Mono-layer thin film adhesive compounds and methods of synthesis and use

Abstract

The invention relates provides synthetic medical adhesives which exploit plant derivatives to form covalent bonds with amines and thiols on tissue surfaces.

Claims

1. A coating comprising a) a compound comprising the formula (I) ##STR00003## wherein each L.sub.2, L.sub.3 and L.sub.4 independently, is a linker; each L.sub.1, L.sub.5, L.sub.6, L.sub.7, L.sub.8, L.sub.9, L.sub.10, L.sub.11 L.sub.12 and L.sub.13 independently, is a linker or a suitable linking group selected from amine, amide, ether, ester, urea carbonate or urethane linking groups; each X.sub.1, X.sub.2, X.sub.3 and X.sub.4 independently, is an oxygen atom or NR; R, if present, is H or a branched or unbranched C1-C10 alkyl group; each R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.7, R.sub.8, R.sub.9, R.sub.10, R.sub.11, R.sub.12, R.sub.13 and R.sub.14 independently, is a branched or unbranched C1-C15 alkyl group; each PD.sub.ii and PD.sub.jj, independently, is a phenyl derivative residue selected from the group consisting of ferulic acid, isoferulic acid, sinapinic acid, syringic acid and vanillic acid; aa is a value from 0 to about 80; bb is a value from 0 to about 80; cc is a value from 0 to about 80; dd is a value from 1 to about 120; ee is a value from 1 to about 120; ff is a value from 1 to about 120; gg is a value from 1 to about 120; and hh is a value from 1 to about 80 and b) an oxidant comprising tetraethylammonium periodate or tetrapropylammonium periodate.

2. The coating of claim 1, wherein L.sub.2 is a residue of a C1-C15 alkyl lactone or lactam, a poly C1-C15 alkyl lactone or lactam, a polyester, or a compound comprising the formula Y.sub.4R.sub.17C(O)Y.sub.6, wherein Y.sub.4 is OH, NHR, a halide, or an activated derivative of OH or NHR; R.sub.17 is a branched or unbranched C1-C15 alkyl group; and Y.sub.6 is NHR, a halide, or OR.

3. The coating of claim 2, wherein said alkyl lactone is a polycaprolactone.

4. The coating of claim 1, wherein L.sub.3 is a residue of an alkylene diol, an alkylene diamine or a poly(alkylene oxide) polyether or derivative thereof.

5. The coating of claim 4, wherein L.sub.3 is a poly(alkylene oxide) or OCH.sub.2CH.sub.2OCH.sub.2CH.sub.2O.

6. The coating of claim 1, wherein L.sub.2 or L.sub.4 is a residue of a C1-C15 alkyl lactone or lactam, a poly C1-C15 alkyl lactone or lactam, or a compound comprising the formula Y.sub.4R.sub.17C(O)Y.sub.6, wherein Y.sub.4 is OH, NHR, a halide, or an activated derivative of OH or NHR; R.sub.17 is a branched or unbranched C1-C15 alkyl group; and Y.sub.6 is NHR, a halide, or OR.

7. The coating of claim 6, wherein said alkyl lactone is polycaprolactone.

8. The coating of claim 1, wherein X.sub.1, X.sub.2, X.sub.3 and X.sub.4 are each O or NH.

9. The coating of claim 1, wherein R.sub.3, R.sub.6, R.sub.10 and R.sub.13 are each CH.sub.2CH.sub.2.

10. The coating of claim 1, wherein X.sub.1, X.sub.2, X.sub.3 and X.sub.4 are each O.

11. The coating of claim 1, wherein R.sub.4, R.sub.5, R.sub.9 and R.sub.12 are each CH.sub.2.

12. The coating of claim 1, wherein R.sub.1, R.sub.2, R.sub.7, R.sub.9, R.sub.11 and R.sub.14 are a branched or unbranched alkane.

13. The coating of claim 12, wherein R.sub.1, R.sub.2, R.sub.7, R.sub.9, R.sub.11 and R.sub.14 are CH.sub.2CH.sub.2 or CH.sub.2CH.sub.2CH.sub.2.

14. The coating of claim 1, wherein L.sub.1, L.sub.5, L.sub.6, L.sub.7, L.sub.8, L.sub.9, L.sub.19, L.sub.11, L.sub.12, and L.sub.13 form an amide, ester or carbamate.

15. The coating of claim 1, wherein L.sub.2 is a residue of a polycaprolactone, a caprolactone, a polylactic acid, a polylactone or a lactic acid or lactone; L.sub.3 is a residue of polyethylene glycol; L.sub.4 is a residue of a polycaprolactone, a caprolactone, a polylactic acid, a polylactone or a lactic acid or lactone; X.sub.1, X.sub.2, X.sub.3 and X.sub.4 are each O or NH; R.sub.1, R.sub.3, R.sub.6, R.sub.8, R.sub.10, and R.sub.13 are each CH.sub.2CH.sub.2; R.sub.4, R.sub.5, R.sub.9 and R.sub.12 are each CH.sub.2; R.sub.2, R.sub.7, R.sub.11 and R.sub.14 are each (CH2).sub.n, wherein n is 2, 3, or 4; L.sub.1, L.sub.5, L.sub.7, L.sub.8, L.sub.10, L.sub.12 form an ester; L.sub.6, L.sub.9, L.sub.ii, and L.sub.13 form an amide; and PD.sub.ii and PD.sub.jj are residues selected from the group consisting of from ferulic acid (FA), isoferulic acid (IFA), syringic acid, and sinapinic acid (SAA).

16. The coating of claim 1, wherein L.sub.2 is a residue of a polycaprolactone, a caprolactone, a polylactic acid, a polylactone or a lactic acid or lactone; L.sub.3 is a residue of polyethylene glycol; L.sub.4 is a residue of a polycaprolactone, a caprolactone, a polylactic acid, a polylactone or a lactic acid or lactone; X.sub.1, X.sub.2, X.sub.3 and X.sub.4 are each O or NH; R.sub.3, R.sub.6, R.sub.10, and R.sub.13 are each CH.sub.2CH.sub.2; R.sub.1, R.sub.8, R.sub.4, R.sub.5, R.sub.9 and R.sub.12 are each CH.sub.2; R.sub.2, R.sub.7, R.sub.11 and R.sub.14 are each (CH2).sub.n, wherein n is 2 or 3; L.sub.1, L.sub.5, L.sub.7, L.sub.8, L.sub.10, L.sub.12 form an ester; L.sub.6, L.sub.9, L.sub.11, and L.sub.13 form an amide; and PD.sub.ii and PD.sub.jj are residues of ferulic acid or syringic acid.

17. A bioadhesive construct, comprising: a support suitable for tissue repair or reconstruction; and the coating of claim 1.

18. The bioadhesive construct of claim 17, wherein said oxidant is formulated with the coating.

19. The bioadhesive construct of claim 17, wherein said oxidant is applied to said coating.

20. The bioadhesive construct of claim 17, wherein said support is a film, a mesh, a membrane, a nonwoven or a prosthetic.

21. The bioadhesive construct of claim 17, comprising: a) a support suitable for tissue repair or reconstruction; b1) a first coating comprising a compound comprising the formula (I) and a polymer; b2) a second coating coated onto said first coating, wherein said second coating comprises a compound comprising the formula (I); and c) an oxidant comprising tetraethylammonium periodate or tetrapropylammonium periodate.

22. The bioadhesive construct of claim 17, comprising: a) a support suitable for tissue repair or reconstruction; b1) a first coating comprising a compound comprising the formula (I) and a first polymer; b2) a second coating coated onto said first coating, wherein said second coating comprises a second compound comprising the formula (I) and a second polymer, wherein said first and second polymer may be the same or different, and wherein said first and said second compound comprising the formula (I) can be the same or different; and c) an oxidant comprising tetraethylammonium periodate or tetrapropylammonium periodate.

23. The bioadhesive construct of claim 17 comprising: a) a support suitable for tissue repair or reconstruction; b1) a first coating comprising a first compound comprising the formula (I); b2) a second coating coated onto said first coating, wherein said second compound comprising the formula (I), wherein said first and second compound comprising the formula (I) can be the same or different; and c) an oxidant comprising tetraethylammonium periodate or tetrapropylammonium periodate.

24. A bioadhesive construct comprising: a support suitable for tissue repair or reconstruction; and the coating of claim 1, wherein the coating comprises a blend of a polymer and a compound comprising formula (I).

25. The bioadhesive construct of claim 24, wherein the polymer is present in a range of about 1 to 50 percent by weight.

26. The bioadhesive construct of claim 25, wherein said polymer is present is present at an amount of about 30 percent by weight.

27. The bioadhesive construct of claim 25, wherein said oxidant is applied to said coating.

28. The coating of claim 1, wherein said oxidant is formulated with the coating.

29. The coating of claim 1, wherein said oxidant is applied to said coating.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) FIG. 1: Depicts general structure of Medhesive-145.

(2) FIG. 2: Depicts general structure of Medhesive-163.

(3) FIG. 3: Depicts general structure of Medhesive-165

(4) FIG. 4: Depicts general structure of Medhesive-167.

(5) FIG. 5: Depicts general structure of Medhesive-169.

(6) FIG. 6: Depicts general structure of Medhesive-171.

(7) FIG. 7: Depicts general structure of Medhesive-179.

(8) FIG. 8: Depicts general structure of Medhesive-181.

(9) FIG. 9: Shows a degradation profile of Medhesive-145, 179, 181 coated onto a polyester mesh. Samples tested were at coating densities of 250 g/m.sup.2 obtained by heat pressing two 125 g/m.sup.2 films into a synthetic mesh. The mesh type they were coated onto was a polyester mesh with a coating density of 30 g/m.sup.2. The oxidant used was sodium periodate. The amount of IO.sub.4.sup.:FA was 1.5:1. For testing, a film 25 mm80 mm in area was activated with 555 uL of 1PBS on both sides for 20 minutes under a glass slide and release liner. A 10 mm hole punch was used to cut out pieces (14). 8 samples were used to collect swelling data. 3 samples were used for a 37 C. pilot degradation study and 3 were used for a 55 C. pilot degradation study. All samples were placed into 15 mL of 1PBS buffer for testing.

