JPS6121529B2 - - Google Patents
Info
- Publication number
- JPS6121529B2 JPS6121529B2 JP14163379A JP14163379A JPS6121529B2 JP S6121529 B2 JPS6121529 B2 JP S6121529B2 JP 14163379 A JP14163379 A JP 14163379A JP 14163379 A JP14163379 A JP 14163379A JP S6121529 B2 JPS6121529 B2 JP S6121529B2
- Authority
- JP
- Japan
- Prior art keywords
- acid
- acetylsalicylate
- acetylsalicylic acid
- injection
- formulation
- 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.)
- Expired
Links
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 claims description 30
- 239000000203 mixture Substances 0.000 claims description 18
- 229960001138 acetylsalicylic acid Drugs 0.000 claims description 16
- 229940068372 acetyl salicylate Drugs 0.000 claims description 15
- 238000009472 formulation Methods 0.000 claims description 15
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 claims description 14
- 238000002360 preparation method Methods 0.000 claims description 13
- 238000002347 injection Methods 0.000 claims description 11
- 239000007924 injection Substances 0.000 claims description 11
- 239000000843 powder Substances 0.000 claims description 9
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 claims description 8
- 239000001110 calcium chloride Substances 0.000 claims description 8
- 229910001628 calcium chloride Inorganic materials 0.000 claims description 8
- 229960002449 glycine Drugs 0.000 claims description 7
- 235000013905 glycine and its sodium salt Nutrition 0.000 claims description 7
- 239000003381 stabilizer Substances 0.000 claims description 6
- 150000001413 amino acids Chemical class 0.000 claims description 5
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 8
- 238000003860 storage Methods 0.000 description 8
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 7
- 239000013078 crystal Substances 0.000 description 7
- 238000004519 manufacturing process Methods 0.000 description 7
- 230000000694 effects Effects 0.000 description 6
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 5
- 238000000034 method Methods 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- JJBCTCGUOQYZHK-UHFFFAOYSA-N 2-acetyloxybenzoate;(5-amino-1-carboxypentyl)azanium Chemical compound OC(=O)C(N)CCCC[NH3+].CC(=O)OC1=CC=CC=C1C([O-])=O JJBCTCGUOQYZHK-UHFFFAOYSA-N 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 3
- 238000004040 coloring Methods 0.000 description 3
- 239000012153 distilled water Substances 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 3
- 229960004889 salicylic acid Drugs 0.000 description 3
- BSYNRYMUTXBXSQ-FOQJRBATSA-N 59096-14-9 Chemical compound CC(=O)OC1=CC=CC=C1[14C](O)=O BSYNRYMUTXBXSQ-FOQJRBATSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- -1 amino acid salt Chemical class 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 230000007774 longterm Effects 0.000 description 2
