BIOADHESIVE COMPOUNDS AND METHODS OF SYNTHESIS AND USE
20170266353 · 2017-09-21
Inventors
- John L MURPHY (Exton, PA, US)
- Christopher P RADANO (Exton, PA, US)
- Jeffrey L. DALSIN (Exton, PA, US)
- Justin T. KOEPSEL (Exton, PA, US)
Cpc classification
A61L31/088
HUMAN NECESSITIES
C08L33/02
CHEMISTRY; METALLURGY
C08L33/02
CHEMISTRY; METALLURGY
A61L2400/18
HUMAN NECESSITIES
A61L2300/404
HUMAN NECESSITIES
International classification
Abstract
Synthesis methods for creating polymeric compounds comprising phenyl derivatives (PD), or PDp i.e., polymers modified with PD, with desired surface active effects are described. The polymer backbone of PDp has structural or performance features that can be tailored to control physical properties of PDp, allowing it to be useful for different applications i.e., tissue adhesives or sealants, adhesion promoting coatings, and antifouling coatings.
Claims
1. A method to reduce microbial fouling on a surface, comprising: a) providing a surface; b) functionalizing said surface; c) providing a phenyl derivative (PD)-poly((meth)acrylic) polymer comprising Formula I: ##STR00059## wherein “a” is selected from the group consisting of DMA, VAMA and DMHPEAMA, “b” is selected from the group consisting of AA, HEMA, HEA and MEA, and “c” is optionally selected from the group consisting of DMAEMAC.sub.12 and DMAPMAmC.sub.12; d) applying an effective amount of said polymer to said functionalized surface; e) providing silver nitrate; f) cross-linking said surface and said polymer with said silver nitrate; and g) reducing said microbial fouling on said surface.
2. The method of claim 1 wherein said phenyl derivative is a multihydroxy phenol derivative.
3. The method of claim 1, wherein the functionalizing said surface comprises providing an ammonia plasma, and treating said surface with said ammonia plasma.
4. The method of claim 3, wherein said functionalizing comprises creating reactive amine groups on said surface.
5. The method of claim 4, wherein said phenyl derivative binds to said reactive amine groups.
6. The method of claim 1, wherein said surface is the surface of a medical device.
7. The method of claim 6, wherein said medical device is a urologic device.
8. The method of claim 7, wherein said urologic device is selected from the group consisting of a urinary stent or catheter.
9. The method of claim 1, wherein said microbial fouling is bacterial fouling.
10. A method of providing a biofouling resistant surface, wherein said method comprises the steps of: a) providing a medical device surface having been functionalized with reactive amine groups; b) providing a multihydroxy phenyl derivative (DHPD)-poly(ethylene glycol) polymer comprising Formula I: ##STR00060## wherein “a” is selected from the group consisting of DMA, VAMA and DMHPEAMA, “b” is selected from the group consisting of AA, HEMA, HEA and MEA, and “c” is optionally selected from the group consisting of DMAEMAC.sub.12 and DMAPMAmC.sub.12; c) providing an effective amount of silver nitrate: and d) applying said polymer of Formula I, and said silver nitrate to said surface.
11. The method of claim 10, wherein said polymer of Formula I and said silver nitrate form a coating on said surface.
12. A biofouling resistant construct, comprising: a biocompatible surface presenting functional reactive groups; and a coating comprising the formula: ##STR00061## wherein “a” is selected from the group consisting of DMA, VAMA and DMHPEAMA, “b” is selected from the group consisting of AA, HEMA, HEA and MEA, and “c” is optionally selected from the group consisting of DMAEMAC.sub.12 and DMAPMAmC.sub.12; wherein the molecule of claim 1 is cross-linked and contains an effective amount of silver(0).
