CN1073605A - The biogum of the improvement by adopting the preparation of low-temperature precipitation thing - Google Patents
The biogum of the improvement by adopting the preparation of low-temperature precipitation thing Download PDFInfo
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- CN1073605A CN1073605A CN 92112470 CN92112470A CN1073605A CN 1073605 A CN1073605 A CN 1073605A CN 92112470 CN92112470 CN 92112470 CN 92112470 A CN92112470 A CN 92112470A CN 1073605 A CN1073605 A CN 1073605A
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Abstract
The invention describes a kind of tissue glue, component A and B component are contained in this tissue glue.Component A contains the low-temperature precipitation thing of whole blood and is equivalent to 3,000-5, the high content of protein enzyme inhibitor of 000KIU/ml unit's aprotinin; B component contains proteolytic enzyme, and this endonuclease capable makes the Fibrinogen cracking that exists among the component A single-mindedly and fibrin polymer is formed.
Described the tissue glue that improves in the concrete scheme of another kind, it contains the component A and the B component of the low-temperature precipitation thing of whole blood.B component contains can be from the proteolytic enzyme of snake venom acquisition, and this endonuclease capable makes the Fibrinogen cracking that exists among the component A single-mindedly and fibrin polymer is formed.
Description
The present invention relates to contain the application that the tissue glue of A and two kinds of components of B, the method for preparing this tissue glue, use high-load aprotinin and venom proteolytic enzyme prepare tissue glue.
The local hemostasis that improves the surgical wound position by the use plasma protein is well-known.Therefore, the fibrin wound adhesive tape has been used for the department of cerebral surgery hemostasis at present.Prepare the fibrin film that surgical wound is used with blood plasma and thrombin.In 20 years, there are a large amount of publications to describe " Fibrin Glue " or " fibrin adhesive " or " fibrin sealant " are used for most surgeries in the past.Be extensive use of commercially available " glue " preparation in the past in 10 years in Europe.This " glue " is grouped into by two kinds of one-tenth, and these mixture of ingredients produce grumeleuse.First kind of composition is fibrinogen concentrate.This concentrate also contains the Fibronectin and the X III factor, and the latter is important for the stable and intensity of grumeleuse.Second kind of composition is thrombin, is about to the organized enzyme that Fibrinogen (last a kind of composition of normal condensed system) is transformed into fibrin clot.This method is walked around normal agglomerative most steps and is imitated its final stage.Some manufacturers add plasminogen (this is a kind of enzyme that makes clot dissolution after some times), and other manufacturers add aprotinin (this is a kind of protease inhibitor that prevents clot dissolution).
Although these products have the patient of hyporrhea disease to obtain gratifying result for those, suffer from serious hemorrhagic disease for example the patient of hemophilia A or B the danger of very high postoperative hemorrhage is still arranged.The hemorrhage complication of delay takes place after average a couple of days at surgical operation sometimes.Those patients that cross with the anti-agglomeration factor in treatment can't treat with the tissue glue of prior art.The another kind of serious unfavorable conditions of commercially available concentrate is the cost height.
WO86/01814 discloses the method that a kind of preparation contains the low-temperature precipitation suspension of the Fibrinogen and the VIII factor, this cryoprecipitate suspension is as the precursor of fibrin glue preparation, this method comprises that (a) is freezing at least completely 6 hours at-80 ℃ with the FFP of single donor (a for example people or other animals that inspection is examined through bloodborne diseases), (b) make the temperature of frozen plasma for example rise to 0 ℃, to form supernatant and to contain the suspension of the low-temperature precipitation of the Fibrinogen and the VIII factor between the room temperature; (c) reclaim this low-temperature precipitation suspension.This patent also discloses a kind of preparation method that is used for the Fibrin Glue of surgery art process, and this method comprises: (a) prepare the low-temperature precipitation suspension as mentioned above; (b) desired area is used the suspension of certain volume; (c) use the compositions that contains the q.s thrombin so that the Fibrinogen in the suspension changes into Fibrin Glue, solidify then to this position.
EP-A-0341007 discloses the surgical glue stick, and it contains patient's self blood plasma, collagen, thrombin with the form of Aquo-composition, and not necessarily can contain the fibrinolysis agent.This adhesive forms from patient's blood plasma, does not need to use to concentrate or the former any additives of separating fibrin.This adhesive is mixed with two parts compositions easily, before use with its mixing.
