JPS60255723A - Freeze-dried crystalline preparation of gabexate mesylate, and its production - Google Patents
Freeze-dried crystalline preparation of gabexate mesylate, and its productionInfo
- Publication number
- JPS60255723A JPS60255723A JP10974484A JP10974484A JPS60255723A JP S60255723 A JPS60255723 A JP S60255723A JP 10974484 A JP10974484 A JP 10974484A JP 10974484 A JP10974484 A JP 10974484A JP S60255723 A JPS60255723 A JP S60255723A
- Authority
- JP
- Japan
- Prior art keywords
- temperature
- freeze
- gabexate mesylate
- frozen
- mesylate
- 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.)
- Granted
Links
Abstract
Description
【発明の詳細な説明】
〔産業上の利用分野〕
本発明は形状、熱安定性及び溶解性のよい用時溶解非経
ロ投与用メシル酸ガベキサート製剤及びその製造方法に
関する。DETAILED DESCRIPTION OF THE INVENTION [Field of Industrial Application] The present invention relates to a preparation of gabexate mesylate for parenteral administration that is dissolved at the time of use and has good shape, thermal stability and solubility, and a method for producing the same.
メシル酸ガベキサートは次の構造式
で示される化合物の一船名であり、蛋白分解酵素逸脱に
伴う急性膵炎、慢性再発性膵炎及び術後の急性膵炎の治
療や汎発性血管内血液凝固症の治療のための用時溶解注
射剤としてエフオーワイ（登録面線）の商品名で商品化
されている。Gabexate mesylate is the name of a compound represented by the following structural formula, and is used to treat acute pancreatitis associated with proteolytic enzyme deficiency, chronic recurrent pancreatitis, and postoperative acute pancreatitis, and to treat generalized intravascular blood coagulation. It has been commercialized under the trade name F-O-Y (registered surface line) as an injectable solution for treatment.
用時溶解注射剤の製剤化の方法としては、医薬品の無菌
結晶粉末を直接容器に充填する方法と、医薬品の水溶液
を無菌濾過し、容器に分注充填し、これを凍結乾燥する
方法がある。しかし前者の製法では、薬剤の安定性は良
好であるが、製法工程上異物が混入しやすい欠点があり
、注射剤としては問題がある。従って、メシル酸ガベキ
サートは、現在後者の製法で商品化されている。しかし
この製法では、異物の混入は大幅に減少されるが、得ら
れた凍結乾燥製品は多孔質で、かつ無定形粉末となって
いるため、一定の結晶形を持ったものに比べて安定性に
劣るという欠点がある。特にメシル酸ガベキサートの場
合、その分解によって生ずる・ぞラヒドロキシ安息香酸
エチル
略記する。）が水に難溶なため、部品中のエチルノｅラ
ペンの生成が問題となる。There are two methods for formulating injections that dissolve at the time of use: one is to directly fill a container with sterile crystalline powder of the drug, and the other is to sterile-filter an aqueous solution of the drug, dispense it into containers, and freeze-dry it. . However, in the former manufacturing method, although the stability of the drug is good, there is a drawback that foreign substances are easily mixed in during the manufacturing process, which poses problems as an injection. Therefore, gabexate mesylate is currently commercialized using the latter method. However, although this manufacturing method greatly reduces the contamination of foreign substances, the resulting freeze-dried product is porous and amorphous powder, so it is less stable than products with a fixed crystalline shape. It has the disadvantage of being inferior to In particular, in the case of gabexate mesylate, ethyl hydroxybenzoate, which is produced by its decomposition, is abbreviated as ethyl hydroxybenzoate. ) is sparingly soluble in water, the formation of ethylno-e-lapene in parts becomes a problem.
凍結乾燥の方法は従来から種々の改善がなされている。Various improvements have been made to freeze-drying methods.