(10) FIG. 10: Depicts general structure of Medhesive-188.

(11) FIG. 11: Depicts general structure of Medhesive-190.

(12) FIG. 12: Depicts general structure of Medhesive-192.

(13) FIG. 13: Depicts general structure of Medhesive-194.

(14) FIG. 14: Depicts general structure of Medhesive-196.

(15) FIG. 15: Depicts general structure of Medhesive-198.

(16) FIG. 16: Shows hydroferulic acid and ferulic acid.

(17) FIG. 17: Shows Medhesive-145 at a 1.5:1 NaIO.sub.4:Ferulic Acid molar ratio coated at 120 g/m.sup.2 and stored at room temperature at Day 1 and Day 30.

(18) FIG. 18: Shows Medhesive-145 at a 1.38:1 NaIO.sub.4:Ferulic Acid molar ratio with a coating density of 90 g/m.sup.2. Samples stored in double pouched Tyvek at ambient temperatures. A) Unsterilized, B) and C) E-Beam Sterilized at 25 kGy.

(19) FIG. 19: Shows lap shear performance of synthesized Medhesives using a monofilament polyester mesh. N=6 for each sample.

(20) FIG. 20: Shows alkyl ammonium periodates as alternatives to sodium periodate.

(21) FIG. 21: Shows lap shear performance of newly synthesized oxidants using a monofilament polyester mesh with Medhesive-145. N=6 for each sample.

(22) FIG. 22: Depicts general structure of Medhesive-202.

(23) FIG. 23: Representative lap shear data for Medhesive polymers shown in Table 1. Comparison between Entries 1 and 2 reveal that the nature of the linking group alone does not strongly impact lap shear strength. The nature of the phenyl derivative (PD) group, however, can influence the overall lap shear strength as shown when Entries 4 and 5 are compared with Entry 2, where the PD group in Entries 4 and 5 are based on isoferulic acid and syringic acid respectively. Comparison between Entry 5 and Entry 2 shows that the nature of polyester residue can also impact the lap shear strength, such that incorporation of a polylactic acid polymer residue results in a polymer film with higher strength. Since all samples exhibited adhesive failure when tested, i.e. breaking occurred between the polymer film and tissue sample, adhesive strength can be tailored by varying molecular structure of the constituent parts of the polymer.

DETAILED DESCRIPTION

(24) In the specification and in the claims, the terms including and comprising are open-ended terms and should be interpreted to mean including, but not limited to . . . . These terms encompass the more restrictive terms consisting essentially of and consisting of.

(25) It must be noted that as used herein and in the appended claims, the singular forms a, an, and the include plural reference unless the context clearly dictates otherwise. As well, the terms a (or an), one or more and at least one can be used interchangeably herein. It is also to be noted that the terms comprising, including, characterized by and having can be used interchangeably.

(26) Unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art to which this invention belongs. All publications and patents specifically mentioned herein are incorporated by reference in their entirety for all purposes including describing and disclosing the chemicals, instruments, statistical analyses and methodologies which are reported in the publications which might be used in connection with the invention. All references cited in this specification are to be taken as indicative of the level of skill in the art. Nothing herein is to be construed as an admission that the invention is not entitled to antedate such disclosure by virtue of prior invention.

(27) Alkyl, by itself or as part of another substituent, refers to a saturated or unsaturated, branched, straight-chain or cyclic monovalent hydrocarbon radical derived by the removal of one hydrogen atom from a single carbon atom of a parent alkane, alkene or alkyne. Typical alkyl groups include, but are not limited to, methyl; ethyls such as ethanyl, ethenyl, ethynyl; propyls such as propan-1-yl, propan-2-yl, cyclopropan-1-yl, prop-1-en-1-yl, prop-1-en-2-yl, prop-2-en-1-yl (allyl), cycloprop-1-en-1-yl; cycloprop-2-en-1-yl, prop-1-yn-1-yl, prop-2-yn-1-yl, etc.; butyls such as butan-1-yl, butan-2-yl, 2-methyl-propan-1-yl, 2-methyl-propan-2-yl, cyclobutan-1-yl, but-1-en-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl, but-2-en-1-yl, but-2-en-2-yl, buta-1,3-dien-1-yl, buta-1,3-dien-2-yl, cyclobut-1-en-1-yl, cyclobut-1-en-3-yl, cyclobuta-1,3-dien-1-yl, but-1-yn-1-yl, but-1-yn-3-yl, but-3-yn-1-yl, etc.; and the like.

(28) The term alkoxy (OR) is specifically to include groups where R is a hydrogen or alkane chain linked to at least one oxygen.

(29) The term alkyl is specifically intended to include groups having any degree or level of saturation, i.e., groups having exclusively single carbon-carbon bonds, groups having one or more double carbon-carbon bonds, groups having one or more triple carbon-carbon bonds and groups having mixtures of single, double and triple carbon-carbon bonds. Where a specific level of saturation is intended, the expressions alkanyl, alkenyl, and alkynyl are used. Preferably, an alkyl group comprises from 1 to 15 carbon atoms (C.sub.1-C.sub.15 alkyl), more preferably from 1 to 10 carbon atoms (C.sub.1-C.sub.10 alkyl) and even more preferably from 1 to 6 carbon atoms (C.sub.1-C.sub.6 alkyl or lower alkyl).

(30) Alkanyl, by itself or as part of another substituent, refers to a saturated branched, straight-chain or cyclic alkyl radical derived by the removal of one hydrogen atom from a single carbon atom of a parent alkane. Typical alkanyl groups include, but are not limited to, methanyl; ethanyl; propanyls such as propan-1-yl, propan-2-yl (isopropyl), cyclopropan-1-yl, etc.; butanyls such as butan-1-yl, butan-2-yl (sec-butyl), 2-methyl-propan-1-yl (isobutyl), 2-methyl-propan-2-yl (t-butyl), cyclobutan-1-yl, etc.; and the like.

(31) Alkenyl, by itself or as part of another substituent, refers to an unsaturated branched, straight-chain or cyclic alkyl radical having at least one carbon-carbon double bond derived by the removal of one hydrogen atom from a single carbon atom of a parent alkene. The group may be in either the cis or trans conformation about the double bond(s). Typical alkenyl groups include, but are not limited to, ethenyl; propenyls such as prop-1-en-1-yl, prop-1-en-2-yl, prop-2-en-1-yl (allyl), prop-2-en-2-yl, cycloprop-1-en-1-yl; cycloprop-2-en-1-yl; butenyls such as but-1-en-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl, but-2-en-1-yl, but-2-en-1-yl, but-2-en-2-yl, buta-1,3-dien-1-yl, buta-1,3-dien-2-yl, cyclobut-1-en-1-yl, cyclobut-1-en-3-yl, cyclobuta-1,3-dien-1-yl, etc.; and the like.

(32) Alkyldiyl by itself or as part of another substituent refers to a saturated or unsaturated, branched, straight-chain or cyclic divalent hydrocarbon group derived by the removal of one hydrogen atom from each of two different carbon atoms of a parent alkane, alkene or alkyne, or by the removal of two hydrogen atoms from a single carbon atom of a parent alkane, alkene or alkyne. The two monovalent radical centers or each valency of the divalent radical center can form bonds with the same or different atoms. Typical alkyldiyl groups include, but are not limited to, methandiyl; ethyldiyls such as ethan-1,1-diyl, ethan-1,2-diyl, ethen-1,1-diyl, ethen-1,2-diyl; propyldiyls such as propan-1,1-diyl, propan-1,2-diyl, propan-2,2-diyl, propan-1,3-diyl, cyclopropan-1,1-diyl, cyclopropan-1,2-diyl, prop-1-en-1,1-diyl, prop-1-en-1,2-diyl, prop-2-en-1,2-diyl, prop-1-en-1,3-diyl, cycloprop-1-en-1,2-diyl, cycloprop-2-en-1,2-diyl, cycloprop-2-en-1,1-diyl, prop-1-yn-1,3-diyl, etc.; butyldiyls such as, butan-1,1-diyl, butan-1,2-diyl, butan-1,3-diyl, butan-1,4-diyl, butan-2,2-diyl, 2-methyl-propan-1,1-diyl, 2-methyl-propan-1,2-diyl, cyclobutan-1,1-diyl; cyclobutan-1,2-diyl, cyclobutan-1,3-diyl, but-1-en-1,1-diyl, but-1-en-1,2-diyl, but-1-en-1,3-diyl, but-1-en-1,4-diyl, 2-methyl-prop-1-en-1,1-diyl, 2-methanylidene-propan-1,1-diyl, buta-1,3-dien-1,1-diyl, buta-1,3-dien-1,2-diyl, buta-1,3-dien-1,3-diyl, buta-1,3-dien-1,4-diyl, cyclobut-1-en-1,2-diyl, cyclobut-1-en-1,3-diyl, cyclobut-2-en-1,2-diyl, cyclobuta-1,3-dien-1,2-diyl, cyclobuta-1,3-dien-1,3-diyl, but-1-yn-1,3-diyl, but-1-yn-1,4-diyl, buta-1,3-diyn-1,4-diyl, etc.; and the like. Where specific levels of saturation are intended, the nomenclature alkanyldiyl, alkenyldiyl and/or alkynyldiyl is used. Where it is specifically intended that the two valencies are on the same carbon atom, the nomenclature alkylidene is used. In preferred embodiments, the alkyldiyl group comprises from 1 to 6 carbon atoms (C1-C6 alkyldiyl). Also preferred are saturated acyclic alkanyldiyl groups in which the radical centers are at the terminal carbons, e.g., methandiyl (methano); ethan-1,2-diyl (ethano); propan-1,3-diyl (propano); butan-1,4-diyl (butano); and the like (also referred to as alkylenos, defined infra).

