CA1168982A - Tissue adhesive - Google Patents
Tissue adhesiveInfo
- Publication number
- CA1168982A CA1168982A CA000407154A CA407154A CA1168982A CA 1168982 A CA1168982 A CA 1168982A CA 000407154 A CA000407154 A CA 000407154A CA 407154 A CA407154 A CA 407154A CA 1168982 A CA1168982 A CA 1168982A
- Authority
- CA
- Canada
- Prior art keywords
- factor xiii
- fibrinogen
- antibiotic
- tissue adhesive
- units
- 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
Abstract
ABSTRACT OF THE DISCLOSURE:
A tissue adhesive based on human or animal proteins con-tains factor XIII, fibrinogen and an antibiotic. In order to achieve a high straining capacity of the adherences and a retarded antimicrobial efficacy, the ratio of factor XIII
to fibrinogen, expressed in units of factor XIII per gram of fibrinogen, amounts to at least 500. The antibiotic is chosen among aminoglucosides, betalactams, polypeptides or tetracyclines. In a method of producing the tissue adhesive the concentration ratio of factor XIII to fibrinogen is adjusted in a fibrinogen-containing blood plasma fraction by the addition of factor XIII. The antibiotic is added either before deepfreezing or lyophilization of the result-ing preparation, or after thawing or reconstitution of the same.
A tissue adhesive based on human or animal proteins con-tains factor XIII, fibrinogen and an antibiotic. In order to achieve a high straining capacity of the adherences and a retarded antimicrobial efficacy, the ratio of factor XIII
to fibrinogen, expressed in units of factor XIII per gram of fibrinogen, amounts to at least 500. The antibiotic is chosen among aminoglucosides, betalactams, polypeptides or tetracyclines. In a method of producing the tissue adhesive the concentration ratio of factor XIII to fibrinogen is adjusted in a fibrinogen-containing blood plasma fraction by the addition of factor XIII. The antibiotic is added either before deepfreezing or lyophilization of the result-ing preparation, or after thawing or reconstitution of the same.
Description
1 168g82 The invention relates to a tissue adhesive based on human or animal proteins, containing factor XIII, fibrino-gen and an antibiotic, as well as to a method of producing the same.
From Canadian patent application Ser. No. 344,717 and Canadian patent No. 1,119,516 methods are already known for producing a tissue adhesive containing fibrinogen and fac-tor XIII, in which certain concentration ratios of factor XIII to fibrinogen and, if desired, albumin are adjusted, and the preparations are deepfrozen or lyophilized. These preparations basically exhibited satisfactory properties, i.e. a high straining capacity of the adherences and a good absorbability; however, it is desirable to improve these preparations with a view to an antimicrobial effi-cacy.
To be sure, it has already keen proposed in U.S. pa-tent No. 2,533,004 as well as by Fellinger et al. in the journal "Der Tuberkulosearzt" (6/11, 1952) to add antibio-tics to fibrinogen solutions and to use them as wound ad-hesives, yet these solutions to be prepared directly atthe bedside do not give the fibrin clots formed therefrom a sufficient durability and straining capacity.
Furthermore, it is known from the work by sosch et al., Archiv fur orthopadische und Unfall-Chirurgie, Vol.
90 (1977), pages 63 to 75, to apply a fibrin adhesive sys-tem for filling bone defects in connection with bone trans-plants, with the fibrin forming at the chosen site imme-diately at the bone cavity by the addition of thrombin to a fibrinogen solution. As required, commonly available com-bination preparations of pulverized neomycin were added.
,~
Finally, it was proposed according to the PCT appli-cation No. 80/00083 to prepare a fibrinogen antibiotic gel, wherein a mixture of cryoprecipitate with tobramycin and gentamicin as antibiotics to be prepared at the bedside is used.
According to experiments carried out by Applicant it was found that the described and known tissue adhesives ~at contain fribrinogen, factor XIII and an antibiotic do not possess the desired combination of properties, i.e. a high straining capacity of the adherences and an antimi-crobial efficacy, but that an adverse interaction between the antibiotics and factor XIII takes place, which results in a strong decrease of the crosslinking ability of fibri-nogen and a negative effect on the coagulability. Con-sequently, the adhesive exhibits a poorer rigidity and ad-hering capacity on the wound and tissue surfaces.
A further disadvantage of the known preparations re-sides in that the release of the antibiotic to the tissue takes place too quickly so that the retardation of the ?O antibiotic does not suffice to be effective over a longer period of time and to achieve a high active substance re-lease.
The invention aims at avoiding these disadvantages and difficulties and has as its object to provide a tissue adhesive of human or animal origin that meets the above-mentioned combination of p~operties and guarantees an im-proved efficacy of the antibiotic.
The set object is achieved with a tissue adhesive of the initially defined kind in that the ratio of factor XIII to fibrinogen, expressed in units of factor XIII per gram of fibrinogen, amounts to at least 500 and that an antibiotic selected from the group consisting of amino-glucosides, betalactams, polypeptides and tetracyclines is contained therein.
Advantageously, factor XIII is contained in a deep-frozen tissue adhesive in an amount of at least 40 units/
ml.
According to another embodiment at least 33 ~ of fibrinogen is contained in a lyophilized tissue adhesive, factGr XIII being present in an amount of at least 170 units/g of lyophilisate.
