JPS6348220A - Production of blood-coagulating factor ix complex - Google Patents
Production of blood-coagulating factor ix complexInfo
- Publication number
- JPS6348220A JPS6348220A JP61190343A JP19034386A JPS6348220A JP S6348220 A JPS6348220 A JP S6348220A JP 61190343 A JP61190343 A JP 61190343A JP 19034386 A JP19034386 A JP 19034386A JP S6348220 A JPS6348220 A JP S6348220A
- Authority
- JP
- Japan
- Prior art keywords
- factor
- blood
- complex
- coagulating
- ammonium sulfate
- 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.)
- Pending
Links
- 108010076282 Factor IX Proteins 0.000 title claims abstract 4
- 238000004519 manufacturing process Methods 0.000 title claims description 7
- 229940024790 prothrombin complex concentrate Drugs 0.000 title claims 2
- 239000003114 blood coagulation factor Substances 0.000 title abstract description 10
- 239000000427 antigen Substances 0.000 claims abstract description 19
- 102000036639 antigens Human genes 0.000 claims abstract description 19
- 108091007433 antigens Proteins 0.000 claims abstract description 19
- BFNBIHQBYMNNAN-UHFFFAOYSA-N ammonium sulfate Chemical compound N.N.OS(O)(=O)=O BFNBIHQBYMNNAN-UHFFFAOYSA-N 0.000 claims abstract description 8
- 229910052921 ammonium sulfate Inorganic materials 0.000 claims abstract description 7
- 235000011130 ammonium sulphate Nutrition 0.000 claims abstract description 7
- 238000005185 salting out Methods 0.000 claims abstract description 4
- 108010054218 Factor VIII Proteins 0.000 claims abstract 4
- 102000001690 Factor VIII Human genes 0.000 claims abstract 4
- 238000002360 preparation method Methods 0.000 claims description 10
- 239000006228 supernatant Substances 0.000 abstract description 6
- 102100022641 Coagulation factor IX Human genes 0.000 abstract description 3
- 150000003839 salts Chemical class 0.000 abstract description 2
- 229960000301 factor viii Drugs 0.000 abstract 3
- 229960004222 factor ix Drugs 0.000 abstract 1
- 108010014173 Factor X Proteins 0.000 description 28
- BTCSSZJGUNDROE-UHFFFAOYSA-N gamma-aminobutyric acid Chemical compound NCCCC(O)=O BTCSSZJGUNDROE-UHFFFAOYSA-N 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 108010094028 Prothrombin Proteins 0.000 description 5
- 238000000034 method Methods 0.000 description 5
- 108010039209 Blood Coagulation Factors Proteins 0.000 description 4
- 102000015081 Blood Coagulation Factors Human genes 0.000 description 4
- 229940019700 blood coagulation factors Drugs 0.000 description 4
- AGVAZMGAQJOSFJ-WZHZPDAFSA-M cobalt(2+);[(2r,3s,4r,5s)-5-(5,6-dimethylbenzimidazol-1-yl)-4-hydroxy-2-(hydroxymethyl)oxolan-3-yl] [(2r)-1-[3-[(1r,2r,3r,4z,7s,9z,12s,13s,14z,17s,18s,19r)-2,13,18-tris(2-amino-2-oxoethyl)-7,12,17-tris(3-amino-3-oxopropyl)-3,5,8,8,13,15,18,19-octamethyl-2 Chemical compound [Co+2].N#[C-].[N-]([C@@H]1[C@H](CC(N)=O)[C@@]2(C)CCC(=O)NC[C@@H](C)OP(O)(=O)O[C@H]3[C@H]([C@H](O[C@@H]3CO)N3C4=CC(C)=C(C)C=C4N=C3)O)\C2=C(C)/C([C@H](C\2(C)C)CCC(N)=O)=N/C/2=C\C([C@H]([C@@]/2(CC(N)=O)C)CCC(N)=O)=N\C\2=C(C)/C2=N[C@]1(C)[C@@](C)(CC(N)=O)[C@@H]2CCC(N)=O AGVAZMGAQJOSFJ-WZHZPDAFSA-M 0.000 description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 4
- 238000000691 measurement method Methods 0.000 description 4
- 238000011084 recovery Methods 0.000 description 4
- 238000000502 dialysis Methods 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000004062 sedimentation Methods 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 102100026735 Coagulation factor VIII Human genes 0.000 description 2