(33) Alkyleno, by itself or as part of another substituent, refers to a straight-chain saturated or unsaturated alkyldiyl group having two terminal monovalent radical centers derived by the removal of one hydrogen atom from each of the two terminal carbon atoms of straight-chain parent alkane, alkene or alkyne. The location of a double bond or triple bond, if present, in a particular alkyleno is indicated in square brackets. Typical alkyleno groups include, but are not limited to, methano; ethylenos such as ethano, etheno, ethyno; propylenos such as propano, prop[1]eno, propa[1,2]dieno, prop[1]yno, etc.; butylenos such as butano, but[1]eno, but[2]eno, buta[1,3]dieno, but[1]yno, but[2]yno, buta[1,3]diyno, etc.; and the like. Where specific levels of saturation are intended, the nomenclature alkano, alkeno and/or alkyno is used. In preferred embodiments, the alkyleno group is (C1-C6) or (C1-C3) alkyleno. Also preferred are straight-chain saturated alkano groups, e.g., methano, ethano, propano, butano, and the like.

(34) Alkylene by itself or as part of another substituent refers to a straight-chain saturated or unsaturated alkyldiyl group having two terminal monovalent radical centers derived by the removal of one hydrogen atom from each of the two terminal carbon atoms of straight-chain parent alkane, alkene or alkyne. The locant of a double bond or triple bond, if present, in a particular alkylene is indicated in square brackets. Typical alkylene groups include, but are not limited to, methylene (methano); ethylenes such as ethano, etheno, ethyno; propylenes such as propano, prop[1]eno, propa[1,2]dieno, prop[1]yno, etc.; butylenes such as butano, but[1]eno, but[2]eno, buta[1,3]dieno, but[1]yno, but[2]yno, buta[1,3]diyno, etc.; and the like. Where specific levels of saturation are intended, the nomenclature alkano, alkeno and/or alkyno is used. In preferred embodiments, the alkylene group is (C1-C6) or (C1-C3) alkylene. Also preferred are straight-chain saturated alkano groups, e.g., methano, ethano, propano, butano, and the like.

(35) Substituted, when used to modify a specified group or radical, means that one or more hydrogen atoms of the specified group or radical are each, independently of one another, replaced with the same or different substituent(s). Substituent groups useful for substituting saturated carbon atoms in the specified group or radical include, but are not limited to R.sup.a, halo, O.sup., O, OR.sup.b, SR.sup.b, S.sup., S, NR.sup.cR.sup.c, NR.sup.b, NOR.sup.b,
trihalomethyl, CF.sub.3, CN, OCN, SCN, NO, NO.sub.2,
N.sub.2, N.sub.3, S(O).sub.2R.sup.b, S(O).sub.2O.sup., S(O).sub.2OR.sup.b, OS(O).sub.2R.sup.b, OS(O).sub.2O.sup., OS(O).sub.2OR.sup.b, P(O)(O.sup.).sub.2, P(O)(OR.sup.b)(O.sup.), P(O)(OR.sup.b)(OR.sup.b), C(O)R.sup.b, C(S)R.sup.b, C(NR.sup.b)R.sup.b, C(O)O.sup., C(O)OR.sup.b, C(S) OR.sup.b, C(O)NR.sup.cR.sup.c, C(NR.sup.b)NR.sup.cR.sup.c, OC(O)R.sup.b, OC(S)R.sup.b, OC(O)O.sup., OC(O)OR.sup.b, OC(S)OR.sup.b, NR.sup.bC(O)R.sup.b, NR.sup.bC(S)R.sup.b, NR.sup.bC(O)O.sup., NR.sup.bC(O)OR.sup.b, NR.sup.bC(S)OR.sup.b, NR.sup.bC(O)NR.sup.cR.sup.c, NR.sup.bC(NR.sup.b)R.sup.b and NR.sup.bC(NR.sup.b)NR.sup.cR.sup.c, where R.sup.a is selected from the group consisting of alkyl, cycloalkyl, heteroalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl; each R.sup.b is independently hydrogen or R.sup.a; and each R.sup.c is independently R.sup.b or alternatively, the two R.sup.cs are taken together with the nitrogen atom to which they are bonded form a 5-, 6- or 7-membered cycloheteroalkyl which may optionally include from 1 to 4 of the same or different additional heteroatoms selected from the group consisting of O, N and S. As specific examples, NR.sup.cR.sup.c is meant to include NH.sub.2, NH-alkyl, N-pyrrolidinyl and N-morpholinyl.

(36) Similarly, substituent groups useful for substituting unsaturated carbon atoms in the specified group or radical include, but are not limited to, R.sup.a, halo, O.sup., OR.sup.b, SR.sup.b, S.sup., NR.sup.cR.sup.c,

(37) trihalomethyl, CF.sub.3, CN, OCN, SCN, NO, NO.sub.2, N.sub.3, S(O).sub.2R.sup.b, S(O).sub.2O.sup., S(O).sub.2OR.sup.b, OS (O).sub.2R.sup.b, OS(O).sub.2O.sup., OS(O).sub.2OR.sup.b, P(O)(O.sup.).sub.2, P(O)(OR.sup.b)(O.sup.), P(O)(OR.sup.b)(OR.sup.b), C(O)R.sup.b, C (S)R.sup.b, C(NR.sup.b)R.sup.b, C(O)O.sup., C(O)OR.sup.b, C(S)OR.sup.b, C(O)NR.sub.cR.sup.c, C(NR.sup.b)NR.sup.cR.sup.c, OC(O)R.sup.b, OC(S)R.sup.b, OC(O)O.sup., OC(O)OR.sup.b, OC(S)OR.sup.b, NR.sup.bC(O)R.sup.b, NR.sup.bC(S)R.sup.b, NR.sup.bC(O)O.sup., NR.sup.bC(O)OR.sup.b, NR.sup.bC(S)OR.sup.b, NR.sup.bC(O)NR.sup.cR.sup.c, NR.sup.bC(NR.sup.b)R.sup.b and NR.sup.bC(NR.sup.b)NR.sup.cR.sup.c, where R.sup.a, R.sup.b and R.sup.c are as previously defined.

(38) Substituent groups useful for substituting nitrogen atoms in heteroalkyl and cycloheteroalkyl groups include, but are not limited to, R.sup.a, O.sup., OR.sup.b, SR.sup.b, S.sup., NR.sup.cR.sup.c, trihalomethyl, CF.sub.3, CN, NO, NO.sub.2, S(O).sub.2R.sup.b, S(O).sub.2O.sup., S(O).sub.2OR.sup.b, OS(O).sub.2R.sup.b, OS(O).sub.2O.sup., OS(O).sub.2OR.sup.b, P(O)(O.sup.).sub.2, P(O)(OR.sup.b)(O.sup.), P(O)(OR.sup.b)(OR.sup.b), C(O)R.sup.b, C(S)R.sup.b, C(NR.sup.b)R.sup.b, C(O)OR.sup.b, C(S)OR.sup.b, C(O)NR.sup.cR.sup.c, C(NR.sup.b)NR.sup.cR.sup.c, OC(O)R.sup.b, OC(S)R.sup.b, OC(O)OR.sup.b, OC(S)OR.sup.b, NR.sup.bC(O)R.sup.b, NR.sup.bC(S)R.sup.b, NR.sup.bC(O)OR.sup.b, NR.sup.bC(S)OR.sup.b, NR.sup.bC(O)NR.sup.cR.sup.c, NR.sup.bC(NR.sup.b)R.sup.b and NR.sup.bC(NR.sup.b)NR.sup.cR.sup.c, where R.sup.a, R.sup.b and R.sup.c are as previously defined.

(39) Substituent groups from the above lists useful for substituting other specified groups or atoms will be apparent to those of skill in the art.

(40) The substituents used to substitute a specified group can be further substituted, typically with one or more of the same or different groups selected from the various groups specified above.

(41) The identifier PA refers to a poly(alkylene oxide) or substantially poly(alkylene oxide) and means predominantly or mostly alkyloxide or alkyl ether in composition. This definition contemplates the presence of heteroatoms e.g., N, O, S, P, etc. and of functional groups e.g., COOH, NH.sub.2, SH, or OH as well as ethylenic or vinylic unsaturation. It is to be understood any such non-alkyleneoxide structures will only be present in such relative abundance as not to materially reduce, for example, the overall surfactant, non-toxicity, or immune response characteristics, as appropriate, of this polymer. It should also be understood that PAs can include terminal end groups such as PA-OCH.sub.2CH.sub.2NH.sub.2, e.g., PEG-OCH.sub.2CH.sub.2NH.sub.2 (as a common form of amine terminated PA). PA-OCH.sub.2CH.sub.2CH.sub.2NH.sub.2, e.g., PEG-OCH.sub.2CH.sub.2CH.sub.2NH.sub.2 is also available as well as PA-O(CH.sub.2CH(CH.sub.3)O).sub.xxCH.sub.2CH(CH.sub.3)NH.sub.2, where xx is 0 to about 3, e.g., PEG-O(CH.sub.2CH(CH.sub.3)O).sub.xxCH.sub.2CH(CH.sub.3)NH.sub.2 and a PA with an acid end-group typically has a structure of PA-OCH.sub.2COOH, e.g., PEG-OCH.sub.2COOH or PA-OCH.sub.2CH.sub.2COOH, e.g., PEG-OCH.sub.2CH.sub.2COOH. These can be considered derivatives of the PA. These are all contemplated as being within the scope of the invention and should not be considered limiting.

(42) Suitable PAs (polyalkylene oxides) include polyethylene oxides (PEOs), polypropylene oxides (PPOs), polyethylene glycols (PEGs) and combinations thereof that are commercially available from SunBio Corporation, JenKem Technology USA, NOF America Corporation or Creative PEGWorks. It should be understood that, for example, polyethylene oxide can be produced by ring opening polymerization of ethylene oxide as is known in the art.

(43) In one embodiment, the PA can be a block copolymer of a PEO and PPO or a PEG or a triblock copolymer of PEO/PPO/PEO.

(44) Suitable MW ranges of the PA's are from about 300 to about 8,000 daltons, 400 to about 5,000 daltons or from about 450 to about 3,500 daltons.