EP-A-0253198 discloses the tissue glue of a component, and it has Fibrinogen, the VIII factor, thrombin inhibitor, prothrombin factor, calcium ion and arbitrarily can contain the aqueous solution of blood plasma enzyme inhibitor.This tissue glue can recover from the lyophilizing sample by adding entry.All active substances of pasteurization form can be contained in this tissue glue, shift to avoid hepatitis and HTLV III.
The purpose of this invention is to provide a kind of tissue glue, this tissue glue also is applicable to the patient who suffers from serious blood clotting disease such as hemophilia A or B.Another object of the present invention provides a kind of tissue glue, and this tissue glue also can be used for those patients who is easy to generate anti-thrombin of beef antibody, and this antibody is the active factors of B component.It is to provide tissue glue for the patient who accepts the anti-agglomeration factor such as heparin therapy that the present invention also has another purpose.Because the danger that tissue glue's composition has the transfer virus disease must guarantee that tissue glue's composition is an inactivation of virus.
Component A is contained in tissue glue of the present invention, and it contains the low-temperature precipitation thing and the high content of protein enzyme inhibitor (being equivalent to 3,000 to 5, the aprotinin of 000KIU/ml unit) of whole blood, preferred aprotinin; B component is also contained in this tissue glue, and it contains proteolytic enzyme, and this endonuclease capable makes the Fibrinogen cracking that exists among the component A single-mindedly and fibrin polymer is formed.
Commercially available low-temperature precipitation thing can be used for preparing tissue glue of the present invention.But factor 2-5, the preferred factor 3 has to be beneficial to and concentrates this low-temperature precipitation thing.
In this low-temperature precipitation thing, add and be equivalent to 3,000-5, the protease inhibitor of the enough concentration of 000KIU/ml unit's aprotinin amount prepares the tissue glue of the present invention that is applicable to the severe haemorrhage patient.Preferred protease inhibitor is aprotinin, and it can be with trade mark Trasylol
Or Antagosan
Buy.
This low-temperature precipitation thing can be before operation be provided from source blood unit by patient oneself and obtains.This method has prevented the danger by blood derivant virus spread., in order to obtain suitable commercially available prod, essential with this low-temperature precipitation thing inactivation of virus.In PCT/EP 91/00503, virus inactivating method has been described.Its ultimate principle is with specific detergent treatment low-temperature precipitation thing, removes cleaning agent then from the low-temperature precipitation thing.
Second kind of component of tissue glue of the present invention is that B component is by the formulations prepared from solutions of proteolytic enzyme that can single-minded ground broken fiber proteinogen.Usually use thrombin, it is for example isolating the blood plasma of cattle from people or mammal.Can make thrombin recover moisture content with the 40mmol calcium chloride solution.Preferred concentration of thrombin is 50-200u/ml.
For the quick tissue glue of preparation, need the calcium chloride solution of the about 100u/ml thrombin of preparation.For preparing the glue that glue at a slow speed for example is used for filling cavity (i.e. exodontia) or sealing transphenoided hypophisectomy hole, thrombin further need be dissolved to the concentration of 25u/ml with suitable calcium chloride solution.
Another concrete scheme of the improved tissue glue of the present invention is to contain from the isolating proteolytic enzyme of snake venom as forming B.This concrete scheme is favourable, also can receive treatment because produce the patient of antithrombase antibody.In addition, the patient who treated in advance with heparin also can be with tissue glue of the present invention treatment, because heparin does not influence the reaction of reptilase.Used reptilase batroxobin in the particularly preferred concrete scheme of the present invention, it can separate from the Shen Wa adder Bothrpos moujeni of South America.Preferably, form the various proteolytic enzymes that B contains 0.5-10 μ/ml snake venom.
The batroxobin that chemical method obtains is that molecular weight is about 36,000 strand glycopeptide.Defibrase
Cause α 16Arg/17Glg bond fission in the Fibrinogen, the fibrin principle causes that fibrinopeptide A discharges and formation monomer fibrin I.
When aprotinin is used with amount of the present invention, contain the Fibrinogen of purification, the tissue glue of the Fibronectin and the X III factor also can be used as component A.The back danger of bleeding has just significantly reduced so.
When the Proteolytic enzyme protease that derives from snake venom is used for the preparation of B component, also can uses and contain Fibrinogen, " routine " component A of the Fibronectin and the X III factor.The present invention preferably uses high-load aprotinin.Best concrete scheme is to contain or do not contain a large amount of aprotiniies from the component A(of the present invention that the low-temperature precipitation thing obtains) combine with the B component of the present invention that has from the isolating proteolytic enzyme of snake venom.
