CA1186995A - Fibrinogen formulation, a process for its preparation and its use - Google Patents
Fibrinogen formulation, a process for its preparation and its useInfo
- Publication number
- CA1186995A CA1186995A CA000420880A CA420880A CA1186995A CA 1186995 A CA1186995 A CA 1186995A CA 000420880 A CA000420880 A CA 000420880A CA 420880 A CA420880 A CA 420880A CA 1186995 A CA1186995 A CA 1186995A
- Authority
- CA
- Canada
- Prior art keywords
- fibrinogen
- formulation
- solution
- urea
- substance containing
- 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
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
- A61L24/04—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials
- A61L24/10—Polypeptides; Proteins
- A61L24/106—Fibrin; Fibrinogen
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/745—Blood coagulation or fibrinolysis factors
- C07K14/75—Fibrinogen
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Abstract
Abstract of the disclosure:
A solid fibrinogen formulation is described, which formulation contains, in addition to fibrinogen, a substance containing the urea or guanidine radical, and a process for its preparation. This formulation is used for the preparation of a fibrinogen solution which is suitable as an adhesive for human and animal tissue and as a fibrinogen concentrate for intravenous administration.
A solid fibrinogen formulation is described, which formulation contains, in addition to fibrinogen, a substance containing the urea or guanidine radical, and a process for its preparation. This formulation is used for the preparation of a fibrinogen solution which is suitable as an adhesive for human and animal tissue and as a fibrinogen concentrate for intravenous administration.
Description
~ 36~
- 2 - HOE ~2/B on2 - Ma 418 The ;nvention relates to a solid f;brinogen formulation and to a process for its preparation~
This formulation can be used for the preparation of a fibrinogen solution wh;ch is suitable as an adhesive for hu~an and animal tissue and as a solution for intravenous aclministration .
It is known that it is only possible slowly, at elevated temperature and only in low concentration to bring into solution again lyophilized fibrinogen and lyophilizates of plasma proteins conta;nin~ a high pro-portion of fibrinogen.
Fibrinogen has been used for some time as a phys;ological adhesive for taking care of ;njuries to parenchymal organs, oones or vessels. For this ind;ca-tion, it ;s necessary to dissolve the f;brinogen ;n as h;gh a concentrat;on as possible, since the adhesive act;on is a funct;orl of the fibr;nocJen concentrat;on.
Since f;br;nogen soLutions having the necessary content of 8 to 10% of coagulable fibr;nogen can only be prepared from fibrinogen lyophilizates wich d;ff;cult~, deep-frozen fibrinogen-containing so called cryoprecipitate is used for tissue adhesion.
Ho~ever, th;s use of deep-frozen cryoprecipitate is associated with dis~dvantages; since preparations of this type are unstable and must be kep~ at a temperature below -20C until used7 A sol;d fibr;nogen formulation, which coulcl be ~'' ' "' ' ~
This formulation can be used for the preparation of a fibrinogen solution wh;ch is suitable as an adhesive for hu~an and animal tissue and as a solution for intravenous aclministration .
It is known that it is only possible slowly, at elevated temperature and only in low concentration to bring into solution again lyophilized fibrinogen and lyophilizates of plasma proteins conta;nin~ a high pro-portion of fibrinogen.
Fibrinogen has been used for some time as a phys;ological adhesive for taking care of ;njuries to parenchymal organs, oones or vessels. For this ind;ca-tion, it ;s necessary to dissolve the f;brinogen ;n as h;gh a concentrat;on as possible, since the adhesive act;on is a funct;orl of the fibr;nocJen concentrat;on.
Since f;br;nogen soLutions having the necessary content of 8 to 10% of coagulable fibr;nogen can only be prepared from fibrinogen lyophilizates wich d;ff;cult~, deep-frozen fibrinogen-containing so called cryoprecipitate is used for tissue adhesion.
Ho~ever, th;s use of deep-frozen cryoprecipitate is associated with dis~dvantages; since preparations of this type are unstable and must be kep~ at a temperature below -20C until used7 A sol;d fibr;nogen formulation, which coulcl be ~'' ' "' ' ~
- 3 d;ssolved to g;ve a fibr;nogen solution containing at least 7 9/100 ml, would thus be a great advantage.
Furthermore, a fibr;nogen solution of th;s type at a lo~er concentrat;on of about 2% of ~ibrinogen can be ernployed as an ;ntravenous preparation for situa~ions invclving acute use of fibrinogen in patien~s wi~h var;-ous diseasesO At present, fibr;nogen concentrates are employed for this purpose, which are prepared from the cryoprecip;tate and contain various additional plasrna proteins. In contrast, pure fibr;nogen ;s not e~ployed nowadays.
Thus, the present invention has the object of makin~ available a forlnulation based on pure fibrinogen which, because OT ;ts propert;es, can he employed both as a fibr;n adhes;ve and as a fibrinogen concentrate for intravenous admin;strat;on to humans and which has good solubility.