- 201000003542 Factor VIII deficiency Diseases 0.000 description 2
- 208000009292 Hemophilia A Diseases 0.000 description 2
- 101000911390 Homo sapiens Coagulation factor VIII Proteins 0.000 description 2
- 239000011543 agarose gel Substances 0.000 description 2
- 238000005119 centrifugation Methods 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 239000007979 citrate buffer Substances 0.000 description 2
- 230000015271 coagulation Effects 0.000 description 2
- 238000005345 coagulation Methods 0.000 description 2
- 230000007812 deficiency Effects 0.000 description 2
- 239000000385 dialysis solution Substances 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 238000001962 electrophoresis Methods 0.000 description 2
- 208000009429 hemophilia B Diseases 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 102100027378 Prothrombin Human genes 0.000 description 1
- 208000007536 Thrombosis Diseases 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000023555 blood coagulation Effects 0.000 description 1
- 208000015294 blood coagulation disease Diseases 0.000 description 1
- 210000001185 bone marrow Anatomy 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 239000000356 contaminant Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 229960000027 human factor ix Drugs 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 239000002075 main ingredient Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 229940039716 prothrombin Drugs 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 210000003556 vascular endothelial cell Anatomy 0.000 description 1
Landscapes
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
Abstract
Description
【発明の詳細な説明】
〔産業上の利用分野〕
本発明は純度の高い血液凝固第X因子(以下、第X因子
ともいう)の製造法に関する。DETAILED DESCRIPTION OF THE INVENTION [Industrial Application Field] The present invention relates to a method for producing highly pure blood coagulation factor X (hereinafter also referred to as factor X).
第X因子は、通常単独で使用されることはなく、たとえ
ばヒト血液凝固節■因子、第■因子、および第X因子等
を含んだ、所謂第X因子複合体として使用される。Factor X is usually not used alone, but is used as a so-called factor
一方、血液凝固筒■因子(以下、単に第■因子という)
関連抗原は全身の血管内皮細胞及び骨髄上核球、血小板
に存在する(Nature (New Biol、)。On the other hand, blood coagulation factor ■ (hereinafter simply referred to as factor ■)
Related antigens are present on vascular endothelial cells, bone marrow suprakaryocytes, and platelets throughout the body (Nature (New Biol)).
241、217 (1973)、J、、’Cl1n、
Invest、+ 52+ 2737(1973)、
Thromb、 Re’s、、 13.871 (19
78))と言われており、血液凝固因子製剤の原料であ
る結晶や血液凝固因子製剤中にも存在するものと考えら
れる。しかして、Sas ら(In vitro 5p
ont aneousthrombin genera
tion in human factor−IX c
on−cen tra tes)は第X因子複合体製剤
中に第■因子関連抗原が存在すると報告している。241, 217 (1973), J., 'Cl1n,
Invest, +52+ 2737 (1973),
Thromb, Re's, 13.871 (19
78)), and is thought to exist in crystals that are raw materials for blood coagulation factor preparations and in blood coagulation factor preparations. However, Sas et al. (In vitro 5p
ont aneousthrombin genera
tion in human factor-IX c
on-centrates) have reported the presence of factor II-related antigens in factor X complex preparations.
血液凝固は約20種の促進および抑制因子の関連するC
a5cadeから成り、これらの血液凝固因子の減少、
増大は血液凝固障害を起こし、種々の疾患をもたらす。Blood coagulation involves about 20 promoting and inhibiting factors.
consisting of a5cade, a decrease in these blood clotting factors,
The increase causes blood coagulation disorders, leading to various diseases.