(45) It should be understood that the PA terminal end groups can be functionalized. Typically the end groups are OH, NH.sub.2, COOH, or SH. However, these groups can be converted into a halide (Cl, Br, I), an activated leaving group, such as a tosylate or mesylate, an ester, an acyl halide, N-succinimidyl carbonate, 4-nitrophenyl carbonate, and chloroformate with the leaving group being N-hydroxy succinimide, 4-nitrophenol, and Cl, respectively. etc.

(46) The notation of L refers to either a linker or a linking group. A linker refers to a moiety that has two points of attachment on either end of the moiety. For example, an alkyl dicarboxylic acid HOOC-alkyl-COOH (e.g., succinic acid) would link a terminal end group of a PA (such as a hydroxyl or an amine to form an ester or an amide respectively) with a reactive group of the PD (such as an NH.sub.2, OH, or COOH). Suitable linkers include an acyclic hydrocarbon bridge (e.g., a saturated or unsaturated alkyleno such as methano, ethano, etheno, propano, prop[1]eno, butano, but[1]eno, but[2]eno, buta[1,3]dieno, and the like), a monocyclic or polycyclic hydrocarbon bridge (e.g., [1,2]benzeno, [2,3]naphthaleno, and the like), a monocyclic or polycyclic heteroaryl bridge (e.g., [3,4]furano [2,3]furano, pyridino, thiopheno, piperidino, piperazino, pyrazidino, pyrrolidino, and the like) or combinations of such bridges, dicarbonyl alkylenes, etc. Suitable dicarbonyl alkylenes include, C2 through C15 dicarbonyl alkylenes such as malonic acid, succinic acid, etc. Additionally, the anhydrides, acid halides and esters of such materials can be used to effect the linking when appropriate and can be considered activated dicarbonyl compounds.

(47) Other suitable linkers include moieties that have two different functional groups that can react and link with an end group of a PA. These include groups such as amino acids (glycine, lysine, aspartic acid, etc.), PA's as described herein, poly(ethyleneglycol) bis(carboxymethyl)ethers, polyesters such as polylactides, lactones, polylactones such as polycaprolactone, lactams, polylactams such as polycaprolactam, polyglycolic acid (PGLA), moieties such as tyramine or dopamine and random or block copolymers of 2 or more types of polyesters.

(48) Linkers further include compounds comprising the formula Y.sub.4R.sub.17C(O)Y.sub.6, wherein Y.sub.4 is OH, NHR, a halide, or an activated derivative of OH or NHR; R.sub.17 is a branched or unbranched C1-C15 alkyl group; and Y.sub.6 is NHR, a halide, or OR, wherein R is defined above. The term activated derivative refers to moieties that make the hydroxyl or amine more susceptible to nucleophilic displacement or for condensation to occur. For example, a hydroxyl group can be esterified by various reagents to provide a more active site for reaction to occur.

(49) A linking group refers to the reaction product of the terminal end moieties of the PA and PD (the situation where b is 0; no linker present) condense to form an amide, ether, ester, urea, carbonate or urethane linkage depending on the reactive sites on the PA and PD. In other words, a direct bond is formed between the PA and PD portion of the molecule and no linker is present.
The term residue is used to mean that a portion of a first molecule reacts (e.g., condenses or is an addition product via a displacement reaction) with a portion of a second molecule to form, for example, a linking group, such an amide, ether, ester, urea, carbonate or urethane linkage depending on the reactive sites on the PA and PD. This can be referred to as linkage.
The denotation PD refers to a phenolic derivative, such as a mono-hydroxy, mono- or di-methoxy phenyl derivative, for example, a 3-methoxy-4-hydroxy phenyl moiety, or 3,5-dimethoxy-4-hydroxy phenyl moiety. Suitable PD derivatives include the formula:

(50) ##STR00002##
wherein Q is an OH or OCH3;
z is 1 to 5;
Each X.sub.1, independently, is H, NH.sub.2, OH, or COOH;
Each Y.sub.1, independently, is H, NH.sub.2, OH, or COOH;
Each X.sub.2, independently, is H, NH.sub.2, OH, or COOH;
Each Y.sub.2, independently, is H, NH.sub.2, OH, or COOH;
Z is COOH, NH.sub.2, OH or SH;
aa is a value of 0 to about 4;
bb is a value of 0 to about 4; and
Optionally provided that when one of the combinations of X.sub.a and X.sub.2, Y.sub.1 and Y.sub.2, X.sub.1 and Y.sub.2 or Y.sub.1 and X.sub.2 are absent, then a double bond is formed between the C.sub.aa and C.sub.bb, further provided that aa and bb are each at least 1 to form the double bond when present.

EXPERIMENTAL EXAMPLES

Example 1: Synthesis of PCL1.25 k-diSA

(51) 10 g of polycaprolactone-diol (PCL-diol, MW=1,250, 8 mmol), 8 g of succinic anhydride (SA, 80 mmol), 6.4 mL of pyridine (80 mmol), and 100 mL of chloroform were added to a round bottom flask (250 mL). The solution was refluxed in a 75-85 C. oil bath with Ar purging for overnight. The reaction mixture was allowed to cool to room temperature and 100 mL of chloroform was added. The mixture was washed successively with 100 mL each of 12.1 mM HCl, saturated NaCl, and deionized water. The organic layer was dried over magnesium sulfate and then the volume of the mixture was reduced by half by rotary evaporator. After pouring the mixture into 800 mL of a 1:1 hexane and diethyl ether, the polymer was allowed to precipitate at 4 C. for overnight. The polymer was collected and dried under vacuum to yield 8.1 g of PCL1.25 k-diSA. .sup.1H NMR (400 MHz, DMSO/TMS): 12.2 (s, 1H, COOH), 4.1 (s, 2H, PCL-COCH.sub.2CH.sub.2COOH) 4.0 (s, 12H, O(COCH.sub.2(CH.sub.2).sub.4O).sub.6COCH.sub.2CH.sub.2COOH), 3.6 (s, 2H, PCL-COCH.sub.2CH.sub.2COOH) 3.3 (s, 2H, CH.sub.2PCL.sub.6-SA), 2.3 (t, 12H, O(COCH.sub.2(CH.sub.2).sub.3CH.sub.2O).sub.6COCH.sub.2CH.sub.2COOH), 1.5 (m, 24H, O(COCH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2O).sub.6COCH.sub.2CH.sub.2COOH), 1.3 (m, 12H, O(COCH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2O).sub.6COCH.sub.2CH.sub.2COOH).

Example 2: Synthesis of PCL2k-diSA (LN011732)

(52) 100 g of polycaprolactone-diol (PCL-diol, MW=2,000, 50 mmol) was dissolved in a 1 L round bottom flask while purging under nitrogen. Once completely dissolved, 50 g of succinic anhydride (SA, 500 mmol) was added followed by the addition of 70 mL of triethylamine (502 mmol). The reaction was allowed to react under nitrogen with stirring for 24 hours. The reaction was cooled in an ice bath for 70 minutes. Any solids that remained were filtered using vacuum filtration. The round bottom flask was rinsed with 50 mL of chloroform and this was filtered as well. The solution was transferred to a separatory funnel. The resulting mixture was washed with 1500 mL of a 380 mM aqueous HCl solution. The organic layer was drained out and the aqueous layer was discarded. The organic layer was again transferred to the separatory funnel and washed with 625 mL of nanopure water. The organic layer was drained and the aqueous layer was discarded. The organic layer was again transferred to the separatory funnel and washed with 625 mL of saturated aqueous sodium chloride. The organic layer was drained into an Erlenmeyer flask and the aqueous layer was discarded. To the organic layer was added 50 g of anhydrous sodium sulfate. The solution was capped and the flask was swirled vigorously by hand for 10 minutes. The sodium sulfate was removed by suction filtration and washed with 50 mL of chloroform. The reaction was poured into 4.05 L of a 2:1 Heptane to MTBE solution and placed at 4 C. for 24 hours. The precipitate was collected through vacuum filtration and washed 3 times with a total of 750 mL of a 2:1 Heptane to MTBE solution. The polymer was dried under vacuum for 24 hours. The yield was 77.23 g. .sup.1H NMR (400 MHz, CDCl3/TMS): 4.19 (t, 2H, OCH.sub.2CH.sub.2OPCL-), 4.02 (m, 16H, O(OC(CH.sub.2).sub.4CH.sub.2O).sub.8COCH.sub.2CH.sub.2COOH), 3.65 (t, 2H, OCH.sub.2CH.sub.2OPCL-) 2.61 (m, 4H, PCL-OOCCH.sub.2CH.sub.2COOH), 2.27 (t, 16H, O(COCH.sub.2(CH.sub.2).sub.4O).sub.8COCH.sub.2CH.sub.2COOH), 1.6 (m, 32H, O(COCH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2O).sub.8COCH.sub.2CH.sub.2COOH), 1.31 (m, 16H, O(COCH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.2O).sub.8COCH.sub.2CH.sub.2COOH).

Example 3: Synthesis of Acetyl Ferulic AcidLN011859

(53) 50 g (.sub.257 mmol) of ferulic acid was dissolved in 100 mL (1.24 mol) of pyridine and 100 mL (1.06 mol) of acetic anhydride and allowed to stir for 1 hour. The solution was poured into 1 L of nanopure water and the pH was adjusted to 2 using concentrated HCl. The precipitate was vacuum filtered off and dried under vacuum for 20 hours. The dry material was heated in 300 mL of methanol until the solution came to a slight boil. The solution was removed from the heat source and placed at 4 C. for 4 hours. The precipitate was suction filtered off, washed with 100 mL of methanol, and placed under vacuum for 18 hours. The dry material was heated in 300 mL of methanol until the solution came to a slight boil. The solution was removed from the heat source and placed at 4 C. for 7 hours. The precipitate was suction filtered off, washed with 100 mL of methanol, and placed under vacuum for 48 hours. 51.66 g of material was obtained. .sup.1H NMR (400 MHz, DMSO/TMS): 12.37 (s, 1H, COOH), 7.54 (d, 1H, CHCHCOOH), 7.44 (s, 1H, C.sub.6H.sub.3), 7.23 (d, 1H, C.sub.6H.sub.3), 7.07 (d, 1H, C.sub.6H.sub.3), 6.55 (d, 1H, CHCHCOOH), 3.79 (s, 1H, CH.sub.3OC.sub.6H.sub.3), 2.23 (s, 3H, CH.sub.3COOC.sub.6H.sub.3).

