JPS629092B2 - - Google Patents

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Publication number
JPS629092B2
JPS629092B2 JP52148343A JP14834377A JPS629092B2 JP S629092 B2 JPS629092 B2 JP S629092B2 JP 52148343 A JP52148343 A JP 52148343A JP 14834377 A JP14834377 A JP 14834377A JP S629092 B2 JPS629092 B2 JP S629092B2
Authority
JP
Japan
Prior art keywords
urokinase
gelatin
aqueous solution
molecular weight
added
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
Application number
JP52148343A
Other languages
Japanese (ja)
Other versions
JPS5480406A (en
Inventor
Kyoshi Harada
Yoshuki Hirakawa
Seiichi Morisono
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Tanabe Seiyaku Co Ltd
Original Assignee
Tanabe Seiyaku Co Ltd
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Tanabe Seiyaku Co Ltd filed Critical Tanabe Seiyaku Co Ltd
Priority to JP14834377A priority Critical patent/JPS5480406A/en
Publication of JPS5480406A publication Critical patent/JPS5480406A/en
Publication of JPS629092B2 publication Critical patent/JPS629092B2/ja
Granted legal-status Critical Current

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  • Medicinal Preparation (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)

Description

【発明の詳細な説明】[Detailed description of the invention]

本発明は注射用ウロキナーゼの製法に関する。
ウロキナーゼは周知の如く血栓溶解剤として繁用
されている医薬であり、静脈注射によつて投与さ
れている。 医薬として用いられるウロキナーゼは人由来の
ものであるが、溶液状態では非常に不安定で失活
し易いため凍結乾燥製剤の型に製剤化され、投与
時に生理的食塩水やブドウ糖液等に溶解させて使
用されている。このウロキナーゼ製剤は、通常精
製ウロキナーゼ原液を蒸留水で希釈し、ついで無
菌ろ過したのち凍結乾燥する如き方法により調製
されるが、上記したようにウロキナーゼは溶液状
態では不安定であるため、精製原液の保存時や製
剤の調製時あるいは更に投与時にもウロキナーゼ
が失活する。 従来、溶液状態におけるウロキナーゼの安定化
法としては、例えばウロキナーゼ含有水溶液にゼ
ラチンを添加する方法が知られている
〔Experimentia,23,261(1967),月刊薬事,
14,163(1972)〕。しかしながら、この方法にお
いてウロキナーゼの安定化に、通常医薬製剤の製
造に繁用されている分子量が約50000乃至100000
であるゼラチンを用いると、ウロキナーゼを殆ど
失活させることなく製剤調製操作を実施し得る
が、ウロキナーゼ含有水溶液に上記ゼラチンを添
加する際、いつたん該ゼラチンを冷水で膨潤さ
せ、ついで加熱する如きはん雑な前処理が必要と
なり、また無菌ろ過の際にはロ過速度の遅延が起
り、更に投与時製剤を生理的食塩水やブドウ糖液
に溶解させる際にはいわゆる“ままこ”を形成し
て速みやかに澄明な溶液となり難い等の不都合の
あることが判つた。 このような不都合が生じる主たる原因は、通常
医薬製剤の製造に使用されているゼラチンは水に
対する溶解性が低いためであり、そこで本発明者
等は水に対する溶解性がより良好と予想される低
分子量のゼラチンの利用につき研究を行なつた。
まず水に対する溶解性が極めて良好な分子量が約
10000以下であるゼラチンを用いる場合について
実験を行なつたところ、無菌ろ過時のろ過速度や
あるいは生理的食塩水やブドウ糖液に対する溶解
性は著しく改善されたものの、ウロキナーゼ活性
が著しく低下することが判つた。 しかるに本発明者等は更に引続き研究を重ねた
結果、ウロキナーゼ含有水溶液に添加するゼラチ
ンとして平均分子量が約10000乃至50000程度であ
るゼラチンを用いれば、前記不都合を解消し、し
かもウロキナーゼを安定化せしめ得ることを見出
し、更にウロキナーゼ含有水溶液にD−マンニツ
トもしくはグリシンを添加すれば、投与時におけ
る製剤の溶解性を著しく改善し得ることを見出し
た。 すなわち、本発明はウロキナーゼ含有水溶液に
平均分子量が約10000乃至50000であるゼラチンを
添加し、ついで無菌ろ過することを特徴とする注
射用ウロキナーゼの製法である。本発明におい
て、ウロキナーゼ含有水溶液としては、例えば人
尿中のウロキナーゼをアクリロニトリル系繊維,
リン酸セルロース等により捕集し、硫安分画処理
したのちイオン交換樹脂またはCMCセルロー
ス、DEAEセルロースの如きイオン交換体に対す
る吸脱着処理してウロキナーゼを濃縮し、更にゲ
ルろ過によりパイロジエンを除去することにより
得られる精製ウロキナーゼ原液またはその蒸留水
希釈液、あるいはこの原液を凍結乾燥して得られ
る精製ウロキナーゼ粉末を蒸留水に溶解させた溶
液等があげられる。 また本発明において、上記ウロキナーゼ含有水
溶液に添加溶解させるゼラチンとしては、平均分
子量が約10000乃至50000,とりわけ分子量が
10000以上で50000以下のものが好ましい。またそ
の所要量はウロキナーゼ含有水溶液に対して約
0.05〜2W/V%程度であればよく、約0.05W/
V%以下ではウロキナーゼ安定化効果が殆ど得ら
れず、また約2W/V%以上ではウロキナーゼの
安定化効果は得られるものの無菌ろ過操作がはん
雑となり、また投与時製剤の溶解性が低下するの
で好ましくない。本発明において、ウロキナーゼ
含有水溶液に上記ゼラチンを添加し、溶解させる
には、該ウロキナーゼ含有水溶液に直接ゼラチン
を添加して溶解させても、また別途ゼラチンを蒸
留水に溶解してゼラチン水溶液を調製しておき、
このゼラチン水溶液をウロキナーゼ含有水溶液に
添加してもよい。いずれの場合にもこれらの操作
はウロキナーゼ活性が失活せず、かつゼラチンが
ゲル化しない温度域下で実施するとよい。また無
菌ろ過に際しては、通常孔径約0.22〜0.45μ程度
のメンブランフイルターが用いられ、約0.3〜5
Kg/cm2程度の加圧下に好適に実施される。 また更に上記ウロキナーゼ水溶液にはD−マン
ニツトまたはグリシンを該水溶液に対して約0.1
〜5W/V%程度溶解させることによりウロキナ
ーゼの凍結乾燥製剤の溶解性を著しく改善するこ
とが出来る。 本発明方法により得られる注射用ウロキナーゼ
はウロキナーゼ含有水溶液の無菌ろ過液の型で得
られるので、直ちに常法によつて凍結乾燥して注
射用ウロキナーゼ製剤に製剤化しても、また一た
ん凍結して保存したのちに常法によつて製剤化し
てもよい。 本発明方法によれば、ウロキナーゼ活性を低下
させることなく、簡便な操作により注射用ウロキ
ナーゼを製造することが出来、また該注射用ウロ
キナーゼを製剤化して得られる注射用ウロキナー
ゼ製剤は生理的食塩水やブドウ糖液に極めてよく