13. A composition comprising the polymer of the formula: ##STR00062## wherein “a” is selected from the group consisting of DMA, VAMA and DMHPEAMA, “b” is selected from the group consisting of AA, HEMA, HEA and MEA, and “c” is optionally selected from the group consisting of DMAEMAC.sub.12 and DMAPMAmC.sub.12; wherein the polymer is configured to be cross-linked to one of a group consisting of: an adjacent polymer molecule from Formula I, a reactive group on a surface, wherein the composition further comprises an effective amount of silver(0).
14. The composition of claim 13, wherein the composition is crosslinked to a surface treated with ammonia gas plasma.
15. A method for adhering an antibacterial coating to a surface consisting of a PD modified polymer (PDp) according to the formula: ##STR00063## wherein LG is an optional linking group; PD is a phenolic derivative selected from vanillylamine, 3-methoxytyramine, 3,5-dimethoxy-4-hydroxyphenethylamine, 4-hydroxy-3-methoxy-L-phenylalanine, or tyramine; R.sub.1 is are monomeric unit which, independently, can be the same or different and is used to form the PDp; pB is a linear polymeric backbone; and applying an effective amount of said PDp to at least one surface; and applying an effective oxidizer to crosslink the PDp.
16. The method of claim 15, wherein said oxidizer is silver.
17. The method of claim 15 where PDp consists of multiple monomeric units.
18. The method of claim 15, wherein the monomeric units which make up PDp are antibacterial.
19. The method of claim 15, wherein the PDp is essentially non-soluble in aqueous solution.
20. The method of claim 15 where the effective oxidizer is antibacterial.
21. The method of claim 15, wherein the PDp-modified linear polymer (PDp) is configured to cure at a predetermined rate.
22. The method of claim 15, wherein the PDp-modified linear polymer (PDp) is configured to degrade at a predetermined rate.
Description
BRIEF DESCRIPTION OF THE FIGURES
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REFERENCE TO TABLES
[0139] Discussed in the following section is Table 1, which provides the monomer composition for certain polymers of the present application as mole percents of constituent monomers. Table 2 provides the chemical description of certain embodiments used herein. Those tables follow the References section as a group.
DETAILED DESCRIPTION OF THE INVENTION
[0140] 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.”
[0141] 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.
[0142] 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.
[0143] “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, cycl obutan-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.
[0144] The term alkoxy (“OR”) includes groups where R is an hydrogen or an alkane chain linked to at least one oxygen.
[0145] 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.
[0146] 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).
[0147] “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.
[0148] “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.
[0149] “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 valences are on the same carbon atom, the nomenclature “alkylidene” is used. In other embodiments, the alkyldiyl group comprises from 1 to 6 carbon atoms (C1-C6 alkyldiyl). In another embodiment there 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).
[0150] “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 locant 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 other embodiments, the alkyleno group is (C1-C6) or (C1-C3) alkyleno. Alternatively, in other embodiment there are provided straight-chain saturated alkano groups, e.g., methano, ethano, propano, butano, and the like.
[0151] “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 some embodiments, the alkylene group is (C1-C6) or (C1-C3) alkylene. In other embodiments there are provided straight-chain saturated alkano groups, e.g., methano, ethano, propano, butano, and the like.
[0152] “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.b, ═N—OR.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.
[0153] 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, 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.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, R.sup.b and R.sup.c are as previously defined.
[0154] 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, —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)(.sub.ORb)(OR.sup.b), —C(O)R.sup.b, —C(S)R.sup.b, —nC(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.
[0155] Substituent groups from the above lists useful for substituting other specified groups or atoms will be apparent to those of skill in the art.
[0156] 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.