Suitably, a plasmin inhibitor or plasminogen-acti-vator inhibitor selected from the group consisting of apro-tinin, ~2-antiplasmin, ~2-macroglobulin, ~1-antitrypsin, ~-aminocaproic acid and tranexamic acid is additionally contained.
Advantageously, the tissue adhesive is a two-compo-nent preparation, factor XIII, fibrinogen and the plasmin inhibitor or plasminogen-activator inhibitor being con-tained in the first component and the antibiotic, throm-bin and bivalent calcium being contained in the second com-ponent.
Preferably, the antibiotic is contained in the form of a hardly soluble derivative. A variant of this embodi-ment consists in that, in addition to the hardly soluble derivative, also an easily soluble one is used, if desired distributed in the two components of the tissue adhesive.
This embodiment has the advantage that the easily soluble derivative is released quickly, thus ensuring a high ini-tial efficacy, whereas the hardly soluble derivative cau-1 16~g82 ses a lasting efficacy.
Moreover, the invention comprises a method of pro-ducing the tissue adhesive with a modification consisting in that a concentration ratio of factor XIII to fibrino-gen, expressed in units of factor XIII/g of fibrinogen, of at least 500 is adjusted in a fibrinogen-containing blood plasma fraction by the addition of factor XIII,whereupon the antibiotic is added and the preparation is deepfrozen or lyophilized.
According to another modification a concentration ratio of factor XIII to fibrinogen, expressed in units of factor XIII/g of fibrinogen, of at least 500 is ad]usted in a fibrinogen-containing blood plasma fraction by the addition of factor XIII, whereupon the preparation is deepfrozen or lyophilized and, after thawing or reconsti-tution,is combined with an antibiotic-containing solu-tion. With this embodiment the antibiotic may be added after thawing or to the reconstituted solution. However, with these embodiments it has to be taken care that the concentration of factor XIII does not fall below a mini-mum concentration; it is to be above 40 uni.ts/ml.
According to a preferred embodiment in which the fi-brinogen-containing blood plasma fraction is washed with a buffer solution, the washing procedure is carried out un-til a factor XIII concentration of 200 units of factor XIII/g of fibrinogen is reached, whereupon factor XIII is supplied in an amount of at least 300 units/g of fibrino-gen in the form of a concentrate or lyophilisate.
The tissue adhesive according to the invention and the method of producing the same will be explained in more ~ ~689~2 detail by way of the following examples.
Example 1:
Cryoprecipitate (100 g) was gained from frozen fresh human plasma by heating to 2C, separated by centrifuga-tion and washed twice in a buffer solution containing Na3 citrate, NaCl, glycine, glucose, aprotinin and heparin at a pH of 6.5, and the separated precipitate was dissolved in a glycine-containing buffer solution (255 ml) at a pH
of 7.9. It was found that a ratio of factor XIII to fibri-nogen of 226 units of factor XIII/g of fibrinogen was con-tained in this solution. To adjust the ratio desired ac-cording to the invention, of more than 500 U/g of fibrino-gen, a pulverized factor XIII preparation with 9,000 units was added to the solution, the concentration ratio of the solution thus having been increased to 826 units of factor XIII/g of fibrinogen. This solution was sterile-filtered; then 1.7 g of gentamicin were added under sterile conditions, the mixture was filled into final containers (2.5 ml), deepfrozen and lyophilized.
Example 2:
The preparation of the tissue adhesive basi~ from cryoprecipitate was effected in the same manner as in Example 1, with the difference that the cryo-preçipita-te was liquefied by heating to 37 C after a single washing, and 13,600 units of pulverized factor XIII were added. A ratio of factor XIII to fibrinogen of 967 factor XIII units/g of fibrinogen was obtained.
5.67 g 7-/(thienyl)-(2)-acetamido7-cephalosporanic acid were added to the solution as an antibiotic. The sus-pension thus obtained was filled into final containers ~ ~8~8~
(1 ml) and deepfrozen. The filled-in preparation has a content of factor XIII amounting to 87 U/ml.
The application of the tissue adhesives prepared ac-cording to Examples 1 and 2 advantageously is realized by mixing the thawed or reconstituted mixture with thrombin and calcium chloride and applying it onto the tissue to be connected. It is also possible to apply the two components separately onto the tissue to be connected or filled.
Example 3:
The method according to Example 1 was repeated ex-cept for adding the antibiotie. The washed precipitate, after dissolving in a buffer solution, was sterile~filter-ed, filled into final containers (2.5 ml), deepfrozen and lyophilized, the first eomponent of the tissue adhesive aecording to the invention thus having been made storable.
The second eomponent was prepared prior to application from a solution of thrombin and caleium ehloride by adding 7-/~thienyl)-(2)-aeetamido7-eephalosporanie aeid (30 mg/
ml).
Example ~:
The proeedure according to Example 2 was repeated, wherein gentamiein (1.89 g) was added after dissolving the eryopreeipitate, the solution was filled into final con-tainers (1 ml) and deepfrozen. Thus, the first eomponent of the adhesive according -to the invention is present in a storable form. The second component containing 30 mg of 7-/(thienyl)-(2)-acetamid 7-cephalosporanic acid per ml of a calcium chloride thrombin solution was prepared prior to application.
Instead of the aprotinin added in accordance with 1 1~8982 Examples 1 to 4, one or more of the following compounds may be used as plasmin inhibitor or plasminogen-activator inhibitor: ~2-antiplasmin, ~2-macroglobulin, d~1-antitryp-sin, ~-aminocaproic acid and tranexamic acid.