溶けるので投与時非常に便利である等の利点があ
る。 実験例 1 蒸留水1にウロキナーゼを3000IU/mlとな
るように溶解し、これに下記第1表に示すゼラチ
ンを0.5W/V%となるように添加溶解する。こ
のウロキナーゼ含有水溶液を室温に放置し、残存
ウロキナーゼ活性を経時的に測定した。その結果
は第1表に示す通りであり、ゼラチンの分子量が
10000以下のものにはウロキナーゼの安定化効果
が殆どないことおよびその安定化効果はゼラチン
分子量が大きくなるにつれて増大することが認め
られた。
The present invention relates to a method for producing injectable urokinase.
As is well known, urokinase is a drug frequently used as a thrombolytic agent, and is administered by intravenous injection. Urokinase, which is used as a medicine, is derived from humans, but it is extremely unstable and easily deactivated when in solution, so it is formulated into a lyophilized product and dissolved in physiological saline, glucose solution, etc. before administration. is used. This urokinase preparation is usually prepared by diluting the purified urokinase stock solution with distilled water, followed by sterile filtration and freeze-drying. However, as mentioned above, urokinase is unstable in a solution state, so the purified stock solution is Urokinase is deactivated during storage, preparation of the drug, or even during administration. Conventionally, as a method for stabilizing urokinase in a solution state, for example, a method of adding gelatin to an aqueous solution containing urokinase is known [Experimentia, 23 , 261 (1967), Monthly Yakuji,
14 , 163 (1972)]. However, in this method, the molecular weight of approximately 50,000 to 100,000, which is commonly used in the production of pharmaceutical preparations, is required for stabilizing urokinase.
When gelatin is used, preparation operations can be carried out without almost inactivating urokinase, but when adding the gelatin to an aqueous solution containing urokinase, it is difficult to swell the gelatin with cold water and then heat it. It requires complicated pretreatment, slows the filtration rate during sterile filtration, and forms so-called "mamako" when the preparation is dissolved in physiological saline or glucose solution. It has been found that there are disadvantages such as difficulty in quickly forming a clear solution. The main reason for this inconvenience is that gelatin, which is commonly used in the production of pharmaceutical preparations, has low solubility in water. We conducted research on the use of molecular weight gelatin.
First, the molecular weight, which has extremely good solubility in water, is approximately
When we conducted experiments using gelatin with a molecular weight of 10,000 or less, we found that although the filtration rate during sterile filtration and the solubility in physiological saline and glucose solutions were significantly improved, urokinase activity was significantly reduced. Ivy. However, as a result of further research, the present inventors found that by using gelatin with an average molecular weight of approximately 10,000 to 50,000 as the gelatin added to the urokinase-containing aqueous solution, the above-mentioned disadvantages can be overcome and urokinase can be stabilized. They have also found that by adding D-mannite or glycine to an aqueous solution containing urokinase, the solubility of the preparation during administration can be significantly improved. That is, the present invention is a method for producing urokinase for injection, which is characterized by adding gelatin having an average molecular weight of about 10,000 to 50,000 to an aqueous solution containing urokinase, and then filtering the solution aseptically. In the present invention, as the urokinase-containing aqueous solution, for example, urokinase in human urine can be mixed with acrylonitrile fiber,