それらの疾患のうち、第■因子の欠乏に基づくものを血
友病A、第X因子の欠乏に基づくものを血友病Bと言う
。血友病Aに対しては、第■因子濃縮製剤を投与するこ
とにより1.障害を除去するが、その連用により、ごく
稀に第■因子抗体の産生が認められる症例が出現する場
合がある。このような場合には、通常第X因子製剤を用
いてバイパス療法を行うが、第X因子製剤中に第■因子
関連抗原が混入している場合には第■因子抗体保持患者
血中に第■因子抗体の著しい増加が起こり、新たな障害
の原因になる。また、血友病Bの患者に対して第■因子
関連抗原の混入した第X因子製剤を投与した場合には、
播種性血管向凝固(D r C)や血栓形成の原因とな
りやすい。Among these diseases, those based on a deficiency of factor (I) are called hemophilia A, and those based on a deficiency of factor X are called hemophilia B. For hemophilia A, administration of factor Ⅰ concentrates can achieve 1. Although it removes the disorder, repeated use may result in very rare cases in which production of factor II antibodies is observed. In such cases, bypass therapy is usually performed using a factor X preparation, but if the factor ■ A significant increase in factor antibodies occurs, causing new disorders. Furthermore, if a factor X preparation containing factor II-related antigen is administered to a patient with hemophilia B
It is likely to cause disseminated vascular coagulation (D r C) and thrombus formation.
以上のような理由から、第X因子製剤中に第■因子関連
抗原が混入する事は好ましくないのであるが、従来、第
X因子と第■因子関連抗原との効率的な分離は極めて困
難であった。For the above reasons, it is undesirable for factor X-related antigens to be mixed into factor X preparations, but until now it has been extremely difficult to efficiently separate factor there were.
本発明の目的は、従来除去することが困難であった第■
因子関連抗原を第■因子含を溶液から分離除去し、純度
の高い安全な第X因子製剤を提供することにある。The purpose of the present invention is to
The purpose of the present invention is to separate and remove factor-related antigens from a solution containing factor (I) and provide a highly pure and safe factor X preparation.
〔問題点を解決するだめの手段及び作用の説明〕本件発
明者らは、上記目的を達成するために鋭意検討した結果
、硫安塩析法によって両者が効率よく分離されることを
見出して本発明を完成した。[Explanation of means and action for solving the problem] As a result of intensive studies to achieve the above object, the inventors of the present invention discovered that the two can be efficiently separated by ammonium sulfate salting out method, and have developed the present invention. completed.
即ち、本発明は血液凝固節■因子関連抗原を含む血液凝
固第X因子含有溶液を硫酸アンモニウムで塩析すること
による純度の高い第X因子複合体製剤の製造法である。That is, the present invention is a method for producing a highly pure factor X complex preparation by salting out a blood coagulation factor
(a)処理対象
本発明の方法の処理対象は、第■因子関連抗原を夾雑す
ることが危惧される第X因子含有溶液である。ここに第
X因子含有溶液とは、第X因子のみを含有するものの他
、たとえば血液分画技術等によって得られる所の第X因
子および他の成分を含む、所謂第X因子複合体含有溶液
であってもよい。(a) Target to be treated The target to be treated in the method of the present invention is a factor The factor X-containing solution herein refers to a so-called factor There may be.