The tissue adhesives prepared according to the inven-tion are generally applicable for the seamless connection of human or animal tissue or organ parts, to dress wounds and stop bleedings, their antimicrobial efficacy being substantially improved.
The improved adhesive properties with an equally im-proved antimicrobial efficacy of the tissue adhesives ac-cording to the invention can be taken from the following comparative examples summarized in a table; the degree of crosslinking of tissue adhesives according to the inven-tion with an increased factor XIII/fibrinogen ratio was compared to the crosslinking degree of known tissue ad-hesives without an increased factor XIII/fibrinogen ratio, using different antibiotics for each case. The d-cross-linking degree has been determined according to the sodium-laurysulfate (SDS) polyacrylamide gel electrophoresis me-thod, which is carried out in a manner that, after having mixed the tissue adhesive with an equal volume of a solu-tion containing 40 ~Mol CaCl2 and 15 NIH units (U.S. Na-tional Institute of ~lealth units) of thrombin per ml, the mixture is incubated at 37 C. The ~-crosslinking degree is determined after stopping the reaction and reductive cleavage of the disulfide bridges contained in the pro-teins, by the addition of a mixture of urea, sodiumdode-cylsulfate and ~-mercap-toethanol by means of gel electro-phoresis.
1 ~68~8~
In a further part of the table the clot rigidity ofa tissue adhesive according to the invention was compared to a known one in a thrombelastograph, with gentamicin having been added as antibiotic.
Finally, the table includes comparative values of the tearing resistance of a tissue adhesive according to the invention and of a known one, with gentamicin being used as an antibiotic.
Fibrin ~-crosslinking (at 37 C after 60 min.) Addition of Tissue adhesive of in- Tissue adhesive antibiotic vention with increased without increased factor XIII content factor XIII con-~500 U/g fibrinogen tent . ....
Gentamicin 70 % 30 %
Neomycin 41 % 21 %
Fosfomycin 47 % 24 %
Azlocillin 66 % 42 %
20 Doxycyclin 65 ~ 26 %
Cefoxitin 54 % 44 %
Clot rigidity in thrombelastograph (37 C - 60 min.) ~= elasticity module Gentamicin 1150 426 Tearing resistance in g/cm2 (37 C - 30 min.) .
30 Gentamicin 1283 999 -- 8 ~
Finally, a comparative example;was carried out with respect to the antibiotics release of a tissue adhesive prepared according to Example 4, 85 ~ of gentamlcln having been released from a clot produced by this tissue adhesive already after 72 hours in an in vitro test. After 96 hours a release of gentamicin was not recognlzed any more, . :
while 7-~ thienyl)-(2)-acetamido7-cephalosporanlc acid ~ was still detectable even after 8 days.
: :
:
~ ; ~
;: :
. :
.
- ~ . :
' ' ~ : : . : `, ~' ' ~''. ," ' ~'
From Canadian patent application Ser. No. 344,717 and Canadian patent No. 1,119,516 methods are already known for producing a tissue adhesive containing fibrinogen and fac-tor XIII, in which certain concentration ratios of factor XIII to fibrinogen and, if desired, albumin are adjusted, and the preparations are deepfrozen or lyophilized. These preparations basically exhibited satisfactory properties, i.e. a high straining capacity of the adherences and a good absorbability; however, it is desirable to improve these preparations with a view to an antimicrobial effi-cacy.
To be sure, it has already keen proposed in U.S. pa-tent No. 2,533,004 as well as by Fellinger et al. in the journal "Der Tuberkulosearzt" (6/11, 1952) to add antibio-tics to fibrinogen solutions and to use them as wound ad-hesives, yet these solutions to be prepared directly atthe bedside do not give the fibrin clots formed therefrom a sufficient durability and straining capacity.
Furthermore, it is known from the work by sosch et al., Archiv fur orthopadische und Unfall-Chirurgie, Vol.
90 (1977), pages 63 to 75, to apply a fibrin adhesive sys-tem for filling bone defects in connection with bone trans-plants, with the fibrin forming at the chosen site imme-diately at the bone cavity by the addition of thrombin to a fibrinogen solution. As required, commonly available com-bination preparations of pulverized neomycin were added.
,~
Finally, it was proposed according to the PCT appli-cation No. 80/00083 to prepare a fibrinogen antibiotic gel, wherein a mixture of cryoprecipitate with tobramycin and gentamicin as antibiotics to be prepared at the bedside is used.
According to experiments carried out by Applicant it was found that the described and known tissue adhesives ~at contain fribrinogen, factor XIII and an antibiotic do not possess the desired combination of properties, i.e. a high straining capacity of the adherences and an antimi-crobial efficacy, but that an adverse interaction between the antibiotics and factor XIII takes place, which results in a strong decrease of the crosslinking ability of fibri-nogen and a negative effect on the coagulability. Con-sequently, the adhesive exhibits a poorer rigidity and ad-hering capacity on the wound and tissue surfaces.
A further disadvantage of the known preparations re-sides in that the release of the antibiotic to the tissue takes place too quickly so that the retardation of the ?O antibiotic does not suffice to be effective over a longer period of time and to achieve a high active substance re-lease.
The invention aims at avoiding these disadvantages and difficulties and has as its object to provide a tissue adhesive of human or animal origin that meets the above-mentioned combination of p~operties and guarantees an im-proved efficacy of the antibiotic.
