Patent US3146012A successfully refreshed from Google Patents.
Patent US5631019A successfully refreshed from Google Patents.
US5631019A
Expired / Lapsed
US
⏱️ 0.0 years remaining
Biologic bioadhesive compositions containing fibrin glue and liposomes, methods of preparation and use
Assignee: New York Blood Center
•
Filing: 1995-06-02
•
Granted: 1997-05-20
•
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 04:58
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: 37
Claim 1
Independent Claim
139 words
A method for inducing coagulation of a liposome-containing fibrin glue bioadhesive composition at a site of injury, wound, or surgery in a mammal, thereby resulting in sealing and healing of the injury, wound, or surgical site, comprising: a) preparing said liposome-containing fibrin glue composition, comprising in admixture: (i) virus-inactivated fibrinogen present in said composition at a concentration of 10 to 90 mg/mL; (ii) virus-inactivated thrombin present in said composition at a concentration of 1 to 200 U/mL; (iii) liposomes present in said composition at a concentration of about 1% to 20%, by volume; and (iv) calcium present in said composition at a concentration of about 1 to 30 mM; and b) administering said composition to said mammal, wherein coagulation of said glue forms a medium for entrapping said liposomes at said site and embeds said liposomes in said glue.
Claim 2
Independent Claim
139 words
A method for inducing coagulation of a liposome-containing fibrin glue bioadhesive composition at a site of injury, wound, or surgery in a mammal, thereby resulting in sealing and healing of the injury, wound, or surgical site, comprising: a) preparing said liposome-containing fibrin glue composition, comprising in admixture: (i) virus-inactivated fibrinogen present in said composition at a concentration of 10 to 90 mg/mL; (ii) virus-inactivated thrombin present in said composition at a concentration of 1 to 200 U/mL; (iii) liposomes present in said composition at a concentration of about 1% to 20%, by volume; and (iv) calcium present in said composition at a concentration of about 1 to 30 mM; and b) administering said composition to said mammal, wherein coagulation of said glue forms a medium for entrapping said liposomes at said site and embeds said liposomes in said glue.
Claim 3
Dependent Claim
19 words
The method according to claim 1, wherein said liposomes contain one or more medicaments within their interior aqueous phases.
Claim 4
Dependent Claim
13 words
The method according to claim 1, wherein said administering step is topical application.
Claim 5
Dependent Claim
156 words
A process for forming a flexible fibrin glue and liposome composition in the form of a film or membrane comprised of said fibrin glue in which said liposomes are embedded, the film or membrane used for coating or implantation in vitro or in vivo, comprising: a) preparing said fibrin glue and liposome composition comprising: i) virus-inactivated fibrinogen at a concentration of about 10 to 90 mg/mL; ii) virus-inactivated thrombin at a concentration of about 1 to 200 U/mL; and iii) liposomes at a concentration of about 1% to 20%, by volume; b) mixing the components of step a); c) sprayably applying the composition onto a substrate; the substrate providing a surface onto which the composition temporarily adheres and gels to form a flexible film or membrane comprising the gelled fibrin glue and liposome composition; d) removing from the substrate surface the film or membrane comprising the fibrin glue and liposome composition after said composition has gelled.
Claim 6
Dependent Claim
156 words
A process for forming a flexible fibrin glue and liposome composition in the form of a film or membrane comprised of said fibrin glue in which said liposomes are embedded, the film or membrane used for coating or implantation in vitro or in vivo, comprising: a) preparing said fibrin glue and liposome composition comprising: i) virus-inactivated fibrinogen at a concentration of about 10 to 90 mg/mL; ii) virus-inactivated thrombin at a concentration of about 1 to 200 U/mL; and iii) liposomes at a concentration of about 1% to 20%, by volume; b) mixing the components of step a); c) sprayably applying the composition onto a substrate; the substrate providing a surface onto which the composition temporarily adheres and gels to form a flexible film or membrane comprising the gelled fibrin glue and liposome composition; d) removing from the substrate surface the film or membrane comprising the fibrin glue and liposome composition after said composition has gelled.
Claim 7
Dependent Claim
22 words
The process according to claim 4, wherein the liposomes are formulated to contain one or more medicaments within their interior aqueous phases.
Claim 8
Independent Claim
155 words
A method for hemostatically sealing and healing a wound or a surgical incision and delivering to the wound or incision medicaments, comprising: a) preparing a liposome-containing fibrin glue composition, comprising in admixture: (i) virus-inactivated fibrinogen present in said composition at a concentration of 10 to 90 mg/mL; (ii) virus-inactivated thrombin present in said composition at a concentration of 1 to 200 U/mL; (iii) liposomes present in said composition at a concentration of about 1% to 20%, by volume, said liposomes formulated to contain one or more medicaments within their interior aqueous phases; and (iv) calcium present in said composition at a concentration of about 1 to 30 mM; b) administering said composition to the surface of said wound or incision, wherein coagulation of said glue forms a medium for entrapping said liposomes at said site, embeds said liposomes in said glue, and allows sustained release of said liposome contents delivered within said wound or incision.
Claim 9
Independent Claim
155 words
A method for hemostatically sealing and healing a wound or a surgical incision and delivering to the wound or incision medicaments, comprising: a) preparing a liposome-containing fibrin glue composition, comprising in admixture: (i) virus-inactivated fibrinogen present in said composition at a concentration of 10 to 90 mg/mL; (ii) virus-inactivated thrombin present in said composition at a concentration of 1 to 200 U/mL; (iii) liposomes present in said composition at a concentration of about 1% to 20%, by volume, said liposomes formulated to contain one or more medicaments within their interior aqueous phases; and (iv) calcium present in said composition at a concentration of about 1 to 30 mM; b) administering said composition to the surface of said wound or incision, wherein coagulation of said glue forms a medium for entrapping said liposomes at said site, embeds said liposomes in said glue, and allows sustained release of said liposome contents delivered within said wound or incision.