第X因子複合体は、第X因子を主成分とし、さらに他の
成分、たとえば他の血液凝固に関与する成分を含むもの
をいい、たとえばヒト血液凝固節■因子、第■因子、お
よび第X因子をも含んでおり、生物学的製剤規準が規定
する規格に適合したものが挙げられる。その組成比は、
たとえば1バイアル(20ml)当たりに換算すると、
第X因子、第■因子、第■因子、第X因子が、各々40
0〜500単位、100〜500単位、5〜150単位
、100〜500単位を含むものである。Factor It also includes factors that meet the standards stipulated by the Biological Products Standards. Its composition ratio is
For example, when converted to 1 vial (20ml),
Factor X, factor ■, factor ■, factor X are each 40
It includes 0 to 500 units, 100 to 500 units, 5 to 150 units, and 100 to 500 units.
第■因子関連抗原の夾雑量については、特に限定はない
。There are no particular limitations on the amount of factor Ⅰ-related antigen contaminant.
(bl硫酸アンモニウム処理
本処理は、通常pH5〜9、好ましくはpH6〜8、さ
らに好ましくはp117程度の条件下で行われ、硫安添
加量は5〜45%、好ましくは15〜35%飽和量であ
る。(bl ammonium sulfate treatment This treatment is usually carried out under conditions of pH 5 to 9, preferably pH 6 to 8, more preferably about pH 117, and the amount of ammonium sulfate added is 5 to 45%, preferably 15 to 35% saturation amount. .
温度は、好ましくは15℃以下、特に好ましくは2〜1
0℃の低温に維持され、処理時間は30分〜3時間で十
分である。The temperature is preferably below 15°C, particularly preferably between 2 and 1
The temperature is maintained at a low temperature of 0° C., and a treatment time of 30 minutes to 3 hours is sufficient.
本処理における第X因子複合体は、通常水溶液の形で本
処理に付される。その際、第X因子ないしは第X因子複
合体は高濃度であることが好ましく、通常は蛋白量は3
〜10%、好ましくは3〜8%、さらに好ましくは4〜
6%に調整される。The factor X complex used in this treatment is usually subjected to this treatment in the form of an aqueous solution. In this case, it is preferable that the factor X or the factor
-10%, preferably 3-8%, more preferably 4-8%
Adjusted to 6%.
本処理により、第■因子関連抗原は沈澱となり、第X因
子ないしは第X因子複合体は上清中に残存する。By this treatment, the factor Ⅰ-related antigen becomes a precipitate, and the factor X or the factor X complex remains in the supernatant.
(c1回収
前記処理が行われた溶液は、たとえば遠心分離(5,0
00〜15.00Or、p、m、 、より好ましくは9
.000〜10.00Or、p、m、)により上清が回
収され、サラニ塩を除去するために、所望によりたとえ
ば透析を行う。(c1 recovery The solution subjected to the above treatment is, for example, centrifuged (5,0
00 to 15.00 Or, p, m, more preferably 9
.. 000 to 10.00 Or, p, m,), and optionally subjected to eg dialysis to remove Salani salt.
(dl製剤化
上記処理に続いて、第X因子を主成分とする医薬品製造
における通例技術に従って処理を行って、第■囚子関連
抗原を夾雑しない、より安全性の高い第X因子製剤を提
供することができる。(dl formulation) Following the above treatment, processing is performed in accordance with the customary technology for manufacturing pharmaceuticals containing factor X as the main ingredient to provide a safer factor can do.
本発明の処理による第X因子ないしは第X因子複合体の
回収率は65〜93%であり、一方、第■因子関連抗原
の残存率は0.5〜10%である。The recovery rate of factor X or factor
従って、本発明は純度の高い第X因子製剤を製造する上
で、極めて有効な方法である。Therefore, the present invention is an extremely effective method for producing highly pure factor X preparations.
(e)測定法
なお、本発明において各因子の力価は以下の方法によっ
て測定した。(e) Measurement method In the present invention, the potency of each factor was measured by the following method.
