Branched end reactants and polymeric hydrogel tissue adhesives therefrom
First Claim
Patent Images
1. A composition of matter comprising at least one compound of the formula:
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Q[(PA)X(RY)z]m;
wherein;
(i) X is selected from the group consisting of;
CH3-z, N, N(acetoacetamide)-CH3-z, S—
R2—
CH3-z, NH—
CH3-z, and NH—
R2—
N, wherein R2 is an alkylene group having from 1 to 5 carbon atoms;
(ii) R is selected from the group consisting of;
a direct bond, an alkylene group having from 1 to 5 carbon atoms, an alkylene ether group having up to a total of 6 backbone atoms, an alkyleneoxy urethane group of the formula R4O(CO)NHCH2 wherein R4 is a linear or branched alkylene group having 2 to 6 carbon atoms and R4 is the group that is adjacent to X, and a C3 to C8 cycloalkylene group;
(iii) Y is a functional group selected from the group consisting of;
—
NH2, —
SH, —
CONHNH2, acetoacetate, and —
COR1, wherein R1 is OH or —
N-hydroxysuccinimidyl;
(iv) Q is a core atom or molecule selected from the group consisting of;
N, a polyol with the hydrogens removed from 3 or more of its OH groups, and N—
R3—
N, wherein R3 is an alkylene group having 2-12 carbon atoms or a C3 to C8 cycloalkylene group;
(v) PA is a linear polymeric arm terminating with a methylene group at both ends of said arm, wherein said arm is a polymer selected from the group consisting of;
polyethylene oxide, poly(trimethyleneoxide), block or random copolymers of polyethylene oxide and polypropylene oxide, and triblock copolymers of polyethylene oxide and polypropylene oxide;
(vi) z is 2 or 3 where X=CH3-z, S—
R2—
CH3-z, N(acetoacetamide)-CH3-z or NH—
CH3-z and z is 2 where X=N, NH—
R2—
N, or S—
R2—
N; and
(vii) m is 3 where Q is N, m is 4 where Q is N—
R3—
N, and m is 3 to 16 where Q is said polyol;
provided that if Y is acetoacetate or COR1, wherein R1 is N-hydroxysuccinimidyl, then X is not NH—
CH3-z, or NH—
R2—
N.
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Abstract
Branched end reactants having two or three functional groups at the ends are disclosed. The branched end reactants are used to prepare crosslinked hydrogel tissue adhesives, which have a good balance of mechanical properties in an aqueous environment. Kits comprising the branched end reactants and methods for applying a coating to an anatomical site on tissue of a living organism are also disclosed.
82 Citations
25 Claims
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1. A composition of matter comprising at least one compound of the formula:
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Q[(PA)X(RY)z]m;wherein; (i) X is selected from the group consisting of;
CH3-z, N, N(acetoacetamide)-CH3-z, S—
R2—
CH3-z, NH—
CH3-z, and NH—
R2—
N, wherein R2 is an alkylene group having from 1 to 5 carbon atoms;(ii) R is selected from the group consisting of;
a direct bond, an alkylene group having from 1 to 5 carbon atoms, an alkylene ether group having up to a total of 6 backbone atoms, an alkyleneoxy urethane group of the formula R4O(CO)NHCH2 wherein R4 is a linear or branched alkylene group having 2 to 6 carbon atoms and R4 is the group that is adjacent to X, and a C3 to C8 cycloalkylene group;(iii) Y is a functional group selected from the group consisting of;
—
NH2, —
SH, —
CONHNH2, acetoacetate, and —
COR1, wherein R1 is OH or —
N-hydroxysuccinimidyl;(iv) Q is a core atom or molecule selected from the group consisting of;
N, a polyol with the hydrogens removed from 3 or more of its OH groups, and N—
R3—
N, wherein R3 is an alkylene group having 2-12 carbon atoms or a C3 to C8 cycloalkylene group;(v) PA is a linear polymeric arm terminating with a methylene group at both ends of said arm, wherein said arm is a polymer selected from the group consisting of;
polyethylene oxide, poly(trimethyleneoxide), block or random copolymers of polyethylene oxide and polypropylene oxide, and triblock copolymers of polyethylene oxide and polypropylene oxide;(vi) z is 2 or 3 where X=CH3-z, S—