Urokinase is collected by cellulose phosphate, etc., subjected to ammonium sulfate fractionation, and then adsorbed and desorbed to an ion exchanger such as ion exchange resin, CMC cellulose, or DEAE cellulose to concentrate urokinase, and further, pyrodiene is removed by gel filtration. Examples include the obtained purified urokinase stock solution, its diluted solution with distilled water, and a solution obtained by dissolving purified urokinase powder obtained by freeze-drying this stock solution in distilled water. In addition, in the present invention, the gelatin added and dissolved in the urokinase-containing aqueous solution has an average molecular weight of about 10,000 to 50,000, particularly a molecular weight of about 10,000 to 50,000.
It is preferably 10,000 or more and 50,000 or less. In addition, the required amount is approximately
It should be about 0.05~2W/V%, about 0.05W/V%.
Below V%, almost no urokinase stabilizing effect can be obtained, and above about 2W/V%, although a urokinase stabilizing effect can be obtained, the sterile filtration operation becomes complicated and the solubility of the preparation at the time of administration decreases. So I don't like it. In the present invention, in order to add and dissolve the gelatin in the urokinase-containing aqueous solution, gelatin can be added directly to the urokinase-containing aqueous solution and dissolved, or gelatin can be separately dissolved in distilled water to prepare a gelatin aqueous solution. Keep it
This gelatin aqueous solution may be added to the urokinase-containing aqueous solution. In either case, these operations are preferably carried out in a temperature range in which urokinase activity is not deactivated and gelatin is not gelled. In addition, for sterile filtration, membrane filters with a pore size of approximately 0.22 to 0.45μ are normally used, and membrane filters with a pore size of approximately 0.3 to 5
It is suitably carried out under pressure of about Kg/cm 2 . Furthermore, D-mannite or glycine is added to the urokinase aqueous solution at a rate of about 0.1% relative to the aqueous solution.
The solubility of the lyophilized preparation of urokinase can be significantly improved by dissolving it to about 5 W/V%. Urokinase for injection obtained by the method of the present invention is obtained in the form of a sterile filtrate of an aqueous solution containing urokinase, so it can be immediately freeze-dried to form an injectable urokinase preparation by a conventional method, or it can be frozen once. After storage, it may be formulated into a formulation by a conventional method. According to the method of the present invention, injectable urokinase can be produced by simple operations without reducing urokinase activity, and the injectable urokinase preparation obtained by formulating the injectable urokinase can be prepared in physiological saline or It has the advantage of being very convenient to administer because it is extremely soluble in glucose solutions. Experimental Example 1 Urokinase is dissolved in distilled water 1 to a concentration of 3000 IU/ml, and gelatin shown in Table 1 below is added and dissolved to a concentration of 0.5 W/V%. This urokinase-containing aqueous solution was left at room temperature, and the residual urokinase activity was measured over time. The results are shown in Table 1, and the molecular weight of gelatin is
It was found that there is almost no stabilizing effect on urokinase when the gelatin molecular weight is less than 10,000, and that the stabilizing effect increases as the gelatin molecular weight increases.