■第■因子ニ
一段法による凝血測定法(tlapaport、 S、
1.+et al、、 New [!ng1. Me
d、、 267、 125〜130■第■因子:
プロトロンビン単独測定法(Owren、 P、^、。■Coagulation measurement method using factor II one-step method (trapaport, S,
1. +et al,, New [! ng1. Me
d,, 267, 125-130 ■Factor ■: Prothrombin alone measurement method (Owren, P, ^,.
et al、、 5cand、 J、 Cl1n、 L
ab、 Invest、+ 3201〜20B (19
51))
■第■因子ニ
一段測定法(Sirridge、 M、 S、、 La
boratoryEvaluation of Hae
matology+ Ph1ladelphia:Le
e and Febiger、 1974. p、 1
45〜14B)■第X因子ニ
一段測定法(Sirridge、 M、 S、、 La
boratoryEvaluation of Hae
matology+ Ph1ladelphia:Le
e and Febiger、 1974+ p、 1
45〜148)■第■因子関連抗原:
血漿中の第■因子関連抗原は抗ヒト第■因子家兎血清と
の間にゲル内沈降反応を示す。よって、抗血清を均一に
混合したアガロースゲルに抗原孔をあけ、これに抗原(
被検血漿)を注入して、免疫ゲル電気泳動(Laure
ll法(Laurell、C,B、: Quanti
tative estimationof prot
eins by electrophoresis
in agarosegel containing
antibodies、 Anal、 Bioc
h、+15 : 45.1966))を行うと、抗原抗
体反応によりロケット状の沈降線を得る。この沈降線の
長さより抗原量を定量する。(ヒトPoolPlasm
aの沈降線の長さをI U/−とした。)〔実施例〕
以下の実施例により、本発明をより詳細に説明するが、
本発明はこれらの実施例により、何隻限定されるもので
はない。et al, 5cand, J, Cl1n, L
ab, Invest, +3201~20B (19
51)) ■ Factor 2 one-step measurement method (Sirridge, M, S,, La
boratoryEvaluation of Hae
matology+ Ph1ladelphia:Le
E and Febiger, 1974. p, 1
45-14B) ■Factor X two-step assay (Sirridge, M, S, La
boratoryEvaluation of Hae
matology+ Ph1ladelphia:Le
e and Febiger, 1974+ p. 1
45-148) ■Factor ■-related antigen: Factor ■-related antigen in plasma exhibits an in-gel precipitation reaction with anti-human factor ■ rabbit serum. Therefore, we made an antigen hole in an agarose gel in which antiserum was evenly mixed, and inserted the antigen (
Test plasma) was injected and immunogel electrophoresis (Laure
ll method (Laurell, C, B,: Quanti
tative estimation of plot
eins by electrophoresis
in agarosegel containing
Antibodies, Anal, Bioc
h, +15: 45.1966)), a rocket-shaped sedimentation line is obtained due to the antigen-antibody reaction. The amount of antigen is determined from the length of this sedimentation line. (Human PoolPlasm
The length of the sedimentation line of a was defined as IU/-. ) [Example] The present invention will be explained in more detail with the following example.
The present invention is not limited to the number of ships by these Examples.