- 208000004296 neuralgia Diseases 0.000 description 2
- 230000001376 precipitating effect Effects 0.000 description 2
- 238000001556 precipitation Methods 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 230000001954 sterilising effect Effects 0.000 description 2
- 238000004659 sterilization and disinfection Methods 0.000 description 2
- DLYUQMMRRRQYAE-UHFFFAOYSA-N tetraphosphorus decaoxide Chemical compound O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- 239000004472 Lysine Substances 0.000 description 1
- 208000000112 Myalgia Diseases 0.000 description 1
- 206010029240 Neuritis Diseases 0.000 description 1
- 208000002193 Pain Diseases 0.000 description 1
- 208000004550 Postoperative Pain Diseases 0.000 description 1
- 206010037660 Pyrexia Diseases 0.000 description 1
- 208000025747 Rheumatic disease Diseases 0.000 description 1
- 230000005856 abnormality Effects 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 231100000215 acute (single dose) toxicity testing Toxicity 0.000 description 1
- 238000011047 acute toxicity test Methods 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 229940035676 analgesics Drugs 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 239000000730 antalgic agent Substances 0.000 description 1
- 230000001754 anti-pyretic effect Effects 0.000 description 1
- 239000002221 antipyretic Substances 0.000 description 1
- 239000003435 antirheumatic agent Substances 0.000 description 1
- 206010003246 arthritis Diseases 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 206010006451 bronchitis Diseases 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 239000000356 contaminant Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- GICLSALZHXCILJ-UHFFFAOYSA-N ctk5a5089 Chemical compound NCC(O)=O.NCC(O)=O GICLSALZHXCILJ-UHFFFAOYSA-N 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 238000004925 denaturation Methods 0.000 description 1
- 230000036425 denaturation Effects 0.000 description 1
- 238000002845 discoloration Methods 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 208000021760 high fever Diseases 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 208000013465 muscle pain Diseases 0.000 description 1
- 201000009240 nasopharyngitis Diseases 0.000 description 1
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 description 1
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 1
- 230000036407 pain Effects 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 238000009877 rendering Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 238000004383 yellowing Methods 0.000 description 1
Description
本発明は、注射用アセチルサリチル酸塩の粉末
製剤に関するものであり、さらに詳しくは、製剤
中にアミノ酢酸を安定化剤として含有することを
特徴とする注射用アセチルサリチル酸塩の粉末製
剤に関する。
アセチルサリチル酸（アスピリン）は鎮痛薬、
解熱薬および抗リウマチ薬として古くから使用さ
れ、近年非ステロイド系抗炎症薬としてリウマ
チ、関節炎、神経痛、筋肉痛などの治療に広く用
いられている。
従来アセチルサリチル酸の投与法としては本品