[0157] 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-O—CH.sub.2—CH.sub.2—NH.sub.2, e.g., PEG-OCH.sub.2—CH.sub.2—NH.sub.2 (as a common form of amine terminated PA). PA-O—CH.sub.2—CH.sub.2—CH.sub.2—NH.sub.2, e.g., PEG—O—CH.sub.2—CH.sub.2—CH.sub.2—NH.sub.2 is also available as well as PA-O—CH.sub.2—CH(CH.sub.3)—O).sub.xx—CH.sub.2—CH(CH.sub.3)—NH.sub.2, where xx is 0 to about 3, e.g., PEG-O—(CH.sub.2—CH(CH.sub.3)—O).sub.xx—CH.sub.2—CH(CH.sub.3)—NH.sub.2 and a PA with an acid end-group typically has a structure of PA-O—CH.sub.2—COOH, e.g., PEG-O—CH.sub.2—COOH or PA-O—CH.sub.2—CH.sub.2—COOH, e.g., PEG-O—CH.sub.2—CH.sub.2—COOH. 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.
[0158] 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.
[0159] 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.
[0160] 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.
[0161] 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.
[0162] 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 DHPD (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.
[0163] 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.
[0164] 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.
[0165] Linkers further include compounds comprising the formula Y.sub.4—R.sub.17—C(═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.
[0166] A linking group refers to the reaction product of the terminal end moieties of the PA and DHPD (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 DHPD. In other words, a direct bond is formed between the PA and DHPD portion of the molecule and no linker is present.
[0167] 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 DHPD. This can be referred to as “linkage”.
[0168] The denotation “DHPD” refers to a multihydroxy phenyl derivative, such as a dihydroxy phenyl derivative, for example, a 3, 4 dihydroxy phenyl moiety. Suitable DHPD derivatives include the formula:
##STR00030##
wherein Q is an OH;
“z” is 2 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;
[0169] 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.1 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.
In one aspect, z is 3.
In particular, “z” is 2 and the hydroxyls are located at the 3 and 4 positions of the phenyl ring.
In one embodiment, each X.sub.1, X.sub.2, Y.sub.1 and Y.sub.2 are hydrogen atoms, aa is 1, bb is 1 and Z is either COOH or NH.sub.2.
[0170] In another embodiment, X.sub.1 and Y.sub.2 are both hydrogen atoms, X.sub.2 is a hydrogen atom, aa is 1, bb is 1, Y.sub.2 is NH.sub.2 and Z is COOH.
In still another embodiment, X.sub.1 and Y.sub.2 are both hydrogen atoms, aa is 1, bb is 0, and Z is COOH or NH.sub.2.
[0171] In still another embodiment, aa is 0, bb is 0 and Z is COOH or NH.sub.2.
[0172] In still yet another embodiment, z is 3, aa is 0, bb is 0 and Z is COOH or NH.sub.2.
[0173] It should be understood that where aa is 0 or bb is 0, then X.sub.1 and Y.sub.1 or X.sub.2 and Y.sub.2, respectively, are not present.
[0174] It should be understood, that upon condensation of the DHPD molecule with the PA that a molecule of water, for example, is generated such that a bond is formed as described above (amide, ether, ester, urea, carbonate or urethane).
[0175] In particular, DHPD molecules include 3, 4-dihydroxyphenethylamine (dopamine), 3, 4-dihydroxy phenylalanine (DOPA), 3, 4-dihydroxyhydrocinnamic acid, 3, 4-dihydroxyphenyl ethanol, 3, 4 dihydroxyphenylacetic acid, 3, 4 dihydroxyphenylamine, 3, 4-dihydroxybenzoic acid, etc.
[0176] In an embodiment, the PD may be a functionalized phenyl derivative, such as a gallate, guaiacolate or catecholate including DHPDs. Some suitable PDs include the formula:
##STR00031##
wherein Q is an OH, OR, or an NH2;
“z” is 1 to 5;
R is CH3, an alkane, an alkylene;
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;
[0177] 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.1 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.
[0178] In one aspect, z is 3.
[0179] In another aspect, “z” is 2 and the hydroxyls are located at the 3 and 4 positions of the phenyl ring.
[0180] In one embodiment, each X.sub.1, X.sub.2, Y.sub.i and Y.sub.2 are hydrogen atoms, aa is 1, bb is 1 and Z is either COOH or NH.sub.2.