A f;brinogen lyophilizal:e, which is said to be suitable as a -tissue adhes;ve, has been disclosed in Gerrrlan Offenlegungsschrift 3,002~934~ This lyophilizate is ~lso a cryoprec;pitate, wh;cn accordingly conta;ns not only fibrino~en and factor XIII, but also plasminoqen~
alburmin and other plasma constituents. An ;nh;b;tor of plasr~inoyel1 ac~ivator ;s ad~ed to stab;l;ze the lyo~
phil;~ate and the reconstituted solution~ Th;s lyo~
philizate ;s spar;ngly~ and only at elevated temperature t~7C~J soluble~ After reconstl~ution~ ~he produc~ ;s stable for a rnaxirnum of 4 hours at roorn temper~ature~
~l~G95~
A ~yophilized Fibrinogen formulation has now been found, ~Ihich -formulation need not contain either an inhibitor of plasrninogen activator or albumin to stabil-ize ;t and wh;ch is suitable For the preparation of highly concentrated Fibrînogen solutions ~about 8%) even at roorn temperature. I~ is unnecessary to employ cryoprecipitate as the startin~ point, since it ;s also possible to employ pure fibrinogen as the starting product~
This slas made possible by the surprising finding that the solubility of ~ibrinogen lyophilizates is increased and the viscosity, which is irnportant for the processability, of the solutions prepared there-From is decreased by the addition of subst~nces which &ontain a urea or guanidino group~
These effects can be further improved by separat~
in~ out the ~Fibrinoyen polymers contained in the starting produc~9 so that not only cryoprecipitates &an be used as starting material, but also other fibr1nogen pre-cipitates. ey this means~ for example~ more econom;c utilizat;on of the costly cryoprecip;tate is possible:
thus, apart -From F VIII concen rate, fibrinogen con-centrates can also be prepared froln a cryoprecip;tate.
Thus, the invention relat~s to a solid fibrino gen Formulation which contains a substance containin~
the urea or guanidine rad;cal.
A guani~ino cornpound is preFerably added~ Ar~;~
nine ;s part;culclrly su;table~ These compounds are 3~ -added ;n an amount such tha~ ~heir content ;n the Formulat;on is D.05 to 5 per cent by weight.
The formulation is dried, preferably lyoph;li~ed.
In order further to improve the solubility of a fibrirlo~en formulation of this type, an arninoacid having a hydrophobic side chain, ~or example, L-leucine, or a water-soluble fatty acid, for exarnple butyric acid~
can be added to it in each case ;n an amount ~rom ().1 to 5 per cent by weiyhtO
An improvement in the rate o~ dissolut;on can be achieved by filling the ~as space above the solid fib-rinogen formulation with at least 20 per cent by vol~
ume of carbon dioxide. The remainder oF the gas atrlos-phere can be nitrogenr anothel inert gas or air.
Furthermore, the formulation can also contain albumin.
~ hen used as a fibrin adhesive, factor XIII from human plasma or placenta can also be added to increase the resistance to tearing in the rat-~skin tearin~ test described~ A concentra~ion bet~Jeen 40 and 60 U of fac~
tor YIII per ml of fibrinogen concentrate has been found to be optimal.
Adclition o-f an inhibitor of Fibrinolysis, for exarnple aprotin;n, can take place durin~ dissolution of the fibr;nogen concentrate: a -Fibrinogen concentrate containing ~0 U of factor XIII~ 1% of albumin and ~% oF
coagulable fibrinogen is~ for exan1plc~ dissol~ed h~ith a solution o-f aprot;nin havin~ 1~000 kallikre;n inhihitor 5~
units and then is induced to coagulate with a mixture of thrombin and calcium chloride. This m;xture ensures a stable wound closure and also substantial protection against too rapid fibrinolysis.
The invention also relates to a process for the preparation o~ a f-ibrino(3en formulation, which com~
pr;ses maintain;ng a fibrino0en solution at a pH of 5 to 8 and at a temperature of 0 to 15C until the fib-r;nogen polymers have precipitated out, separating these off, adding a substance containing the urea or guani~
dine rad;cal and ~rying.
The solid fibrinogen -formulat;on according to the invention dissolves rnore rapidly and gives higher concentrat;ons than those prepared according to the state of the art~ A~UPOUS solut;ons can be obtained at roorn temperature which contain up to 14 g/100 ml of fib~
rinogen~ If dissolution is carried out at 37C, for exarnple~ even hi~her concentrations can be obta;ned~
S;nce, when fibr;nogen solut;ons of this type are used as tissue adhesives, the tenacity of adhes;on increases with the content of f;br;nogen, greater tena-city is obtained with tissue adhesives derived from concentrates prepared according to the invent;on.
This can be demonstrated in the rat~-skin tear~
in~ test: a circular piece of skin is rernoved frorh an anesthetized experimental an;mal using a punch~ This piece of skin is painted with a rnixture of one part by volume of the fibril1ogen solution according to the -- 7 ~
invention and one part by volume of ~hrombin solut;on (IJOO NIH units/ml)~ then pressed onto the wound mlade by the punch, left there for 15 minutes and thereafter the tear off weight is determined.
Table: Dependency of the tenacîty of adhesion on the fihr;nogen concentration in the rat-skin tearing test ___ Fibrinogen concentration, % Tear-off ~eight in g;
_ _ X ~=
12 206 i 39 B ~Z
0 (control) 16 ~ _ . .
A fùrther advantage of the fibr;nogen concen-trates prepared in the manner described is their stabil~
;ty after reconst;tutionO Since ;mpur;~ies of pro-thrombin factors and plasminogen are r~ormalLy present in cryoprecip1tates, the stabil;ty of cryoprecipitate solutions at room temperature is limited to 2 to 4 hours~
Fibr;nogen concentrates prepared accordin~ to the -fol-lowin~ Example 2 are, in contrast~ stable at room temperature for a ~Jork;ng day.
The followil~g examples are intended to illus~
~rate the invention~
_a~le 1 Preparat;on of a fibrinogen concentrate from cryo-precipitate ._ _ _ _ _ A cryoprecipitate fr~m citrated plasrna was dis solved in a 0.01 M Na citrate solution o-f p~l ~.5 contain-ing 1~ v~ of arginine at 37C. The undissolved fraction was removed by centrifugation in an ultra centrifuge (Beckman J 21-B, Rotor Jh 14) t45 minwtes, 15,000 rpm) and discarded.
