JPH0424331B2 - - Google Patents
Info
- Publication number
- JPH0424331B2 JPH0424331B2 JP60293195A JP29319585A JPH0424331B2 JP H0424331 B2 JPH0424331 B2 JP H0424331B2 JP 60293195 A JP60293195 A JP 60293195A JP 29319585 A JP29319585 A JP 29319585A JP H0424331 B2 JPH0424331 B2 JP H0424331B2
- Authority
- JP
- Japan
- Prior art keywords
- plasminogen
- solubility
- preparation
- present
- 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 - Lifetime
Links
- 102000013566 Plasminogen Human genes 0.000 claims description 22
- 108010051456 Plasminogen Proteins 0.000 claims description 22
- 238000002360 preparation method Methods 0.000 claims description 13
- 239000000843 powder Substances 0.000 claims description 5
- 150000001413 amino acids Chemical class 0.000 claims description 4
- 239000000126 substance Substances 0.000 claims description 4
- 150000005846 sugar alcohols Chemical class 0.000 claims description 4
- 239000003795 chemical substances by application Substances 0.000 claims description 3
- 238000000034 method Methods 0.000 description 7
- 230000000694 effects Effects 0.000 description 4
- 229940012957 plasmin Drugs 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 3
- 235000001014 amino acid Nutrition 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 210000002966 serum Anatomy 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 208000007536 Thrombosis Diseases 0.000 description 2
- 239000003527 fibrinolytic agent Substances 0.000 description 2
- 230000003480 fibrinolytic effect Effects 0.000 description 2
- 235000010355 mannitol Nutrition 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 229940124597 therapeutic agent Drugs 0.000 description 2
- 102000009027 Albumins Human genes 0.000 description 1
- 108010088751 Albumins Proteins 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- 206010003445 Ascites Diseases 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 102000009123 Fibrin Human genes 0.000 description 1
- 108010073385 Fibrin Proteins 0.000 description 1
- BWGVNKXGVNDBDI-UHFFFAOYSA-N Fibrin monomer Chemical compound CNC(=O)CNC(=O)CN BWGVNKXGVNDBDI-UHFFFAOYSA-N 0.000 description 1
- 102000008946 Fibrinogen Human genes 0.000 description 1
- 108010049003 Fibrinogen Proteins 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-N L-arginine Chemical compound OC(=O)[C@@H](N)CCCN=C(N)N ODKSFYDXXFIFQN-BYPYZUCNSA-N 0.000 description 1
- 229930064664 L-arginine Natural products 0.000 description 1
- 235000014852 L-arginine Nutrition 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 229920002684 Sepharose Polymers 0.000 description 1
- 102000003990 Urokinase-type plasminogen activator Human genes 0.000 description 1
- 108090000435 Urokinase-type plasminogen activator Proteins 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 235000009697 arginine Nutrition 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 239000003124 biologic agent Substances 0.000 description 1
- BECPQYXYKAMYBN-UHFFFAOYSA-N casein, tech. Chemical group NCCCCC(C(O)=O)N=C(O)C(CC(O)=O)N=C(O)C(CCC(O)=N)N=C(O)C(CC(C)C)N=C(O)C(CCC(O)=O)N=C(O)C(CC(O)=O)N=C(O)C(CCC(O)=O)N=C(O)C(C(C)O)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=O)N=C(O)C(CCC(O)=O)N=C(O)C(COP(O)(O)=O)N=C(O)C(CCC(O)=N)N=C(O)C(N)CC1=CC=CC=C1 BECPQYXYKAMYBN-UHFFFAOYSA-N 0.000 description 1