The preparation method of Fibrin Glue of the present invention comprises the step of making component A, comprises the step for preparing low temperature thing solution from the low-temperature precipitation thing,
-inactivation of virus,
-remove antiviral,
-add protease inhibitor and
The protein enzyme solution that-preparation is suitable.
Preferably the low temperature paste is thawed in advance at 4-10 ℃ and spend the night.The low temperature paste is dissolved in the buffer that contains sodium chloride, trisodium citrate and glycine of PH7.0-7.2, is heated to 30-35 ℃ then.The low temperature paste should be easy to dissolving, otherwise it is not suitable for said preparation.After thawing the low temperature paste cut into pieces and can accelerate its dissolving.Solution is cooled near room temperature and regulates pH value to 7.0-7.2, add aluminium hydroxide while stirring.Centrifugal and decant precipitate.Can carry out nonessential filtration step.Add calcium chloride then to required final calcium chloride concentration.
Solution is heated to 30 ℃ makes inactivation of virus.Add cleaning agent then.Restir a period of time changes solution in the virus-free container over to, and under the stirring condition it is heated up several hours gradually.
Remove antiviral by adding a certain amount of Oleum Ricini and stirring a few minutes gently.When oil/aqueous phase separation, solution is cooled to room temperature.Water layer is moved in the container of virus safe and the decant oil-yielding stratum.Filtration makes the water layer clarification.PH must be controlled at 7.0-7.2.Make it pass through reversed-phase column at room temperature suction protein solution then.Measuring protein content (scope of 10-60mg/ml) afterwards, to filter concentrate eluant to protein content thoroughly be 60-100mg/ml and dialyse in buffer, and this buffer is identical with above-mentioned buffer, just contains the calcium chloride of additional higher concentration.Add protease inhibitor then.Carry out aseptic filtration and with the sample low-temperature freeze drying in the suitable containers of packing into.
Preferred ingredients B is the lyophilized protein enzyme.Particularly preferably be the lyophilizing fraction of lyophilized thrombin or South America Shen Wa adder Bothrpos moujeni.The commodity of known this proteolytic enzyme are called reptilase (Reptilase) and are enzyme batroxobin.
Proteolytic enzyme is dissolved in the calcium chloride buffer.
Adopt the double injection technology for example to use A and two kinds of components of B by plastic connector.Two kinds of components form grumeleuse once mixing.Can or be sprayed onto on three lumens by intubate and use.With each chamber of inject separating of two kinds of components, and some atmospheric pneumatic supplies are connected on the 3rd chamber with this mixture of spraying.
Tissue glue of the present invention is advantageous, because the patient that it can be suffered from serious blood clotting disease uses, and more cheap than known tissue glue.Suffer from serious haemophiliachemophiliac patient and still can for example have tooth pulled out and do not need preventative injection VIII factor concentrate, its success rate surpasses 80%.This just means to have only about 1/5 patient to need infusion VIII factor concentrate because of postextraction hemorrhage.This class patient that this external heparin was treated in advance can accept the treatment of tissue glue of the present invention.Another advantage is the treatment that patient that antithrombase (second kind of component of this tissue glue) antibody raises can accept tissue glue of the present invention, and thrombin is by snake venom proteinase De-fibrase particularly in this tissue glue
Substitute Defibrase
Be from the isolating serine protease batroxobin of South America Shen Wa adder Bothrpos moujeni poison.
The following examples have further described the present invention rather than restriction the present invention.
Human fibrinogen's (L level) derives from Kabi(Stockholm), thrombin of beef derives from Merz-Dade.Product coloring matter N-a-benzoyl-DL-arginine-p-nitroanilide (BAPNA) and analytical grade reagent are derived from Sigma(st.Louis, MO).Use 0.015M Tris, the 0.15M NaCl of PH7.4 to dilute reagent and salt.Fibrinogen is dialysed with the Tris buffer, and its concentration adopts E
1% 280=15 conversion factor is from Abs
280Measure.
Thrombin of beef is commercially available (Merz-Dade or Parke Davis), and its activity is measured by manufacturer.Peptilase
(a kind of snake venom that discharges FPA) derives from Pen-tapharm(Basel).37 ℃, in the Tris/ of PH8.0 saline, by Reptilase relatively
Non-specific product coloring matter BAPNA(0.25mM with thrombin) Proteolytic enzyme speed makes Reptilase
Proteolytic activity to the proteolytic activity standardization of thrombin, 405nm monitoring 15 minutes.