After adjustrnent of the fibrinogen concentration to about 5% (w~v~ protein, the pH was maintained between 7~0 and gØ After sterilization by filtration, fiLling out and flooding the container ~ith 100~ by volume of carbon dioxide, a lyophilizate was obtairied, froM which aqueous fibrinoyen solutions containing up to 12~
Sw:v~ of fibrinogen could be prepared a~ room temperature.
le_2 Preparation of a_fibrino~en concentrate ~rom_a f~brino-~en precipitate ~ kg o~ a fibrino~en precipitate~ which had been precipitated from ci cryoplecipitate from citra~ed plasma using a 2 M ylycine solution, were washed w;th 35 liters of buffer (0~15 M NaCl~ 0.01 M citrate and 1 M
glycine) of p~l 8.0 and the supernatant ~as rcmoved by sentriiugation~ The residue was dissolved in 9 lite.rs of O~U1 M citrate and 0~15 M NaCl of pH 8.0 at 37C~
The pll must be below 8~ rhe solution was allowed to stand overnighi at 8 to 10~C and the precipitate llas c~e n~
G~
removed by centr;fugation at 8C.
The supernatant was dialyzed twice against a buf~
fer of pH 8~ which was composed o~ 0~05 M NaCl, 0~005 ~l c;trate, 1 g/100 mt. of L-arg;nine and 0O8 y/100 ml of L-leucine.
For use as a fibrin adhesive, after d1alysis, 60 U of factor XIII per ml and 10 mg of human albumin per ml are added.
The solution was steril;zed by f;ltrat;on, lyophiLized and the product was covered with a mixture of 50% by volurne of carbon d;oxide and 50% by volume of nitrogen.
For intravenous use, the lyophilizates can be dissolved in the concentration for filling out of about 2-3% of fibrinogen, for use as fibrin adhes;ves, they ~re d;ssolved ;n correspond;n~ly less solvent~ so that concentrations bet~!een 8 and 10~, of fibrinogen are obtalned.
Furthermore, a fibr;nogen solution of th;s type at a lo~er concentrat;on of about 2% of ~ibrinogen can be ernployed as an ;ntravenous preparation for situa~ions invclving acute use of fibrinogen in patien~s wi~h var;-ous diseasesO At present, fibr;nogen concentrates are employed for this purpose, which are prepared from the cryoprecip;tate and contain various additional plasrna proteins. In contrast, pure fibr;nogen ;s not e~ployed nowadays.
Thus, the present invention has the object of makin~ available a forlnulation based on pure fibrinogen which, because OT ;ts propert;es, can he employed both as a fibr;n adhes;ve and as a fibrinogen concentrate for intravenous admin;strat;on to humans and which has good solubility.
A f;brinogen lyophilizal:e, which is said to be suitable as a -tissue adhes;ve, has been disclosed in Gerrrlan Offenlegungsschrift 3,002~934~ This lyophilizate is ~lso a cryoprec;pitate, wh;cn accordingly conta;ns not only fibrino~en and factor XIII, but also plasminoqen~
alburmin and other plasma constituents. An ;nh;b;tor of plasr~inoyel1 ac~ivator ;s ad~ed to stab;l;ze the lyo~
phil;~ate and the reconstituted solution~ Th;s lyo~
philizate ;s spar;ngly~ and only at elevated temperature t~7C~J soluble~ After reconstl~ution~ ~he produc~ ;s stable for a rnaxirnum of 4 hours at roorn temper~ature~
~l~G95~
A ~yophilized Fibrinogen formulation has now been found, ~Ihich -formulation need not contain either an inhibitor of plasrninogen activator or albumin to stabil-ize ;t and wh;ch is suitable For the preparation of highly concentrated Fibrînogen solutions ~about 8%) even at roorn temperature. I~ is unnecessary to employ cryoprecipitate as the startin~ point, since it ;s also possible to employ pure fibrinogen as the starting product~
This slas made possible by the surprising finding that the solubility of ~ibrinogen lyophilizates is increased and the viscosity, which is irnportant for the processability, of the solutions prepared there-From is decreased by the addition of subst~nces which &ontain a urea or guanidino group~
These effects can be further improved by separat~
in~ out the ~Fibrinoyen polymers contained in the starting produc~9 so that not only cryoprecipitates &an be used as starting material, but also other fibr1nogen pre-cipitates. ey this means~ for example~ more econom;c utilizat;on of the costly cryoprecip;tate is possible:
thus, apart -From F VIII concen rate, fibrinogen con-centrates can also be prepared froln a cryoprecip;tate.
Thus, the invention relat~s to a solid fibrino gen Formulation which contains a substance containin~
the urea or guanidine rad;cal.
A guani~ino cornpound is preFerably added~ Ar~;~
nine ;s part;culclrly su;table~ These compounds are 3~ -added ;n an amount such tha~ ~heir content ;n the Formulat;on is D.05 to 5 per cent by weight.
The formulation is dried, preferably lyoph;li~ed.
In order further to improve the solubility of a fibrirlo~en formulation of this type, an arninoacid having a hydrophobic side chain, ~or example, L-leucine, or a water-soluble fatty acid, for exarnple butyric acid~
can be added to it in each case ;n an amount ~rom ().1 to 5 per cent by weiyhtO
An improvement in the rate o~ dissolut;on can be achieved by filling the ~as space above the solid fib-rinogen formulation with at least 20 per cent by vol~
ume of carbon dioxide. The remainder oF the gas atrlos-phere can be nitrogenr anothel inert gas or air.