[0181] In another embodiment, X.sub.1 and Y.sub.2 are both hydrogen atoms, X.sub.2 is a hydrogen atom, aa is 1, bb is 1, Y.sub.2 is NH.sub.2 and Z is COOH.
[0182] In still another embodiment, X.sub.1 and Y.sub.2 are both hydrogen atoms, aa is 1, bb is 0, and Z is COOH or NH.sub.2.
[0183] In still another embodiment, aa is 0, bb is 0 and Z is COOH or NH.sub.2.
[0184] In still yet another embodiment, z is 3, aa is 0, bb is 0 and Z is COOH or NH.sub.2. It should be understood that where aa is 0 or bb is 0, then X.sub.1 and Y.sub.1 or X.sub.2 and Y.sub.2, respectively, are not present.
[0185] It should be understood, that upon condensation of either the DHPD or FPD molecule with the PA that a molecule of water, for example, is generated such that a bond is formed as described above (amide, ether, ester, urea, carbonate or urethane).
[0186] In particular, DHPD molecules include 3, 4-dihydroxyphenethylamine (dopamine), 3, 4-dihydroxy phenylalanine (DOPA), 3, 4-dihydroxyhydrocinnamic acid, 3, 4-dihydroxyphenyl ethanol, 3, 4 dihydroxyphenylacetic acid, 3, 4 dihydroxyphenylamine, 3, 4-dihydroxybenzoic acid, etc.
Polymer Synthesis
[0187] The general structure of the multi-PD adhesive polymer is shown in
[0188] The polymer backbone can be used to control different physical properties in these multi-PD polymers. A hydrophilic and water-soluble polymer backbone such as poly(ethylene glycol) (PEG) can be used to create a water soluble PDp. Additionally, PEG has a very good biocompatability profile and has been used in many products approved for clinical applications. Hydrophobic segments can be incorporated to increase the stiffness of the polymer backbone, which can result in aggregation of these hydrophobic regions in an aqueous media as well as increasing the mechanical strength of the chemically cured PDp. Different types of chemical linkages can be used to control the stability and the rate of degradation of the polymer backbone. These linkages can vary from stable carbon-carbon, ether, urea, and amide linkages to urethane, ester and carbonate linkages that are easily hydrolysable. Finally, branched polymer backbones can be used to increase the curing rate of PDp.
[0189] Three general types of synthetic methods were used to create multi-PD adhesive polymers. In the first method (
Synthetic Method 1
PD Polymerization
[0190] In this section, a series of PDp were created by copolymerizing PD-modified acrylate or methacrylate, acrylamide, methacrylamide (DMA) with one or multiple comonomer(s) using an initiator such as 2,2′-azobis(2-methylpropionitrile) (AIBN). Polymerization was carried out without protection of the reactive PD side chain, which reduces the number of synthetic steps and allows the polymers to be prepared with a higher yield. Although phenolic compounds are known to be inhibitors and radical scavengers, the removal of atmospheric oxygen allowed us to synthesize high molecular weight PDp. Although AIBN-initiated free-radical polymerization is reported here, other polymerization techniques such as atom transfer radical polymerization (ATRP) and reversible addition-fragmentation chain transfer (RAFT) polymerization can potentially be used. However, PD side chain may be required to be protected during polymerization as the metallic catalyst used in ATRP could oxidize PD.
[0191] The PDp of various embodiment herein may be linear, random copolymers of DMA and one or more other monomers. Changes can be made to the chemical architecture to further control the physical properties of these adhesive molecules. For example, branching in the polymer backbone can be used to decrease the rate of curing and a branching point can be introduced by using a small amount (<1 mol %) of diacrylated monomers in the polymerization. A larger amount of these bifunctional monomers will result in the formation of a gel network. In addition to branching points, block copolymers can be created using living polymerization methods such as ATRP and RAFT.
