US5607694A
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Biologic bioadhesive compositions containing fibrin glue and liposomes, methods of preparation and use
Assignee: New York Blood Center
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Filing: 1995-06-02
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Granted: 1997-03-04
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Expires: 2015-06-02
Abstract
Abstract The present invention describes a biologically compatible bioadhesive sealant composition comprising fibrin glue and liposomes for use in mammals, including humans. Fibrin glue of the invention comprises fibrinogen and thrombin which are mixed together in various modes with liposomes and applied to a site of injury, to a wound, or to a surgical or nonsurgical incision or opening. In accordance with the invention, the liposomes are embedded within the fibrin glue after coagulation has occurred, and may release bioactive substances contained within their aqueous interiors to promote healing and protection during the recovery process. The bioadhesive composition of the invention promises to maintain hemostasis after surgeries and improves upon existing glues or gel formulations due to its complete biological compatibility, its formation in situ, and its provision of bioactive therapeutics via entrapped liposomes directly to the site. Long-lasting biophysical and biomechanical properties as well as therapeutic value are imparted to the fibrin glue components by the liposome component of the composition. The biocompatible fibrin glue and liposome composition is also amenable for fabrication into films, coatings, or membranes for in vitro and in vivo uses.
Inventors
- 👤 Gerard Marx
Bibliographic Details
Application Number
—
Jurisdiction
US
Data Source
google_patents
Last Synchronized
2026-10-23 04:03
CPC Classifications
A; A61; A61L; A61L24/00; A61L24/04; A61L24/10; A61L24/106; A61K; A61K47/00; A61K47/30; A61K47/42; A61K9/00; A61K9/10; A61K9/127; A61L24/001; A61L24/0015; A61L24/043; A61P; A61P17/00; A61P17/02; A61P7/00; A61P7/04; A61L2300/00; A61L2300/10; A61L2300/102; A61L2300/40; A61L2300/404; A61L2300/406; A61L2300/412; A61L2300/414; A61L2300/428; A61L2300/60; A61L2300/62; A61L2300/626; Y; Y10; Y10T; Y10T428/00; Y10T428/29; Y10T428/2982; Y10T428/2984
Claims Analysis
Total Claims: 46
Claim 1
Independent Claim
165 words
A method for producing a liposome-containing fibrin glue bioadhesive sealant, comprising: a) preparing: i) virus inactivated fibrinogen; ii) virus inactivated thrombin; and iii) liposomes containing one or more medicaments entrapped therein and deliverable within a wound site or surgical or nonsurgical opening; b) mixing said fibrinogen with said thrombin and said liposomes of step a) with calcium to form a mixture, wherein said fibrinogen is present in said mixture at a concentration of about 10 to 90 mg/mL; said thrombin is present in said mixture at a concentration of about 1 to 200 U/mL; and said liposomes are present in said mixture at a concentration of about 1% to 20%, by volume; and said calcium is present in said mixture at a concentration of about 1 to 30 mM, and further wherein said thrombin catalyzes formation of a fibrin glue clot in which said liposomes are entrapped, said entrapped liposomes releasing their biologically active contents within the site of application of said fibrin glue clot.
Claim 2
Independent Claim
165 words
A method for producing a liposome-containing fibrin glue bioadhesive sealant, comprising: a) preparing: i) virus inactivated fibrinogen; ii) virus inactivated thrombin; and iii) liposomes containing one or more medicaments entrapped therein and deliverable within a wound site or surgical or nonsurgical opening; b) mixing said fibrinogen with said thrombin and said liposomes of step a) with calcium to form a mixture, wherein said fibrinogen is present in said mixture at a concentration of about 10 to 90 mg/mL; said thrombin is present in said mixture at a concentration of about 1 to 200 U/mL; and said liposomes are present in said mixture at a concentration of about 1% to 20%, by volume; and said calcium is present in said mixture at a concentration of about 1 to 30 mM, and further wherein said thrombin catalyzes formation of a fibrin glue clot in which said liposomes are entrapped, said entrapped liposomes releasing their biologically active contents within the site of application of said fibrin glue clot.