The set object is achieved with a tissue adhesive of the initially defined kind in that the ratio of factor XIII to fibrinogen, expressed in units of factor XIII per gram of fibrinogen, amounts to at least 500 and that an antibiotic selected from the group consisting of amino-glucosides, betalactams, polypeptides and tetracyclines is contained therein.
Advantageously, factor XIII is contained in a deep-frozen tissue adhesive in an amount of at least 40 units/
ml.
According to another embodiment at least 33 ~ of fibrinogen is contained in a lyophilized tissue adhesive, factGr XIII being present in an amount of at least 170 units/g of lyophilisate.
Suitably, a plasmin inhibitor or plasminogen-acti-vator inhibitor selected from the group consisting of apro-tinin, ~2-antiplasmin, ~2-macroglobulin, ~1-antitrypsin, ~-aminocaproic acid and tranexamic acid is additionally contained.
Advantageously, the tissue adhesive is a two-compo-nent preparation, factor XIII, fibrinogen and the plasmin inhibitor or plasminogen-activator inhibitor being con-tained in the first component and the antibiotic, throm-bin and bivalent calcium being contained in the second com-ponent.
Preferably, the antibiotic is contained in the form of a hardly soluble derivative. A variant of this embodi-ment consists in that, in addition to the hardly soluble derivative, also an easily soluble one is used, if desired distributed in the two components of the tissue adhesive.
This embodiment has the advantage that the easily soluble derivative is released quickly, thus ensuring a high ini-tial efficacy, whereas the hardly soluble derivative cau-1 16~g82 ses a lasting efficacy.
Moreover, the invention comprises a method of pro-ducing the tissue adhesive with a modification consisting in that a concentration ratio of factor XIII to fibrino-gen, expressed in units of factor XIII/g of fibrinogen, of at least 500 is adjusted in a fibrinogen-containing blood plasma fraction by the addition of factor XIII,whereupon the antibiotic is added and the preparation is deepfrozen or lyophilized.
According to another modification a concentration ratio of factor XIII to fibrinogen, expressed in units of factor XIII/g of fibrinogen, of at least 500 is ad]usted in a fibrinogen-containing blood plasma fraction by the addition of factor XIII, whereupon the preparation is deepfrozen or lyophilized and, after thawing or reconsti-tution,is combined with an antibiotic-containing solu-tion. With this embodiment the antibiotic may be added after thawing or to the reconstituted solution. However, with these embodiments it has to be taken care that the concentration of factor XIII does not fall below a mini-mum concentration; it is to be above 40 uni.ts/ml.
According to a preferred embodiment in which the fi-brinogen-containing blood plasma fraction is washed with a buffer solution, the washing procedure is carried out un-til a factor XIII concentration of 200 units of factor XIII/g of fibrinogen is reached, whereupon factor XIII is supplied in an amount of at least 300 units/g of fibrino-gen in the form of a concentrate or lyophilisate.
The tissue adhesive according to the invention and the method of producing the same will be explained in more ~ ~689~2 detail by way of the following examples.
Example 1:
Cryoprecipitate (100 g) was gained from frozen fresh human plasma by heating to 2C, separated by centrifuga-tion and washed twice in a buffer solution containing Na3 citrate, NaCl, glycine, glucose, aprotinin and heparin at a pH of 6.5, and the separated precipitate was dissolved in a glycine-containing buffer solution (255 ml) at a pH
of 7.9. It was found that a ratio of factor XIII to fibri-nogen of 226 units of factor XIII/g of fibrinogen was con-tained in this solution. To adjust the ratio desired ac-cording to the invention, of more than 500 U/g of fibrino-gen, a pulverized factor XIII preparation with 9,000 units was added to the solution, the concentration ratio of the solution thus having been increased to 826 units of factor XIII/g of fibrinogen. This solution was sterile-filtered; then 1.7 g of gentamicin were added under sterile conditions, the mixture was filled into final containers (2.5 ml), deepfrozen and lyophilized.
Example 2:
The preparation of the tissue adhesive basi~ from cryoprecipitate was effected in the same manner as in Example 1, with the difference that the cryo-preçipita-te was liquefied by heating to 37 C after a single washing, and 13,600 units of pulverized factor XIII were added. A ratio of factor XIII to fibrinogen of 967 factor XIII units/g of fibrinogen was obtained.
5.67 g 7-/(thienyl)-(2)-acetamido7-cephalosporanic acid were added to the solution as an antibiotic. The sus-pension thus obtained was filled into final containers ~ ~8~8~
(1 ml) and deepfrozen. The filled-in preparation has a content of factor XIII amounting to 87 U/ml.
The application of the tissue adhesives prepared ac-cording to Examples 1 and 2 advantageously is realized by mixing the thawed or reconstituted mixture with thrombin and calcium chloride and applying it onto the tissue to be connected. It is also possible to apply the two components separately onto the tissue to be connected or filled.
Example 3:
The method according to Example 1 was repeated ex-cept for adding the antibiotie. The washed precipitate, after dissolving in a buffer solution, was sterile~filter-ed, filled into final containers (2.5 ml), deepfrozen and lyophilized, the first eomponent of the tissue adhesive aecording to the invention thus having been made storable.
The second eomponent was prepared prior to application from a solution of thrombin and caleium ehloride by adding 7-/~thienyl)-(2)-aeetamido7-eephalosporanie aeid (30 mg/
ml).