例えば、医薬品の水溶液を急冷の後０℃附近まで昇温し
で長時間その温度を保持して結晶化させてから減圧乾燥
させる方法や水溶液に有機溶媒を加えて結晶転化を速め
たりする方法（ｆ￥ｆ開昭５１−１２３８１３号、特開
昭５４−７３１１５号及び特開昭５６−１２０６１５号
明細書参照のこと）が知られているが、これらはいずれ
も一部のごく限られた医薬品にのみ適用されているだけ
である。For example, methods include rapidly cooling an aqueous solution of a pharmaceutical, raising the temperature to around 0°C, holding that temperature for a long time to crystallize, and then drying under reduced pressure; or adding an organic solvent to the aqueous solution to accelerate crystal conversion ( f￥f (see the specifications of JP-A-51-123813, JP-A-54-73115, and JP-A-56-120615), but these are all limited to a limited number of pharmaceutical products. It is only applied to.
本発明は用時溶解非経ロ投与用メシル酸ガベキサート製
剤における従来の欠点を解消し、安定な製剤及びその製
造方法を提供することを目的とする。The object of the present invention is to eliminate the conventional drawbacks of gabexate mesylate preparations for parenteral administration that are dissolved at the time of use, and to provide a stable preparation and a method for producing the same.
〔問題点を解決するだめの手段及び作用〕本発明者等は
メシル酸ガベキサートの凍結乾燥法について検討を行な
った結果、結晶性を有する凍結乾燥品を短時間で得るこ
とに成功し、さらに驚くべきことに得られた結晶性凍結
乾燥製剤はエチル・ぞラベンの生成が非常に押えられた
安定な製剤であることを１い出し本発明を完成した。[Means and actions for solving the problem] As a result of studying the freeze-drying method of gabexate mesylate, the present inventors succeeded in obtaining a freeze-dried product with crystallinity in a short time, which was even more surprising. The present invention was completed by finding out that the obtained crystalline freeze-dried preparation was a stable preparation in which the formation of ethyl zolaben was extremely suppressed.
本発明によれば、溶解性が良く、原薬結晶と同様の安定
性を持ち、用時、水に溶解した場合に不溶性異物を含１
ずかつ吸湿して収縮することのない結晶性凍結乾燥粉末
である用時溶解非経ロ投与用メノル酸ガベキサート製剤
が得られる。According to the present invention, it has good solubility, has the same stability as the drug substance crystal, and contains no insoluble foreign substances when dissolved in water at the time of use.
A preparation of gabexate menolic acid for parenteral administration, which is a crystalline lyophilized powder that does not absorb water or shrink due to moisture absorption, is obtained.
本発明に従えば、目的と−するメシル酸ガベキサート製
剤は次のようにしてｌｌ’Ｊ ＩＨ”（することができ
る。According to the present invention, the desired gabexate mesylate formulation can be prepared as follows.
メシル酸ガベキサートの２３〜２５％（Ｗ／Ｖ）の濃度
の水浴液を、０．２２μｍのメンブランフィルタ−で無
菌濾過し、・Ｚイアルに分注し、−２５℃以下、好まし
くｌｌ−４０℃棟で冷却する。次いで一２℃〜−１８℃
、々了＋ｔ、ｌ：ｔ−３℃〜−１５℃、より好ましく
ｒ、ｔ−７℃〜−１０℃捷で昇温し、同温度で３０分間
以上、好ましくは２時間以上、より好１しくを１２〜３
時間維持し、［［）び−２５℃以下、好ましくは一４０
℃に冷却する。得られた凍結塊を常法に従って減圧下に
加温しながら真空乾燥した後密栓する。A water bath solution containing gabexate mesylate at a concentration of 23 to 25% (W/V) is sterile-filtered through a 0.22 μm membrane filter, dispensed into a . Cool in the ridge. Then -2℃~-18℃
, +t, l: t-3°C to -15°C, more preferably
r, t Raise the temperature by shaking at -7°C to -10°C, and keep at the same temperature for 30 minutes or more, preferably 2 hours or more, more preferably 12 to 3
Maintain the temperature at -25°C or below, preferably -40°C.
Cool to ℃. The obtained frozen mass is vacuum-dried under reduced pressure while being heated in a conventional manner, and then sealed.
以下に実施例をボし本発明を具体的に説明するが、本発
明はこれらの実施例に限定されるものではない。The present invention will be specifically described below with reference to Examples, but the present invention is not limited to these Examples.