Claim 3
Dependent Claim
41 words
The method according to claim 1, wherein said fibrinogen is purified human fibrinogen, said thrombin is purified human or bovine thrombin, and said liposomes are formulated to contain noncharged chemical groups exposed on the liposome surface, thereby resulting in neutral liposomes.
Claim 4
Dependent Claim
40 words
The method according to claim 1, wherein said fibrinogen is purified human fibrinogen, said thrombin is purified human or bovine thrombin, and said liposomes are formulated to contain amine groups exposed on the liposome surface, thereby resulting in amine liposomes.
Claim 5
Dependent Claim
42 words
The method according to claim 1, wherein said fibrinogen is purified human fibrinogen, said thrombin is purified human or bovine thrombin, and said liposomes are formulated to contain carboxylic acid groups exposed on the liposome surface, thereby resulting in carboxylic acid liposomes.
Claim 6
Independent Claim
156 words
A method for producing a liposome-containing fibrin glue bioadhesive sealant, comprising: a) preparing: i) virus inactivated fibrinogen; ii) virus inactivated thrombin; and iii) liposomes containing one or more medicaments entrapped therein and deliverable within a wound site or surgical or nonsurgical opening; b) mixing said fibrinogen of step a)i) with said liposomes of step a)iii) to form a fibrinogen and liposome first mixture; and c) adding said thrombin of step a)ii) to said first mixture of step b) to form a second mixture comprising fibrinogen at a concentration of about 10 to 90 mg/mL, liposomes at about 1% to 20%, by volume, and thrombin at a concentration of about 1 to 200 U/mL; wherein calcium is added to said second mixture at a concentration of about 1 to 30 mM, and further wherein said thrombin promotes coagulation and formation of said fibrin glue sealant in which said liposomes are embedded and release their biologically active contents.
Claim 7
Independent Claim
156 words
A method for producing a liposome-containing fibrin glue bioadhesive sealant, comprising: a) preparing: i) virus inactivated fibrinogen; ii) virus inactivated thrombin; and iii) liposomes containing one or more medicaments entrapped therein and deliverable within a wound site or surgical or nonsurgical opening; b) mixing said fibrinogen of step a)i) with said liposomes of step a)iii) to form a fibrinogen and liposome first mixture; and c) adding said thrombin of step a)ii) to said first mixture of step b) to form a second mixture comprising fibrinogen at a concentration of about 10 to 90 mg/mL, liposomes at about 1% to 20%, by volume, and thrombin at a concentration of about 1 to 200 U/mL; wherein calcium is added to said second mixture at a concentration of about 1 to 30 mM, and further wherein said thrombin promotes coagulation and formation of said fibrin glue sealant in which said liposomes are embedded and release their biologically active contents.
Claim 8
Dependent Claim
35 words
The method according to claim 5, comprising the further step of: d) inducing said coagulation of step c) at a site of wound or injury or in a surgical or nonsurgical opening in an animal.
Claim 9
Dependent Claim
41 words
The method according to claim 5, wherein said fibrinogen is purified human fibrinogen, said thrombin is purified human or bovine thrombin, and said liposomes are formulated to contain noncharged chemical groups exposed on the liposome surface, thereby resulting in neutral liposomes.
Claim 10
Dependent Claim
40 words
The method according to claim 5, wherein said fibrinogen is purified human fibrinogen, said thrombin is purified human or bovine thrombin, and said liposomes are formulated to contain amine groups exposed on the liposome surface, thereby resulting in amine liposomes.
Claim 11
Dependent Claim
42 words
The method according to claim 5, wherein said fibrinogen is purified human fibrinogen, said thrombin is purified human or bovine thrombin, and said liposomes are formulated to contain carboxylic acid groups exposed on the liposome surface, thereby resulting in carboxylic acid liposomes.