Example ~:
The proeedure according to Example 2 was repeated, wherein gentamiein (1.89 g) was added after dissolving the eryopreeipitate, the solution was filled into final con-tainers (1 ml) and deepfrozen. Thus, the first eomponent of the adhesive according -to the invention is present in a storable form. The second component containing 30 mg of 7-/(thienyl)-(2)-acetamid 7-cephalosporanic acid per ml of a calcium chloride thrombin solution was prepared prior to application.
Instead of the aprotinin added in accordance with 1 1~8982 Examples 1 to 4, one or more of the following compounds may be used as plasmin inhibitor or plasminogen-activator inhibitor: ~2-antiplasmin, ~2-macroglobulin, d~1-antitryp-sin, ~-aminocaproic acid and tranexamic acid.
The tissue adhesives prepared according to the inven-tion are generally applicable for the seamless connection of human or animal tissue or organ parts, to dress wounds and stop bleedings, their antimicrobial efficacy being substantially improved.
The improved adhesive properties with an equally im-proved antimicrobial efficacy of the tissue adhesives ac-cording to the invention can be taken from the following comparative examples summarized in a table; the degree of crosslinking of tissue adhesives according to the inven-tion with an increased factor XIII/fibrinogen ratio was compared to the crosslinking degree of known tissue ad-hesives without an increased factor XIII/fibrinogen ratio, using different antibiotics for each case. The d-cross-linking degree has been determined according to the sodium-laurysulfate (SDS) polyacrylamide gel electrophoresis me-thod, which is carried out in a manner that, after having mixed the tissue adhesive with an equal volume of a solu-tion containing 40 ~Mol CaCl2 and 15 NIH units (U.S. Na-tional Institute of ~lealth units) of thrombin per ml, the mixture is incubated at 37 C. The ~-crosslinking degree is determined after stopping the reaction and reductive cleavage of the disulfide bridges contained in the pro-teins, by the addition of a mixture of urea, sodiumdode-cylsulfate and ~-mercap-toethanol by means of gel electro-phoresis.
1 ~68~8~
In a further part of the table the clot rigidity ofa tissue adhesive according to the invention was compared to a known one in a thrombelastograph, with gentamicin having been added as antibiotic.
Finally, the table includes comparative values of the tearing resistance of a tissue adhesive according to the invention and of a known one, with gentamicin being used as an antibiotic.
Fibrin ~-crosslinking (at 37 C after 60 min.) Addition of Tissue adhesive of in- Tissue adhesive antibiotic vention with increased without increased factor XIII content factor XIII con-~500 U/g fibrinogen tent . ....
Gentamicin 70 % 30 %
Neomycin 41 % 21 %
Fosfomycin 47 % 24 %
Azlocillin 66 % 42 %
20 Doxycyclin 65 ~ 26 %
Cefoxitin 54 % 44 %
Clot rigidity in thrombelastograph (37 C - 60 min.) ~= elasticity module Gentamicin 1150 426 Tearing resistance in g/cm2 (37 C - 30 min.) .
30 Gentamicin 1283 999 -- 8 ~
Finally, a comparative example;was carried out with respect to the antibiotics release of a tissue adhesive prepared according to Example 4, 85 ~ of gentamlcln having been released from a clot produced by this tissue adhesive already after 72 hours in an in vitro test. After 96 hours a release of gentamicin was not recognlzed any more, . :
while 7-~ thienyl)-(2)-acetamido7-cephalosporanlc acid ~ was still detectable even after 8 days.
: :
:
~ ; ~
;: :
. :
.
- ~ . :
' ' ~ : : . : `, ~' ' ~''. ," ' ~'
Claims (10)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A deepfrozen or lyophilized tissue adhesive based on human or animal proteins which comprises factor XIII, fibrinogen and an antibiotic, wherein the ratio of fac-tor XIII to fibrinogen, expressed in units of factor XIII per gram of fibrinogen, amounts to at least 500, and said antibiotic is selected from the group consist-ing of aminoglucosides, betalactams, polypeptides and tetracyclines.
2. A deepfrozen tissue adhesive as set forth in claim 1, wherein factor XIII is contained in an amount of at least 40 units/ml.
3. A lyophilized tissue adhesive as set forth in claim 1, wherein at least 33 % by weight of fibrinogen is con-tained, factor XIII being present in an amount of at least 170 units/gram of lyophilisate.
4. A tissue adhesive as set forth in claim 1, further com-prising a plasmin inhibitor or plasminogen-activator in-hibitor selected from the group consisting of aprotinin, ?-antiplasmin, ?2-macroglobulin, ?1-antitrypsin, ?--aminocaproic acid and tranexamic acid.
5. A tissue adhesive as set forth in claim 1, comprising a first component and a second component, said first component containing factor XIII and fibrinogen and said second component containing said antibiotic, thrombin and bivalent calcium.
6. A tissue adhesive as set forth in claim 4, comprising a first component and a second component, said first component containing factor XIII, fibrinogen and said plasmin inhibitor or plasminogen-activator inhibitor and said second component containing said antibiotic, thrombin and bivalent calcium.
7. A tissue adhesive as set forth in claim 1, wherein said antibiotic is present in the form of a hardly soluble derivative.