Example 4: Synthesis of PEG10k-(GABA)4LN010828

(54) 300 g of PEG10k-(OH).sub.4 (30 mmol) was weighed out and placed in a 2 L round bottom flask. To this was added 675 mL of chloroform. The mixture was capped, placed in a water bath and allowed to stir at ambient temperature while purging with argon. Once dissolved, 73.2 g of Boc-GABA-OH (360 mmol) was added. In a 1 L beaker, 74.25 g (360 mmol) of DCC was dissolved in 675 mL of chloroform and then added to the reaction. 1.47 g (12 mmol) of DMAP was added to the reaction and allowed to stir for 24 hours while purging with nitrogen. The insoluble urea was vacuum filtered off. The polymer solution was transferred to 3 L round bottom flask and purged with argon for 10 minutes. 1275 mL of 4M HCl in dioxane was added to the polymer solution. The reaction was allowed to stir under argon for 30 minutes. Once the reaction was finished, the solvent was evaporated off at 40 C. The polymer was then dissolved in 6 L of nanopure water and placed into 2000 MWCO dialysis membrane. The polymer was dialyzed against 42 L of nanopure water with 6 changes of the dialysate over 20 hours. The polymer solution was suction filtered to remove any insoluble urea. The solution was then frozen and placed on a lyophilizer to dry. 234.11 g of material was obtained. .sup.1H NMR (400 MHz, D2O/TMS): 4.15 (t, 2H, PEG-OCH.sub.2CH.sub.2OOC), 3.8-3.2 (m, 224H, PEG), 2.91 (t, 2H, OOCCH.sub.2CH.sub.2CH.sub.2NH.sub.2), 2.43 (t, 2H, OOCCH.sub.2CH.sub.2CH.sub.2NH.sub.2), 1.84 (m, 2H, OOCCH.sub.2CH.sub.2CH.sub.2NH.sub.2).

Example 5: Synthesis of PEG5k-(AVA)4LN012436

(55) 50 g of PEG10k-(OH).sub.4 (10 mmol) was weighed out and placed in a 500 mL round bottom flask. To this was added 125 mL of chloroform. The mixture was capped, placed in a water bath and allowed to stir at ambient temperature while purging with argon. Once dissolved, 26.1 g of Boc-AVA-OH (120 mmol) was added. In a 125 mL beaker, 24.76 g (120 mmol) of DCC was dissolved in 125 mL of chloroform and then added to the reaction. 0.98 g (8 mmol) of DMAP was added to the reaction and allowed to stir for 24 hours while purging with argon. The insoluble urea was vacuum filtered off. The polymer solution was transferred to 1 L round bottom flask and purged with argon for 10 minutes. 425 mL of 4M HCl in dioxane was added to the polymer solution. The reaction was allowed to stir under argon for 30 minutes. Once the reaction was finished, the solvent was evaporated off at 40 C. with gradual increases in temperature such that the final temperature was 80 C. The polymer was then dissolved in 1 L of nanopure water and placed into 2000 MWCO dialysis membrane. The polymer was dialyzed against 9 L of nanopure water with 18 changes of the dialysate over 48 hours. The polymer solution was suction filtered to remove any insoluble urea. The solution was then frozen and placed on a lyophilizer to dry. 14.41 g of material was obtained. .sup.1H NMR (400 MHz, D2O/TMS): 4.18 (t, 2H, PEG-OCH.sub.2CH.sub.2OOC), 3.8-3.2 (m, 112H, PEG), 2.91 (t, 2H, OOCCH.sub.2CH.sub.2CH.sub.2CH.sub.2NH.sub.2), 2.38 (t, 2H, OOCCH.sub.2CH.sub.2CH.sub.2CH.sub.2NH.sub.2), 1.59 (m, 4H, OOCCH.sub.2CH.sub.2CH.sub.2CH.sub.2NH.sub.2).

Example 6: Synthesis of PEG10k-(AVA)4LN011861

(56) 50 g of PEG10k-(OH).sub.4 (5 mmol) was weighed out and placed in a 250 mL round bottom flask. To this was added 4.4 g (20.2 mmol) of Boc-AVA-OH, 0.247 g (2.02 mmol) of DMAP, and 60 mL of DCM. The mixture was capped, placed in a water bath and allowed to stir at ambient temperature while purging with Argon. Once dissolved, 4.17 g of DCC (20.2 mmol) was dissolved with 15 mL of DCM and added to the reaction mixture. The reaction was allowed to stir while purging with Argon for 20 hours. The insoluble urea was vacuum filtered off. The polymer solution was transferred to 250 mL round bottom flask and purged with argon for 10 minutes. 75 mL of 4M HCl in dioxane were added to the polymer solution. The reaction was allowed to stir under argon for 30 minutes. Once the reaction was finished, the solvent was evaporated off at 40 C. with gradual increases till the temperature reached 80 C. The polymer was then placed under vacuum overnight. The resulting polymer was dissolved in 670 mL of nanopure water with impure solids being vacuum filtered off. The polymer was purified with tangential flow filtration, frozen, and then placed on a lyophilizer until dry. 32.71 g of material was obtained. .sup.1H NMR (400 MHz, D2O/TMS): 4.18 (t, 2H, PEG-OCH.sub.2CH.sub.2OOC), 3.8-3.2 (m, 224H, PEG), 2.91 (t, 2H, OOCCH.sub.2CH.sub.2CH.sub.2CH.sub.2NH.sub.2), 2.38 (t, 2H, OOCCH.sub.2CH.sub.2CH.sub.2CH.sub.2NH.sub.2), 1.59 (m, 4H, OOCCH.sub.2CH.sub.2CH.sub.2CH.sub.2NH.sub.2).

Example 7: Synthesis of PEG10k-(-Ala)4LN011868

(57) 50 g of PEG10k-(OH)4 (5 mmol) was weighed out and placed in a 250 mL round bottom flask. To this was added 3.82 g (20.2 mmol) of Boc--Ala-OH, 0.247 g (2.02 mmol) of DMAP, and 60 mL of DCM. The mixture was capped, placed in a water bath and allowed to stir at ambient temperature while purging with Argon. Once dissolved, 4.17 g of DCC (20.2 mmol) was dissolved with 15 mL of DCM and added to the reaction mixture. The reaction was allowed to stir while purging with Argon for 20 hours. The insoluble urea was vacuum filtered off. The polymer solution was transferred to 250 mL round bottom flask and purged with argon for 10 minutes. 75 mL of 4M HCl in dioxane was added to the polymer solution. The reaction was allowed to stir under argon for 30 minutes. Once the reaction was finished, the solvent was evaporated off at 40 C. with gradual increases till the temperature reached 80 C. The resulting polymer was dissolved in 800 mL of nanopure water and concentrated to 600 mL. The polymer was purified with tangential flow filtration, frozen, and then placed on a lyophilizer until dry.

(58) 33.28 g of material was obtained. .sup.1H NMR (400 MHz, D2O/TMS): 4.22 (t, 2H, PEG-OCH.sub.2CH.sub.2OOC), 3.8-3.25 (m, 224H, PEG), 3.2 (t, 2H, OOCCH.sub.2CH.sub.2NH.sub.2), 2.75 (t, 2H, OOCCH.sub.2CH.sub.2NH.sub.2).

Example 8: Synthesis of Medhesive-145JLM-664-06

(59) 7.34 g (3.4 mmol) of PCL2k-diSA, 35 g (3.34 mmol) of PEG10k-(GABA)4, and 1.98 g (8.34 mmol) of Acetyl Ferulic Acid were dissolved in 275 mL DMF and 200 mL of chloroform. 6.34 g (16.69 mmol) of HBTU was dissolved in 255 mL of DMF. The HBTU solution was then added to the reaction mixture along with 3.23 mL (23.19 mmol) of triethylamine. The reaction was allowed to stir for 2 hours. 1.58 g (6.68 mmol) of Acetyl Ferulic Acid was added to the reaction followed by 0.70 mL (5.03 mmol) of triethylamine. The reaction was allowed to stir for another hour. The reaction was poured into 4 L of a 1:1 Heptane-to-MTBE mix and placed at 4 C. for 24 hours. The precipitate was removed and dried under vacuum for 24 hours (called polymer Medhesive-159). Once dry, the polymer (Medhesive-159), was dissolved in 550 mL of chloroform and purged with argon for at least 10 minutes. 90 mL of piperidine was added to the polymer solution. The reaction was allowed to proceed with stirring while purging with argon, for 45 minutes. The polymer was poured into 3.4 L of a 1:1 Heptane-to-MTBE solution and placed at 15 C. for 20 hours. The precipitate was suction filtered off and placed under vacuum for 3 days. The polymer was dissolved with 675 mL of methanol and placed into 15000 MWCO dialysis membrane. The polymer solution was dialyzed against 9 L of nanopure water, acidified with 0.9 mL of concentrated HCl. 10 changes of dialysate were made over 43 hours. The dialysate was changed to 9 L of nanopure water and changed 5 times over the next 5 hours. The polymer was frozen and freeze dried until dry. 37.5 g of material was obtained. UV-VIS Wt % FA=3.05+/0.05%, 0.159+/0.003 umol FA/mg polymer; DSC (2.sup.nd heat)=40.87 C.