Synthetic Method 2
Polymer Chain Extension
[0192] As shown in
[0193] In an embodiment, the chain extender consists of a small molecular weight (MW 500 Da) compound that contains two functional groups y that can react with functional groups x on the prepolymer, and at least one functional group Z that can react with PD. The reaction between functional groups x and y results in the formation of ester, amide, urethane, urea, or carbonate linkages between the prepolymer and the chain extender, which leads to the formation of a functionalized polymer. During the chain extension reaction, either x or y needs to be activated for the coupling to occur, which can be done during, or prior to, the reaction.
[0194] It may be beneficial for the Z group to be protected, since the functional group may react with either x or y during the polymer chain extension reaction
Synthetic Method 3
PD Modification of Functionalized Polymers
[0195] In this section, PD is grafted onto pre-made functionalized polymers (FP) that contain pendant functional groups such as —NH.sub.2, —COOH, —OH, or —SH throughout the length of the polymer (
[0196] Gelatin is a protein produced by partial hydrolysis of collagen extracted from the connective tissues of animals such as cows, pigs, and fish. Gelatin contains 10% glutamic acid, 6% aspartic acid, and 4% lysine that can react with PD through amide, ester, or urethane link formation. In an embodiment, water soluble carbodiimide may be used to couple a PD to gelatin (75 Bloom, MW≈22,000). It is contemplated that gelatins may be prepared with a PD content of as much as 8 wt %. It is anticipated that gelatin-based adhesive polymers would be water soluble at concentrations as high as 30 wt % and can undergo physical gelation like unmodified gelatin.
Applications
[0197] It is contemplated that the PDps according to various embodiments described herein may function as 1) tissue adhesives and sealants, 2) adhesive coatings, and 3) antifouling coatings. As a tissue adhesive or sealant , PD in PDp can be used to achieve both cohesive crosslinking and curing of the adhesive as well as interfacial adhesive interaction with both biological and inorganic surface substrates. To function as an adhesive coating, PDp with an elevated PD content may be utilized so that after a portion of the PD was used to attach to the support substrate, there are still unbound PD for binding to a second substrate. For an antifouling adhesive , a relatively low quantity of PD is desired as the majority of an antifouling PDp by weight needs to be constructed of polymers that prevent non-specific adhesion. Depending on the desired applications, PDp were created with different PD contents, physical properties, and chemical compositions.
Tissue Adhesive and Sealant
[0198] To be used as a tissue adhesive or sealant, PDp needs to satisfy a set of stringent criteria. First and most importantly, it should have an adequate safety profile, (i.e., low toxicity, non-immunogenic, non-mutagenic, non-irritating, and non-antigenic) and the bioadhesive should be able to retain its adhesiveness after rigorous sterilization. In the liquid state, the adhesive should have sufficient flow characteristics so that it can be easily applied to the entire wound surface and should be able to displace water from the boundary layer to maximize interfacial interactions. The adhesive must be able to transform from the liquid state into the solid state under mild physiological conditions, and this transition should be rapid to minimize surgery time and to reduce the possibility of infection. After curing, the bioadhesive needs to maintain strong adhesion to different types of tissue in a moist environment while possessing suitable bulk mechanical properties to withstand the different stresses present during functional use. Unlike sutures and other commonly used wound closure materials, adhesives can act as a barrier for tissue growth at the union of the wound edges. Thus, the adhesive must be able to degrade at a rate that approximates the rate of cell growth for satisfactory wound healing, and the degradation products must be nontoxic and capable of being easily reabsorbed or excreted from the body.
[0199] Various PDps beneficially undergo a rapid transition from a free flowing liquid to a viscoelastic hydrogel. An aqueous solution of PDp and an equal volume of NaIO.sub.4 solution (0.5 molar equivalent to DHPD) may be mixed using a dual syringe set-up. The amount of time a selected adhesive formulation takes to cure is may be tailored to be under 30 sec, or up to 7 min. Curing time is dependent on such factors as PD content, PDp chemical architecture, and molecular weight. Cohesive crosslinking of DHPDs results in the curing of PDp, thus an elevated PD content is necessary for a fast curing time. Additionally, the rate of curing is also strongly dependent on the chemical structure of the PDp. The brush-like chemical structure of may obstruct pB-bound DMA from making crosslinks efficiently. By providing a short oligomeric linker between PD and a methacrylate group, which allows the PD to be more exposed for crosslink formation rather than buried in a brush of PEG polymers, a shorter cure time would be predicted, on the range of less than 2 minutes.