Furthermore, the formulation can also contain albumin.
~ hen used as a fibrin adhesive, factor XIII from human plasma or placenta can also be added to increase the resistance to tearing in the rat-~skin tearin~ test described~ A concentra~ion bet~Jeen 40 and 60 U of fac~
tor YIII per ml of fibrinogen concentrate has been found to be optimal.
Adclition o-f an inhibitor of Fibrinolysis, for exarnple aprotin;n, can take place durin~ dissolution of the fibr;nogen concentrate: a -Fibrinogen concentrate containing ~0 U of factor XIII~ 1% of albumin and ~% oF
coagulable fibrinogen is~ for exan1plc~ dissol~ed h~ith a solution o-f aprot;nin havin~ 1~000 kallikre;n inhihitor 5~
units and then is induced to coagulate with a mixture of thrombin and calcium chloride. This m;xture ensures a stable wound closure and also substantial protection against too rapid fibrinolysis.
The invention also relates to a process for the preparation o~ a f-ibrino(3en formulation, which com~
pr;ses maintain;ng a fibrino0en solution at a pH of 5 to 8 and at a temperature of 0 to 15C until the fib-r;nogen polymers have precipitated out, separating these off, adding a substance containing the urea or guani~
dine rad;cal and ~rying.
The solid fibrinogen -formulat;on according to the invention dissolves rnore rapidly and gives higher concentrat;ons than those prepared according to the state of the art~ A~UPOUS solut;ons can be obtained at roorn temperature which contain up to 14 g/100 ml of fib~
rinogen~ If dissolution is carried out at 37C, for exarnple~ even hi~her concentrations can be obta;ned~
S;nce, when fibr;nogen solut;ons of this type are used as tissue adhesives, the tenacity of adhes;on increases with the content of f;br;nogen, greater tena-city is obtained with tissue adhesives derived from concentrates prepared according to the invent;on.
This can be demonstrated in the rat~-skin tear~
in~ test: a circular piece of skin is rernoved frorh an anesthetized experimental an;mal using a punch~ This piece of skin is painted with a rnixture of one part by volume of the fibril1ogen solution according to the -- 7 ~
invention and one part by volume of ~hrombin solut;on (IJOO NIH units/ml)~ then pressed onto the wound mlade by the punch, left there for 15 minutes and thereafter the tear off weight is determined.
Table: Dependency of the tenacîty of adhesion on the fihr;nogen concentration in the rat-skin tearing test ___ Fibrinogen concentration, % Tear-off ~eight in g;
_ _ X ~=
12 206 i 39 B ~Z
0 (control) 16 ~ _ . .
A fùrther advantage of the fibr;nogen concen-trates prepared in the manner described is their stabil~
;ty after reconst;tutionO Since ;mpur;~ies of pro-thrombin factors and plasminogen are r~ormalLy present in cryoprecip1tates, the stabil;ty of cryoprecipitate solutions at room temperature is limited to 2 to 4 hours~
Fibr;nogen concentrates prepared accordin~ to the -fol-lowin~ Example 2 are, in contrast~ stable at room temperature for a ~Jork;ng day.
The followil~g examples are intended to illus~
~rate the invention~
_a~le 1 Preparat;on of a fibrinogen concentrate from cryo-precipitate ._ _ _ _ _ A cryoprecipitate fr~m citrated plasrna was dis solved in a 0.01 M Na citrate solution o-f p~l ~.5 contain-ing 1~ v~ of arginine at 37C. The undissolved fraction was removed by centrifugation in an ultra centrifuge (Beckman J 21-B, Rotor Jh 14) t45 minwtes, 15,000 rpm) and discarded.
After adjustrnent of the fibrinogen concentration to about 5% (w~v~ protein, the pH was maintained between 7~0 and gØ After sterilization by filtration, fiLling out and flooding the container ~ith 100~ by volume of carbon dioxide, a lyophilizate was obtairied, froM which aqueous fibrinoyen solutions containing up to 12~
Sw:v~ of fibrinogen could be prepared a~ room temperature.
le_2 Preparation of a_fibrino~en concentrate ~rom_a f~brino-~en precipitate ~ kg o~ a fibrino~en precipitate~ which had been precipitated from ci cryoplecipitate from citra~ed plasma using a 2 M ylycine solution, were washed w;th 35 liters of buffer (0~15 M NaCl~ 0.01 M citrate and 1 M
glycine) of p~l 8.0 and the supernatant ~as rcmoved by sentriiugation~ The residue was dissolved in 9 lite.rs of O~U1 M citrate and 0~15 M NaCl of pH 8.0 at 37C~
The pll must be below 8~ rhe solution was allowed to stand overnighi at 8 to 10~C and the precipitate llas c~e n~
G~
removed by centr;fugation at 8C.
The supernatant was dialyzed twice against a buf~
fer of pH 8~ which was composed o~ 0~05 M NaCl, 0~005 ~l c;trate, 1 g/100 mt. of L-arg;nine and 0O8 y/100 ml of L-leucine.
For use as a fibrin adhesive, after d1alysis, 60 U of factor XIII per ml and 10 mg of human albumin per ml are added.
The solution was steril;zed by f;ltrat;on, lyophiLized and the product was covered with a mixture of 50% by volurne of carbon d;oxide and 50% by volume of nitrogen.
For intravenous use, the lyophilizates can be dissolved in the concentration for filling out of about 2-3% of fibrinogen, for use as fibrin adhes;ves, they ~re d;ssolved ;n correspond;n~ly less solvent~ so that concentrations bet~!een 8 and 10~, of fibrinogen are obtalned.
