mill (high-speed rotation type)
- a tumbler set such as a pulverizer or a pole mill (medium type)
- a fluid type (pneumatic type) such as a pulverizer or a jet mill Pulverization by a pulverizer is preferable, but not particularly limited.
- a binder in producing the granular preparation of the present invention, can be used.
- the binder include cellulose derivatives such as methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose and hydroxypropylmethylcellulose, starches such as corn starch and wheat starch, polyvinylpyrrolidone, and acrylic acid polymers. Any molecule can be used without particular limitation as long as it can be used for medical purposes, such as molecules, natural polymers such as gum arabic and gelatin. Also, the amount used is within the range where normal granulation is possible.
- Granules containing the three types of branched chain amino acid particles in the pharmaceutical granule preparation of the present invention include a high-speed stirring granulator, a fluidized bed granulator, a planetary mixer, a dry press granulator, a crush granulator, Any of an extrusion granulator, a tumbling granulator, a spray-drying granulator, and a coating granulator can be used, but a high-speed stirring granulator and an extrusion granulator are preferable.
- Extrusion granulation is a method of granulating plasticized powder by extruding it through a screen with many holes.Pre-extrusion granulator, disk pellets, Yuichi granulator, ring die granulator Machine, basket type granulator, oscillating type granulator, cylinder type granulator, etc. are used.
- the high-speed stirring granulation method is a method in which water or a binder liquid is charged or sprayed into a powder, and the powder is subjected to shearing, rolling, and compaction by rotating a stirring blade to granulate.
- a vertical and horizontal stirring granulator is used. Is used.
- the fluidized-bed granulation method is a granulation method performed by spraying water or a binder liquid while flowing the powder to agglomerate the powder.
- the fluidized-bed granulator, the stirred fluidized-bed granulator, A tumbling fluidized bed type granulator and a stirring tumbling fluidized bed type granulator are used.
- Dry press granulation is a method of compressing and molding powder without using water or a binder solution. Roll presses, pre-ketting machines, single-shot tablet presses, and one-stop tablet presses are used. used.
- the tumbling granulation method is a method of rolling and granulating powder, and a drum-type granulator, a dish-type granulator, a vibrating granulator, and a disk-type granulator are used.
- Figure 1 is a diagram showing the dust explosive properties of the pulverized product of three types of branched-chain amino acids (leucine, isoleucine, and palin).
- the present invention makes it possible to safely manufacture a pharmaceutical granule preparation as a therapeutic agent for liver disease of the present invention.
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Abstract
A process for producing a granular drug preparation containing isoleucine, leucine and valine as the principal agents wherein a solid isoleucine material is ground as a mixture with a solid leucine material and/or a solid valine material in the step of grinding these three solid amino acid materials to thereby control the grain size. Thus, the granular drug preparation containing these three amino acids (i.e., isoleucine, leucine and valine) as the principal agents can be safely produced with lowering the risk of the dust explosion in grinding the solid isoleucine.
Description
分岐鎖アミノ酸含有医薬用顆粒製剤の製造方法 技術分野 Method for producing pharmaceutical granules containing branched-chain amino acids
本発明は、 イソロイシン、 ロイシン及ぴバリンからなる 3種の分岐鎖アミノ酸 を主薬 （有効成分） として含む医薬用顆粒製剤の製造方法に関し、 特に、 該顆粒 製剤の造粒原料である 3種の分岐鎖アミノ酸の粒子をそれぞれの固体原料から粉 砕して調整する工程における粉塵爆発の危険を回避するための粉碎方法に関する。 背景技術 The present invention relates to a method for producing a pharmaceutical granule preparation containing three kinds of branched-chain amino acids consisting of isoleucine, leucine and valine as a main drug (active ingredient), and in particular, to three kinds of branching materials which are granulation raw materials for the granule preparation. The present invention relates to a pulverizing method for avoiding a risk of dust explosion in a step of pulverizing particles of a chain amino acid from each solid raw material to prepare the same. Background art
イソロイシン、 ロイシン及びバリンからなる 3種の分岐鎖アミノ酸を主薬とし て含む医薬用顆粒製剤は肝疾患に有効な治療薬である。 この 3種のアミノ酸を含 む顆粒製剤は、 顆粒製剤を構成する 3種のアミノ酸の含有量の均一性の保証及び 造粒工程における造粒性の改善のために所定粒度に調整するために粉砕処理され ている。 Pharmaceutical granules containing three types of branched-chain amino acids consisting of isoleucine, leucine and valine as the main drug are effective therapeutic agents for liver diseases. The granule formulation containing these three amino acids is ground to adjust the particle size to the specified size to ensure uniformity of the content of the three amino acids that make up the granule formulation and to improve granulation in the granulation process. Is being processed.