【表】 実験例 2 実験例1と同様にして調製したウロキナーゼ含
有水溶液を孔径0.22μのメンブランフイルタ−
(直径42mm)で1Kg/cm2の加圧下に無菌ろ過し、
ろ液1得られるまでの時間を測定した。その結
果は第2表に示す通りであり、ゼラチンの分子量
が大きくなるにつれてろ過速度が遅延することが
認められた。
[Table] Experimental Example 2 A urokinase-containing aqueous solution prepared in the same manner as Experimental Example 1 was filtered through a membrane filter with a pore size of 0.22μ.
(diameter 42mm) under a pressure of 1Kg/ cm2 ,
The time until filtrate 1 was obtained was measured. The results are shown in Table 2, and it was found that as the molecular weight of gelatin increased, the filtration rate was delayed.

【表】 実験例 3 実験例1と同様にして調製したウロキナーゼ含
有水溶液にD−マンニツトまたはグリシンを
0.5W/V%溶解する。この溶液を実験例2と同
一の条件下に無菌ろ過し、得られるろ液2mlをバ
イアルビンに充填したのち常法により凍結乾燥し
て注射用ウロキナーゼ製剤を得る。このバイアル
ビンに生理的食塩水3mlを注加し、静置した状態
で該製剤が完全に溶解するまでの時間を測定し
た。その結果は第3表に示す通りであり、ゼラチ
ン分子量が大きいものほどウロキナーゼ製剤の溶
解性が低下するが、D−マンニツトまたはグリシ
ンを添加しておくことにより、溶解性が著しく改
善されることが認められた。 尚、D−マンニツトおよびグリシンを添加しな
い場合を対照とした。
[Table] Experimental Example 3 D-mannite or glycine was added to a urokinase-containing aqueous solution prepared in the same manner as in Experimental Example 1.
Dissolves at 0.5W/V%. This solution is sterile-filtered under the same conditions as in Experimental Example 2, and 2 ml of the resulting filtrate is filled into a vial, followed by freeze-drying in a conventional manner to obtain an injectable urokinase preparation. 3 ml of physiological saline was poured into this vial, and the vial was allowed to stand, and the time until the preparation was completely dissolved was measured. The results are shown in Table 3. The larger the gelatin molecular weight, the lower the solubility of the urokinase preparation, but the addition of D-mannite or glycine significantly improves the solubility. Admitted. In addition, the case where D-mannite and glycine were not added was used as a control.