8. A method of producing a tissue adhesive based on human or animal proteins and comprising factor XIII, fibrino-gen, a plasmin inhibitor or plasminogen-activator inhi-bitor, and an antibiotic selected from the group con-sisting of aminoglucosides, betalactams, polypeptides and tetracyclines, which method comprises the steps of adjusting in a fibrinogen-containing blood plasma fraction a concentration ratio of factor XIII to fibri-nogen, expressed in units of factor XIII/gram of fibri-nogen, of at least 500 by adding factor XIII, adding said antibiotic, and deepfreezing or lyophilizing the resulting prepara-tion.
9. A method of producing a tissue adhesive based on human or animal proteins and comprising factor XIII, fibrino-gen, a plasmin inhibitor or plasminogen-activator inhi-bitor, and an antibiotic selected from the group con-sisting of aminoglucosides, betalactams, polypeptides and tetracyclines, which method comprises the steps of adjusting in a fibrinogen-containing blood plasma fraction a concentration ratio of factor XIII to fibri-nogen, expressed in units of factor XIII/gram of fibri-nogen, of at least 500 by adding factor XIII, deepfreezing or lyophilizing the resulting prepara-tion, thawing or reconstituting the preparation, and combining the preparation with a solution contain-ing said antibiotic.
10. A method as set forth in claim 8 or 9, further com-prising washing said fibrinogen-containing blood plas-ma fraction with a buffer solution in a washing proce-dure, and wherein said washing procedure is carried out until a factor XIII concentration of 200 units of factor XIII/gram of fibrinogen is reached, whereupon factor XIII is added in an amount of at least 300 units/gram of fibrinogen in the form of a concentrate or lyophilisate.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AT0333781A AT369990B (en) | 1981-07-28 | 1981-07-28 | METHOD FOR PRODUCING A TISSUE ADHESIVE |
| ATA3337/81 | 1981-07-28 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1168982A true CA1168982A (en) | 1984-06-12 |
Family
ID=3548998
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000407154A Expired CA1168982A (en) | 1981-07-28 | 1982-07-13 | Tissue adhesive |
Country Status (14)
| Country | Link |
|---|---|
| JP (1) | JPH0696039B2 (en) |
| AR (1) | AR227252A1 (en) |
| AT (1) | AT369990B (en) |
| BE (1) | BE893851A (en) |
| CA (1) | CA1168982A (en) |
| CH (1) | CH659187B (en) |
| DE (1) | DE3225102A1 (en) |
| DK (1) | DK157977C (en) |
| ES (1) | ES8306023A1 (en) |
| FR (1) | FR2510408B1 (en) |
| GB (1) | GB2102811B (en) |
| IT (1) | IT1157313B (en) |
| NL (1) | NL192665C (en) |
| SE (1) | SE459848B (en) |
Cited By (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4909251A (en) * | 1988-05-31 | 1990-03-20 | Immuno Aktiengesellschaft Fur Chemisch-Medizinische Produkte | Tissue adhesive |
| US6054122A (en) * | 1990-11-27 | 2000-04-25 | The American National Red Cross | Supplemented and unsupplemented tissue sealants, methods of their production and use |
| US6117425A (en) * | 1990-11-27 | 2000-09-12 | The American National Red Cross | Supplemented and unsupplemented tissue sealants, method of their production and use |
| US6197325B1 (en) | 1990-11-27 | 2001-03-06 | The American National Red Cross | Supplemented and unsupplemented tissue sealants, methods of their production and use |
| US6506365B1 (en) | 2000-09-25 | 2003-01-14 | Baxter Aktiengesellschaft | Fibrin/fibrinogen binding conjugate |
| US6559119B1 (en) | 1990-11-27 | 2003-05-06 | Loyola University Of Chicago | Method of preparing a tissue sealant-treated biomedical material |
| US6762336B1 (en) | 1998-01-19 | 2004-07-13 | The American National Red Cross | Hemostatic sandwich bandage |
| US7189410B1 (en) | 1990-11-27 | 2007-03-13 | The American National Red Cross | Supplemented and unsupplemented tissue sealants, methods of their production and use |
| US8445009B2 (en) | 2006-08-04 | 2013-05-21 | Stb, Ltd | Processes for the production of solid dressings for treating wounded tissue |
| US8679528B2 (en) | 2002-09-10 | 2014-03-25 | American National Red Cross | Hemostatic dressing |
| US9131929B2 (en) | 2007-08-06 | 2015-09-15 | Stb, Ltd. | Methods and dressings for sealing internal injuries |
Families Citing this family (27)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH06102628B2 (en) * | 1984-03-27 | 1994-12-14 | イムノ・アクチエンゲゼルシャフト | Tissue adhesive manufacturing method |
| JPS6185304A (en) * | 1984-10-01 | 1986-04-30 | Green Cross Corp:The | Auxiliary for dental treatment |
| DE3622642A1 (en) * | 1986-07-05 | 1988-01-14 | Behringwerke Ag | ONE-COMPONENT TISSUE ADHESIVE AND METHOD FOR THE PRODUCTION THEREOF |