Claims (12)
OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for the preparation of a solid fibrinogen formulation comprising fibrinogen and a substance containing the urea or guanidine radical in which a solution of fibrinogen is maintained at a pH between 6 and 8 and at a temperature of 0 to 15°C until the fibrinogen polymers have precipitated out, the polymers are separated off, a substance containing the urea or guanidine radical is added to the solution and the solution is dried.
2. A solid fibrinogen formulation comprising fibrinogen and a substance containing the urea or guanidine radical, whenever obtained according to a process as claimed in claim 1 or by an obvious chemical equivalent thereof.
3. A process as claimed in claim 1 in which the substance containing the guanidine radical is arginine and it is present in an amount comprising 0.05 to 5% by weight.
4. A solid fibrinogen formulation comprising fibrinogen and 0.05 to 5% by weight of arginine, whenever obtained according to a process as claimed in claim 3 or by an obvious chemical equivalent thereof.
5. A process as claimed in claim 3 in which 0.1 to 5% by weight of an aminoacid having a hydrophobic side chain or a water-soluble fatty acid is added to the solution.
6. A solid fibrinogen formulation comprising fibrinogen, 0.05 to 5% by weight of arginine and 0.1 to 5% by weight of an aminoacid having a hydrophobic side chain or a water-soluble fatty acid, whenever obtained according to a process as claimed in claim 5 or by an obvious chemical equivalent thereof.
7. A process as claimed in claim 1 in which factor XIII and aprotinin are added to the solution.
8. A solid fibrinogen formulation comprising fibrinogen, a substance containing the urea or guanidine radical, factor XIII and aprotinin, whenever obtained according to a process as claimed in claim 7 or by an obvious chemical equivalent thereof.
9. A process as claimed in claim 1 in which the dried formulation is introduced into a container under a gas atmosphere containing at least 20% by volume of carbon dioxide.
10. A solid fibrinogen formulation comprising fibrinogen and a substance containing the urea or guanidine radical in a container under a gas atmosphere containing at least 20%
by volume of carbon dioxide, whenever obtained according to a process as claimed in claim 9 or by an obvious chemical equivalent thereof.
by volume of carbon dioxide, whenever obtained according to a process as claimed in claim 9 or by an obvious chemical equivalent thereof.
11. A process as claimed in claim 1 in which thrombin and calcium ions are also added to the solution.
12. A solid fibrinogen formulation, suitable for use as a tissue adhesive, comprising fibrinogen, a substance containing the urea or guanidine radical, thrombin and calcium ions, whenever obtained according to a process as claimed in claim 11 or by an obvious chemical equivalent thereof.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DEP3203775.9 | 1982-02-04 | ||
| DE19823203775 DE3203775A1 (en) | 1982-02-04 | 1982-02-04 | FIBRINOGEN PREPARATION, METHOD FOR THEIR PRODUCTION AND THEIR USE |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1186995A true CA1186995A (en) | 1985-05-14 |
Family
ID=6154769
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000420880A Expired CA1186995A (en) | 1982-02-04 | 1983-02-03 | Fibrinogen formulation, a process for its preparation and its use |
Country Status (18)
| Country | Link |
|---|---|
| US (1) | US4650678A (en) |
| EP (1) | EP0085923B2 (en) |
| JP (1) | JPS58135817A (en) |
| AR (1) | AR231233A1 (en) |
| AT (1) | ATE22806T1 (en) |
| AU (1) | AU556068B2 (en) |
| CA (1) | CA1186995A (en) |
| DE (2) | DE3203775A1 (en) |
| DK (1) | DK158282C (en) |
| ES (1) | ES8403321A1 (en) |
| FI (1) | FI77985C (en) |
| GR (1) | GR77184B (en) |
| IE (1) | IE54547B1 (en) |
| IL (1) | IL67823A (en) |
| NO (1) | NO155177B (en) |
| NZ (1) | NZ203164A (en) |
| PT (1) | PT76193B (en) |
| ZA (1) | ZA83726B (en) |
Families Citing this family (84)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH0672105B2 (en) * | 1985-10-02 | 1994-09-14 | 持田製薬株式会社 | Thrombolytic agent and manufacturing method thereof |
| DE3622642A1 (en) * | 1986-07-05 | 1988-01-14 | Behringwerke Ag | ONE-COMPONENT TISSUE ADHESIVE AND METHOD FOR THE PRODUCTION THEREOF |
| DK475386D0 (en) | 1986-10-03 | 1986-10-03 | Weis Fogh Ulla Sivertsen | METHOD AND APPARATUS FOR MANUFACTURING BIOLOGICAL SUBSTANCES |
| US4743632A (en) * | 1987-02-25 | 1988-05-10 | Pfizer Hospital Products Group, Inc. | Polyetherurethane urea polymers as space filling tissue adhesives |