- 239000000356 contaminant Substances 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 229940088598 enzyme Drugs 0.000 description 1
- 229950003499 fibrin Drugs 0.000 description 1
- 229940012952 fibrinogen Drugs 0.000 description 1
- 230000020764 fibrinolysis Effects 0.000 description 1
- 238000005194 fractionation Methods 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 108010074605 gamma-Globulins Proteins 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 230000002934 lysing effect Effects 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 238000001470 plasma protein fractionation Methods 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 239000012264 purified product Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 229960005356 urokinase Drugs 0.000 description 1
Landscapes
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Description
【発明の詳細な説明】
〔産業上の利用分野〕
本発明は、プラスミノゲン製剤の改良、詳しく
は、再溶解時の溶解性の改良をなした製剤に関す
るものである。
〔従来技術〕
プラスミノゲンは、ウロキナーゼ等によつて活
性化されてプラスミンとなり、これがフイブリン
を分解して線溶現象をもたらすものである。プラ
スミンは、線溶現象の研究用として用いられる
他、近年線溶系の治療剤（血栓治療剤）としての
臨床応用もなされている。
プラスミン製剤において、プラスミノゲン自体
は前駆型酵素で安定な物質であり、夾雑物として
製剤中にプラスミン等を含まないかぎり安定であ
る。しかし、プラスミゲンは、乾燥製剤とするこ
とにより、その再溶解時に、水に対する溶解性及
び溶状が悪くなる。
〔発明が解決しようとする問題点〕
本発明の目的は、乾燥粉末化されたプラスミノ
ゲンの水に対する溶解性及び溶状を良好にするプ
ラスミノゲン製剤を提供することである。
〔問題点を解決するための手段〕
本発明は、プラスミノゲンの乾燥粉末に、再溶
解時のにごり、糸状様物質の発生を抑止する有効
量の溶解剤として、糖アルコールと塩基性アミノ
酸を総和で、プラスミノゲン100〜500CU／mlに
対して、0.5％（Ｗ／Ｎ）〜10％（Ｗ／Ｖ）を添
加したことを特徴とするプラスミノゲン製剤であ
る。
本発明に使用するプラスミノゲン液は、特に限
定されるものではなく、人、動物等の血清、血
漿、腹水、タイバン抽出液、タイバン組織抽出液
さらにこれら以外にも血漿のフイブリノーゲン、
γ−グロブリンおよびアルブミンなど重要な生物
学的薬剤の製造に一般に用いられる血漿タンパク
分画法におけるコーンの低温アルコール分画法の
画分のようにプラスミノゲンを含有する画分か
ら広く公知の方法によつて精製されたものがあげ
られ、またプラスミノゲンの乾燥粉末としては、
上記水溶液の乾燥粉末、特に凍結乾燥粉末があげ
られる。
プラスミノゲン精製法としては例えば、先に出
願中の本発明者等の方法（特開55−153592）、リ
ジン−セフアロースによる精製法（Science，
170，1095，1970年）等が代表的な方法として例
示できる。
本発明で使用される溶解剤は、マンニトール、
ソルビトールのような糖アルコールおよびアルギ
ニンのような塩基性アミノ酸が併用され、各少な
くとも一種が使用される。
溶解剤の使用量は、プラスミノゲンの100〜
500CU／mlに対して、0.5％（Ｗ／Ｖ）〜10％
（Ｗ／Ｖ）、より好ましくは、0.5〜５％（Ｗ／Ｖ）
である。この添加量の範囲において、製剤の安定
剤、水溶解性、溶状と製剤化のバランスが最も良
好である。糖アルコール(A)と塩基性アミノ酸(B)に
おけるＢ／Ａの重量比は、0.1〜３の混合比率の
範囲で利用できるが、最適には１である。
プラスミノゲンは、通常凍結乾燥品として使用
に供するが、溶解剤は、乾燥処理の前に添加して
おくことが好ましい。
かくして調整されたプラスミノゲン製剤は、用
時生理食塩液注射用蒸留水等で溶解され治療に供
される。治療に際しては、一般的には静脈内投与
がおこなわれ、１回当り100〜3000CUの投与がお
こなわれる。
なお、本発明からなる製剤は、医薬品製造の通
例技術に準じて、賦形剤を有効量添加してもよ
い。
〔効果〕
本発明からなる製剤は、際溶解時ににごり、糸
状用物質の発生を抑制するから、医療用製剤とし
て、より安全であり、実用に即したものである。
本製剤の適用対象は各種血栓症の治療に期待がで
きる。
〔実施例・実験例〕
以下、本発明を実施例及び実験例により説明す
るが、本発明はこれらによつて何ら限定されるも
のではない。なお説明中で使用したCU単位は、
カゼイン単位：Vox Sanguinis ５，357〜376
（1960）を意味する。
実施例 １
人血清由来のプラスミノゲン溶液300CU／ml
に、Ｄ−マンニトールを１％（Ｗ／Ｖ）、Ｌ−ア
ルギニンを１％（Ｗ／Ｖ）を添加し、pHの本品
につき、プラスミノゲン活性及び溶解性を試験し
た結果、活性の減少はなく、溶解性・溶状共に良
好であつた。
実験例 １
人血清由来のプラスミノゲン溶液150CU／ml、
50mMリン酸緩衝液pH7.2に各種の溶解剤を添加
し、その後凍結乾燥した。１ケ月間室温保存後、
各製剤のプラスミノゲン比活性の残存力価及び溶
解性・溶状を検討した。結果は、第１表に示し
た。表中、○は易溶、△はやや不溶物あり、×は
不溶物ありを示す。