| US4837379A (en) * | 1988-06-02 | 1989-06-06 | Organogenesis Inc. | Fibrin-collagen tissue equivalents and methods for preparation thereof |
| NZ229385A (en) * | 1989-06-01 | 1992-02-25 | Life Technologies Inc | Treatment of processed fish product (surimi) with alpha-2-macroglobulin to neutralise alkaline proteases in the fish |
| IT1243180B (en) * | 1990-07-31 | 1994-05-24 | Nunzio Rapisarda | USE OF PHOSPHOMYCIN AND ITS SALTS AS A TOPICAL CICATRIZING AGENT |
| SK5095A3 (en) * | 1992-07-18 | 1995-07-11 | Opperbas Holding Bv | Two component fibrin-glue composition for improving in vitro fertilization |
| US5330974A (en) * | 1993-03-01 | 1994-07-19 | Fibratek, Inc. | Therapeutic fibrinogen compositions |
| AU696691C (en) † | 1993-03-12 | 2003-09-18 | American National Red Cross, The | Supplemented and unsupplemented tissue sealants, methods of their production and use |
| DK0691858T3 (en) * | 1993-03-30 | 2000-05-08 | Omrix Biopharm Sa | Two-component fibrin glue |
| DE19521324C1 (en) * | 1995-06-12 | 1996-10-31 | Immuno Ag | Tissue adhesive and use thereof as a hemostatic |
| DE19617369A1 (en) * | 1996-04-30 | 1997-11-06 | Immuno Ag | Storage-stable fibrinogen preparations |
| AT406120B (en) | 1997-08-28 | 2000-02-25 | Immuno Ag | TISSUE ADHESIVE |
| AT407484B (en) | 1997-11-12 | 2001-03-26 | Bio Prod & Bio Eng Ag | MEDICINES FOR PROMOTING Wound Healing |
| DE60042343D1 (en) | 1999-12-23 | 2009-07-16 | Csl Ltd | SEPARATION OF FIBRINOGES OF PLASMAPROTEASES |
| IL144446A0 (en) * | 2001-07-19 | 2002-05-23 | Prochon Biotech Ltd | Plasma protein matrices and methods for their preparation |
| US7067123B2 (en) | 2003-04-29 | 2006-06-27 | Musculoskeletal Transplant Foundation | Glue for cartilage repair |
| US7901457B2 (en) | 2003-05-16 | 2011-03-08 | Musculoskeletal Transplant Foundation | Cartilage allograft plug |
| CN101010333B (en) | 2004-08-27 | 2013-08-14 | 诺和诺德医疗保健公司 | Purification of factor XIII polypeptides from biological materials |
| US7837740B2 (en) | 2007-01-24 | 2010-11-23 | Musculoskeletal Transplant Foundation | Two piece cancellous construct for cartilage repair |
| ATE540974T1 (en) | 2004-11-23 | 2012-01-15 | Zymogenetics Inc | PURIFICATION OF RECOMBINANT HUMAN FACTOR XIII |
| US7815926B2 (en) | 2005-07-11 | 2010-10-19 | Musculoskeletal Transplant Foundation | Implant for articular cartilage repair |
| US8921109B2 (en) | 2005-09-19 | 2014-12-30 | Histogenics Corporation | Cell-support matrix having narrowly defined uniformly vertically and non-randomly organized porosity and pore density and a method for preparation thereof |
| US8435551B2 (en) | 2007-03-06 | 2013-05-07 | Musculoskeletal Transplant Foundation | Cancellous construct with support ring for repair of osteochondral defects |
| EP2265220A1 (en) | 2008-03-05 | 2010-12-29 | Musculoskeletal Transplant Foundation | Cancellous constructs, cartilage particles and combinations of cancellous constructs and cartilage particles |
| US10077420B2 (en) | 2014-12-02 | 2018-09-18 | Histogenics Corporation | Cell and tissue culture container |
| WO2023129802A1 (en) | 2021-12-30 | 2023-07-06 | Baxter International Inc. | Fibrinogen and thrombin solutions for a fibrin sealant and fibrin sealant kit |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| WO1981000516A1 (en) * | 1979-08-31 | 1981-03-05 | Merck Patent Gmbh | Gel containing fibrine and antibiotic for treating infected bones and preparation process thereof |
-
1981
- 1981-07-28 AT AT0333781A patent/AT369990B/en not_active IP Right Cessation
-
1982
- 1982-07-01 SE SE8204064A patent/SE459848B/en not_active IP Right Cessation
- 1982-07-05 DE DE19823225102 patent/DE3225102A1/en active Granted
- 1982-07-05 CH CH409482A patent/CH659187B/de unknown
- 1982-07-05 DK DK300682A patent/DK157977C/en active
- 1982-07-06 GB GB08219500A patent/GB2102811B/en not_active Expired
- 1982-07-13 CA CA000407154A patent/CA1168982A/en not_active Expired
- 1982-07-16 BE BE0/208601A patent/BE893851A/en not_active IP Right Cessation
- 1982-07-21 AR AR290039A patent/AR227252A1/en active
- 1982-07-22 JP JP57126829A patent/JPH0696039B2/en not_active Expired - Lifetime
- 1982-07-23 FR FR8212918A patent/FR2510408B1/en not_active Expired
- 1982-07-23 NL NL8202982A patent/NL192665C/en not_active IP Right Cessation
- 1982-07-27 ES ES514441A patent/ES8306023A1/en not_active Expired
- 1982-07-27 IT IT22595/82A patent/IT1157313B/en active
Cited By (19)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4909251A (en) * | 1988-05-31 | 1990-03-20 | Immuno Aktiengesellschaft Fur Chemisch-Medizinische Produkte | Tissue adhesive |