しかし、 これらの 3種の分岐鎖アミノ酸の固形物に限らず、 粉砕処理工程では 常に粉塵爆発の危険が付きまとい、 その防止対策に多大の設備投資がなされてい る。 However, not only the solids of these three types of branched-chain amino acids, but also the risk of dust explosion in the pulverization process, there is a great deal of capital investment in measures to prevent it.
上記 3種の分岐鎖アミノ酸の場合も例外ではなく、 特にイソロイシンの粉砕処 理時における粉塵爆発の危険が伴うことから、 窒素雰囲気下での粉砕、 遠隔操作 による粉碎、 爆発放散口の設置等の安全対策が講じられているのが現状である。 発明の開示 The above three types of branched-chain amino acids are no exception.Particularly, there is the danger of dust explosion during the isoleucine pulverization process.Therefore, pulverization under nitrogen atmosphere, pulverization by remote control, installation of explosion vent, etc. At present, safety measures are being taken. Disclosure of the invention
本発明は、 肝疾患に対する有効な治療薬であるイソロイシン、 ロイシン及びバ リンからなる 3種の分岐鎖アミノ酸を含有する医薬用顆粒製剤の製造に使用され る該 3種のアミノ酸の原料粒子を調製するために行われるアミノ酸の固形原料の 粉砕工程における粉塵爆発の危険性を回避することができる、 大掛かりな装置を 必要としない、 安全かつ安価な手段を提供することを目的とするものである。 上記の課題を解決するための本発明は、 特に爆発危険性の高い固形ィソロイシ
ンの粉碎時に他の固形ロイシン及び/又は固形バリンからなる 2種の固形アミノ 酸の少なくとも 1種を混合粉砕することを特徴とする発明であり、 さらに以下の 発明を包含する。 The present invention provides raw particles of three amino acids used in the manufacture of a pharmaceutical granule formulation containing three types of branched-chain amino acids consisting of isoleucine, leucine and valine, which are effective therapeutic agents for liver diseases. It is an object of the present invention to provide a safe and inexpensive means that can avoid the danger of dust explosion in the pulverization process of a solid raw material of amino acid that is carried out, does not require a large-scale device. SUMMARY OF THE INVENTION The present invention for solving the above-mentioned problems is particularly advantageous for solid-state And pulverizing at least one of two kinds of solid amino acids consisting of other solid leucine and / or solid valine at the time of pulverizing the powder, and further includes the following inventions.
(1) 固形イソロイシンを固形ロイシン及び/又は固形パリンと混合粉砕すること を特徴とする、 固形イソロイシンの粉碎方法。 (1) A method for pulverizing solid isoleucine, comprising mixing and pulverizing solid isoleucine with solid leucine and / or solid palin.
(2) 固形イソロイシンを固形ロイシン及び/又は固形パリンと混合粉砕すること を特徴とする、 イソロイシン、 ロイシン及びパリンを主薬とする医薬用顆粒製剤 製造用の造粒原料粒子混合物の製造方法。 (2) A method for producing a granulated raw material particle mixture for producing a pharmaceutical granule preparation comprising isoleucine, leucine and palin as a main ingredient, comprising mixing and grinding solid isoleucine with solid leucine and / or solid parin.
(3) ィソロイシン、 ロイシン及びパリンの 3種の分岐鎖アミノ酸の固形原料を粉 砕して粒度を調整する工程、 次いで該粒度調整した各アミノ酸粒子を含有する原 料を造粒する工程を有するイソロイシン、 ロイシン及びバリンを主薬とする医薬 用顆粒製剤を製造する方法において、 該 3種の分岐鎖アミノ酸の固形原料を粉碎 して粒度を調整する工程における固形原料ィソロイシンの粉砕は固形原料口イシ ン及び/又は固形原料パリンとの混合粉砕であることを特徴とする、 イソ口イシ ン、 ロイシン及びパリンを主薬とする医薬用顆粒製剤の製造方法。 (3) A step of pulverizing a solid raw material of three types of branched-chain amino acids of isoloisin, leucine and palin to adjust the particle size, and then granulating a raw material containing the amino acid particles having the adjusted particle size. In the method for producing a pharmaceutical granule preparation containing leucine and valine as the main drugs, the solid raw material isoloisin in the step of pulverizing the solid raw material of the three kinds of branched-chain amino acids to adjust the particle size is obtained by solid raw material mouth and A method for producing a pharmaceutical granule preparation containing iso-isocyanine, leucine and palin as main drugs, characterized by being mixed and pulverized with solid raw material parin.