が水に難溶（約0.3％）であるため現在まで内服
薬として使用されている。しかし内服の場合は胃
液の強い酸性により加水分解を受けてサリチル酸
を形成し、これが胃壁を刺戟するので腸溶錠その
他の製剤上の工夫がなされているが、製剤上の修
飾によつても内服の場合は完全に吸収されず、特
にアスピリン分子の血中濃度は静脈内に投与した
時の約半量でしかない。又、アセチルサリチル酸
を静脈内に投与したときの効果は、同量を経口投
与したときの効果より約４倍高いと云われてい
る。本発明者らはさきにアセチルサリチル酸の投
与法を改善するため注射液の調整に適した誘導体
の製造を企図し、アセチルサリチル酸と塩基性ア
ミノ酸を１：１モル比で結合させて水に易溶（40
％以上）の水溶性塩を得ることに成功した（特開
昭48―56815号）。このアセチルサリチル酸の塩基
性アミノ酸塩（以下アセチルサリチル酸塩とい
う）は水溶液中で不安定なため、注射剤として使
用時まで安定に保持するには粉末の剤形が必要と
される。粉末化の方法は上記公開公報においては
凍結乾燥法および含水アルコール溶液に析出剤を
加える結晶化法により実施されている。
アセチルサリチル酸塩は熱に対しても安定性に
乏しく、このため注射剤として工業的に製造する
際に多くの困難があつた。すなわちアセチルサリ
チル酸塩を注射剤として使用するための加熱によ
る滅菌処理及び乾燥方法において、通常の滅菌法
および乾燥法では多量のアセチルサリチル酸塩の
分解が起こるので、本発明者らはこれらの欠点を
解決するためさきに反応条件を研究し、反応溶
媒、析出剤等の適正なものを選定することによつ
てその製法を完成した（特開昭51―44623）。
かくして本発明者らは、注射用アセチルサリチ
ル酸塩の工業的製法を完成したのであるが、この
ものの粉末製剤は、なお保存安定性にとぼしく、
４℃保存では安定と言えるが、温度の上昇と共に
アセチルサリチル酸が分解してサリチル酸が生成
し、室温における長期保存には不安定であつた。
注射用アセチルサリチル酸塩は、静脈投与のよう
な生体内における早急な効果を期待して製造され
た医薬品であり、その必要時にそなえていつでも
使用できる状態で各病院に備えられていることは
大切なことである。このことは、該製剤が安定性
高く、長期保存に耐えるものであることが要求さ
れる。それにもかかわらず、提供されうる製剤
が、保存にともなつて夾雑物を生成することは、
製剤の副作用の原因ともなり、商品価値の著しい
低下とともに、さらには不良品として商品の無価
値化ともなるものである。
本発明者らは、先にアセチルサリチル酸塩の粉
末製剤の保存安定性の改善のための方策を種々検
討し、その結果、安定剤として塩化カルシウムを
添加することで、より安定な製剤を完成した（特
願昭54―88596）。
この研究と同時に、本発明者らは保存安定性の
別の観点として着色化防止の検討をなした。製品
の着色化は、かならずしもその製品の分解・生理
活性の低下を導くものではないが、何等かの製品
における変性がおこつていることは推測され、商
品の市場価値を低めることになる。そこで本発明
者らは、アセチルサリチル酸塩の粉末製剤の着色
防止法として選ばれた安定剤を添加することで目
的を達成することが可能であることを見い出し本
発明を完成した。
本発明の目的は、アセチルサリチル酸と塩基性
アミノ酸を反応させて得られる注射用アセチルサ
リチル酸塩の粉末製剤においてアミノ酢酸を１〜
15％（W/W）含有することを特徴とする医薬組
成物を提供することである。
本発明のアセチルサリチル酸塩は、特開昭51―
44623、特開昭48―56815等の方法に従つて製造で
きるが、反応に供される塩基性アミノ酸として
は、DL―形のリジンが用いられる。この塩基性
アミノ酸とアセチルサリチル酸との塩は、両者が
１：１のモル比で結合している。
その一般式は、
一般名：DL―リジンモノアセチルサリシレート
分子式：C15H22O6N2
M.W.：326.35
であり、白色の結晶粉末で、臭気はない。その製
造例を以下に示す。
製造例
反応液調製工程
蒸留水（パイロジエン・フリー）100中に、
DL―リジン23.25Kgを加えて溶解させ、活性炭約
600ｇを加えて処理し、主にDL―リジンに由来す
る着色物質を除く。この液に、別に準備した、
アセトン60中にアセチルサリチル酸30Kgを懸濁
した液を加えて混合する。加えたアセチルサリチ
ル酸が澄明に溶解したのち、この反応液を除菌
過して、次の結晶析出槽中に入れる。
結晶析出工程
除菌過した上記の反応液中に、アセトン150
を除菌過して加える。ゆるくかくはんしたの
ち、冷室（０〜６℃）に約20時間静置し、結晶の
種を析出させる。それに、除菌過したアセトン
150を追加して、冷室に24時間静置し結晶を成
長させる。この結晶を無菌的に取する。
洗浄・乾燥工程
取した結晶に、除菌過した90％アセトン水
溶液100を加えて洗浄したのち、更にアセトン
200を用いて洗浄し、含水分を1.0％以下となる
まで通気乾燥して無菌の結晶約33Kgを得る。
製剤は、塩化カルシウムの含有により安定化さ
れたものが好ましく、その調製は清浄にした分注
用容器に安定化剤として塩化カルシウムを適量
（製剤中１％（W/W）以上、好ましくは３〜５％
（W/W）となる量）分注し、後これを150〜180℃
で４時間加熱し、デシケーター（五酸化燐上）ま
たは乾燥箱中で放冷する。室温以下に冷却した塩
化カルシウム入り容器にアセチルサリチル酸塩１
ｇ及び着色防止剤としてグリシン（アミノ酢酸）
を１〜15％（W/W）となる量の割合で無菌的に
バイヤルに分注し、熔封又は巻締して製剤とす
る。この際各製剤成分を粉末状で混合することが
好ましく、例えば無菌のボールミルなどがこのた
めに用いられる。なお各成分の添加順序はどのよ
うであつてもよい。また、安定剤としての塩化カ
ルシウムが存在しなくとも、本発明はアセチルサ
リチル酸塩の黄色化を防止する。
アミノ酢酸の添加効果に関する実験。
アミノ酢酸の添加効果を検討するため試料を次
のように調製した。
アミノ酢酸添加量：前記製造例に於いて製造さ
れたアセチルサリチル酸―DL―リジ
ン塩１ｇ当り200、100、10、５、０mg
の５群
塩化カルシウムの添加量：アセチルサリチル酸
―DL―リジン塩１ｇ当り各50mg及び
０mgの７群
保存温度：37℃、45℃、日光下の３群
４℃保存群及び製造直後の製剤群を対照とし
て、各々の試料について、10週目に試験を行つ
た。試験項目としては、外観の着色状態、O.