Example 9: Synthesis of Medhesive-179JLM-664-48

(60) 6.853 g (3.12 mmol) of PCL2k-diSA, 32.6 g (3.11 mmol) of PEG10k-(AVA).sub.4, and 1.847 g (7.82 mmol) of Acetyl Ferulic Acid were dissolved in 250 mL DMF and 185 mL of chloroform. 5.899 g (15.56 mmol) of HBTU was dissolved in 250 mL of DMF. The HBTU solution was then added to the reaction mixture along with 3.01 mL (21.6 mmol) of triethylamine. The reaction was allowed to stir for 2 hours. 1.479 g (6.26 mmol) of Acetyl Ferulic Acid was added to the reaction followed by 0.653 mL (4.69 mmol) of triethylamine. The reaction was allowed to stir for another hour. The reaction was poured into 4 L of a 1:1 Heptane-to-MTBE mix and placed at 4 C. for 16 hours. The precipitate was removed and dried under vacuum for 6 hours (called polymer Medhesive-178). Once dry, the polymer (Medhesive-178), was dissolved in 325 mL of chloroform and purged with argon for at least 10 minutes. 65 mL of piperidine was added to the polymer solution. The reaction was allowed to proceed with stirring while purging with argon, for 45 minutes. The polymer was poured into 3.2 L of a 1:1 Heptane-to-MTBE solution and placed at 4 C. for 20 hours. The precipitate was suction filtered off and placed under vacuum for 22 hours. The polymer was dissolved with 550 mL of methanol and placed into 15000 MWCO dialysis membrane. The polymer solution was dialyzed against 9 L of nanopure water, acidified with 0.9 mL of concentrated HCl. 10 changes of dialysate were made over 44 hours. The dialysate was changed to 9 L of nanopure water and changed 5 times over the next 6 hours. The polymer was frozen and freeze dried until dry. 36.19 g of material was obtained; DSC (2.sup.nd heat)=40.09+/0.07 C.; IV=1.2+/0.021 dl/g

Example 10: Synthesis of Medhesive-181LN011885

(61) 7.04 g (3.2 mmol) of PCL2k-diSA, 33.31 g (3.17 mmol) of PEG10k-(-Ala).sub.4, and 1.89 g (8.0 mmol) of Acetyl Ferulic Acid were dissolved in 250 mL DMF and 200 mL of chloroform. 6.06 g (15.98 mmol) of HBTU was dissolved in 250 mL of DMF. The HBTU solution was then added to the reaction mixture along with 3.09 mL (22.17 mmol) of triethylamine. The reaction was allowed to stir for 2 hours. 1.51 g (6.39 mmol) of Acetyl Ferulic Acid was added to the reaction followed by 0.670 mL (4.80 mmol) of triethylamine. The reaction was allowed to stir for another hour. The reaction was poured into 4 L of diethyl ether and placed at 4 C. for 19 hours. The precipitate was removed and dried under vacuum for 6 days (called polymer Medhesive-180). Once dry, the polymer (Medhesive-180), was dissolved in 350 mL of chloroform and purged with argon for at least 10 minutes. 67 mL of piperidine was added to the polymer solution. The reaction was allowed to proceed with stirring while purging with argon, for 45 minutes. The polymer was poured into 3.4 L of a 1:1 Heptane-to-MTBE solution and placed at 15 C. for 18 hours. The precipitate was suction filtered off and placed under vacuum for 5 days. The polymer was dissolved with 450 mL of methanol and placed into 15000 MWCO dialysis membrane. The polymer solution was dialyzed against 7 L of nanopure water, acidified with 0.7 mL of concentrated HCl. 10 changes of dialysate were made over 47 hours. The dialysate was changed to 9 L of nanopure water and changed 5 times over the next 4 hours. The polymer was frozen and freeze dried until dry. 33.09 g of material was obtained.

Example 11: Synthesis of Acetyl Isoferulic AcidJLM-664-92

(62) 10.07 g (51.9 mmol) of isoferulic acid was dissolved in 22 mL (273 mmol) of pyridine and 22 mL (233 mmol) of acetic anhydride and allowed to stir for 2 hour. The solution was poured into 500 mL of nanopure water and the pH was adjusted to 2 using concentrated HCl. The precipitate was vacuum filtered off and dried under vacuum for 20 hours. The dry material was heated in 200 mL of methanol until the solution came to a slight boil. The solution was removed from the heat source and placed at 4 C. for 2 hours. The precipitate was suction filtered off, washed with 100 mL of methanol, and placed under vacuum for 3 weeks. The dry material was heated in 300 mL of methanol until the solution came to a slight boil. The solution was removed from the heat source and placed at 4 C. for 1 hour. The precipitate was suction filtered off, washed with 100 mL of methanol, and placed under vacuum for 16 hours. 4.84 g of material was obtained.

Example 12: Synthesis of Acetyl Vanillic AcidLN011035

(63) 20.04 g (112 mmol) of Vanillic Acid was dissolved in 50 mL (618 mmol) of pyridine and 50 mL (529 mmol) of acetic anhydride and allowed to stir for 2 hour. The solution was poured into 1200 mL of nanopure water and the pH was adjusted to 2 using concentrated HCl. The solution was extracted twice with a total of 700 mL of ethyl acetate and dried with anhydrous magnesium sulfate. The magnesium sulfate was suction filtered off and the organic solvent was evaporated off. The compound was dried for 23 hours under vacuum. The compound was recrystallized in 400 mL of a 1:1 mixture of water:methanol. The precipitate was suction filtered and placed under vacuum. 21.58 g of material was obtained.

Example 13: Synthesis of Acetyl Sinapic AcidJLM-688-50

(64) 14.95 g (66.7 mmol) of Sinapic acid was dissolved in 30 mL (372 mmol) of pyridine and 30 mL (317 mmol) of acetic anhydride and allowed to stir for 2 hour. The solution was poured into 300 mL of nanopure water and the pH was adjusted to 2 using concentrated HCl. The precipitate was vacuum filtered off and dried under vacuum for 3 hours. The dry material was heated in 150 mL of methanol until the solution came to a slight boil. The solution was removed from the heat source and placed at 4 C. for 1 hour. The precipitate was suction filtered off, washed with 100 mL of methanol, and placed under vacuum for 16 hours. The dry material was heated in 150 mL of methanol until the solution came to a slight boil. The solution was removed from the heat source and placed at 4 C. for 3 hours. The precipitate was suction filtered off, washed with 100 mL of methanol, and placed under vacuum for 20 hours. 2.0 g of material was obtained.

Example 14: Synthesis of Acetyl Syringic AcidJLM-688-52

(65) 14.90 g (75.2 mmol) of Syringic acid was dissolved in 30 mL (372 mmol) of pyridine and 30 mL (317 mmol) of acetic anhydride and allowed to stir for 2 hour. The solution was poured into 300 mL of nanopure water and the pH was adjusted to 2 using concentrated HCl. The precipitate was vacuum filtered off and dried under vacuum for 3 hours. The dry material was heated in 150 mL of methanol until the solution came to a slight boil. 150 mL of nanopure water was added to the solution. The solution was removed from the heat source and placed at 4 C. for 2 hours. The precipitate was suction filtered off, washed with 100 mL of nanopure water, and placed under vacuum for 15 hours. The dry material was heated in 150 mL of methanol until the solution came to a slight boil. 150 mL of nanopure water was added to the solution. The solution was removed from the heat source and placed at 4 C. for 4 hours. The precipitate was suction filtered off, washed with 100 mL of nanopure water, and placed under vacuum for 20 hours. 10.54 g of material was obtained.

Example 15: Synthesis of Acetyl p-Coumaric AcidJLM-688-67

(66) 25.03 g (152 mmol) of p-Coumaric Acid was dissolved in 50 mL (620 mmol) of pyridine and 50 mL (529 mmol) of acetic anhydride and allowed to stir for 1.5 hour. The solution was poured into 500 mL of nanopure water and the pH was adjusted to 2 using concentrated HCl. The precipitate was vacuum filtered off and dried under vacuum for 24 hours. The dry material was heated in 150 mL of methanol until the solution came to a slight boil. 150 mL of nanopure water was added to the solution. The solution was removed from the heat source and placed at 4 C. for 17 hours. The precipitate was suction filtered off, washed with 150 mL of nanopure water, and placed under vacuum for 24 hours. The dry material was heated in 150 mL of methanol until the solution came to a slight boil. 150 mL of nanopure water was added to the solution. The solution was removed from the heat source and placed at 4 C. for 3 hours. The precipitate was suction filtered off, washed with 150 mL of nanopure water, and placed under vacuum for 20 hours. 29.73 g of material was obtained.

Example 16: Synthesis of 4-Acetoxybenzoic AcidJLM-688-64

(67) 25.22 g (183 mmol) of 4-Hydroxybenzoic Acid was dissolved in 50 mL (620 mmol) of pyridine and 50 mL (529 mmol) of acetic anhydride and allowed to stir for 1.5 hour. The solution was poured into 500 mL of nanopure water and the pH was adjusted to 2 using concentrated HCl. The precipitate was vacuum filtered off and dried under vacuum for 24 hours. The dry material was heated in 150 mL of methanol until the solution came to a slight boil. 150 mL of nanopure water was added to the solution. The solution was removed from the heat source and placed at 4 C. for 17 hours. The precipitate was suction filtered off, washed with 150 mL of nanopure water, and placed under vacuum for 24 hours. The dry material was heated in 150 mL of methanol until the solution came to a slight boil. 150 mL of nanopure water was added to the solution. The solution was removed from the heat source and placed at 4 C. for 3 hours. The precipitate was suction filtered off, washed with 150 mL of nanopure water, and placed under vacuum for 20 hours. 24.44 g of material was obtained.