【表】DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] The present invention relates to improvements in plasminogen preparations, and more particularly, to preparations with improved solubility upon redissolution. [Prior Art] Plasminogen is activated by urokinase and the like to become plasmin, which decomposes fibrin and causes fibrinolysis. Plasmin is used for research on fibrinolytic phenomena, and in recent years has also been clinically applied as a fibrinolytic therapeutic agent (thrombus therapeutic agent). In plasmin preparations, plasminogen itself is a precursor enzyme and is a stable substance, and is stable as long as the preparation does not contain plasmin or the like as a contaminant. However, when plasmigen is prepared as a dry preparation, its solubility and solubility in water deteriorates when it is redissolved. [Problems to be Solved by the Invention] An object of the present invention is to provide a plasminogen preparation that improves the solubility and solubility of dry powdered plasminogen in water. [Means for Solving the Problems] The present invention provides a combination of sugar alcohol and basic amino acid in the dry powder of plasminogen as an effective amount of a dissolving agent to suppress the generation of cloudy and filamentous substances during redissolution. , is a plasminogen preparation characterized in that 0.5% (W/N) to 10% (W/V) is added to 100 to 500 CU/ml of plasminogen. The plasminogen solution used in the present invention is not particularly limited, and may include human, animal serum, plasma, ascites, Tyban extract, Tyban tissue extract, plasma fibrinogen,
by widely known methods from fractions containing plasminogen, such as Cohn's cold alcohol fractionation fractions in plasma protein fractionation methods commonly used for the production of important biological agents such as gamma-globulin and albumin. Purified products are listed, and dry powder of plasminogen is
Mention may be made of dry powders of the above aqueous solutions, especially freeze-dried powders. Examples of plasminogen purification methods include the previously pending method of the present inventors (Japanese Unexamined Patent Application Publication No. 55-153592), and the lysine-sepharose purification method (Science,
170, 1095, 1970) etc. can be exemplified as representative methods. The solubilizing agents used in the present invention include mannitol,
Sugar alcohols such as sorbitol and basic amino acids such as arginine are used in combination, and at least one of each is used. The amount of solubilizer used is 100 to 100% of plasminogen.
0.5% (W/V) to 10% for 500CU/ml
(W/V), more preferably 0.5-5% (W/V)
It is. Within this addition amount range, the balance between stabilizer, water solubility, solubility, and formulation of the formulation is best. The weight ratio of B/A in sugar alcohol (A) and basic amino acid (B) can be used in a mixing ratio of 0.1 to 3, but is optimally 1. Plasminogen is usually used as a freeze-dried product, but a solubilizer is preferably added before drying. The thus prepared plasminogen preparation is dissolved in distilled water for physiological saline injection and used for treatment. For treatment, intravenous administration is generally performed, with doses ranging from 100 to 3000 CU per administration. In addition, an effective amount of excipients may be added to the formulation of the present invention according to the usual techniques for manufacturing pharmaceuticals. [Effect] The preparation of the present invention suppresses the generation of cloudy and filamentous substances during dissolution, so it is safer and more suitable for practical use as a medical preparation.