D.440nmでの吸光度、高速液体クロマトグラフイ
ー法によつてアセチルサリチル酸塩の定量をおこ
なつた。得られた結果を表１に示した。
表１よりにるとアミノ酢酸量に応じて製剤の着
色化が抑制されていることが判る。この結果より
塩化カルシウムは、本発明においてもサリチル酸
の生成を抑制することが示される。
The present invention relates to a powder formulation of acetylsalicylate for injection, and more particularly to a powder formulation of acetylsalicylate for injection, which is characterized in that the formulation contains aminoacetic acid as a stabilizer. Acetylsalicylic acid (aspirin) is an analgesic,
It has long been used as an antipyretic and antirheumatic drug, and in recent years it has been widely used as a nonsteroidal anti-inflammatory drug to treat rheumatism, arthritis, neuralgia, muscle pain, etc. Up until now, acetylsalicylic acid has been administered orally as this product is sparingly soluble in water (approximately 0.3%). However, when taken internally, it is hydrolyzed by the strong acidity of gastric fluid to form salicylic acid, which irritates the stomach wall. In this case, it is not completely absorbed, and the concentration of aspirin molecules in the blood is only about half of that when administered intravenously. It is also said that the effect when acetylsalicylic acid is administered intravenously is about four times higher than the effect when the same amount is administered orally. In order to improve the administration method of acetylsalicylic acid, the present inventors attempted to produce a derivative suitable for preparing an injection solution, and combined acetylsalicylic acid and a basic amino acid in a 1:1 molar ratio to easily dissolve in water. (40
% or more) (Japanese Patent Application Laid-open No. 56815/1983). Since this basic amino acid salt of acetylsalicylic acid (hereinafter referred to as acetylsalicylic acid salt) is unstable in an aqueous solution, a powdered dosage form is required to keep it stable until use as an injection. The powdering method is carried out in the above publication by a freeze-drying method and a crystallization method in which a precipitating agent is added to a hydroalcoholic solution. Acetyl salicylate has poor stability against heat, and for this reason, many difficulties have arisen when producing it industrially as an injection. That is, in the sterilization treatment and drying method by heating for use of acetylsalicylate as an injection, a large amount of acetylsalicylate decomposes in the usual sterilization and drying methods, so the present inventors have solved these drawbacks. In order to do so, he first researched the reaction conditions and selected appropriate reaction solvents, precipitating agents, etc., and completed the manufacturing method (Japanese Patent Application Laid-Open No. 44623/1983). Thus, the present inventors completed an industrial method for producing acetylsalicylate for injection, but the powder formulation of this product still had poor storage stability.
Although it can be said to be stable when stored at 4°C, acetylsalicylic acid decomposes as the temperature rises to produce salicylic acid, making it unstable for long-term storage at room temperature.
Injectable acetylsalicylate is a drug manufactured with the expectation that it will have immediate effects in the body, such as when administered intravenously, and it is important that each hospital has it ready for use when it is needed. That's true. This requires that the formulation be highly stable and durable for long-term storage. Nevertheless, the formulations that may be provided may generate contaminants upon storage.
This can cause side effects of the preparation, significantly lowering the product value, and even rendering the product worthless as a defective product. The present inventors previously investigated various measures to improve the storage stability of powdered acetylsalicylate formulations, and as a result, they completed a more stable formulation by adding calcium chloride as a stabilizer. (Special application 1988-88596). Simultaneously with this research, the present inventors investigated prevention of coloration as another aspect of storage stability. Although coloring a product does not necessarily lead to decomposition of the product or a decrease in its physiological activity, it is presumed that some kind of denaturation has occurred in the product, which lowers the market value of the product. Therefore, the present inventors have discovered that the objective can be achieved by adding a stabilizer selected as a method for preventing discoloration of a powder preparation of acetylsalicylate, and have completed the present invention. The object of the present invention is to provide a powder preparation of acetylsalicylic acid for injection obtained by reacting acetylsalicylic acid with a basic amino acid, in which aminoacetic acid is added to
An object of the present invention is to provide a pharmaceutical composition characterized in that it contains 15% (W/W). The acetylsalicylate of the present invention is disclosed in Japanese Patent Application Laid-open No.
44623, JP-A No. 48-56815, etc., but DL-type lysine is used as the basic amino acid used in the reaction. In this salt of basic amino acid and acetylsalicylic acid, both are combined in a molar ratio of 1:1. Its general formula is Generic name: DL-lysine monoacetylsalicylate Molecular formula: C 15 H 22 O 6 N 2 MW: 326.35, white crystalline powder with no odor. A manufacturing example thereof is shown below. Production example Reaction solution preparation process In distilled water (pyrogene free) 100%,
Add 23.25Kg of DL-lysine and dissolve it, then add activated carbon to approx.