| US7189410B1 (en) | 1990-11-27 | 2007-03-13 | The American National Red Cross | Supplemented and unsupplemented tissue sealants, methods of their production and use |
| US7208179B1 (en) | 1990-11-27 | 2007-04-24 | The American National Red Cross | Methods for treating disease and forming a supplemented fibrin matrix |
| USRE39298E1 (en) * | 1990-11-27 | 2006-09-19 | The American National Red Cross | Supplemented and unsupplemented tissue sealants, methods of their production and use |
| USRE39321E1 (en) * | 1990-11-27 | 2006-10-03 | The American National Red Cross | Supplemented and unsupplemented tissue sealants, methods of their production and use |
| US6559119B1 (en) | 1990-11-27 | 2003-05-06 | Loyola University Of Chicago | Method of preparing a tissue sealant-treated biomedical material |
| US7229959B1 (en) | 1990-11-27 | 2007-06-12 | The American National Red Cross | Supplemented fibrin matrix delivery systems |
| US6117425A (en) * | 1990-11-27 | 2000-09-12 | The American National Red Cross | Supplemented and unsupplemented tissue sealants, method of their production and use |
| USRE39192E1 (en) * | 1990-11-27 | 2006-07-18 | American National Red Cross | Supplemented and unsupplemented tissue sealants, methods of their production and use |
| US7196054B1 (en) | 1990-11-27 | 2007-03-27 | The American National Red Cross | Methods for treating wound tissue and forming a supplemented fibrin matrix |
| 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 |
| US6762336B1 (en) | 1998-01-19 | 2004-07-13 | The American National Red Cross | Hemostatic sandwich bandage |
| US6506365B1 (en) | 2000-09-25 | 2003-01-14 | Baxter Aktiengesellschaft | Fibrin/fibrinogen binding conjugate |
| US6713453B2 (en) | 2000-09-25 | 2004-03-30 | Baxter Aktiengesellschaft | Fibrin/fibrinogen-binding conjugate |
| US7091325B2 (en) | 2000-09-25 | 2006-08-15 | Baxter Aktiengesellschaft | Fibrin/fibrinogen-binding conjugate |
| US8679528B2 (en) | 2002-09-10 | 2014-03-25 | American National Red Cross | Hemostatic dressing |
| US8445009B2 (en) | 2006-08-04 | 2013-05-21 | Stb, Ltd | Processes for the production of solid dressings for treating wounded tissue |
| US9131929B2 (en) | 2007-08-06 | 2015-09-15 | Stb, Ltd. | Methods and dressings for sealing internal injuries |
Also Published As
| Publication number | Publication date |
|---|---|
| FR2510408A1 (en) | 1983-02-04 |
| ES514441A0 (en) | 1983-05-01 |
| IT8222595A0 (en) | 1982-07-27 |
| ES8306023A1 (en) | 1983-05-01 |
| GB2102811B (en) | 1985-01-30 |
| DK157977B (en) | 1990-03-12 |
| IT1157313B (en) | 1987-02-11 |
| FR2510408B1 (en) | 1987-02-27 |
| CH659187B (en) | 1987-01-15 |
| DK157977C (en) | 1990-08-13 |
| AR227252A1 (en) | 1982-09-30 |
| NL192665C (en) | 1997-12-02 |
| DE3225102A1 (en) | 1983-02-17 |
| DE3225102C2 (en) | 1990-05-31 |
| SE8204064D0 (en) | 1982-07-01 |
| NL192665B (en) | 1997-08-01 |
| SE8204064L (en) | 1983-01-29 |
| JPS5826821A (en) | 1983-02-17 |
| GB2102811A (en) | 1983-02-09 |
| AT369990B (en) | 1983-02-25 |
| ATA333781A (en) | 1982-07-15 |
| BE893851A (en) | 1982-11-16 |
| SE459848B (en) | 1989-08-14 |
| NL8202982A (en) | 1983-02-16 |
| JPH0696039B2 (en) | 1994-11-30 |
| DK300682A (en) | 1983-01-29 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CA1168982A (en) | Tissue adhesive | |
| KR100276372B1 (en) | Stable Fibrinogen Solution | |
| US4407787A (en) | Collagenous dressing | |
| US4650678A (en) | Readily dissolvable lyophilized fibrinogen formulation | |
| US4414976A (en) | Tissue adhesive | |
| US6500427B1 (en) | One-component tissue adhesive and a process for the production thereof | |
| DE69333080T2 (en) | Fibrin sealant compositions and methods of using them | |
| EP1568709B1 (en) | Purification of fibrinogen | |
| AU2004201982B2 (en) | A Method for Producing a Preparation Based on Fibrinogen and Fibronectin as Well as Protein Compositions Obtainable According to This Method | |
| US4683142A (en) | Resorptive sheet material for closing and healing wounds and method of making the same | |
| KR100858830B1 (en) | Stabilised protein preparations for a tissue adhesive | |
| JPS5838216A (en) | Condensed blood plasma derivative | |
| US20120156284A1 (en) | Enhanced biological autologous tissue adhesive composition and methods of preparation and use | |
| US6916911B1 (en) | Use of fibrinogen multimers | |
| JP2002539087A (en) | Method for producing formulations based on fibrinogen and fibronectin and protein compositions obtainable by this method | |
| BUGARSKI et al. | The use of single-donor brin glue prepared by recycled cryoprecipitation in experimental liver surgery |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MKEX | Expiry |