Example 17: Synthesis of Medhesive-188JLM-688-54

(68) 3.675 g (1.67 mmol) of PCL2k-diSA, 17.484 g (1.67 mmol) of PEG10k-(AVA).sub.4, and 0.99 g (4.19 mmol) of Acetyl Isoferulic Acid was dissolved in 133 mL DMF and 100 mL of chloroform. 3.16 g (8.33 mmol) of HBTU was dissolved in 133 mL of DMF. The HBTU solution was then added to the reaction mixture along with 1.615 mL (11.59 mmol) of triethylamine. The reaction was allowed to stir for 2 hours. 0.794 g (3.36 mmol) of Acetyl Isoferulic Acid was added to the reaction followed by 0.350 mL (2.51 mmol) of triethylamine. The reaction was allowed to stir for another hour. The reaction was poured into 3.2 L of a 1:1 Heptane-to-MTBE solution and placed at 4 C. for 23 hours. The precipitate was removed and dried under vacuum for 3 days (called polymer Medhesive-187). Once dry, the polymer (Medhesive-187), was dissolved in 180 mL of chloroform and purged with argon for at least 10 minutes. 40 mL of piperidine was added to the polymer solution. The reaction was allowed to proceed with stirring while purging with argon, for 45 minutes. The polymer was poured into 1.8 L of a 1:1 Heptane-to-MTBE solution and placed at 15 C. for 20 hours. The precipitate was suction filtered off and placed under vacuum for 25 hours. The polymer was dissolved with 280 mL of methanol and placed into 15000 MWCO dialysis membrane. The polymer solution was dialyzed against 5 L of nanopure water, acidified with 0.5 mL of concentrated HCl. 10 changes of dialysate were made over 45 hours. The dialysate was changed to 5 L of nanopure water and changed 5 times over the next 4 hours. The polymer was frozen and freeze dried until dry. 18.66 g of material was obtained.

Example 18: Synthesis of Medhesive-190JLM-688-57

(69) 1.832 g (0.83 mmol) of PCL2k-diSA, 8.737 g (0.83 mmol) of PEG10k-(AVA).sub.4, and 0.439 g (2.09 mmol) of Acetyl Vanillic Acid was dissolved in 67 mL DMF and 50 mL of chloroform. 1.587 g (4.19 mmol) of HBTU was dissolved in 67 mL of DMF. The HBTU solution was then added to the reaction mixture along with 0.81 mL (5.81 mmol) of triethylamine. The reaction was allowed to stir for 2 hours. 0.359 g (1.71 mmol) of Acetyl Vanillic Acid was added to the reaction followed by 0.175 mL (1.26 mmol) of triethylamine. The reaction was allowed to stir for another hour. The reaction was poured into 1.6 L of a 1:1 Heptane-to-MTBE solution and placed at 4 C. for 3 days. The precipitate was removed and dried under vacuum for 3 days (called polymer Medhesive-189). Once dry, the polymer (Medhesive-189), was dissolved in 90 mL of chloroform and purged with argon for at least 10 minutes. 20 mL of piperidine was added to the polymer solution. The reaction was allowed to proceed with stirring while purging with argon, for 45 minutes. The polymer was poured into 900 mL of a 1:1 Heptane-to-MTBE solution and placed at 15 C. for 20 hours. The precipitate was suction filtered off and placed under vacuum for 25 hours. The polymer was dissolved with 145 mL of methanol and placed into 15000 MWCO dialysis membrane. The polymer solution was dialyzed against 2.5 L of nanopure water, acidified with 0.25 mL of concentrated HCl. 10 changes of dialysate were made over 45 hours. The dialysate was changed to 2.5 L of nanopure water and changed 5 times over the next 4 hours. The polymer was frozen and freeze dried until dry. 9.56 g of material was obtained.

Example 19: Synthesis of Medhesive-192JLM-688-74

(70) 3.147 g (1.43 mmol) of PCL2k-diSA, 15.03 g (1.43 mmol) of PEG10k-(AVA).sub.4, and 0.953 g (3.58 mmol) of Acetyl Sinapic Acid was dissolved in 115 mL DMF and 85 mL of chloroform. 2.722 g (7.18 mmol) of HBTU was dissolved in 115 mL of DMF. The HBTU solution was then added to the reaction mixture along with 1.38 mL (9.9 mmol) of triethylamine. The reaction was allowed to stir for 2 hours. 0.76 g (2.85 mmol) of Acetyl Sinapic Acid was added to the reaction followed by 0.3 mL (2.15 mmol) of triethylamine. The reaction was allowed to stir for another hour. The reaction was poured into 2.4 L of a 1:1 Heptane-to-MTBE solution and placed at 4 C. for 15 hours. The precipitate was removed and dried under vacuum for 17 hours (called polymer Medhesive-191). Once dry, the polymer (Medhesive-191), was dissolved in 150 mL of chloroform and purged with argon for at least 10 minutes. 36 mL of piperidine was added to the polymer solution. The reaction was allowed to proceed with stirring while purging with argon, for 45 minutes. The polymer was poured into 1.7 L of a 1:1 Heptane-to-MTBE solution and placed at 15 C. for 23 hours. The precipitate was suction filtered off and placed under vacuum for 2 days. The polymer was dissolved with 240 mL of methanol and placed into 15000 MWCO dialysis membrane. The polymer solution was dialyzed against 5 L of nanopure water, acidified with 0.5 mL of concentrated HCl. 10 changes of dialysate were made over 45 hours. The dialysate was changed to 5 L of nanopure water and changed 5 times over the next 4 hours. The polymer was frozen and freeze dried until dry. 14.95 g of material was obtained.

Example 20: Synthesis of Medhesive-194JLM-688-71

(71) 3.15 g (1.43 mmol) of PCL2k-diSA, 14.99 g (1.43 mmol) of PEG10k-(AVA).sub.4, and 0.867 g (3.61 mmol) of Acetyl Syringic Acid was dissolved in 115 mL DMF and 85 mL of chloroform. 2.714 g (7.16 mmol) of HBTU was dissolved in 115 mL of DMF. The HBTU solution was then added to the reaction mixture along with 1.38 mL (9.9 mmol) of triethylamine. The reaction was allowed to stir for 2 hours. 0.69 g (2.87 mmol) of Acetyl Syringic Acid was added to the reaction followed by 0.3 mL (2.15 mmol) of triethylamine. The reaction was allowed to stir for another hour. The reaction was poured into 2.4 L of a 1:1 Heptane-to-MTBE solution and placed at 4 C. for 15 hours. The precipitate was removed and dried under vacuum for 17 hours (called polymer Medhesive-193). Once dry, the polymer (Medhesive-193), was dissolved in 150 mL of chloroform and purged with argon for at least 10 minutes. 36 mL of piperidine was added to the polymer solution. The reaction was allowed to proceed with stirring while purging with argon, for 45 minutes. The polymer was poured into 1.7 L of a 1:1 Heptane-to-MTBE solution and placed at 150 C. for 23 hours. The precipitate was suction filtered off and placed under vacuum for 2 days. The polymer was dissolved with 240 mL of methanol and placed into 15000 MWCO dialysis membrane. The polymer solution was dialyzed against 5 L of nanopure water, acidified with 0.5 mL of concentrated HCl. 10 changes of dialysate were made over 45 hours. The dialysate was changed to 5 L of nanopure water and changed 5 times over the next 4 hours. The polymer was frozen and freeze dried until dry. 16.07 g of material was obtained.

Example 21: Synthesis of Medhesive-196JLM-688-81

(72) 1.378 g (0.626 mmol) of PCL2k-diSA, 6.56 g (0.626 mmol) of PEG10k-(AVA).sub.4, and 0.325 g (1.58 mmol) of 4-Acetyl Coumaric Acid is dissolved in 50 mL DMF and 40 mL of chloroform. 1.204 g (3.18 mmol) of HBTU is dissolved in 50 mL of DMF. The HBTU solution is then added to the reaction mixture along with 0.605 mL (4.34 mmol) of triethylamine. The reaction is allowed to stir for 2 hours. 0.256 g (1.24 mmol) of 4-Acetyl Coumaric Acid is added to the reaction followed by 0.131 mL (0.94 mmol) of triethylamine. The reaction is allowed to stir for another hour. The reaction is poured into 800 mL of a 1:1 Heptane-to-MTBE solution and placed at 4 C. for 16 hours. The precipitate is removed and dried under vacuum for 17 hours (called polymer Medhesive-195). Once dry, the polymer (Medhesive-195), is dissolved in 70 mL of chloroform and purged with argon for at least 10 minutes. 17 mL of piperidine is added to the polymer solution. The reaction is allowed to proceed with stirring while purging with argon, for 45 minutes. The polymer is poured into 800 mL of a 1:1 Heptane-to-MTBE solution and placed at 15 C. for 24 hours. The precipitate is suction filtered off and placed under vacuum for 2 days. The polymer is dissolved with 110 mL of methanol and placed into 15000 MWCO dialysis membrane. The polymer solution is dialyzed against 3 L of nanopure water, acidified with 0.3 mL of concentrated HCl. 10 changes of dialysate are made over 45 hours. The dialysate is changed to 3 L of nanopure water and changed 5 times over the next 4 hours. The polymer is frozen and freeze dried until dry.

Example 22: Synthesis of Medhesive-198JLM-688-84

(73) 1.379 g (0.627 mmol) of PCL2k-diSA, 6.58 g (0.627 mmol) of PEG10k-(AVA).sub.4, and 0.285 g (1.58 mmol) of 4-Acetoxybenzoic Acid is dissolved in 50 mL DMF and 40 mL of chloroform. 1.201 g (3.17 mmol) of HBTU is dissolved in 50 mL of DMF. The HBTU solution is then added to the reaction mixture along with 0.605 mL (4.34 mmol) of triethylamine. The reaction is allowed to stir for 2 hours. 0.228 g (1.27 mmol) of 4-Acetoxybenzoic Acid is added to the reaction followed by 0.131 mL (0.94 mmol) of triethylamine. The reaction is allowed to stir for another hour. The reaction is poured into 800 mL of a 1:1 Heptane-to-MTBE solution and placed at 4 C. for 16 hours. The precipitate is removed and dried under vacuum for 17 hours (called polymer Medhesive-197). Once dry, the polymer (Medhesive-197), is dissolved in 70 mL of chloroform and purged with argon for at least 10 minutes. 17 mL of piperidine is added to the polymer solution. The reaction is allowed to proceed with stirring while purging with argon, for 45 minutes. The polymer is poured into 800 mL of a 1:1 Heptane-to-MTBE solution and placed at 15 C. for 24 hours. The precipitate is suction filtered off and placed under vacuum for 2 days. The polymer is dissolved with 110 mL of methanol and placed into 15000 MWCO dialysis membrane. The polymer solution is dialyzed against 3 L of nanopure water, acidified with 0.3 mL of concentrated HCl. 10 changes of dialysate are made over 45 hours. The dialysate is changed to 3 L of nanopure water and changed 5 times over the next 4 hours. The polymer is frozen and freeze dried until dry.