[0200] The various adhesive formulations may function as surgical sealants, such as being used to seal an opening around 3 mm diameter, on a wetted collagen substrate under pressure. ASTM standard F2392 may be followed to determine the burst strength of PDps. Since this experiment tests the ability of a given PDp to bind to a biological substrate in an aqueous environment under stress, the cured adhesives require a good balance of water-resistant adhesive properties as well as bulk mechanical properties. The burst strength of various PDp formulations may range from 5 to 230 mmHg/mm. Various factors, such as adhesive wt %, the polymer backbone chemical structure, and the crosslinking pathway of the PD will have an affect on the burst strength of the adhesive. It is anticipated that the burst strength will increase when the concentration of the polymer was increased, such as from 15 to 30 wt %. This increase may provide improved cohesive properties and crosslinking density in the cured adhesive.
[0201] One important criterion for any wound closure material is the ability to biodegrade with time as the wound heals. This is especially important for tissue adhesives and sealants, as a non-degradable material may act as a barrier to the union of wound edges. In vitro degradation analysis of PDp may be performed by submerging the cured adhesives in PBS (pH 7.4) at 37° C. The rate of degradation would likely be dependent on the hydrophilicity of the polymer backbone (pB), since it dictates the rate and the amount of water uptake by the polymer backbone. Thus, various factors such as the synthesis method, the polymer backbone composition, and the prepolymer molecular weight can be used to tailor adhesives with different rates and potentially different modes of degradation.
Adhesive Coatings
[0202] Adhesive-coated tapes, labels, and protective films of all kinds are ubiquitous in everyday life. In the medical field, these adhesive products are used in first-aid bandages, wound dressings, bioelectrodes, transdermal drug delivery patches, and for adhering medical devices to the skin. Good water resistance is needed for these adhesive coatings, both to water applied from outside (i.e. shower), and to water from under the tape or dressing (i.e. perspiration, blood, or wound exudate). Apart from being able to adhere quickly to a biological substrate (i.e., skin), these adhesives also must remain attached to the backing material (i.e., tape or wound dressing backing) so that the adhesive does not transfer onto the skin. Therefore the adhesive should not be water soluble. Although various hydrophobic medical-grade adhesives are available as coatings or films, these lose their ability to adhere to skin when its surface is moistened. Newer generations of adhesives are based on hydrophilic, amphiphilic, or hydrogel-based adhesives, and some of them have demonstrated some level of resistance to moisture. However, the performance of these new adhesives is significantly weakened by high levels of water adsorption or in the presence of water (i.e., showering). Thus a true water-resistant adhesive that can remain adhered to skin during prolonged periods of strenuous exercise and under humid conditions is needed.
Antifouling Coatings
[0203] Unlike the adhesive coatings in the previous section, where the adhesive is designed to adhere to two separate surfaces, polymers for antifouling coating applications are designed to adhere to one surface while preventing other materials from adhering to this surface. For medical devices and implants, preventing proteins, cells, bacteria and other unwanted materials from attaching to the surface of a material is essential in maintaining the desired functionality, longevity, and safety of these devices. Proteins that non-specifically adsorb to material surfaces from extracellular fluids can trigger adverse biological responses, and may interfere with medical device function, as is the case with contact and intraocular lenses, blood-contacting devices, and medical implants and surgical tools. Furthermore, the surfaces of implants, tissue engineering scaffolds, and biosensors functionalized with bioactive ligands (e.g., peptides, proteins and oligonucleotides) benefit from a bioinert background that will not interfere with the desired biological response. Thus, for many biomaterial systems there are tangible benefits to reducing, or eliminating entirely, non-specific interactions between the biomaterial and the fluid or extracellular matrix with which it is in contact.