R2—
CH3-z, N(acetoacetamide)-CH3-z or NH—
CH3-z and z is 2 where X=N, NH—
R2—
N, or S—
R2—
N; and(vii) m is 3 where Q is N, m is 4 where Q is N—
R3—
N, and m is 3 to 16 where Q is said polyol;provided that if Y is acetoacetate or COR1, wherein R1 is N-hydroxysuccinimidyl, then X is not NH—
CH3-z, or NH—
R2—
N. - View Dependent Claims (2)
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3. A kit comprising:
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a) at least one compound of the formula;
(YR)zX(PS)X(RY)z;
or
(i)
Q[(PA)X(RY)z]m;
(ii)
wherein;(A) PS is a linear polymeric segment terminating with a methylene group at both ends of said segment, wherein said segment is a polymer selected from the group consisting of;
polyethylene oxide, poly(trimethyleneoxide), block or random copolymers of polyethylene oxide and polypropylene oxide, and triblock copolymers of polyethylene oxide and polypropylene oxide;(B) X is selected from the group consisting of;
CH3-z, N, N(acetoacetamide)-CH3-z, S—
R2—
N, S—
R2—
CH3-z, NH—
CH3-z, and NH—
R2—
N, wherein R2 is an alkylene group having from 1 to 5 carbon atoms;(C) R is selected from the group consisting of;
a direct bond, an alkylene group having from 1 to 5 carbon atoms, an alkylene ether group having up to a total of 6 backbone atoms, an alkyleneoxy urethane group of the formula R4O(CO)NHCH2 wherein R4 is a linear or branched alkylene group having 2 to 6 carbon atoms and R4 is the group that is adjacent to X, and a C3 to C8 cycloalkylene group;(D) Y is a functional group selected from the group consisting of;
—
NH2, —
SH, —
CONHNH2, acetoacetate, and —
COR1, wherein R1 is OH or —
N-hydroxysuccinimidyl;(E) Q is a core atom or molecule selected from the group consisting of;
N, a polyol with the hydrogens removed from 3 or more of its OH groups, and N—
R3—
N, wherein R3 is an alkylene group having 2-12 carbon atoms or a C3 to C8 cycloalkylene group;(F) PA is a linear polymeric arm terminating with a methylene group at both ends of said arm, wherein said arm is a polymer selected from the group consisting of;
polyethylene oxide, poly(trimethyleneoxide), block or random copolymers of polyethylene oxide and polypropylene oxide, and triblock copolymers of polyethylene oxide and polypropylene oxide;(G) z is 2 or 3 where X=CH3-z, S—
R2—
CH3-z, N(acetoacetamide)-CH3-z, or NH—
CH3-z and z is 2 where X=N, NH—
R2—
N, or S—
R2—
N;(H) m is 3 where Q is N, m is 4 where Q is N—
R3—
N, and m is 3 to 16 where Q is said polyol; andb) at least one water-dispersible polymer;
provided that;(1) if Y is acetoacetate or COR1, wherein R1 is N-hydroxysuccinimidyl, then X is not NH—
CH3-z, or NH—
R2—
N;(2) if the functional group Y is NH2, SH, or CONHNH2, then the at least one water-dispersible polymer is a water-dispersible polymer having 3 or more electrophilic groups which are capable of reacting with Y; (3) if the functional group Y is SH and the at least one water-dispersible polymer is a water-dispersible polymer having 3 or more thiol groups, then the kit further comprises an oxidizer which is capable of oxidizing the SH groups to disulfide groups; (4) if the functional group Y is acetoacetate or COR1, wherein R1 is OH or N-hydroxysuccinimidyl, then the at least one water-dispersible polymer is a water-dispersible polymer having 3 or more nucleophilic groups which are capable of reacting with Y; (5) if the functional group Y is COR1, wherein R1 is OH, then optionally the kit further comprises;
(c) a water-soluble carbodiimide. - View Dependent Claims (4, 5, 6, 7, 8, 9, 10, 11, 12, 13)
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14. A hydrogel made by a process comprising reacting:
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a) at least one compound of the formula;
(YR)zX(PS)X(RY)z;
or
(i)
Q[(PA)X(RY)z]m;
(ii)wherein; (A) PS is a linear polymeric segment terminating with a methylene group at both ends of said segment, wherein said segment is a polymer selected from the group consisting of;
