US 8,282,959 B2 · Branched end reactants and polymeric hydrogel tissue adhesives therefrom

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.

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Claims25

Dependent claims

A composition of matter comprising at least one compound of the formula:

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.

13 more elements

A kit comprising:

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;
and
b) 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.

26 more elements

A hydrogel made by a process comprising reacting:

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;
with
b) 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 10:1
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 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.

26 more elements

A method for applying a coating to an anatomical site on tissue of a living organism comprising:

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.

31 more elements

Dependencies are inferred from the claim text.

Description24,819 words

Summary2,945 words

#The invention relates to the field of medical adhesives. More specifically, the invention relates to branched end reactants that can used to prepare hydrogel tissue adhesives with improved mechanical properties. The invention also relates to kits and methods for applying a coating to an anatomical site on tissue of a living organism using a polymer tissue adhesive formed using at least one branched end reactant.

#Tissue adhesives have many potential medical applications, including wound closure, supplementing or replacing sutures or staples in internal surgical procedures, adhesion of synthetic onlays or inlays to the cornea, drug delivery devices, and as anti-adhesion barriers to prevent post-surgical adhesions. Conventional tissue adhesives are generally not suitable for a wide range of adhesive applications. For example, cyanoacrylate-based adhesives have been used for topical wound closure, but the release of toxic degradation products limits their use for internal applications. Fibrin-based adhesives are slow curing, have poor mechanical strength, and pose a risk of viral infection. Additionally, the Fibrin-based adhesives do not covalently bind to the underlying tissue.

#Several types of hydrogel tissue adhesives have been developed, which have improved adhesive and cohesive properties and are nontoxic. These hydrogels are generally formed by reacting a component having nucleophilic groups with a component having electrophilic groups, which are capable of reacting with the nucleophilic groups of the first component, to form a crosslinked network via covalent bonding. However, these hydrogels typically swell or dissolve away too quickly, or lack sufficient adhesion or mechanical strength, thereby decreasing their effectiveness as surgical adhesives.

Detailed description21,874 words

#In various embodiments, the invention provides branched end reactants that are useful as crosslinking agents for preparing hydrogels having a good balance of mechanical properties (i.e., elongation to break, tensile strength, and water swell) in an aqueous environment. The branched end reactants can be linear or branched polymers having two or three functional groups at each of the ends of the polymer chain or at the end of the polymer arms. The multiplicity of functional groups increases the statistical probability of reaction at a given chain end and allows more efficient incorporation of the linear or branched molecules into a polymer network. As a result, hydrogels formed using the branched end reactants disclosed herein have a reduced degree of swelling and a slower rate of hydrolytic degradation compared to hydrogels prepared with similar crosslinking molecules having only a single functional group at each end. Therefore, linear or branched crosslinking molecules which promote better elongation can be employed in the hydrogel without also incurring high water swelling and fast degradation. Additionally, branched end reactants having a limited number of two or three functional groups at the ends of the polymer chain or at the end of the polymer arms provide better control of crosslinking than multi-functional site containing polymers, which are known in the art, that have polymeric end blocks with a large multiplicity of functional groups.

#The hydrogels formed using the branched end reactants disclosed herein may be useful as an adhesive for medical and veterinary applications including, but not limited to, wound closure, supplementing or replacing sutures or staples in internal surgical procedures such as intestinal anastomosis and vascular anastomosis, tissue repair, ophthalmic procedures, and as a plug to seal a fistula or the punctum. Additionally, the hydrogels may have utility in drug delivery, and in anti-adhesive applications.

#The following definitions are used herein and should be referred to for interpretation of the claims and the specification.

Facts

Application

12/445,470Filed 27 Nov 2007 · us provisional application

Priority

27 Nov 2006

Published

US 2010/0086678 A18 Apr 2010

Granted

9 Oct 2012

Term ends

20 Feb 2030

Estimated · how

20 years from earliest known nonprovisional domestic filing plus recorded patent term adjustment, including 816 days of adjustment. Maintenance-fee lapses, terminal disclaimers and statutory extensions have not been checked. The continuity chain may be incomplete; this is not an enforceability determination.

Classification9 codes

C08G 65/329
Polymers modified by chemical after-treatment: with organic compounds
C08G 65/33306
Containing amino group: acyclic
C09J 171/02
Adhesives based on polyethers obtained by reactions forming an ether link in the main chain ; Adhesives based on derivatives of such polymers:…
C08G 2650/50
Characterised by the polymer type: containing nitrogen, e.g. polyetheramines or Jeffamines

Timeline

27 Nov 2006Priority claimedParent application 60/861,167
27 Nov 2007Application filedUS 12/445,470
20 Jul 2009Assigned to E. I. Du Pont De Nemours and Companyassignment of assignor's interest
8 Apr 2010PublishedUS 2010/0086678 A1
31 Mar 2011Assigned to Actamax Surgical Materials, LLCassignment of assignor's interest
9 Oct 2012GrantedUS 8,282,959 B2
12 Oct 2026TodayWithin its term
20 Feb 2030Term endsEstimated, includes 816 days of adjustment

Branched end reactants and polymeric hydrogel tissue adhesives therefrom

Life of this patent

Branched end reactants and polymeric hydrogel tissue adhesives therefrom

Life of this patent

Life of this patent

Abstract

Drawings

Drawings

Claims25

Description24,819 words

Drawings

Classification9 codes

Life of this patent

Description24,819 words