| US5449759A (en) * | 1987-05-16 | 1995-09-12 | Somatogen, Inc. | Hemoglobins with intersubunit desulfide bonds |
| FR2618784B1 (en) * | 1987-07-30 | 1990-04-06 | Lille Transfusion Sanguine | CONCENTRATE OF THROMBIN-COAGULABLE PROTEINS, PROCESS FOR OBTAINING SAME AND ITS USE AS A BIOLOGICAL GLUE |
| AT407834B (en) * | 1987-10-08 | 2001-06-25 | Aventis Behring Gmbh | Single-component tissue adhesive and process for its preparation |
| DE3734923C1 (en) * | 1987-10-15 | 1989-01-26 | Biotest Pharma Gmbh | Process for the preparation of a sterile plasma protein solution containing fibrinogen and coagulation factor XIII |
| AT397203B (en) * | 1988-05-31 | 1994-02-25 | Immuno Ag | FABRIC ADHESIVE |
| FR2639958B1 (en) * | 1988-12-06 | 1992-08-21 | Lille Transfusion Sanguine | BIOLOGICAL SUPPORT FOR CELL CULTURES CONSISTING OF PLASMATIC PROTEINS COAGULATED BY THROMBIN, ITS USE FOR THE CULTURE OF KERATINOCYTES, THEIR RECOVERY AND THEIR TRANSPORT FOR THERAPEUTIC USE |
| US4980165A (en) * | 1989-01-27 | 1990-12-25 | Genetics Institute, Inc. | Pharmaceutical formulations of plasminogen activator proteins |
| FR2663226B1 (en) * | 1990-06-15 | 1994-11-18 | Fondation Nale Transfusion San | FLUID BIOLOGICAL GLUE. |
| IE912528A1 (en) * | 1990-07-19 | 1992-01-29 | Scripps Clinic Res | Inhabition of mac-1 receptor binding fibrinogen using d30¹homologs |
| US5420250A (en) * | 1990-08-06 | 1995-05-30 | Fibrin Corporation | Phase transfer process for producing native plasma protein concentrates |
| US5644032A (en) * | 1990-08-06 | 1997-07-01 | Fibrin Corporation | Process for producing fibrinogen concentrates |
| US6197325B1 (en) * | 1990-11-27 | 2001-03-06 | The American National Red Cross | Supplemented and unsupplemented tissue sealants, methods of their production and use |
| US6054122A (en) | 1990-11-27 | 2000-04-25 | The American National Red Cross | Supplemented and unsupplemented tissue sealants, methods of their production and use |
| DE4202667C1 (en) | 1992-01-29 | 1993-05-13 | Behringwerke Ag, 3550 Marburg, De | |
| AU670793B2 (en) * | 1992-04-30 | 1996-08-01 | Alpha Therapeutic Corporation | Improved solubilization and stabilization of factor VIII complex |
| ES2165366T3 (en) * | 1992-06-11 | 2002-03-16 | Scripps Research Inst | PROCEDURES AND COMPOSITIONS TO INHIBIT THE INFLAMMATION MEDIATED BY ENDOTELIAL CELLS AND FIBRINOGEN. |
| US5599790A (en) | 1992-06-11 | 1997-02-04 | The Scripps Research Institute | Fibrinogen γ chain polypeptide and compositions thereof |
| US5385606A (en) * | 1992-07-06 | 1995-01-31 | Kowanko; Nicholas | Adhesive composition and method |
| CN1091315A (en) * | 1992-10-08 | 1994-08-31 | E·R·斯奎布父子公司 | Fibrin sealant compositions and using method thereof |
| US5554345A (en) * | 1992-10-14 | 1996-09-10 | Novozone (N.V.) Limited | Ozone generation apparatus and method |
| US5330974A (en) * | 1993-03-01 | 1994-07-19 | Fibratek, Inc. | Therapeutic fibrinogen compositions |
| EP0726749B1 (en) * | 1993-11-03 | 2004-08-11 | Clarion Pharmaceuticals, Inc. | Hemostatic patch |
| DE758903T1 (en) * | 1994-03-31 | 1997-07-10 | Fibrin Corp | CONCENTRATES OF CRYOPRECIPTED, NATURAL FIBRINOGEN |
| US5585007A (en) | 1994-12-07 | 1996-12-17 | Plasmaseal Corporation | Plasma concentrate and tissue sealant methods and apparatuses for making concentrated plasma and/or tissue sealant |
| ATE309006T1 (en) * | 1996-03-15 | 2005-11-15 | Chemo Sero Therapeut Res Inst | SPRAY DEVICE FOR APPLYING FABRIC ADHESIVE |
| JP2000509374A (en) | 1996-04-19 | 2000-07-25 | アルファ セラピュティック コーポレイション | Method for virus inactivation of lyophilized blood proteins |
| DE19617369A1 (en) * | 1996-04-30 | 1997-11-06 | Immuno Ag | Storage-stable fibrinogen preparations |
| US6503527B1 (en) | 1997-11-17 | 2003-01-07 | Haemacure Corporation | Fibrin sealants or adhesives comprising a hyaluronic acid derivative material |
| AUPP276098A0 (en) * | 1998-04-01 | 1998-04-30 | Nokuta Pty Ltd | A method for treating gelatine |
| DE69941498D1 (en) * | 1998-11-12 | 2009-11-12 | Internat Mfg Group Inc | Hemostatic cross-linked dextran beads useful for rapid blood clotting and hemostasis |
| WO2000047621A1 (en) | 1999-02-12 | 2000-08-17 | Baxter Aktiengesellschaft | A method for producing a preparation based on fibrinogen and fibronectin as well as protein compositions obtainable according to this method |
| ES2156731B1 (en) * | 1999-05-31 | 2002-02-16 | Grifols Grupo Sa | USE OF TRANEXAMIC ACID FOR THE PREPARATION OF A HUMAN FIBRINOGEN COMPOSITION. |