According to its ester lytic activity, make of the units activity standardization of the units activity of reptilase to thrombin.
Fibrin Glue comes down to produce by bi-injection method, contains Fibrinogen material pure or low-temperature precipitation in the syringe, contains the reptilase (20u/ml) or the thrombin that have calcium chloride (20mM) in another syringe.
(IL Milan) measures the grumeleuse time (CT) with Research Model 300-R ACL coagulation assay instrument.On 3 logical Heiliger teg instruments, measure viscoelasticity (TEG) at 37 ℃.By staple fibre sheet (the epoxy glue component between 0.5 * 1cm) of slightly knitting at two, make the gel that formation is interweaved fully between two coarse mesh fabrics, and 24 ℃ after 2 hours with Accuforce Cadet Tensionometer(AMATEK, Mansfield ﹠amp; Greene USA) draws back the integral body of net-glue-net, measures the fracture strength (BS) of glue (in gram).
Prepare sterile cryogenic precipitate (cryo) from the human plasma of freezing (30 ℃), this blood plasma thaws and removes supernatant blood plasma at 4 ℃.Five parts of such units are injected in the protein of mensuration, and before or after low-temperature precipitation thing (1:5 dilution) condenses, measure fibrinogenic concentration with the 2U/ml thrombin by the Buiret method.With the 4U/ml thrombin of beef after 22 ℃ make sample activation 10 minutes, by measure with the dimethyl casein bonded [
3H] putrescine mensuration X III factor.
The marked feature of CT-fibrin virgin curve is to be that two-phase (is 1U/ml, Figure 1A), and reaches minima in 1-8mM Fibrinogen scope for the thrombin of constant concentration or reptilase.These are slightly different with maximum turbidity (after 10 minutes), and maximum turbidity reaches peak value in 20-40mM Fibrinogen scope.Opposite test shows that CT depends on the content of thrombin or reptilase.The gelation rate antidependence that it is approaching linearity that this curve shows in low enzyme concentration (being lower than 2U/ml), and on high level, reach steady statue.
The development of pure fibrin viscoelastic degree is slower slightly than its turbidity.In inductive protein chain covalency interlocking reinforcement gel by the X III a factor, the Ca(II) be main cofactor.This gel is crosslinked to be the main source of gel mechanical strength, reaches steady statue after 20 minutes.
The attention of the ability of snake poison blood coagulation enzyme induction X III a factor active seemingly is fit to.
The protein content of blended low-temperature precipitation thing:
Obtain following meansigma methods from the mixing low temp precipitate of 5 units preparation:
Protein: 75mg/ml
Fibrinogen: 36mg/ml
The X III factor: 4.10U/ml
Rate of set:
The grumeleuse time (CT) of low-temperature precipitation thing is linear dependence to thrombin or reptilase content.But, being higher than 3U/ml, the content that increases enzyme does not almost exert an influence to CT.For the enzyme of constant concentration, obtain being equivalent to the dependent two-phase CT curve of Fibrinogen shown in the pure fibrin system with the diluent of a series of low-temperature precipitation things.
The viscoelasticity (TEG) of low-temperature precipitation thing glue and fracture strength (BS).
With thrombin or reptilase the viscoelasticity formation of low-temperature precipitation thing glue is studied.The development reduced turbidity of this parameter is slower.But, use excess amount of Ca Cl
2In roughly the same time range, obtained the TEG value that equates with the low-temperature precipitation thing glue of thrombin or reptilase preparation.As if after initial gelling begins, the X III a factor is inductive crosslinkedly to support the gel rubber structure, so two brood lac TEG values were met in one hour.Use excess amount of Ca Cl
2The final BS value of two kinds of low-temperature precipitation thing glue that form also is same.Two kinds of low-temperature precipitation thing glue all rupture at 50-60g.These tests show that the gelatinous fibre in this glue scope strengthened by the inductive covalent cross-linking of the X III a factor.