実施例１
メシル酸ガペキサー）１００Ｆを注射用蒸留水で溶解し
て全量を１ｏｏｏ−ｒとし、０．２２μｍのメンブラン
フィルタ−で無菌濾過した後、洗浄滅菌済バイアルに１
．Ｏｄずつ分注する。次いで６時間かけて一４０℃まで
冷却し、凍結させた後、−７℃まで昇温し、−７℃に２
時間維持する。再び一４０℃まで冷却し蒸気圧をＱ、
１ｍｂａｒに制御しながら真空乾燥する。乾燥中の棚温
の加温は、４時間かけて一４０℃から＋２０℃′まで昇
温させ、＋２０’Ｃを６時間維持し、＋４０１：まで１
時間かけて昇温し、この温度で５時間真空乾燥してメシ
ル酸ガベキサートの結晶性凍結乾燥粉末を得た。Example 1 Gapexor mesylate) 100F was dissolved in distilled water for injection to make a total volume of 100F, and after sterile filtration with a 0.22 μm membrane filter, 100F was added to a washed and sterilized vial.
．． Dispense in Od increments. Next, it was cooled to -40°C over 6 hours, frozen, then heated to -7°C, and then cooled to -7°C for 2 hours.
Keep time. Cool it again to -40℃ and reduce the vapor pressure to Q.
Vacuum drying is performed while controlling the pressure to 1 mbar. The shelf temperature during drying was raised from -40°C to +20°C over 4 hours, maintained at +20°C for 6 hours, and then
The temperature was raised over time, and vacuum drying was performed at this temperature for 5 hours to obtain a crystalline lyophilized powder of gabexate mesylate.
実施例２
メシル酸ガベキサート６９２ｆｔ、注射用蒸留水で溶解
し全量３１とし、この浴液を０．２２μｍのメンブレン
フィルターで無菌ソ過した後、バイアルに１３．Ｏｄず
つ分注する。次いで５時間かけて一４０℃まで冷却し凍
結さ−Ｉまた後、−１０℃まで昇温し一１０℃に６時間
維持する。次いで再び一４０℃１で冷却し、蒸気圧を０
．１ｍｂａｒに制御しながらＡ空乾燥する。乾燥中棚温
は４時間かけて一４０℃から＋１５℃まで昇温させ、＋
１５℃を６０時間維持した後、４０℃まで昇温し４０℃
で８時間Ａ空乾燥して、メシル酸ガベキサートの結晶性
凍結乾燥粉末を得た。Example 2 692 ft of gabexate mesylate was dissolved in distilled water for injection to make a total volume of 31. After sterile filtering of this bath solution through a 0.22 μm membrane filter, 13. Dispense in Od increments. Next, the mixture was cooled to -40°C over 5 hours and frozen, and then heated to -10°C and maintained at -10°C for 6 hours. Then, it was cooled again to -40℃1, and the vapor pressure was reduced to 0.
．． A: Dry in the air while controlling the pressure to 1 mbar. During drying, the shelf temperature was raised from -40℃ to +15℃ over 4 hours.
After maintaining the temperature at 15℃ for 60 hours, the temperature was increased to 40℃.
The mixture was air-dried for 8 hours to obtain a crystalline lyophilized powder of gabexate mesylate.
安定性の比軟実験
実幅例１で得た結晶性凍結乾燥粉末と服薬結晶及び従来
の凍結乾燥法により１４られた凍結乾燥製品の熱安定性
を表−１に示す（表中の数値はメシル酸ガベキサートの
分解物であるエチルＡラベンの生成率（％）である）。Table 1 shows the thermal stability of the crystalline freeze-dried powder and drug crystals obtained in Example 1 of the stability experiment and the freeze-dried product obtained by the conventional freeze-drying method (the numerical values in the table are This is the production rate (%) of ethyl A-laben, which is a decomposition product of gabexate mesylate.
表−１
湿度１００％中に放置した時、従来の凍結乾燥製品Ｆｉ
２時間以内に収縮するが、実施例１で得た結晶性凍結乾
燥粉末は２４時間でも収縮等の外観変化を生じなかった
。Table 1: Conventional freeze-dried product Fi when left in 100% humidity
Although it shrunk within 2 hours, the crystalline freeze-dried powder obtained in Example 1 did not show any change in appearance such as shrinkage even after 24 hours.