(4) イソロイシン、 ロイシン及びパリンの 3種の分岐鎖アミノ酸の固形原料を混 合粉碎して造粒用粒子混合物を調製する工程、 次いで該造粒用粒子混合物を造粒 する工程を有することを特徴とする、 （3) 項記載のイソロイシン、 ロイシン及ぴ バリンを主薬とする医薬用顆粒製剤の製造方法。 (4) a step of preparing a particle mixture for granulation by mixing and pulverizing solid raw materials of three types of branched-chain amino acids of isoleucine, leucine and palin, and then a step of granulating the particle mixture for granulation. The method for producing a pharmaceutical granule preparation comprising isoleucine, leucine and valine as the main drug as described in (3), which is characterized in that:
(5) 前記固形原料イソロイシンと固形原料ロイシン及び Z又は固形原料パリンと の混合粉砕は、 重量割合でイソロイシン 1に対してロイシン 0〜4 . 4及びバリ ン 0〜2 . 6であり、 ロイシン及び/又はバリン、 好ましくはロイシンとの共存 下に行われることを特徴とする、 上記（3) 項又は（4) 項に記載のイソロイシン、 ロイシン及びバリンを主薬とする医薬用顆粒製剤の製造方法。 (5) The mixing and grinding of the solid raw material isoleucine and the solid raw material leucine and Z or the solid raw material parin is such that leucine 0 to 4.4 and valin 0 to 2.6 are weight ratio to isoleucine 1; And / or a method for producing a pharmaceutical granule preparation comprising isoleucine, leucine and valine as the main drug according to the above (3) or (4), which is carried out in the presence of valine, preferably leucine.
(6) 前記固形原料イソロイシンと固形原料ロイシン及びノ又は固形原料パリンと の混合粉砕は、 ハンマ一ミル等の衝撃式 （高速回転式） 粉砕機、 ポールミル等の タンブラ一式 （媒体式） 粉砕機又はジェットミル等の流体式 （気流式） 粉砕機に よる混合粉碎であることを特徴とする、 （1) 項〜（5) 項のいずれか 1項に記載の 方法。
(7) 前記混合粉碎物は、 粒度が 5〜7 0 0 ίΐ πι, 好ましくは 1 0〜 5 0 0 の 範囲とであることを特徴とする、 上記（3) 項〜（6) 項のいずれか 1項に記載のィ ソロイシン、 ロイシン及びバリンを主薬とする医薬用顆粒製剤の製造方法。(6) The mixing and pulverization of the solid raw material isoleucine and the solid raw material leucine and the solid raw material palin is performed by a shock type (high-speed rotation type) pulverizer such as a hammer mill, a tumbler type (medium type) pulverizer such as a pole mill or the like. The method according to any one of the above items (1) to (5), characterized in that the powder is mixed and pulverized by a fluid type (air flow type) pulverizer such as a jet mill. (7) The mixed ground material has a particle size of 5 to 7006πι, preferably in a range of 10 to 500, and any one of the above items (3) to (6). 4. The method for producing a pharmaceutical granular preparation comprising isoleucine, leucine and valine as the main drug according to item 1.
(8) 前記造粒用粒子混合物は、 イソロイシン、 ロイシン及びパリンの配合割合が 重量比で、 イソロイシン/ロイシン/バリン = 1ノ 1 . 9〜 2 . 2 / 1 . 1〜： 1 .(8) In the granulation particle mixture, isoleucine / leucine / valine = 1: 1.9-2.2 / 1.1-: 1.
3であることを特徴とする上記（3) 項〜（7) 項のいずれか 1項に記載のイソロイ シン、 ロイシン及びバリンを主薬とする医薬用顆粒製剤の製造方法。 3. The method for producing a pharmaceutical granular preparation comprising isoleucine, leucine and valine as the main drug according to any one of the above items (3) to (7).