polyethylene oxide, poly(trimethyleneoxide), block or random copolymers of polyethylene oxide and polypropylene oxide, and triblock copolymers of polyethylene oxide and polypropylene oxide;(B) X is selected from the group consisting of;
CH3-z, N, N(acetoacetamide)-CH3-z, S—
R2—
N, S—
R2—
CH3-z, NH—
CH3-z, and NH—
R2—
N, wherein R2 is an alkylene group having from 1 to 5 carbon atoms;(C) R is selected from the group consisting of;
a direct bond, an alkylene group having from 1 to 5 carbon atoms, an alkylene ether group having up to a total of 6 backbone atoms, an alkyleneoxy urethane group of the formula R4O(CO)NHCH2 wherein R4 is a linear or branched alkylene group having 2 to 6 carbon atoms and R4 is the group that is adjacent to X, and a C3 to C8 cycloalkylene group;(D) Y is a functional group selected from the group consisting of;
—
NH2, —
SH, —
CONHNH2, acetoacetate, and —
COR1, wherein R1 is OH or —
N-hydroxysuccinimidyl;(E) Q is a core atom or molecule selected from the group consisting of;
N, a polyol with the hydrogens removed from 3 or more of its OH groups, and N—
R3—
N, wherein R3 is an alkylene group having 2-12 carbon atoms or a C3 to C8 cycloalkylene group;(F) PA is a linear polymeric arm terminating with a methylene group at both ends of said arm, wherein said arm is a polymer selected from the group consisting of;
polyethylene oxide, poly(trimethyleneoxide), block or random copolymers of polyethylene oxide and polypropylene oxide, and triblock copolymers of polyethylene oxide and polypropylene oxide;(G) z is 2 or 3 where X=CH3-z, S—
R2—
CH3-z, N(acetoacetamide)-CH3-z, or NH—
CH3-z and z is 2 where X=N, NH—
R2—
N, or S—
R2—
N;(H) m is 3 where Q is N, m is 4 where Q is N—
R3—
N, and m is 3 to 16 where Q is said polyol;
withb) at least one water-dispersible polymer having three or more electrophilic or nucleophilic groups in the presence of water;
wherein the ratio of electrophilic or nucleophilic groups to functional groups of (i) or (ii) is about 1;
10 to about 10;
1provided that; (1) if Y is acetoacetate or COR1, wherein R1 is N-hydroxysuccinimidyl, then X is not NH—
CH3-z, or NH—
R2—
N;(2) if the functional group Y is NH2, SH, or CONHNH2, then the at least one water-dispersible polymer is a water-dispersible polymer having 3 or more electrophilic groups which are capable of reacting with Y; (3) if the functional group Y is SH and the at least one water-dispersible polymer is a water-dispersible polymer having 3 or more thiol groups, then the reacting is done in the presence of an oxidizer which is capable of oxidizing the SH groups to disulfide groups; (4) if the functional group Y is acetoacetate or COR1, wherein R1 is OH or N-hydroxysuccinimidyl, then the at least one water-dispersible polymer is a water-dispersible polymer having 3 or more nucleophilic groups which are capable of reacting with Y; (5) if the functional group Y is COR1, wherein R1 is OH, then optionally said functional group is activated by reaction with a water-soluble carbodiimide to form an activated functional group and the at least one water-dispersible polymer is a water-dispersible polymer having 3 or more nucleophilic groups which are capable of reacting with said activated functional group. - View Dependent Claims (15, 16, 17, 18, 19)
b) the at least one water-dispersible polymer having 3 or more electrophilic groups is an oxidized dextran containing aldehyde groups.
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18. The composition according to claim 14 wherein the water-dispersible polymer having 3 or more nucleophilic groups is a linear or branched poly(ether) comprising amine groups, thiol groups, or carboxyhydrazide groups.
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19. The composition according to claim 14 wherein the at least one water-dispersible polymer is a mixture of two different oxidized dextrans having different weight-average molecular weights, different degrees of oxidation, or different weight-average molecular weights and different degrees of oxidation.