Add 600g and process to remove colored substances mainly derived from DL-lysine. In this liquid, separately prepared
Add a suspension of 30 kg of acetylsalicylic acid in 60% acetone and mix. After the added acetylsalicylic acid is clearly dissolved, the reaction solution is sterilized and placed in the next crystal precipitation tank. Crystal precipitation step Add 150% acetone to the above sterilized reaction solution.
Sterilize and add. After stirring gently, the mixture is left to stand in a cold room (0 to 6°C) for about 20 hours to precipitate crystal seeds. In addition, acetone that has been sterilized
150 and leave it in a cold room for 24 hours to grow crystals. The crystals are removed aseptically. Washing/drying process: After washing the collected crystals by adding 100% sterilized 90% acetone aqueous solution,
200 and air dried until the water content was 1.0% or less to obtain about 33 kg of sterile crystals. Preferably, the preparation is stabilized by containing calcium chloride, and its preparation involves adding an appropriate amount of calcium chloride (at least 1% (W/W) in the preparation, preferably 3% (W/W) in the preparation) as a stabilizer to a clean dispensing container. ~5%
Dispense the amount (W/W) and then heat it to 150-180℃.
Heat for 4 hours and leave to cool in a desiccator (over phosphorus pentoxide) or dry box. 1 acetylsalicylate in a container containing calcium chloride cooled to below room temperature.
g and glycine (aminoacetic acid) as a color inhibitor.
The mixture is aseptically dispensed into vials at a ratio of 1 to 15% (W/W) and sealed or rolled to form a preparation. At this time, it is preferable to mix each formulation component in powder form, and for example, a sterile ball mill or the like is used for this purpose. Note that the addition order of each component may be arbitrary. The present invention also prevents yellowing of acetylsalicylate even in the absence of calcium chloride as a stabilizer. Experiment on the effect of adding aminoacetic acid. In order to examine the effect of adding aminoacetic acid, samples were prepared as follows. Amount of aminoacetic acid added: 200, 100, 10, 5, 0 mg per gram of acetylsalicylic acid-DL-lysine salt produced in the above production example
5 groups Calcium chloride addition amount: 7 groups of 50 mg and 0 mg each per gram of acetylsalicylic acid-DL-lysine salt Storage temperature: 37°C, 45°C, 3 groups under sunlight 4°C storage group and formulation group immediately after manufacture As a control, each sample was tested at week 10. Test items include appearance coloring, O.
D. Acetyl salicylate was determined by absorbance at 440 nm and high performance liquid chromatography. The results obtained are shown in Table 1. According to Table 1, it can be seen that the coloring of the preparations is suppressed depending on the amount of aminoacetic acid. This result shows that calcium chloride also suppresses the production of salicylic acid in the present invention.
【表】【table】
【表】
本発明により得られる製剤の使用に際しては、
注射用蒸留水を加えて（製剤１ｇに対して約５〜
20ml）静脈内又は筋肉内に投与する。投与量は、
成人に対しては、通常１バイアル（1050mg）乃至
２バイアルである。反復使用の場合は、１日用量
５バイアルを超えないことが好ましい。乳幼児に
対する常用１日量は体重Kg当りアセチルサリチル
酸として10〜25mgを１日２〜３回に分けて投与す
る。
本発明製剤の適応疾患は
鎮痛剤の経口投与を適応とする手術後疼痛およ
びその他のすべての疼痛、
リウマチ疾患（特に進行性のものに効果が期待
しうる）、神経痛ならびに神経炎、
高熱（感冒、気管支炎、その他中枢原因の発
熱）である。
急性毒性試験
実験動物として体量20±１ｇのdd系のマウス
の雌雄（週令４〜５）を用いた。後記製剤例に示
した製剤を蒸留水で各種濃度に溶解し、静脈内、
皮下および経口の経路より投与した。各投与群と
も雌雄各々10匹を使用した。
薬剤投与後７日間まで、その毒性症状および死
亡状況を観察し、観察期間中に死亡した動物およ
び投与後７日間まで生存した動物についても全例
剖検を行ない、肉眼的に異常の有無を観察した。
マウスのLD50値についてまとめ表２に示す。[Table] When using the preparation obtained according to the present invention,
Add distilled water for injection (approximately 5 to 1 g of preparation)
20ml) Administer intravenously or intramuscularly. The dosage is
For adults, the dosage is usually 1 to 2 vials (1050 mg). For repeated use, it is preferred not to exceed a daily dose of 5 vials. The usual daily dose for infants and young children is 10 to 25 mg of acetylsalicylic acid per kilogram of body weight, divided into two or three times a day. The indications for the formulation of the present invention are post-surgical pain and all other pains for which oral administration of analgesics is indicated, rheumatic diseases (particularly effective for progressive ones), neuralgia and neuritis, high fever (common cold, etc.). , bronchitis, and fever of other central causes). Acute Toxicity Test Male and female DD mice (4 to 5 weeks old) weighing 20±1 g were used as experimental animals. The formulations shown in the formulation examples below are dissolved in distilled water to various concentrations, and administered intravenously.