本発明の各方法における固形原料イソロイシン、 固形原料ロイシン及び固形原 料バリンは、 肝疾患に有効な治療薬である該 3種の分岐鎖アミノ酸の粒子を造粒 して製造されている医薬用顆粒製剤用の原料物質として有用なアミノ酸である。 本発明の医薬用顆粒製剤において、 主薬の一つであるイソロイシンとしては、 一般的に発酵法で製造されている粒度が l mm以下の粒子であり日本薬局方、 ョ —口ッパ薬局方、 アメリカ薬局方のいずれかの規格を満たすものであるが、 それ に限るものではない。 The solid raw material isoleucine, the solid raw material leucine and the solid raw material valine in each method of the present invention are pharmaceutical granules produced by granulating particles of the three kinds of branched-chain amino acids, which are effective therapeutic agents for liver diseases. It is an amino acid useful as a raw material for pharmaceuticals. In the pharmaceutical granule preparation of the present invention, isoleucine, which is one of the main drugs, is generally a particle having a particle size of 1 mm or less produced by a fermentation method, and is a Japanese Pharmacopoeia; It meets any of the standards of the United States Pharmacopeia, but is not so limited.
ロイシンとしては、 一般的に発酵法又は抽出法で製造されている粒度が l mm 以下の粒子であり日本薬局方、 ヨーロッパ薬局方、 アメリカ薬局方のいずれかの 規格を満たすものであるが、 それに限るものではない。 Leucine is generally manufactured by fermentation or extraction and has a particle size of lmm or less and meets the standards of the Japanese Pharmacopoeia, European Pharmacopoeia or the United States Pharmacopeia. It is not limited.
また、 パリンとしては、 一般的に発酵法もしくは合成法で製造されている粒度 が l mm以下の粒子であり日本薬局方、 ヨーロッパ薬局方、 アメリカ薬局方のい ずれかの規格を満たすものが使用されるが、 それに限るものではない。 In addition, palin, which is generally produced by fermentation or synthesis and has a particle size of lmm or less and meets any of the standards of the Japanese Pharmacopoeia, European Pharmacopoeia, and US Pharmacopoeia, is used. But not limited to.
ここでいう混合粉砕とは、 イソロイシン、 ロイシン及びパリンを予め混合した 後に粉砕する方法、 又はイソロイシン、 ロイシン及びパリンを混合しながら粉碎 する方法いずれでも良い。 As used herein, the term “mixed grinding” refers to a method in which isoleucine, leucine and palin are mixed in advance and then crushed, or a method in which isoleucine, leucine and parin are mixed and ground while being mixed.
ここでいう混合とはコンテナ式混合機等の容器回転型混合機、 流動層型混合機 等のエアー撹拌型混合機、 撹拌羽根及び撹拌リポンの回転による撹拌混合機、 粉 体輸送ライン中で混合するライン混合機、 粉砕機等の原料供給口に設置されるフ ィ―ダ一型混合機による混合が好ましいが、 特に限定されるものでは無い。 ここでいう粉砕とは、 ハンマーミル等の衝撃式 （高速回転式） 粉碎機、 ポール ミル等のタンブラ一式 （媒体式） 粉砕機又はジェットミル等の流体式 （気流式）
粉碎機による粉砕が好ましいが、 特に限定されるものでは無い。 The term "mixing" as used herein refers to a container rotary mixer such as a container mixer, an air stirring mixer such as a fluidized bed mixer, a stirring mixer by rotating stirring blades and stirring lipons, and mixing in a powder transport line. Mixing by a feeder type mixer installed at a raw material supply port such as a line mixer or a pulverizer is not particularly limited. Pulverization here means an impact type such as a hammer mill (high-speed rotation type) A tumbler set such as a pulverizer or a pole mill (medium type) A fluid type (pneumatic type) such as a pulverizer or a jet mill Pulverization by a pulverizer is preferable, but not particularly limited.
本発明の顆粒製剤におけるイソロイシン、 口イシン及びパリンの配合割合は重 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。 The mixing ratio of isoleucine, mouth isine and palin in the granule preparation of the present invention is isoleucine / leucine / valine = 1 / 1.9 to 2.2 / 1.