Ｘ線回折図
実織例２で得た結晶性凍結乾燥粉末のＸ線回折図を第１
図に示す。図からこの粉末は一定の結晶性を有している
ことが明らかである（非結晶質の無定形粉末の場合には
、フラットなピークがみられるだけである）。X-ray diffraction diagram The X-ray diffraction diagram of the crystalline freeze-dried powder obtained in Actual Example 2 is
As shown in the figure. It is clear from the figure that this powder has a certain degree of crystallinity (in the case of an amorphous powder, only a flat peak is observed).
本発明によりＤｊられるメシル酸ガベキサートの結晶性
凍結乾燥粉末は、水に速やかに溶解し、不溶性異物を含
捷ず、さらに服薬結晶と同様の高い安定性を有し、高湿
度に放置しても収縮等の現象を生じないといった優れた
特徴を有する。The crystalline freeze-dried powder of gabexate mesylate prepared by the present invention dissolves quickly in water, does not contain insoluble foreign substances, and has high stability similar to that of drug crystals, even when left in high humidity. It has an excellent feature of not causing phenomena such as shrinkage.
Claims (1)
ガベキサートの水溶液を一２５℃以下に急速冷却して凍
結させ、 （ロ）（イ）の凍結塊を一２℃〜−１８℃まで昇温し、 （ハ）（ロ）の凍結塊を同温度で６０分間以上維持し、 に）（ハ）の凍結塊を再び一２５℃以下に冷却し、（ホ
）に）の凍結塊を減圧下で真空乾燥することを特徴とす
るメシル酸ガベキサートの結晶性凍結乾燥製剤の製造方
法。 ６）（イ）及びに）の温度が一４０℃である特許請求の
範囲第２項記載の製造方法。 ４）（ロ）の温度が、−６℃〜−１５℃である特許請求
の範囲第２項記載の製造方法。 ５）（ロ）の温度が、−７℃〜−１０℃である特許請求
の範囲第２項又は第４項記載の製造方法。 ６）（ハ）の時間が２時間以上である特許請求の範囲第
２項記載の製造方法、 ハ （ハ）の時間が２〜６時間である特許請求の範囲第
２項又は第６項記載の製造方法。 ８）（ホ）の真空乾燥を凍結塊が溶解しないように加温
下で行う特許請求の範囲第２項記載の製造方法。[Scope of Claims] 1) Crystalline lyophilized preparation of gabexate mesylate. 2) (a) An aqueous solution of gabexate mesylate with a concentration of 2% to 25% (W/V) is rapidly cooled to below -25°C and frozen, and (b) the frozen mass of (b) is frozen at -2°C to -25°C. Raise the temperature to -18°C, maintain the frozen mass of (c) and (b) at the same temperature for more than 60 minutes, and cool the frozen mass of (c) again to below -25°C, and (e)) 1. A method for producing a crystalline freeze-dried preparation of gabexate mesylate, which comprises vacuum drying a frozen mass of gabexate mesylate under reduced pressure. 6) The manufacturing method according to claim 2, wherein the temperature in (a) and (b) is 140°C. 4) The manufacturing method according to claim 2, wherein the temperature in (b) is -6°C to -15°C. 5) The manufacturing method according to claim 2 or 4, wherein the temperature in (b) is -7°C to -10°C. 6) The manufacturing method according to claim 2, wherein the time in (c) is 2 hours or more, and (c) the manufacturing method according to claim 2 or 6, wherein the time in (c) is 2 to 6 hours. manufacturing method. 8) The manufacturing method according to claim 2, wherein the vacuum drying in (e) is carried out under heating so that the frozen mass does not melt.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP10974484A JPS60255723A (en) | 1984-05-31 | 1984-05-31 | Freeze-dried crystalline preparation of gabexate mesylate, and its production |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP10974484A JPS60255723A (en) | 1984-05-31 | 1984-05-31 | Freeze-dried crystalline preparation of gabexate mesylate, and its production |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS60255723A true JPS60255723A (en) | 1985-12-17 |
| JPH0374643B2 JPH0374643B2 (en) | 1991-11-27 |
Family
ID=14518144