[0204] The general design of an antifouling polymer is illustrated in
[0205] For an effective antifouling application, the polymer requires a relatively small amount of adhesive PD compared to adhesive coatings, while having a large percentage by weight of the polymer with antifouling properties.
[0206] Advancing water contact angle analysis is a rapid and convenient means of determining if a coating was successfully applied. Advancing contact angles of various hydrophilic PDp-coated surfaces decreased from that of uncoated polyurethane sheets (approximately 110 degrees) down to approximately 58 degrees for the S-099 polymer, signifying that the antifouling coatings were successfully applied to the Polyurethane sheets.
Antimicrobial Antifouling Coatings
[0207] In certain embodiments, antifouling polymers of the present invention comprise antimicrobial properties and compositions. In some embodiments, antifouling polymers of the present invention comprise 3 monomers (monomers a, b, and c as depicted in
[0208] For polymers prepared under standard free radical conditions, the molecular weight is commonly controlled by the stoichiometry of initiators (e.g. AIBN: Azobisisobutyronitrile, tertiary butylperoctoate, etc.) or through common alkylthiol-containing chain transfer agents (e.g. dodecylmercaptan).
[0209] For polymers prepared by controlled free radical processes such as Atom Transfer Radical polymerization (ATRP), Reversible Addition-Fragmentation Chain Transfer (RAFT), Nitroxide-Mediated Radical Polymerization (NMRP), and Cobalt Catalytic Chain Transfer (CCCT), molecular weight and polydispersity is determined by radical equilibria that is controlled by transition metals, thioesters and carbonates, nitroxides, and cobalt complexes respectively..sup.1
[0210] In some embodiments, a surface of a device, for example a polyurethane (PU) surface, is activated with, for example, ammonia (NH.sub.3) plasma gas surface treatment. (
[0211] Among the benefits provided by the embodiments described herein is the improved coating performance provided by binding the PDp embodiments depicted in
EXAMPLES
Example 1
General Route for the Synthesis of Surphys S-093-S-107
[0212] Monomer compositions in mole percent monomers a, b, and c of S-093-S-107 antimicrobial antifouling polymers of the present invention are provided in Table 1 (
[0213] For clarity, examples of synthesis for specific molecules and monomers will be presented below.
Example 2
Synthesis of Dopamine Methacrylate (DMA)
[0214] 20 g (238.1 mmol) of sodium bicarbonate and 50.1 g (131.1 mmol) of sodium tetraborate was added to a 1000 mL round bottom flask. 500 mL of nanopure water was added to the round bottom flask which was purged with nitrogen while heating at 50° C. Heating and stirring allowed for the complete dissolution of sodium bicarbonate and sodium tetraborate. The mixture was removed from the heat source and 25 g (131.8 mmol) of dopamine hydrochloride was added and stirred until dissolved. 100 mL of 1N sodium hydroxide was added to the reaction mixture. 23.5 mL (221.4 mmol) of methacrylic anhydride was dissolved in 125 mL of anhydrous THF and added dropwise to the solution over a period of 15 minutes. The reaction was stirred for 21 hours under argon. Once complete, 105 mL of THF was rotary evaporated off. The remaining solution was poured into 1 L of nanopure water. 50 mL of concentrated HCl was added to adjust the pH to ˜0.5. Four extractions with a total of 2 L of ethyl acetate was performed. 1300 mL of ethyl acetate was rotary evaporated off. The remaining solution was added to 1 L of diethyl ether and placed at −15° C. for 45 minutes. The precipitate was suction filtered off and placed under vacuum for 18 hours.