This preparation is expected to be applied to the treatment of various thromboses. [Examples/Experimental Examples] The present invention will be explained below using Examples and Experimental Examples, but the present invention is not limited by these in any way. The CU unit used in the explanation is
Casein unit: Vox Sanguinis 5 , 357-376
(1960). Example 1 Plasminogen solution derived from human serum 300CU/ml
To this, 1% (W/V) of D-mannitol and 1% (W/V) of L-arginine were added, and the plasminogen activity and solubility of this product at pH were tested. As a result, there was no decrease in activity. It had good solubility and solubility. Experimental example 1 Plasminogen solution derived from human serum 150CU/ml,
Various lysing agents were added to 50 mM phosphate buffer pH 7.2, followed by freeze-drying. After storing at room temperature for one month,
The residual potency of plasminogen specific activity and solubility and solubility of each preparation were examined. The results are shown in Table 1. In the table, ◯ indicates easily soluble, △ indicates slightly insoluble matter, and × indicates insoluble matter. 【table】
Claims (1)
ごり、糸状様物質の発生を抑止する有効量の溶解
剤として、糖アルコールと塩基性アミノ酸を総和
で、プラスミノゲン100〜500CU／mlに対して、
0.5％（Ｗ／Ｖ）〜10％（Ｗ／Ｖ）を添加したこ
とを特徴とするプラスミノゲン製剤。1 Add sugar alcohol and basic amino acids to the dry powder of plasminogen in an effective amount as a dissolving agent to suppress the generation of cloudiness and filamentous substances during redissolution, for a total of 100 to 500 CU/ml of plasminogen.
A plasminogen preparation characterized in that 0.5% (W/V) to 10% (W/V) is added.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP60293195A JPS62153224A (en) | 1985-12-27 | 1985-12-27 | Plasminogen preparation |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP60293195A JPS62153224A (en) | 1985-12-27 | 1985-12-27 | Plasminogen preparation |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS62153224A JPS62153224A (en) | 1987-07-08 |
| JPH0424331B2 true JPH0424331B2 (en) | 1992-04-24 |
Family
ID=17791645
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP60293195A Granted JPS62153224A (en) | 1985-12-27 | 1985-12-27 | Plasminogen preparation |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS62153224A (en) |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH06211691A (en) * | 1993-01-11 | 1994-08-02 | Green Cross Corp:The | Dry pharmaceutical preparation of plasminogen |
| LT3233111T (en) | 2014-12-19 | 2024-10-10 | Kedrion Biopharma Inc. | Pharmaceutical composition comprising plasminogen and uses thereof |
| WO2017101866A1 (en) | 2015-12-18 | 2017-06-22 | 深圳瑞健生命科学研究院有限公司 | Method for preventing or treating acute thrombosis and chronic thrombosis |
| JP7168990B2 (en) | 2016-12-15 | 2022-11-10 | タレンゲン インターナショナル リミテッド | Methods and drugs for preventing and treating obesity |
| US11547746B2 (en) | 2016-12-15 | 2023-01-10 | Talengen International Limited | Method for treating coronary atherosclerosis and complications thereof |
| US11389515B2 (en) | 2016-12-15 | 2022-07-19 | Talengen International Limited | Method for mitigating heart disease |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS57193418A (en) * | 1981-05-14 | 1982-11-27 | Behringwerke Ag | Manufacture of plasminogen |
-
1985
- 1985-12-27 JP JP60293195A patent/JPS62153224A/en active Granted
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS57193418A (en) * | 1981-05-14 | 1982-11-27 | Behringwerke Ag | Manufacture of plasminogen |
Also Published As
| Publication number | Publication date |
|---|---|
| JPS62153224A (en) | 1987-07-08 |
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