The preparation of low-temperature precipitation thing solution.Commercially available low temperature paste thawed in advance at 4 ℃-10 ℃ spend the night.With 1 kilogram of this low temperature thing be dissolved in 2 liters of buffer A (120mM/L NaCl, 10mM/L trisodium citrate, 120mM/L glycine, PH7.0-7.2) in and be preheated to 30-35 ℃.This low temperature paste should dissolve easily, otherwise will not be suitable for this preparation.In order to accelerate dissolution velocity, after thawing, the low temperature pastel is cut into pieces.Then solution is cooled to 20 ℃-22 ℃ and regulate PH.Must be by selectively adding dilute sodium hydroxide or acid adjusting PH to 7.0-7.2.Added 100ml aluminium hydroxide and restir 30 minutes.Centrifugal and decant precipitates.With 1 μ m filter filtering supernatant.Add 0.1M/L CaCl
2Make Ca
2+Ultimate density is 1mM/L.Regulate PH once more.
Inactivation of virus.
Solution is heated to 30 ℃.Add 1%w/vTNBP and 1%w/v Triton X-100.Mixture was stirred 1/2 hour gently.Then solution is changed in the virus-free container, and do not placing 3 1/2 hours at 30 ℃ under the stirring condition.
Remove antiviral.
The 150ml Oleum Ricini is added to as mentioned above in the mixture of preparation and stirred gently 30 minutes.When waiting for oil/separated form water (30-45 minute), make solution be cooled to 20 ℃.Water layer is moved in the container of virus safe.And oil reservoir is discarded.Stepwise filters and makes the water layer clarification on 1 μ m/0.45 μ m filter.Make its speed pass through reversed-phase column (C-18 post) at room temperature suction protein solution then with 3 liters/hour.With uv monitoring throughput and collect component and be returned to 50% up to absorbance.Measure as the protein analysis method, this fraction contains about 40mg/ml.
It is 70-80mg/ml that the saturating filter of eluent is concentrated into protein content, and the buffer B of q.s (identical with the composition of buffer A, just added 1mM/L CaCl in addition
2) middle dialysis.In every liter of solution, add 4mio KIU aprotinin then.Carry out stepwise aseptic filtration with 0.45 μ m+0.2 μ m filter.Then solution is packed in the plastic bag with extremely low temperature fast refrigeration, also can lyophilizing.The preparation of thrombin solution.
Lyophilized thrombin is dissolved in the 40mM/L calcium chloride solution.The amount of thrombin is 100u/ml in glue.For the glue of fast-acting, for example be sprayed onto the glue of wound surface, at CaCl
2In the thrombin solution of 100u/ml just enough.For glue at a slow speed, for example fill the glue in the hole or the sealing transphenoided hypophisectomy hole of exodontia, need to add a large amount of CaCl
2Thrombin further is dissolved to the ultimate density of 25u/ml.
The preparation of reptilase and thrombin class are seemingly.But the amount of reptilase is about 2u/ml.
The clinical case report:
MY patient (21 years old male) suffered from the severe haemorrhage disease because of needs antithrombase inhibitor in 21 years old.There is not background disease (being tumor or auto-immune disease) can explain this problem.Two outer laboratory tests that confirm of experiment show that MY has high-load antithrombase IgG antibody.The previous year, this patient caused that because of its maximum size in renal pelvis renal colic shows effect once more.Ultrasonic selection lithotrity is carried out in plan.According to IgG and the bonded technology of a-protein affinity post, the patient is carried out and the bonded immunodepression treatment of external immune absorption process.By the a-protein post, after 8 treatments, inhibitor is tired and is descended 98% with 60L patient's blood plasma.This be by adopt before the affinity with affinity after the MJ blood plasma of purification time (TT) that blood leads of normally smouldering of measuring thrombin measure.Yet TT, PT and APTT value all are extended.At this moment, renal calculus moves to urethra, causes the kidney total blockage and with hydronephrosis.This patient has accepted more than 10 immunity and has absorbed concentrated then blood plasma (about 50 liters) and the infusion high dose immunoglobulin (2g/kg) of taking out of treatment (about 80 liters of blood plasma).This time point, the content of thrombin inhibitor reduces to 0.5%.PTT reduces to 47 seconds (with respect to the 85-90 pretreatment of second), and TT is 35 seconds (pretreatment with respect to 90 seconds and 27 seconds normal control).Decision is used by the biological gellant low temperature glue surgery of low-temperature precipitation thing and the preparation of high-load (200u/ml) thrombin and is removed calculus.Along with mixing this low-temperature precipitation thing in case through the gelling immediately of spraying.But in this patient, gelling does not take place, and by sewing up local hemostasis.Surgical operation finishes the back wound and looks it is " doing ".But after 6 hours, this patient is hemorrhage from surgical drainage tube.Carry out the immune absorption process treatment of 10 liters of blood plasma, but to hemorrhage not effect, hemorrhage rapid increase.