| WO2001012244A1 (en) * | 1999-08-13 | 2001-02-22 | Omrix Biopharmaceuticals S.A. | Use of fibrinogen multimers |
| US6916911B1 (en) | 1999-08-13 | 2005-07-12 | Omrix Biopharmaceuticals Sa | Use of fibrinogen multimers |
| US6960463B2 (en) * | 1999-12-23 | 2005-11-01 | Csl Limited | Separation of fibrinogen from plasma proteases |
| US6468660B2 (en) | 2000-12-29 | 2002-10-22 | St. Jude Medical, Inc. | Biocompatible adhesives |
| US20020146409A1 (en) * | 2001-01-30 | 2002-10-10 | Herring Steven W. | Methods for stabilizing lyophilized blood proteins |
| US20020173770A1 (en) * | 2001-05-16 | 2002-11-21 | Flory Alan R. | Adhesive delivery system |
| US20030224994A1 (en) * | 2002-04-05 | 2003-12-04 | Newton Colin John | Storage stable liquid sealer protein complex |
| US7832566B2 (en) | 2002-05-24 | 2010-11-16 | Biomet Biologics, Llc | Method and apparatus for separating and concentrating a component from a multi-component material including macroparticles |
| US7992725B2 (en) | 2002-05-03 | 2011-08-09 | Biomet Biologics, Llc | Buoy suspension fractionation system |
| US20030205538A1 (en) | 2002-05-03 | 2003-11-06 | Randel Dorian | Methods and apparatus for isolating platelets from blood |
| US7374678B2 (en) * | 2002-05-24 | 2008-05-20 | Biomet Biologics, Inc. | Apparatus and method for separating and concentrating fluids containing multiple components |
| DE10392686T5 (en) * | 2002-05-24 | 2005-07-07 | Biomet Mfg. Corp., Warsaw | Apparatus and method for separating and concentrating liquids containing multiple components |
| US7845499B2 (en) | 2002-05-24 | 2010-12-07 | Biomet Biologics, Llc | Apparatus and method for separating and concentrating fluids containing multiple components |
| US20060278588A1 (en) | 2002-05-24 | 2006-12-14 | Woodell-May Jennifer E | Apparatus and method for separating and concentrating fluids containing multiple components |
| FR2857267B1 (en) * | 2003-07-09 | 2006-03-10 | Lab Francais Du Fractionnement | STABILIZING AND SOLUBILIZING FORMULATION FOR CRYOPRECIPITABLE PROTEINS. |
| EP1763552A1 (en) * | 2004-07-08 | 2007-03-21 | Symatese | Collagen-based lyophilised glue and the use thereof for producing an adhesive prosthesis |
| FR2872821B1 (en) * | 2004-07-08 | 2006-09-29 | Symatese Soc Par Actions Simpl | COLLAGEN-BASED LYOPHILIZED GLUE AND USE THEREOF FOR THE MANUFACTURE OF COLLANT PROSTHESES |
| WO2006086199A1 (en) * | 2005-02-07 | 2006-08-17 | Hanuman Llc | Platelet rich plasma concentrate apparatus and method |
| EP1848474B1 (en) | 2005-02-07 | 2013-06-12 | Hanuman LLC | Platelet rich plasma concentrate apparatus and method |
| US7866485B2 (en) | 2005-02-07 | 2011-01-11 | Hanuman, Llc | Apparatus and method for preparing platelet rich plasma and concentrates thereof |
| US20070248653A1 (en) * | 2006-04-20 | 2007-10-25 | Cochrum Kent C | Hemostatic compositions and methods for controlling bleeding |
| US8567609B2 (en) | 2006-05-25 | 2013-10-29 | Biomet Biologics, Llc | Apparatus and method for separating and concentrating fluids containing multiple components |
| US8430813B2 (en) * | 2006-05-26 | 2013-04-30 | Depuy Spine, Inc. | Illuminated surgical access system including a surgical access device and integrated light emitter |
| KR20090122279A (en) | 2007-03-22 | 2009-11-26 | 자이단호진 가가쿠오요비겟세이료호겐쿠쇼 | Solid fibrinogen preparation |
| US8328024B2 (en) | 2007-04-12 | 2012-12-11 | Hanuman, Llc | Buoy suspension fractionation system |
| JP5479319B2 (en) | 2007-04-12 | 2014-04-23 | バイオメット・バイオロジックス・リミテッド・ライアビリティ・カンパニー | Buoy suspension fractionation system |
| EP2567692B1 (en) | 2008-02-27 | 2016-04-06 | Biomet Biologics, LLC | Use of a device for obtaining interleukin-1 receptor antagonist rich solutions |
| US8337711B2 (en) * | 2008-02-29 | 2012-12-25 | Biomet Biologics, Llc | System and process for separating a material |
| US8012077B2 (en) * | 2008-05-23 | 2011-09-06 | Biomet Biologics, Llc | Blood separating device |
| US8187475B2 (en) | 2009-03-06 | 2012-05-29 | Biomet Biologics, Llc | Method and apparatus for producing autologous thrombin |
| US8313954B2 (en) * | 2009-04-03 | 2012-11-20 | Biomet Biologics, Llc | All-in-one means of separating blood components |
| US9011800B2 (en) * | 2009-07-16 | 2015-04-21 | Biomet Biologics, Llc | Method and apparatus for separating biological materials |
| US8591391B2 (en) | 2010-04-12 | 2013-11-26 | Biomet Biologics, Llc | Method and apparatus for separating a material |
| CA3078563A1 (en) | 2011-12-29 | 2013-07-04 | Omrix Biopharmaceuticals Ltd. | Method and device for fast dissolution of solid protein composition |