本発明の顆粒製剤の製造に際しては、 結合剤を使用することができる。 結合剤 としては、 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一ト等のセ 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、 ァクリス酸ポリマーなどの合成高分子類、 アラビアゴム、 ゼ ラチン等の天然高分子類等の医薬用として使用できるものであれば特に制限なく 使用できる。 また、 その使用量も通常の造粒が可能な範囲である。 In producing the granular preparation of the present invention, a binder can be used. Examples of the binder include cellulose derivatives such as methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose and hydroxypropylmethylcellulose, starches such as corn starch and wheat starch, polyvinylpyrrolidone, and acrylic acid polymers. Any molecule can be used without particular limitation as long as it can be used for medical purposes, such as molecules, natural polymers such as gum arabic and gelatin. Also, the amount used is within the range where normal granulation is possible.
本発明の医薬用顆粒製剤における前記 3種の分岐鎖アミノ酸粒子を含む顆粒剤 は、 高速攪拌造粒機、 流動層造粒機、 プラネタリーミキサー、 乾式圧扁造粒機、 破碎造粒機、 押出し造粒機、 転動造粒機、 噴霧乾燥造粒機、 コ一ティング造粒機 のどの機器を使用しても作ることができるが、 高速攪拌造粒機、 押し出し造粒機 が好ましい。 Granules containing the three types of branched chain amino acid particles in the pharmaceutical granule preparation of the present invention include a high-speed stirring granulator, a fluidized bed granulator, a planetary mixer, a dry press granulator, a crush granulator, Any of an extrusion granulator, a tumbling granulator, a spray-drying granulator, and a coating granulator can be used, but a high-speed stirring granulator and an extrusion granulator are preferable.
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、 前押し出し式造粒機、 ディスクペレツ 夕一式造粒機、 リングダイ式造粒機、 バスケット式造粒機、 オシレ一ティング式 造粒機、 シリンダー式造粒機等が使用される。 Extrusion granulation is a method of granulating plasticized powder by extruding it through a screen with many holes.Pre-extrusion granulator, disk pellets, Yuichi granulator, ring die granulator Machine, basket type granulator, oscillating type granulator, cylinder type granulator, etc. are used.
高速攪拌造粒法とは、 粉に水あるいはバインダー液を投入あるいは噴霧し、 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竪型 ·横型 の攪拌造粒機が使用される。 The high-speed stirring granulation method is a method in which water or a binder liquid is charged or sprayed into a powder, and the powder is subjected to shearing, rolling, and compaction by rotating a stirring blade to granulate.A vertical and horizontal stirring granulator is used. Is used.
流動層造粒法とは、 粉を流動しながら水あるいはバインダー液を噴霧し、 粉を 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が使用される。 The fluidized-bed granulation method is a granulation method performed by spraying water or a binder liquid while flowing the powder to agglomerate the powder. The fluidized-bed granulator, the stirred fluidized-bed granulator, A tumbling fluidized bed type granulator and a stirring tumbling fluidized bed type granulator are used.
乾式圧扁造粒法とは水あるいはバインダ一液を使用せず粉を圧縮して成形する 方法であり、 ロールプレス、 プリケッティングマシン、 単発式打錠機、 口一タリ 一式打錠機が使用される。
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、 円盤回転式造粒機が使用される。 図面の簡単な説明 Dry press granulation is a method of compressing and molding powder without using water or a binder solution. Roll presses, pre-ketting machines, single-shot tablet presses, and one-stop tablet presses are used. used. The tumbling granulation method is a method of rolling and granulating powder, and a drum-type granulator, a dish-type granulator, a vibrating granulator, and a disk-type granulator are used. BRIEF DESCRIPTION OF THE FIGURES
図 1は、 3種の分岐鎖アミノ酸 （ロイシン、 イソロイシン、 パリン） 粉砕物の 粉塵爆発性を示す図である。 発明を実施するための最良の形態 Figure 1 is a diagram showing the dust explosive properties of the pulverized product of three types of branched-chain amino acids (leucine, isoleucine, and palin). BEST MODE FOR CARRYING OUT THE INVENTION
次に、 実施例を挙げて本発明をより具体的に説明するが、 本発明は以下の実施 例によって限定されるものではない。 Next, the present invention will be described more specifically with reference to examples, but the present invention is not limited to the following examples.