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP10974484A Granted JPS60255723A (en) | 1984-05-31 | 1984-05-31 | Freeze-dried crystalline preparation of gabexate mesylate, and its production |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS60255723A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2017517476A (en) * | 2014-05-09 | 2017-06-29 | スーチョアン チウチャン バイオロジカル サイエンス アンド テクノロジー カンパニー リミテッド | Chlorogenic acid crystal form and preparation method thereof |
| CN109761858A (en) * | 2019-02-12 | 2019-05-17 | 成都苑东生物制药股份有限公司 | A kind of refining methd of gabexate mesilate |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP4533115B2 (en) | 2004-12-03 | 2010-09-01 | 三井・デュポンフロロケミカル株式会社 | Fluororesin molding method and fluororesin molding |
| JP5174365B2 (en) * | 2007-03-23 | 2013-04-03 | 第一三共株式会社 | Method for producing lyophilized preparation containing quinolone |
| ES2758507T3 (en) | 2012-05-30 | 2020-05-05 | Meiji Seika Pharma Co Ltd | Novel B-lactamase inhibitor and method of producing the same |
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| JP6617029B2 (en) | 2013-10-08 | 2019-12-04 | Ｍｅｉｊｉ Ｓｅｉｋａファルマ株式会社 | Crystals of diazabicyclooctane derivatives and their production |
| SG11201704576SA (en) | 2014-12-05 | 2017-07-28 | Meiji Seika Pharma Co Ltd | Method for producing crystals of diazabicyclooctane derivative and stable lyophilized preparation |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS519711A (en) * | 1974-07-09 | 1976-01-26 | Meiji Seika Co | Mushokeinioite fuanteinabiryoiyakuhino anteiniseizosuruhoho |
| JPS5112381A (en) * | 1974-07-22 | 1976-01-30 | Mitsubishi Mining & Cement Co | |
| JPS5369821A (en) * | 1976-11-24 | 1978-06-21 | Lilly Co Eli | Production of cephazoline sodium for nonnoral dose |
| JPS56120615A (en) * | 1980-02-27 | 1981-09-22 | Nippon Chemiphar Co Ltd | Preparation of lyophilized powder of cephalothin |
| JPS5728613A (en) * | 1980-07-25 | 1982-02-16 | Kobe Steel Ltd | Method and apparatus for treating clogging billet in metal extrusion press |
-
1984
- 1984-05-31 JP JP10974484A patent/JPS60255723A/en active Granted
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS519711A (en) * | 1974-07-09 | 1976-01-26 | Meiji Seika Co | Mushokeinioite fuanteinabiryoiyakuhino anteiniseizosuruhoho |
| JPS5112381A (en) * | 1974-07-22 | 1976-01-30 | Mitsubishi Mining & Cement Co | |
| JPS5369821A (en) * | 1976-11-24 | 1978-06-21 | Lilly Co Eli | Production of cephazoline sodium for nonnoral dose |
| JPS56120615A (en) * | 1980-02-27 | 1981-09-22 | Nippon Chemiphar Co Ltd | Preparation of lyophilized powder of cephalothin |
| JPS5728613A (en) * | 1980-07-25 | 1982-02-16 | Kobe Steel Ltd | Method and apparatus for treating clogging billet in metal extrusion press |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2017517476A (en) * | 2014-05-09 | 2017-06-29 | スーチョアン チウチャン バイオロジカル サイエンス アンド テクノロジー カンパニー リミテッド | Chlorogenic acid crystal form and preparation method thereof |
| CN109761858A (en) * | 2019-02-12 | 2019-05-17 | 成都苑东生物制药股份有限公司 | A kind of refining methd of gabexate mesilate |
| CN109761858B (en) * | 2019-02-12 | 2021-05-14 | 成都苑东生物制药股份有限公司 | Refining method of gabexate mesylate |
Also Published As
| Publication number | Publication date |
|---|---|
| JPH0374643B2 (en) | 1991-11-27 |
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