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20. A method for applying a coating to an anatomical site on tissue of a living organism comprising:
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applying to the site a) a first aqueous solution or dispersion comprising at least one compound of the formula;
(YR)zX(PS)X(RY)z;
or
(i)
Q[(PA)X(RY)z]m;
(ii)
wherein;(A) PS is a linear polymeric segment terminating with a methylene group at both ends of said segment, wherein said segment is a polymer selected from the group consisting of;
polyethylene oxide, poly(trimethyleneoxide), block or random copolymers of polyethylene oxide and polypropylene oxide, and triblock copolymers of polyethylene oxide and polypropylene oxide;(B) X is selected from the group consisting of;
CH3-z, N, N(acetoacetamide)-CH3-z, S—
R2—
N, S—
R2—
CH3-z, NH—
CH3-z, and NH—
R2—
N, wherein R2 is an alkylene group having from 1 to 5 carbon atoms;(C) R is selected from the group consisting of;
a direct bond, an alkylene group having from 1 to 5 carbon atoms, an alkylene ether group having up to a total of 6 backbone atoms, an alkyleneoxy urethane group of the formula R4O(CO)NHCH2 wherein R4 is a linear or branched alkylene group having 2 to 6 carbon atoms and R4 is the group that is adjacent to X, and a C3 to C8 cycloalkylene group;(D) Y is a functional group selected from the group consisting of;
—
NH2, —
SH, —
CONHNH2, acetoacetate, and —
COR1, wherein R1 is OH or —
N-hydroxysuccinimidyl;(E) Q is a core atom or molecule selected from the group consisting of;
N, a polyol with the hydrogens removed from 3 or more of its OH groups, and N—
R3—
N, wherein R3 is an alkylene group having 2-12 carbon atoms or a C3 to C8 cycloalkylene group;(F) PA is a linear polymeric arm terminating with a methylene group at both ends of said arm, wherein said arm is a polymer selected from the group consisting of;
polyethylene oxide, poly(trimethyleneoxide), block or random copolymers of polyethylene oxide and polypropylene oxide, and tri block copolymers of polyethylene oxide and polypropylene oxide;(G) z is 2 or 3 where X=CH3-z, S—
R2—
CH3-z, N(acetoacetamide)-CH3-z, or NH—
CH3-z and z is 2 where X=N, NH—
R2—
N, or S—
R2—
N;(H) m is 3 where Q is N, m is 4 where Q is N—
R3—
N, and m is 3 to 16 where Q is said polyol;(I) said first aqueous solution or dispersion contains from about 5% to about 70% by weight of said compound relative to the total weight of the solution or dispersion; followed by b) a second aqueous solution or dispersion comprising at least one water-dispersible polymer having three or more electrophilic or nucleophilic groups, said solution or dispersion containing from about 5% to about 70% by weight of said water-dispersible polymer relative to the total weight of the solution or dispersion, or applying the second aqueous solution or dispersion followed by the first aqueous solution or dispersion and mixing the first and second aqueous solutions or dispersions on the site, or premixing the first and second aqueous solutions or dispersions and applying the resulting mixture to the site before the resulting mixture completely cures;
wherein the ratio of electrophilic or nucleophilic groups to functional groups of (i) or (ii) is about 1;
10 to about 10;
1;
provided that(1) if Y is acetoacetate or COR1, wherein R1 is N-hydroxysuccinimidyl, then X is not NH—
CH3-z, or NH—
R2—
N;(2) if the functional group Y is NH2, SH, or CONHNH2, then the at least one water-dispersible polymer in the second aqueous solution or dispersion is a water-dispersible polymer having 3 or more electrophilic groups which are capable of reacting with Y; (3) if the functional group Y is SH and the at least one water-dispersible polymer in the second aqueous solution or dispersion is a water-dispersible polymer having 3 or more thiol groups, then at least one of the first or second aqueous solution or dispersion further comprises an oxidizer which is capable of oxidizing the SH groups to disulfide groups; (4) if the functional group Y is acetoacetate or COR1, wherein R1 is OH or N-hydroxysuccinimidyl, then the at least one water-dispersible polymer in the second aqueous solution or dispersion is a water-dispersible polymer having 3 or more nucleophilic groups which are capable of reacting with Y; (5) if the functional group Y is COR1, wherein R1 is OH, then optionally said functional group is activated by reaction with a water-soluble carbodiimide to form an activated functional group and the at least one water-dispersible polymer in the second aqueous solution or dispersion is a water-dispersible polymer having 3 or more nucleophilic groups which are capable of reacting with said activated functional group. - View Dependent Claims (21, 22, 23, 24, 25)
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Specification
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Current AssigneeActamax Surgical Materials, LLC (DSM-Firmenich AG)
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Original AssigneeActamax Surgical Materials, LLC (DSM-Firmenich AG)
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InventorsArthur, Samuel David, Figuly, Garret D.
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Primary Examiner(s)Sajjadi, Fereydoun G
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Assistant Examiner(s)Pipic, Alma
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Application NumberUS12/445,470Publication NumberTime in Patent Office1,778 DaysField of SearchNoneUS Class Current424/486CPC Class CodesC08G 2650/50 containing nitrogen, e.g. p...C08G 65/329 with organic compoundsC08G 65/33306 acyclicC08L 2203/02 for biomedical useC08L 2666/26 Natural polymers, natural r...C09J 171/02 Polyalkylene oxides