実施例 1 Example 1
3種の分岐鎖アミノ酸 （ロイシン、 イソロイシン、 パリン） をそれぞれ単品で 粉砕した粉砕物と 3種の分岐鎖アミノ酸を混合した後に粉碎した混合粉砕物の粉 塵爆発性を比較した。 爆発危険度は単品粉砕ではロイシンがクラス I I、 イソロイ シンがクラス Iでバリンがクラス I Iであったが、 混合粉碎物はクラス I Iになり、 3種類をそれぞれ単品で粉枠するよりも混合して粉碎する方が爆発危険度が著し く低下することが分かった。 We compared the dust explosive properties of three types of branched-chain amino acids (leucine, isoleucine, and palin), each of which was crushed separately, and the three types of branched-chain amino acids, which were then ground and mixed. The explosion risk was as follows: In the case of single-piece grinding, leucine was class II, isoleucine was class I, and valine was class II, but the mixed ground material was class II, and the three types were mixed rather than individually powdered. It was found that the risk of explosion was significantly reduced by grinding.
なお、 クラス別爆発対策は以下のとおりである。 The explosion measures for each class are as follows.
クラス特 I ：窒素パージ必要、 Class I: Nitrogen purge required
クラス I ：爆発放散口等の防爆対策必要 Class I: Explosion-proof measures such as explosion vents are required
クラス I I ： アース設置 Class I I: Ground installation
クラス I I I ：対策必要なし Class I I I: No action required
3種の分岐鎖アミノ酸に対する粉塵爆発性評価結果を表 1及び図 1にまとめて 示す。
ロイシン イリロイシン ハ'リン t ?«S7C下 Γ Ι¾¾鬼通 σ 75 45 60 最大爆発圧力上昇速度 [kg/cm2/Sec] 190 291 225 The results of the dust explosion evaluation for the three types of branched-chain amino acids are summarized in Table 1 and FIG. Leucine Iriroishin Ha 'phosphate t? «Ι¾¾ demon passing under Γ S7C σ 75 45 60 maximum explosion pressure rise rate [kg / cm 2 / Se c ] 190 291 225
危険クラス クラス Π クラス I クラス Π Danger class Class Π Class I class Π
Dイシン · イリリイシン · ハ'リン (2:1: 1.2)混合物 爆発下限界濃度 [mg 60 D Isin / Irilysin / Ha'lin (2: 1: 1.2) mixture Lower explosive limit (mg 60
最大爆発圧力上昇速度 [kg/cm2/sec] 207 Maximum explosion pressure rise rate [kg / cm 2 / sec] 207
危険クラス クラス Π Danger class Class Π
産業上の利用可能性 Industrial applicability
以上の結果から明らかなように、 本発明の 3種のアミノ酸の混合粉砕法によれ ば、その粉碎工程における粉塵爆発性を大幅に低下させることができ、その結果、 該 3種のアミノ酸を含む本発明の肝疾患治療薬である医薬用顆粒製剤の製造を安 全に実施することを可能ならしめるものである。
As is clear from the above results, according to the method of the present invention for mixing and grinding three kinds of amino acids, dust explosion in the pulverizing step can be significantly reduced, and as a result, the three kinds of amino acids are contained. The present invention makes it possible to safely manufacture a pharmaceutical granule preparation as a therapeutic agent for liver disease of the present invention.
Claims
1 . イソロイシン、 ロイシン及びパリンの 3種の固形原料アミノ酸を粉砕して粒 度を調整する工程、 次いで該粒度調整した各ァミノ酸粒子を含有する原料を造粒 する工程を有するイソロイシン、 ロイシン及びパリンを主薬とする医薬用顆粒製 剤を製造する方法において、 該 3種の固形原料アミノ酸を粉砕して粒度を調整す る工程における固形原料イソロイシンの粉砕は固形原料ロイシン及び/又は固形 原料パリンとの混合粉碎であることを特徴とする、 イソロイシン、 ロイシン及び パリンを主薬とする医薬用顆粒製剤の製造方法。 1. Isoleucine, leucine, and parin having a step of pulverizing three kinds of solid raw material amino acids of isoleucine, leucine, and palin to adjust the particle size, and then granulating a raw material containing each of the adjusted amino acid particles. In the method for producing a pharmaceutical granule product comprising a drug as a main ingredient, the pulverization of the solid raw material isoleucine in the step of pulverizing the three solid raw material amino acids to adjust the particle size is carried out by mixing the solid raw material leucine and / or the solid raw material parin. A method for producing a pharmaceutical granule preparation comprising isoleucine, leucine and palin as a main ingredient, characterized by being mixed and ground.