Claim 12
Independent Claim
192 words
A method for producing a liposome-containing fibrin glue bioadhesive sealant for administration at a wound, ulcer injury, or surgical or nonsurgical site, comprising: a) preparing: i) virus inactivated fibrinogen; ii) virus inactivated thrombin; and iii) liposomes containing one or more medicaments entrapped therein and deliverable within a wound site or surgical or nonsurgical opening; b) mixing an effective amount of said thrombin with said liposomes of step a) to form a thrombin and liposome first mixture; and c) adding an effective amount of said fibrinogen of step a) to said first mixture of step b) to form a second mixture comprising thrombin and liposomes and fibrinogen; wherein said thrombin is present in the second mixture at a concentration of about 1-200 U/mL and said fibrinogen is present in said second mixture at a concentration of about 10-90 mg/mL; and said liposomes are present at about 1% to 20%, by volume, wherein calcium is present in said second mixture at a concentration of about 1 to 30 mM, and further wherein said thrombin promotes the formation of a fibrin glue clot in which said liposomes are embedded to release their biologically active contents.
Claim 13
Independent Claim
192 words
A method for producing a liposome-containing fibrin glue bioadhesive sealant for administration at a wound, ulcer injury, or surgical or nonsurgical site, comprising: a) preparing: i) virus inactivated fibrinogen; ii) virus inactivated thrombin; and iii) liposomes containing one or more medicaments entrapped therein and deliverable within a wound site or surgical or nonsurgical opening; b) mixing an effective amount of said thrombin with said liposomes of step a) to form a thrombin and liposome first mixture; and c) adding an effective amount of said fibrinogen of step a) to said first mixture of step b) to form a second mixture comprising thrombin and liposomes and fibrinogen; wherein said thrombin is present in the second mixture at a concentration of about 1-200 U/mL and said fibrinogen is present in said second mixture at a concentration of about 10-90 mg/mL; and said liposomes are present at about 1% to 20%, by volume, wherein calcium is present in said second mixture at a concentration of about 1 to 30 mM, and further wherein said thrombin promotes the formation of a fibrin glue clot in which said liposomes are embedded to release their biologically active contents.
Claim 14
Dependent Claim
41 words
The method according to claim 10, wherein said fibrinogen is purified human fibrinogen, said thrombin is purified human or bovine thrombin, and said liposomes are formulated to contain noncharged chemical groups exposed on the liposome surface, thereby resulting in neutral liposomes.
Claim 15
Dependent Claim
40 words
The method according to claim 10, wherein said fibrinogen is purified human fibrinogen, said thrombin is purified human or bovine thrombin, and said liposomes are formulated to contain amine groups exposed on the liposome surface, thereby resulting in amine liposomes.
Claim 16
Dependent Claim
42 words
The method according to claim 10, wherein said fibrinogen is purified human fibrinogen, said thrombin is purified human or bovine thrombin, and said liposomes are formulated to contain carboxylic acid groups exposed on the liposome surface, thereby resulting in carboxylic acid liposomes.
Claim 17
Dependent Claim
75 words
The method according to claim 1, wherein said liposome entrapped medicament is selected from the group consisting of neuroleptics, vitamins, growth factors, steroids, antibiotics, antibacterial compounds, bacteriocidal compounds, bacteriostatic compounds, antiviral compounds, antifungal compounds, antiparasitic compounds, tumoricidal compounds, tumoristatic compounds, toxins, enzymes, enzyme inhibitors, proteins, peptides, minerals, neurotransmitters, lipoproteins, glycoproteins, immunomodulators, immunoglobulins, dyes, radiolabels, radiopaque compounds, fluorescent compounds, fatty acids, polysaccharides, cell receptor binding molecules, anti-inflammatories, antiglaucomic compounds, mydriatic compounds, anesthetics, nucleic acids, and polynucleotides.