【表】 実施例 1 精製ウロキナーゼを3000IU/mlとなるように
蒸留水に溶解し、これにゼラチン(分子量20000
〜30000)3mg/mlとなるように添加溶解する。
この水溶液を孔径0.22μのメンブランフイルター
(直径42mm)で1Kg/cm2の条件下に無菌ろ過す
る。この際ろ過時間はろ液1当り8分であつ
た。ろ液を2ml容バイアルびんに分注したのち−
40℃で真空下に凍結乾燥することにより注射用ウ
ロキナーゼ製剤を得る。 実施例 2 実施例1と同様にして得られたウロキナーゼ含
有水溶液にゼラチン(分子量:30000〜50000)を
3mg/mlとなるように添加溶解し、実施例1と同
様に無菌ろ過.凍結乾燥することにより、注射用
ウロキナーゼ製剤を得る。尚、無菌ろ過時間はろ
液1当り約9分であつた。 実施例 3 実施例1と同様にして得られた精製ウロキナー
ゼ含有水溶液にゼラチン(分子量20000〜30000)
を5mg/mlおよびD−マンニツトを5mg/mlとな
るように添加溶解し、以下実施例1と同様に処理
して注射用ウロキナーゼ製剤を得る。 実施例 4 実施例1と同様にして得られたウロキナーゼ含
有水溶液にゼラチン(分子量30000〜50000)を5
mg/mlおよびグリシンを3mg/mlとなるように添
加溶解し、以下実施例1と同様にして注射用ウロ
キナーゼ製剤を得る。 実施例 5 アクリロニトリル系繊維またはリン酸セルロー
ス等により人尿中のウロキナーゼを捕集し、硫安
分画を行なつたのち、アンバーライトIRC−50,
CMCセルロース,DEAEセルロース等のイオン
交換体を単独または組合せて処理して精製し、つ
いでセフアデツクスG−100によるゲルロ過して
パイロジエン除去処理することにより、精製ウロ
キナーゼ原液(約50000IU/ml)を得る。この原
液にゼラチン(分子量20000〜30000)を3mg/ml
となるように添加溶解したのち実施例1と同一条
件下に無菌ろ過する。無菌ろ過時間はロ液1当
り10分であつた。得られたろ液は凍結し、3ケ月
間保存したがウロキナーゼ活性の低下は殆ど認め
られなかつた。
[Table] Example 1 Purified urokinase was dissolved in distilled water to a concentration of 3000 IU/ml, and gelatin (molecular weight 20000
~30000) Add and dissolve to a concentration of 3 mg/ml.
This aqueous solution is sterile-filtered using a membrane filter (diameter 42 mm) with a pore size of 0.22 μ under conditions of 1 Kg/cm 2 . At this time, the filtration time was 8 minutes per filtrate. After dispensing the filtrate into 2 ml vials,
Obtain the injectable urokinase formulation by lyophilization under vacuum at 40 °C. Example 2 Gelatin (molecular weight: 30,000 to 50,000) was added to and dissolved in an aqueous solution containing urokinase obtained in the same manner as in Example 1 at a concentration of 3 mg/ml, and sterile filtered in the same manner as in Example 1. An injectable urokinase preparation is obtained by freeze-drying. The sterile filtration time was approximately 9 minutes per filtrate. Example 3 Gelatin (molecular weight 20,000 to 30,000) was added to a purified urokinase-containing aqueous solution obtained in the same manner as in Example 1.
and D-mannite were added and dissolved to a concentration of 5 mg/ml and 5 mg/ml, followed by treatment in the same manner as in Example 1 to obtain an injectable urokinase preparation. Example 4 Gelatin (molecular weight 30,000 to 50,000) was added to a urokinase-containing aqueous solution obtained in the same manner as in Example 1.
mg/ml and glycine were added and dissolved to a concentration of 3 mg/ml, and a urokinase preparation for injection was obtained in the same manner as in Example 1. Example 5 After collecting urokinase in human urine with acrylonitrile fibers or cellulose phosphate, etc. and performing ammonium sulfate fractionation, Amberlite IRC-50,
A purified urokinase stock solution (approximately 50,000 IU/ml) is obtained by treating with an ion exchanger such as CMC cellulose or DEAE cellulose alone or in combination, followed by gel filtration through Sephadex G-100 to remove pyrogen. Add 3 mg/ml of gelatin (molecular weight 20,000 to 30,000) to this stock solution.
After addition and dissolution, the mixture was sterilized and filtered under the same conditions as in Example 1. Sterile filtration time was 10 minutes per filtrate. The obtained filtrate was frozen and stored for 3 months, but almost no decrease in urokinase activity was observed.