Example 23: Mono-Layered Thin Film Adhesives

(74) Switching the hydroferulic acid adhesive moiety to ferulic acid (FIG. 16) in a bi-layer formulation increases the stability of the film. It has been found that using novel adhesive moieties, oxidants may be added directly into the adhesive film using existing solvent casting methods without observing significant preoxidation. Solvents used consisted of a mixture of methanol and chloroform which evaporated off in 30-45 minutes. The resulting film was opaque with a slight yellow color. The material only begins to lose its ability to adhere to tissue surfaces when it has turned a deep brown.

Example 24: Mono-Layered Thin Film Adhesives Able to Undergo Sterilization

(75) By switching the hydroferulic acid of the adhesive thin film with ferulic acid the oxidant could be directly incorporated into the thin film. Additionally, it was shown that these films were stable over a period of 30 days (FIG. 17). Further monitoring of these films over time has shown that they may be stored at ambient condition up to 4 months without significant color change. The films may undergo sterilization without any visible activation. Ferulic acid containing polymers offer the ability to create a mono-layered film able to undergo sterilization while at the same time improving stability.

Example 25: Polymer Synthesis

(76) Polymers have been synthesized to increase mechanical performance, and to slow degradation profiles by varying the degradable ester linkage in the adhesive polymer. By increasing and varying the polyester content of the adhesive film, the lap shear performance of the thin film construct may be increased. Medhesive-179, 163, and 165 were synthesized to measure the effect of increasing polycaprolactone content on the lap shear results (Table 1). Additionally, Medhesive-177, 167, and 169, which contain polylactic acid, were tested to observe the difference between polyester material as well as the effect of higher polylactic acid content (Table 1). Medhesive-171 was synthesized to measure the effect of increasing the ferulic acid concentration (Table 1). Medhesive-145 and Medhesive-179 consist of two degradation profiles useful in determining the duration the adhesive must be present in vivo to be effective (Table 1).

(77) TABLE-US-00001 TABLE 1 Proposed Compounds to Synthesize and Relative Wt % Components; FA PCL PLA PEG Acc Deg. Compound Wt % Wt % Wt % Wt % (55 C.) Med-145 2.73% 16.86% 80.41% 14-15 days Med-177 2.73% 16.86%.sup. 80.41% Med-179 2.73% 16.86% 80.41% 18-19 days Med-163 .sup.~3% ~53%% .sup.~44% Med-167 .sup.~3% ~53% .sup.~44% Med-165 ~3.2% ~75% .sup.~22% Med-169 ~3.2% ~75% .sup.~22% Med-171 4.96% 17.60% 77.44% Acc. Deg. = Accelerated degradation at 55 C. in 1x PBS buffer (pH = 7.4)
Medhesive-163 and Medhesive-165 contain a significant amount of tin (2.5-5 wt %) associated with the polymerization process of the PCL. Because of this, their lower synthetic yields and the fact that they either did not have good lap shear results (M-163) or did not form a workable thin film (M-165), the two polymers were discarded from further development. Medhesive-167 was synthesized in low yield and had a low transition temperature which made it overly tacky. The tackiness made it difficult to handle and therefore unsuitable in a medical settings. Additionally, lap shear results indicate it had poor adhesive qualities when activated. A similar profile was noticed with Medhesive-171. As such these 2 polymers are not selected for further development.

(78) Lap shear testing of the compounds was performed according to ASTM D5868. Briefly, Medhesive polymers solvent cast or heat-pressed onto a polyester mesh were cut into 1 by 2 segments with 1 cm area of adhesive overlap. The samples were activated by adding a known quantity of 1PBS buffer to bovine pericardium substrate, and adhesive coated meshes were applied to the construct for a 20 min activation period. Samples were subsequently conditioned in PBS-soaked gauze for 1 hour at 37 C. After conditioning, samples were pull-tested at a rate of 10 mm/min until failure. Peak load and failure mode (adhesive/cohesive) were recorded and average peak stress was calculated and normalized to area of adhesive overlap. Medhesive-145 and Medhesive-179 performed well in lap shear testing (FIG. 19).

Example 26: Oxidant Synthesis

(79) A requirement for compression molding of a thin film, and for spraying a polymer solution, is that the oxidant be in direct contact within the polymer at a large scale. While the oxidant may be solvent casted into the thin film at small scale (<2.5 g), scale up is desired. The oxidant is soluble in water, which activates the thin film, and weakly soluble in methanol, which contains some residual moisture. Conventionally, solvent casting is done by dissolving the oxidant in a dilute solution of methanol (7.5 mg/mL). This solution is then added to the polymer in chloroform. The solvent is subsequently evaporated in a hood to produce the thin film adhesive containing oxidant. However, as the process is scaled up, more methanol is required which increases the amount of moisture present. Additionally, as more solvent is required, longer evaporation times are needed. Scaling up the process past 2.5 g risks pre-activation of the polymer. Accordingly, it would be beneficial to use oxidants which are soluble in solvents that do not contain residual moisture (e.g., chloroform) which may help prevent pre-activation of the thin film during processing. Additionally, the oxidant would be required to be soluble in an aqueous environment so that when placed into contact with moist tissue it is released to activate the thin film.

(80) An effective and biocompatible oxidant is periodate. To make periodate more soluble in organic solvent, the counter-ion (sodium) was exchanged with an organic counter-ion. Counter-ions (TMAP, TEAP, TPAP and TBAP) are shown in FIG. 20. Lap shear testing was performed according to ASTM D5868 as described above. Both TPAP and TEAP are soluble in a wide variety of organic solvents (including chloroform) as well as in aqueous solutions (FIG. 21). TMAP showed lower than anticipated results, and is not soluble in many organic solvents. TBAP was soluble in many organic solvents but was not soluble in aqueous solutions.

Example 27: Synthesis of PLA2k-diSA

(81) 45 g of poly(L-lactide-co-D,L-lactide)-diol (PLA-diol prepared by known literature methods, 2,400 g/mol, 36 mmol) was dissolved in 160 mL Dichloromethane in a 500 mL round bottom flask while purging under nitrogen. Once completely dissolved, 11 g of succinic anhydride (108 mmol) was added followed by the addition of 15.3 mL of triethylamine (110 mmol). The reaction was allowed to react under nitrogen with stirring for 24 hours. The solvent was removed via rotary evaporation and the redissolved in 600 mL of ethyl acetate. The solution was transferred to a separatory funnel. The mixture was extracted with two 100 mL portions of aqueous phosphoric acid (112 mmol), followed by three 100 mL portions of 10% w/w sodium chloride solution, and three 100 mL portions of nanopure water. The organic phase was collected and dried with anhydrous sodium sulfate. The dichloromethane solution was concentrated to a viscous oil and precipitated into 1500 mL of Heptane/IPA solvent mixture (70/30w/w). The solid polymer was filtered and dried under vacuum for 24 hours. The yield was 39.45 g. .sup.1H NMR (400 MHz, CDCl.sub.3/TMS): 4.8-5.3 (m, 37H, O(OC(CH.sub.3)CHO)9COCH.sub.2CH.sub.2COOH), 4.19 (m, 4H, OCH.sub.2CH.sub.2CH.sub.2CH.sub.2O-PLA-), 2.68 (m, 8H, PLAOOCCH.sub.2CH.sub.2COOH), 1.68 (m, 4H, OCH.sub.2CH.sub.2CH.sub.2CH.sub.2O-PLA-), 1.3-1.6 (m, 111H, (OC(CH.sub.3)CHO)9.

Example 28: Synthesis of Medhesive-202

(82) 7.47 g (6.23 mmol) of PLA2k-diSA, 33.3 g (12.7 mmol) of PEG10k-(AVA).sub.4, and 1.84 g (7.80 mmol) of Acetyl Ferulic Acid were dissolved in 250 mL DMF and 188 mL of chloroform. 5.917 g (15.60 mmol) of HBTU was dissolved in 250 mL of DMF. The HBTU solution was then added to the reaction mixture along with 3.01 mL (21.6 mmol) of triethylamine. The reaction was allowed to stir for 20 hours. 1.49 g (6.32 mmol) of Acetyl Ferulic Acid was added to the reaction followed by 0.654 mL (4.69 mmol) of triethylamine. The reaction was allowed to stir for another hour. The reaction was poured into 4 L of a heptane/IPA solvent mixture (90/10w/w) and precipitated. The supernatant was decanted off and the polymer solid was washed with two 1 L portions of heptane-IPA (9/1), followed by two 1 L portions of hexane. The precipitate was removed and dried under vacuum for 6 hours. Once dry, the polymer was dissolved in 475 mL of chloroform and purged with nitrogen for 10 minutes. 98 mL of piperidine was added to the polymer solution. The reaction was allowed to proceed with stirring while purging with argon, for 40-45 minutes. The polymer was poured into 4 L of a heptane/IPA solvent mixture (70/30w/w) and precipitated. The supernatant was decanted off and the polymer solid was washed with two 1 L portions of heptane-IPA (9/1), followed by two 1 L portions of hexane. The precipitate was vacuum filtered off and dried under vacuum. The polymer was purified by standard dialysis techniques and freeze dried. 36 g of material was obtained; IV=0.79+/0.03 dl/g.

(83) All publications and patents mentioned in the above specification are herein incorporated by reference in their entirety for all purposes. Various modifications and variations of the described compositions, methods, and uses of the technology will be apparent to those skilled in the art without departing from the scope and spirit of the technology as described. Although the technology has been described in connection with specific exemplary embodiments, it should be understood that the technology as claimed should not be unduly limited to such specific embodiments. Indeed, various modifications of the described modes for carrying out the technology that are obvious to those skilled in pharmacology, biochemistry, medical science, or related fields are intended to be within the scope of the following claims.