Claim 18
Dependent Claim
75 words
The method according to claim 5, wherein said liposome entrapped medicament is selected from the group consisting of neuroleptics, vitamins, growth factors, steroids, antibiotics, antibacterial compounds, bacteriocidal compounds, bacteriostatic compounds, antiviral compounds, antifungal compounds, antiparasitic compounds, tumoricidal compounds, tumoristatic compounds, toxins, enzymes, enzyme inhibitors, proteins, peptides, minerals, neurotransmitters, lipoproteins, glycoproteins, immunomodulators, immunoglobulins, dyes, radiolabels, radiopaque compounds, fluorescent compounds, fatty acids, polysaccharides, cell receptor binding molecules, anti-inflammatories, antiglaucomic compounds, mydriatic compounds, anesthetics, nucleic acids, and polynucleotides.
Claim 19
Dependent Claim
75 words
The method according to claim 10, wherein said liposome entrapped medicament is selected from the group consisting of neuroleptics, vitamins, growth factors, steroids, antibiotics, antibacterial compounds, bacteriocidal compounds, bacteriostatic compounds, antiviral compounds, antifungal compounds, antiparasitic compounds, tumoricidal compounds, tumoristatic compounds, toxins, enzymes, enzyme inhibitors, proteins, peptides, minerals, neurotransmitters, lipoproteins, glycoproteins, immunomodulators, immunoglobulins, dyes, radiolabels, radiopaque compounds, fluorescent compounds, fatty acids, polysaccharides, cell receptor binding molecules, anti-inflammatories, antiglaucomic compounds, mydriatic compounds, anesthetics, nucleic acids, and polynucleotides.
Claim 20
Dependent Claim
32 words
The method according to claim 1, wherein said fibrinogen is mixed with other proteins selected from the group consisting of proteins in uncoagulated whole blood and proteins in plasma and platelet-rich plasma.
Claim 21
Dependent Claim
32 words
The method according to claim 5, wherein said fibrinogen is mixed with other proteins selected from the group consisting of proteins in uncoagulated whole blood and proteins in plasma and platelet-rich plasma.
Claim 22
Dependent Claim
32 words
The method according to claim 10, wherein said fibrinogen is mixed with other proteins selected from the group consisting of proteins in uncoagulated whole blood and proteins in plasma and platelet-rich plasma.
Claim 23
Dependent Claim
31 words
The composition according to claim 17, 18 or 19, wherein said blood and plasma proteins are selected from the group consisting of fibrinogen, factor XIII, fibronectin, thrombin, immunoglobulin, plasminogen, and albumin.
Claim 24
Dependent Claim
189 words
The method according to claim 1, claim 5, or claim 10, wherein one biological additive is contained within the aqueous compartment of a first set of liposomes selected from the group consisting of liposomes formulated to contain noncharged chemical groups exposed on the liposome surface, thereby resulting in neutral liposomes; liposomes formulated to contain amine groups exposed on the liposome surface, thereby resulting in amine liposomes; and liposomes formulated to contain carboxylic acid groups exposed on the liposome surface, thereby resulting in carboxylic acid liposomes, or a mixture thereof, and another biological additive is contained within the aqueous compartment of a second set of liposomes selected from the group consisting of liposomes formulated to contain noncharged chemical groups exposed on the liposome surface, thereby resulting in neutral liposomes; liposomes formulated to contain amine groups exposed on the liposome surface, thereby resulting in amine liposomes; and liposomes formulated to contain carboxylic acid groups exposed on the liposome surface, thereby resulting in carboxylic acid liposomes, or a mixture thereof, said first and second sets of liposomes being mixed and sequestered in said fibrin glue from which the biological additives are released.
Claim 25
Dependent Claim
44 words
The method according to claim 21, wherein said first set of liposomes comprises neutral liposomes formulated to contain noncharged chemical groups exposed on their surfaces, and said second set of liposomes comprises neutral liposomes formulated to contain noncharged chemical groups exposed on their surfaces.
Claim 26
Dependent Claim
42 words
The method according to claim 21, wherein said first set of liposomes comprises neutral liposomes formulated to contain noncharged chemical groups exposed on their surfaces and said second set of liposomes comprises liposomes formulated to contain amine groups exposed on their surfaces.
Claim 27
Dependent Claim
43 words
The method according to claim 21, wherein said first set of liposomes comprises neutral liposomes formulated to contain noncharged chemical groups exposed on their surfaces and said second set of liposomes comprises liposomes formulated to contain carboxylic acid groups exposed on their surfaces.