Claim 10
Dependent Claim
13 words
The method according to claim 6, wherein said administering step is topical application.
Claim 11
Dependent Claim
14 words
The method according to claim 7, wherein said topical application comprises spraying or spreading.
Claim 12
Dependent Claim
14 words
The method according to claim 3, wherein said topical application comprises spraying or spreading.
Claim 13
Dependent Claim
80 words
The method according to claim 2 or claim 6, wherein said medicament contained within said liposomes 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 14
Dependent Claim
78 words
The process according to claim 5, wherein said medicament contained within said liposomes is selected from the group consisting of neuroleptics, vitamins, growth factors, steroids, antibiotics, antibacterial compounds, bacteriocidal compounds, bacteriostatic compounds, antiviral compounds, antifungal compounds, and parasitic 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 15
Dependent Claim
35 words
The method according to claim 1 or claim 6, 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 16
Dependent Claim
32 words
The process according to claim 4, 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 17
Dependent Claim
28 words
The composition according to claim 12, wherein said blood and plasma proteins are selected from the group consisting of fibrinogen, factor XIII, fibronectin, thrombin, immunoglobulin, plasminogen, and albumin.
Claim 18
Dependent Claim
28 words
The composition according to claim 13, wherein said blood and plasma proteins are selected from the group consisting of fibrinogen, factor XIII, fibronectin, thrombin, immunoglobulin, plasminogen, and albumin.
Claim 19
Dependent Claim
75 words
The method according to claim 1 or claim 6, wherein said liposomes are 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.
Claim 20
Dependent Claim
72 words
The process according to claim 4, wherein said liposomes are 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.
Claim 21
Dependent Claim
184 words
The method according to claim 2 or claim 6, wherein one medicament 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 mine 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 medicament 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 medicaments are released.
Claim 22
Dependent Claim
181 words
The process according to claim 5, wherein one medicament 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 medicament 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 medicaments are released.
Claim 23
Dependent Claim
16 words
The method according to claim 16, wherein said noncharged or neutral lipids are lecithin or phosphatidylcholine.
Claim 24
Dependent Claim
16 words
The process according to claim 17, wherein said noncharged or neutral lipids are lecithin or phosphatidylcholine.
Claim 25
Dependent Claim
14 words
The method according to claim 16, wherein said amine is stearyl amine or diethylstearylamine.
Claim 26
Dependent Claim
14 words
The process according to claim 17, wherein said amine is stearyl amine or diethylstearylamine.
Claim 27
Dependent Claim
13 words
The method according to claim 16, wherein said carboxylic acid is stearic acid.
Claim 28
Dependent Claim
13 words
The process according to claim 17, wherein said carboxylic acid is stearic acid.
Claim 29
Dependent Claim
51 words
The method according to claim 1 or claim 6, 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 30
Dependent Claim
26 words
The method according to claim 26, wherein said double chemical bond-containing photoactivable compounds are selected from the group consisting of lecithins of retinoic acid and α-tocopherol.
Claim 31
Dependent Claim
18 words
The method according to claim 27, wherein said lecithins of retinoic acid are 1,2, diretinoyl-sn-3-glycerophosphocholine, 2-retinoylsolecithin, or 1-palmitoyl-2-retinoyl-sn-3-glycerophosphocholine.
Claim 32
Dependent Claim
48 words
The process according to claim 4, 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 33
Dependent Claim
26 words
The method according to claim 29, wherein said double chemical bond-containing photoactivable compounds are selected from the group consisting of lecithins of retinoic acid and α-tocopherol.
Claim 34
Dependent Claim
18 words
The method according to claim 30, wherein said lecithins of retinoic acid are 1,2, diretinoyl-sn-3-glycerophosphocholine, 2-retinoylisolecithin, or 1-palmitoyl-2-retinoyl-sn-3-glycerophosphocholine.
Claim 35
Dependent Claim
22 words
The method according to claim 1, wherein said fibrinogen is purified human fibrinogen and said thrombin is purified human or bovine thrombin.
Claim 36
Dependent Claim
22 words
The method according to claim 6, wherein said fibrinogen is purified human fibrinogen and said thrombin is purified human or bovine thrombin.
Claim 37
Dependent Claim
22 words
The process according to claim 4, wherein said fibrinogen is purified human fibrinogen and said thrombin is purified human or bovine thrombin.
References Cited (Backward Citations)
US4351337A
Cited
US4224179A
Cited
US4235871A
Cited
WO1985003640A1
Cited
US4708861A
Cited
EP0160266A2
Cited
US4853225A
Cited
US5290552A
Cited
US5209776A
Cited
US5206023A
Cited
US5246452A
Cited
USPTO Annuity & Maintenance Windows
| Annuity Stage | Window Opens | Payment Deadline | Surcharge Period Until | Estimated Fee | Status |
|---|---|---|---|---|---|
| 3.5 Years (Year 4) | 2000-05-19 | 2000-11-18 | 2001-05-20 | $2000.00 | Window Closed / Lapsed |
| 7.5 Years (Year 8) | 2004-05-19 | 2004-11-18 | 2005-05-20 | $3760.00 | Window Closed / Lapsed |
| 11.5 Years (Year 12) | 2008-05-19 | 2008-11-18 | 2009-05-20 | $7700.00 | Window Closed / Lapsed |