It was administered by subcutaneous and oral routes. Ten male and female animals were used in each administration group. Toxicity symptoms and mortality conditions were observed for up to 7 days after drug administration, and all animals that died during the observation period and animals that survived up to 7 days after administration were necropsied to visually observe the presence or absence of abnormalities. .
Table 2 summarizes the LD 50 values of mice.
【表】【table】
【表】
を含有する。
有効成分のアセチルサリチル酸―DL―リジン
塩900mgは、アセチルサリチル酸498mgとDL―リ
ジン402mgとからなる塩である。[Table] Contains. The active ingredient, 900 mg of acetylsalicylic acid-DL-lysine salt, is a salt consisting of 498 mg of acetylsalicylic acid and 402 mg of DL-lysine.
Claims (1)
させて得られる注射用アセチルサリチル酸塩を含
む粉末製剤において、アミノ酢酸を１〜15％
（W/W）以上含有することを特徴とする医薬組成
物。 ２ 注射用アセチルサリチル酸塩を含む粉末製剤
が安定剤としての塩化カルシウムを含む製剤であ
る特許請求の範囲の第１項記載の医薬組成物。[Claims] 1. A powder preparation containing acetylsalicylate for injection obtained by reacting acetylsalicylic acid with a basic amino acid, containing 1 to 15% aminoacetic acid.
(W/W) or more. 2. The pharmaceutical composition according to claim 1, wherein the powder formulation containing acetylsalicylate for injection is a formulation containing calcium chloride as a stabilizer.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP14163379A JPS5665816A (en) | 1979-11-01 | 1979-11-01 | Acetylsalicylate pharmaceutical for injection |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP14163379A JPS5665816A (en) | 1979-11-01 | 1979-11-01 | Acetylsalicylate pharmaceutical for injection |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS5665816A JPS5665816A (en) | 1981-06-03 |
| JPS6121529B2 true JPS6121529B2 (en) | 1986-05-27 |
Family
ID=15296572
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP14163379A Granted JPS5665816A (en) | 1979-11-01 | 1979-11-01 | Acetylsalicylate pharmaceutical for injection |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS5665816A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH01112835U (en) * | 1988-01-26 | 1989-07-28 |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS63307824A (en) * | 1987-06-09 | 1988-12-15 | Teisan Seiyaku Kk | Stabilized powdery preparation for injection |
| EP1039905B1 (en) * | 1997-10-14 | 2006-07-05 | Eisai Co., Ltd. | Pharmaceutical formulation comprising glycine as a stabilizer |
| US7230014B1 (en) | 1997-10-14 | 2007-06-12 | Eisai Co., Ltd. | Pharmaceutical formulation comprising glycine as a stabilizer |
| DE102005025283A1 (en) * | 2005-06-02 | 2006-12-07 | Bayer Healthcare Ag | Stable complex of salts of o-acetylsalicylic acid with basic amino acids and glycine |
| JP2008114896A (en) * | 2006-11-07 | 2008-05-22 | Kyocera Mita Corp | Auxiliary plate for taking out packed product |
-
1979
- 1979-11-01 JP JP14163379A patent/JPS5665816A/en active Granted
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH01112835U (en) * | 1988-01-26 | 1989-07-28 |
Also Published As
| Publication number | Publication date |
|---|---|
| JPS5665816A (en) | 1981-06-03 |
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