2 . 前記固形原料イソロイシンと固形原料ロイシン及び/又は固形原料パリンと の混合粉砕は、 重量割合でイソロイシン 1に対してロイシン 0 ~ 4 . 4及びバリ ン 0〜2 . 6であることを特徴とする、 請求の範囲第 1項記載のイソロイシン、 口イシン及ぴパリンを主薬とする医薬用顆粒製剤の製造方法。 2. The mixing and grinding of the solid raw material isoleucine and the solid raw material leucine and / or the solid raw material palin is characterized in that leucine 0 to 4.4 and valin 0 to 2.6 are weight ratio to isoleucine 1. 2. A method for producing a pharmaceutical granule preparation comprising isoleucine, oral isine and paparin as the principal agent according to claim 1.
• 3 . 前記固形原料イソロイシンと固形原料ロイシン及び Z又は固形原料パリンと の混合粉碎は、 ハンマ一ミル等の衝撃式 （高速回転式） 粉碎機、 ポールミル等の タンブラ一式 （媒体式） 粉砕機又はジェットミル等の流体式 （気流式） 粉砕機に よる混合粉碎であることを特徴とする、 請求の範囲第 1項又は第 2項に記載のィ ロイシン及びパリンを主薬とする医薬用顆粒製剤の製造方法。
• 3. Mixing of the solid raw material isoleucine with the solid raw material leucine and Z or the solid raw material parin is performed by a shock (high-speed rotation) crusher such as a hammer mill, a tumbler (media) crusher such as a pole mill, or the like. 3. A pharmaceutical granule formulation comprising leucine and parin as the principal drug according to claim 1 or 2, characterized in that the powder is mixed and pulverized by a fluid (air flow) pulverizer such as a jet mill. Production method.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2000-326514 | 2000-10-26 | ||
| JP2000326514A JP3228288B1 (en) | 2000-10-26 | 2000-10-26 | Method for producing pharmaceutical granule preparation containing branched chain amino acids |
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| Publication Number | Publication Date |
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| WO2002034256A1 true WO2002034256A1 (en) | 2002-05-02 |
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| Application Number | Title | Priority Date | Filing Date |
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| PCT/JP2001/009333 WO2002034256A1 (en) | 2000-10-26 | 2001-10-24 | Process for producing granular drug preparation containing branched amino acids |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1334722A1 (en) * | 2000-10-26 | 2003-08-13 | Ajinomoto Co., Inc. | Granular drug preparations containing branched amino acids and process for producing the same |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1839502A4 (en) * | 2004-12-07 | 2010-03-24 | Ajinomoto Kk | Fine powder of amino acid and suspension thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0184999A2 (en) * | 1984-12-12 | 1986-06-18 | Boehringer Mannheim Italia S.P.A. | Granular dietetic products based on amino acids and process for their preparation |
| JPH08198748A (en) * | 1995-01-27 | 1996-08-06 | Ajinomoto Co Inc | Amino acid nutrient composition |
-
2000
- 2000-10-26 JP JP2000326514A patent/JP3228288B1/en not_active Expired - Lifetime
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2001
- 2001-10-24 WO PCT/JP2001/009333 patent/WO2002034256A1/en active Application Filing
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0184999A2 (en) * | 1984-12-12 | 1986-06-18 | Boehringer Mannheim Italia S.P.A. | Granular dietetic products based on amino acids and process for their preparation |
| JPH08198748A (en) * | 1995-01-27 | 1996-08-06 | Ajinomoto Co Inc | Amino acid nutrient composition |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1334722A1 (en) * | 2000-10-26 | 2003-08-13 | Ajinomoto Co., Inc. | Granular drug preparations containing branched amino acids and process for producing the same |
| EP1334722A4 (en) * | 2000-10-26 | 2007-05-23 | Ajinomoto Kk | Granular drug preparations containing branched amino acids and process for producing the same |
Also Published As
| Publication number | Publication date |
|---|---|
| JP2002128668A (en) | 2002-05-09 |
| JP3228288B1 (en) | 2001-11-12 |
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