| MX351340B (en) | 2012-03-13 | 2017-10-11 | Octapharma Ag | Improved process for production of fibrinogen and fibrinogen produced thereby. |
| US9642956B2 (en) | 2012-08-27 | 2017-05-09 | Biomet Biologics, Llc | Apparatus and method for separating and concentrating fluids containing multiple components |
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| US20140271589A1 (en) | 2013-03-15 | 2014-09-18 | Biomet Biologics, Llc | Treatment of collagen defects using protein solutions |
| EP3769618A1 (en) | 2014-06-09 | 2021-01-27 | Terumo BCT, Inc. | Lyophilization container |
| US9713810B2 (en) | 2015-03-30 | 2017-07-25 | Biomet Biologics, Llc | Cell washing plunger using centrifugal force |
| US9757721B2 (en) | 2015-05-11 | 2017-09-12 | Biomet Biologics, Llc | Cell washing plunger using centrifugal force |
| US20170136070A1 (en) * | 2015-11-18 | 2017-05-18 | Dregalla Patent Holdco, LLC | Acellular Regenerative Products and Methods of Their Manufacture |
| JP7110360B2 (en) | 2017-10-09 | 2022-08-01 | テルモ ビーシーティー バイオテクノロジーズ，エルエルシー | Freeze-drying method |
| JP2022525742A (en) | 2019-03-14 | 2022-05-19 | テルモ ビーシーティー バイオテクノロジーズ，エルエルシー | Freeze-drying loading tray assembly and system |
| CN117794516A (en) | 2021-08-13 | 2024-03-29 | 生物测试股份公司 | Fibrinogen compositions and methods of preparation |
Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2461969A1 (en) * | 1974-12-31 | 1976-07-08 | Behringwerke Ag | STABLE BLOOD PLASMA, THE PROCESS FOR PRODUCING IT AND ITS USE AS A COMPARATIVE PLASMA IN COOLAGE EXAMINATIONS |
| JPS5598196A (en) * | 1979-01-16 | 1980-07-25 | Meito Sangyo Kk | Fractionation of fibrinogen or its constituents and their use |
| AT359653B (en) * | 1979-02-15 | 1980-11-25 | Immuno Ag | METHOD FOR PRODUCING A TISSUE ADHESIVE |
| AT359652B (en) * | 1979-02-15 | 1980-11-25 | Immuno Ag | METHOD FOR PRODUCING A TISSUE ADHESIVE |
| US4362661A (en) * | 1979-08-09 | 1982-12-07 | Teijin Limited | Immunoglobulin composition having a high monomer content, and process for production thereof |
| US4440679A (en) * | 1980-03-05 | 1984-04-03 | Cutter Laboratories, Inc. | Pasteurized therapeutically active protein compositions |
| US4294753A (en) * | 1980-08-04 | 1981-10-13 | The Regents Of The University Of California | Bone morphogenetic protein process |
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1983
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- 1983-01-31 EP EP83100869A patent/EP0085923B2/en not_active Expired - Lifetime
- 1983-01-31 AT AT83100869T patent/ATE22806T1/en not_active IP Right Cessation
- 1983-02-02 GR GR70394A patent/GR77184B/el unknown
- 1983-02-02 NZ NZ203164A patent/NZ203164A/en unknown
- 1983-02-02 IL IL67823A patent/IL67823A/en not_active IP Right Cessation
- 1983-02-02 AR AR292015A patent/AR231233A1/en active
- 1983-02-02 FI FI830361A patent/FI77985C/en not_active IP Right Cessation
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- 1983-02-03 AU AU11105/83A patent/AU556068B2/en not_active Ceased
- 1983-02-03 DK DK044483A patent/DK158282C/en active
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- 1983-02-03 NO NO830371A patent/NO155177B/en not_active IP Right Cessation
- 1983-02-03 ZA ZA83726A patent/ZA83726B/en unknown
- 1983-02-03 PT PT76193A patent/PT76193B/en not_active IP Right Cessation
- 1983-02-03 IE IE207/83A patent/IE54547B1/en not_active IP Right Cessation
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1984
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| IL67823A (en) | 1986-01-31 |
| JPH047328B2 (en) | 1992-02-10 |
| ZA83726B (en) | 1983-10-26 |
| JPS58135817A (en) | 1983-08-12 |
| EP0085923A1 (en) | 1983-08-17 |
| FI77985C (en) | 1989-06-12 |
| DK44483D0 (en) | 1983-02-03 |
| ES519469A0 (en) | 1984-03-16 |
| PT76193A (en) | 1983-03-01 |
| PT76193B (en) | 1986-01-10 |
| DE3366841D1 (en) | 1986-11-20 |
| DK158282B (en) | 1990-04-30 |
| ATE22806T1 (en) | 1986-11-15 |
| FI830361L (en) | 1983-08-05 |
| IE830207L (en) | 1983-08-04 |
| EP0085923B2 (en) | 1991-01-23 |
| FI77985B (en) | 1989-02-28 |
| NZ203164A (en) | 1985-08-30 |
| DK44483A (en) | 1983-08-05 |
| AU1110583A (en) | 1983-08-11 |
| NO155177B (en) | 1986-11-17 |
| NO830371L (en) | 1983-08-05 |
| IE54547B1 (en) | 1989-11-08 |
| EP0085923B1 (en) | 1986-10-15 |
| DE3203775A1 (en) | 1983-08-11 |
| IL67823A0 (en) | 1983-06-15 |
| GR77184B (en) | 1984-09-11 |
| DK158282C (en) | 1990-10-01 |
| ES8403321A1 (en) | 1984-03-16 |
| US4650678A (en) | 1987-03-17 |
| FI830361A0 (en) | 1983-02-02 |
| AR231233A1 (en) | 1984-10-31 |
| AU556068B2 (en) | 1986-10-23 |
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