Claims (1)

【特許請求の範囲】 1 ウロキナーゼ含有水溶液に平均分子量が約
10000乃至50000であるゼラチンを添加し、ついで
無菌ろ過することを特徴とする注射用ウロキナー
ゼの製法。 2 ウロキナーゼ含有水溶液に添加するゼラチン
の分子量が約10000乃至50000である特許請求の範
囲第1項記載の製法。 3 ウロキナーゼ含有水溶液に更にD−マンニツ
トまたはグリシンを添加する特許請求の範囲第2
項記載の製法。 4 ウロキナーゼ含有水溶液に対してゼラチンを
約0.05〜2W/V%.D−マンニツトを約0.1〜
5W/V%添加する特許請求の範囲第3項記載の
製法。 5 ウロキナーゼ含有水溶液に対してゼラチンを
約0.05〜2W/V%.グリシンを約0.1〜5W/V
%添加する特許請求の範囲第3項記載の製法。
[Claims] 1. The urokinase-containing aqueous solution has an average molecular weight of about
A method for producing urokinase for injection, which is characterized by adding gelatin having a molecular weight of 10,000 to 50,000, followed by sterile filtration. 2. The method according to claim 1, wherein the gelatin added to the urokinase-containing aqueous solution has a molecular weight of about 10,000 to 50,000. 3. Claim 2 in which D-mannite or glycine is further added to the urokinase-containing aqueous solution.
Manufacturing method described in section. 4 Add gelatin to the urokinase-containing aqueous solution at approximately 0.05 to 2 W/V%. D-mannite from about 0.1 to
The manufacturing method according to claim 3, in which 5W/V% is added. 5 Add gelatin to the urokinase-containing aqueous solution at approximately 0.05 to 2 W/V%. Approximately 0.1 to 5 W/V of glycine
% of the manufacturing method according to claim 3.
JP14834377A 1977-12-09 1977-12-09 Preparation of urokinase for injection Granted JPS5480406A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
JP14834377A JPS5480406A (en) 1977-12-09 1977-12-09 Preparation of urokinase for injection

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
JP14834377A JPS5480406A (en) 1977-12-09 1977-12-09 Preparation of urokinase for injection

Publications (2)

Publication Number Publication Date
JPS5480406A JPS5480406A (en) 1979-06-27
JPS629092B2 true JPS629092B2 (en) 1987-02-26

Family

ID=15450638

Family Applications (1)

Application Number Title Priority Date Filing Date
JP14834377A Granted JPS5480406A (en) 1977-12-09 1977-12-09 Preparation of urokinase for injection

Country Status (1)

Country Link
JP (1) JPS5480406A (en)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4370417A (en) * 1980-04-03 1983-01-25 Abbott Laboratories Recombinant deoxyribonucleic acid which codes for plasminogen activator
US6372716B1 (en) * 1994-04-26 2002-04-16 Genetics Institute, Inc. Formulations for factor IX
WO2011149016A1 (en) * 2010-05-26 2011-12-01 公立大学法人奈良県立医科大学 Complex containing thrombolytic enzyme

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Publication number Publication date
JPS5480406A (en) 1979-06-27

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