The patient is performed the operation once more to find out hemorrhage source.But do not find that surgery is hemorrhage.Find that whole wound surface is at oozing of blood.At this moment, with low-temperature precipitation thing and reptilase (2U/ml; Defibrase) mixing is sprayed onto on the wound face.Spraying is coagulated fast immediately, and wound surface presents muddiness and stops hemorrhage.The patient is proceeded other 5 days day immunity absorb treatment, do not have hemorrhage.This has just proved that using Serpentis protease is useful as the B component of tissue glue of the present invention.
Claims (15)
1, tissue glue, component A and B component are contained in this tissue glue, component A contains the low-temperature precipitation thing of whole blood and high-loadly is equivalent to 3,000-5, the protease inhibitor of 000KIU/ml unit's aprotinin, B component contains proteolytic enzyme, and this endonuclease capable makes the Fibrinogen cracking that exists among the component A single-mindedly and fibrin polymer is formed.
2, the tissue glue of claim 1, wherein the low-temperature precipitation thing of component A is spissated.
3, the tissue glue of claim 1, wherein protease inhibitor is 3,000-5, the aprotinin of 000KIU/ml unit.
4, each tissue glue among the claim 1-3, wherein proteolytic enzyme is the thrombin that obtains from mammal or people.
5, tissue glue, component A and B component are contained in this tissue glue, component A contains the low-temperature precipitation thing of whole blood, and B component contains the proteolytic enzyme that can obtain from snake venom, and this endonuclease capable makes the Fibrinogen cracking that exists among the component A single-mindedly and fibrin polymer is formed.
6, the tissue glue of claim 5, wherein reptilase is from the isolating batroxobin of South America Shen Wa adder Bothrpos moujeni.
7, claim 5 or 6 tissue glue contain and high-loadly are equivalent to 3,000-5, the protease inhibitor of 000KIU/ml unit's aprotinin, preferred aprotinin.
8, the tissue glue of each of claim 1-7, wherein the low-temperature precipitation thing is an inactivation of virus.
9, the manufacture method of the Fibrin Glue of claim 1-8, this method comprises the following steps:
-make component A, comprise the step for preparing low temperature thing solution from the low-temperature precipitation thing,
-inactivation of virus,
-remove antiviral,
-adding protease inhibitor and preparation are as the suitable solution of the suitable protease of B component.
10, tissue glue, Fibrinogen is contained in this tissue glue, the Fibronectin and the X III factor and be equivalent to 3,000-5, the protease inhibitor of 000KIU/ml aprotinin is as component A.
11, the tissue glue of claim 10, its B component is the proteolytic enzyme or the thrombin of claim 5 and/or 6.
12, tissue glue, Fibrinogen is contained in this tissue glue, and the Fibronectin and the X III factor are as component A, and B component is the proteolytic enzyme of claim 5 and/or 6.
13, with 3,000-5, the aprotinin of 000KIU/ml high-load and low-temperature precipitation thing or Fibrinogen, the conjugate of the Fibronectin and the X III factor is in conjunction with the application that is used to prepare tissue glue.
14, snake venom proteinase is used to prepare the application of tissue glue.
15, will be used to prepare the application of tissue glue from the isolating batroxobin of Bothrpos moujeni.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP9100018 | 1991-09-27 | ||
| EPPCT/EP91/01850 | 1991-09-27 |
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| Publication Number | Publication Date |
|---|---|
| CN1073605A true CN1073605A (en) | 1993-06-30 |
Family
ID=8165556
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 92112470 Pending CN1073605A (en) | 1991-09-27 | 1992-09-26 | The biogum of the improvement by adopting the preparation of low-temperature precipitation thing |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109316599A (en) * | 2018-08-24 | 2019-02-12 | 上海交通大学医学院附属瑞金医院 | A kind of Aprotinin or its mutant, derivative, analog or its application for forming segment |
-
1992
- 1992-09-26 CN CN 92112470 patent/CN1073605A/en active Pending
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109316599A (en) * | 2018-08-24 | 2019-02-12 | 上海交通大学医学院附属瑞金医院 | A kind of Aprotinin or its mutant, derivative, analog or its application for forming segment |
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