Claim 28
Dependent Claim
41 words
The method according to claim 21, wherein said first set of liposomes comprises liposomes formulated to contain amine groups exposed on their surfaces and said second set of liposomes comprises liposomes formulated to contain carboxylic acid groups exposed on their surfaces.
Claim 29
Dependent Claim
19 words
The method according to claim 2, 7, or 11, wherein said noncharged or neutral lipids are lecithin or phosphatidylcholine.
Claim 30
Dependent Claim
16 words
The method according to claim 21, wherein said noncharged or neutral lipids are lecithin or phosphatidylcholine.
Claim 31
Dependent Claim
17 words
The method according to claim 3, 8, or 12, wherein said amine is stearyl amine or diethylstearylamine.
Claim 32
Dependent Claim
14 words
The method according to claim 21, wherein said amine is stearyl amine or diethylstearylamine.
Claim 33
Dependent Claim
16 words
The method according to claim 4, 9, or 13, wherein said carboxylic acid is stearic acid.
Claim 34
Dependent Claim
13 words
The method according to claim 21, wherein said carboxylic acid is stearic acid.
Claim 35
Dependent Claim
47 words
The method according to claim 23, wherein said first set of neutral or noncharged liposomes is formulated to contain phosphatidylcholine or lecithin exposed on the liposome surface and said second set of amine liposomes is formulated to contain stearyl amine or diethylstearylamine exposed on the liposome surface.
Claim 36
Dependent Claim
46 words
The method according to claim 24, wherein said first set of neutral or noncharged liposomes is formulated to contain phosphatidylcholine or lecithin exposed on the liposome surface and said second set of carboxylic acid liposomes is formulated to contain stearic acid exposed on the liposome surface.
Claim 37
Dependent Claim
45 words
The method according to claim 25, wherein said first set of amine liposomes is formulated to contain stearyl amine or diethylstearylamine exposed on the liposome surface and said second set of carboxylic acid liposomes is formulated to contain stearic acid exposed on the liposome surface.
Claim 38
Dependent Claim
20 words
The method according to claim 1, 5, or 10, wherein said liposomes comprise a mixture of saturated and unsaturated lipids.
Claim 39
Dependent Claim
51 words
The method according to claim 1, 5, or 10, wherein said liposomes are formulated to contain on their surfaces compounds having at least one light sensitive chemical double bond, said double bond predisposing the compounds to undergo conformational change when exposed to light, thereby resulting in photoactivable or light sensitive liposomes.
Claim 40
Dependent Claim
26 words
The method according to claim 36, wherein said double chemical bond-containing photoactivable compounds are selected from the group consisting of lecithins of retinoic acid and α-tocopherol.
Claim 41
Dependent Claim
18 words
The method according to claim 37, wherein said lecithins of retinoic acid are 1,2, diretinoyl-sn-3-glycerophosphocholine, 2-retinoylisolecithin, or 1-palmitoyl-2-retinoyl-sn-3-glycerophosphocholine.
Claim 42
Dependent Claim
37 words
The method according to claim 1, 5, or 10, further comprising the step of applying said fibrinogen, thrombin, and liposome mixture as a liquid or spray or paste to form a fibrin glue-containing liposome film or membrane.
Claim 43
Dependent Claim
37 words
The method according to claim 1, 5, or 10, further comprising the stept of applying said fibrinogen, thrombin, and liposome mixture as a liquid or spray ex vivo to form a fibrin glue-containing liposome foam or clot.
Claim 44
Dependent Claim
23 words
The method according to claim 39, wherein said film or membrane coats the surface of an implantable device for temporary or permanent implantation.
Claim 45
Dependent Claim
23 words
The method according to claim 40, wherein said foam or clot coats the surface of an implantable device for temporary or permanent implantation.
Claim 46
Dependent Claim
20 words
The method according to claim 42, wherein said foam or clot comprises an implantable device for temporary or permanent implantation.
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