実施例1
予め第■因子関連抗原濃度を0.12511 / ml
に調整した第X因子複合体(第X因子、第■因子、第■
因子、第X因子の含量は、各々27. OU/mZ、3
6、 OU/mf、 6. OU/m!、40. Ou
/ mlで蛋白濃度は38.0■/ mZ )濃m溶液
のpt+を7.0〜7.5に調整し、粉末状の固形硫酸
アンモニウムを少量ずつ添加し、25〜33%飽和とし
た後、4℃で1〜2時間攪拌した。攪拌後、4℃、9,
000〜10.000r、p、m、で1時間冷却遠心を
行い、得られた上清を、上清の10倍量のクエン酸緩衝
液(pH7,0)を用いて、4℃、−夜透析した。透析
後、透析内液の第X因子活性、第■因子関連抗原量の測
定を行った。その結果、第X因子の回収率は出発原料の
75〜93%であり、第■因子関連抗原の含量は出発原
料の0.5〜5%であった。Example 1 Factor Ⅰ-related antigen concentration was set in advance to 0.12511/ml
Factor X complex (factor X, factor ■, factor ■
The content of factor and factor X is 27. OU/mZ, 3
6. OU/mf, 6. OU/m! , 40. Ou
/ml, the protein concentration is 38.0■/mZ) Adjust the pt+ of the concentrated m solution to 7.0 to 7.5, add powdered solid ammonium sulfate little by little to make it 25 to 33% saturated, Stirred at 4°C for 1-2 hours. After stirring, 4℃, 9,
Refrigerated centrifugation was performed at 000 to 10.000 r, p, m for 1 hour, and the resulting supernatant was incubated at 4°C overnight using 10 times the volume of the supernatant in citrate buffer (pH 7,0). Dialyzed. After dialysis, the factor X activity and the amount of factor Ⅰ-related antigen in the dialysis fluid were measured. As a result, the recovery rate of factor
実施例2
予め第■因子関連抗原濃度を0.25 U/ mlに調
整した第X因子複合体(第X因子、第■因子、第■因子
、第X因子の含量は、各々24. OU/ ml、30
、OU/mZ、10.0117m7.30. Ou/
mZで、蛋白濃度は35.0■/m7)濃縮溶液のpH
を6.0〜6.5に調整し、飽和硫酸アンモニウム溶液
を少量ずつ添加し、最終濃度を15〜35%飽和とした
後、4℃で1〜2時間攪拌した。攪拌後、4℃、9.0
00〜10.00Or、p、m、で1時間冷却遠心を行
い、得られた上清を、上清の10倍量のクエン酸緩衝液
(pH7,0)を用いて、4℃、−夜透析した。透析後
、透析内液の第X因子活性、第■因子関連抗原量の測定
を行った。その結果、前者の回収率は出発原料の65〜
78%であり、後者の含量は出発原料の3〜lO%であ
った。Example 2 A factor ml, 30
, OU/mZ, 10.0117m7.30. Ou/
mZ, protein concentration is 35.0 / m7) pH of concentrated solution
was adjusted to 6.0 to 6.5, and a saturated ammonium sulfate solution was added little by little to give a final concentration of 15 to 35% saturation, followed by stirring at 4°C for 1 to 2 hours. After stirring, 4℃, 9.0
Refrigerated centrifugation was performed for 1 hour at 00 to 10.00 Or, p, m, and the resulting supernatant was incubated at 4°C overnight using 10 times the volume of the supernatant in citrate buffer (pH 7,0). Dialyzed. After dialysis, the factor X activity and the amount of factor Ⅰ-related antigen in the dialysis fluid were measured. As a result, the recovery rate of the former was 65 to 65% of the starting material.
78%, the content of the latter being 3-10% of the starting material.
手続補正書印釦 昭和61年9月30日Procedural amendment stamp button September 30, 1986
Claims (1)
有溶液を硫酸アンモニウムで塩析することを特徴とする
純度の高い第IX因子複合体製剤の製造法。A method for producing a highly pure factor IX complex preparation, which comprises salting out a blood coagulation factor IX-containing solution containing a blood coagulation factor VIII-related antigen with ammonium sulfate.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP61190343A JPS6348220A (en) | 1986-08-13 | 1986-08-13 | Production of blood-coagulating factor ix complex |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP61190343A JPS6348220A (en) | 1986-08-13 | 1986-08-13 | Production of blood-coagulating factor ix complex |
Publications (1)
Publication Number | Publication Date |
---|---|
JPS6348220A true JPS6348220A (en) | 1988-02-29 |
Family
ID=16256616
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP61190343A Pending JPS6348220A (en) | 1986-08-13 | 1986-08-13 | Production of blood-coagulating factor ix complex |
Country Status (1)
Country | Link |
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JP (1) | JPS6348220A (en) |
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1986
- 1986-08-13 JP JP61190343A patent/JPS6348220A/en active Pending
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