[0215] The material was added to 500 mL of nanopure water and stirred for 90 minutes. The insoluble material was suction filtered and placed under vacuum for 2 hours. The material was dissolved in 400 mL of ethyl acetate and 75 mL of methanol through heating. The mixture was allowed to cool to room temperature and 500 mL of diethyl ether was added to the solution which was placed at −15° C. for 90 minutes. The insoluble material was suction filtered off and the remaining solution was poured into 900 mL of heptanes and 300 mL of diethyl ether. The mixture was placed at −15° C. for 2 hours. The precipitate was suction filtered off and washed with diethyl ether. The material was placed under vacuum overnight. 13.83 g of pure material was obtained.
.sup.1H NMR (400 MHz, DMSO/TMS): δ8.73; (s, 1H, —C.sub.6H.sub.3—(OH).sub.2), 8.62; (s, 1H, —C.sub.6H.sub.3—(OH).sub.2), 7.92; (s, 1H, —CH.sub.2—C(CH.sub.3)—CONH—CH.sub.2—), 6.61; (d, 1H, —C.sub.6H.sub.3—(OH).sub.2), 6.56; (s, 1H, —C.sub.6H.sub.3—(OH).sub.2), 6.41; (d, 1H, —C.sub.6H.sub.3—(OH).sub.2), 5.60; (s, 1H, CH.sub.2═C(CH.sub.3)—CONH—), 5.28; (s, 1H, CH.sub.2═C(CH.sub.3)—CONH—), 3.22; (m, 2H, —CH.sub.2—CH.sub.2—NHCO—), 2.54; (m, 2H, —CH.sub.2—CH.sub.2—NHCO—), 1.83; (s, 3H, CH.sub.2═C(CH.sub.3)—CONH—).
Example 3
Synthesis of DMAEMAC.SUB.12
[0216] 75 mL (309.8 mmol) of 1-Bromododecane was added to a 1 L round bottom flask. 210 mL of acetonitrile and 110 mL of chloroform was added to the flask which was purged with argon for 10 minutes. 46 mL (272.4 mmol) of 2-(dimethylamino)ethyl methacrylate was added to the reaction. The reaction was placed at 40-45° C. with argon purging for 20 hours. ˜½ of the solvent was rotary evaporated off. The solution was poured into 1.7 L of diethyl ether and placed at −15° C. for 90 minutes. The precipitate was suction filtered off, washed with MTBE and placed under vacuum overnight. The precipitate was dissolved in 200 mL of chloroform and poured into 1.7 L of diethyl ether. The solution was placed at −15° C. for 3 hours. The precipitate was suction filtered and placed under vacuum until dry. 72.92 g of pure material was obtained.
.sup.1H NMR (400 MHz, DMSO/TMS): δ6.06; (s, 1H, CH.sub.2═C(CH.sub.3)—COO—), 5.75; (s, 1H, CH.sub.2═C(CH.sub.3)—COO—), 4.50; (t, 2H, —COO—CH.sub.2—CH.sub.2—N.sup.+(CH.sub.3).sub.2—CH.sub.2—), 3.69; (t, 2H, —COO—CH.sub.2—CH.sub.2—N.sup.+(CH.sub.3).sub.2—CH.sub.2—), 3.35; (t, 2H, —COO—CH.sub.2—CH.sub.2—N.sup.+(CH.sub.3).sub.2—CH.sub.2—), 3.08; (s, 6H, —COO—CH.sub.2—CH.sub.2—N.sup.+(CH.sub.3).sub.2—CH.sub.2—), 1.89; (t, 3H, CH.sub.2═C(CH.sub.3)—COO—), 1.66; (m, 2H, —COO—CH.sub.2—CH.sub.2—N.sup.+(CH.sub.3).sub.2—CH.sub.2—CH.sub.2—), 1.24; (m, 2H, —COO—CH.sub.2—CH.sub.2—N.sup.+(CH.sub.3).sub.2—CH.sub.2—CH.sub.2—(CH.sub.2).sub.8—), 0.84; (t, 3H, —COO—CH.sub.2—CH.sub.2—N.sup.+(CH.sub.3).sub.2—CH.sub.2—CH.sub.2—(CH.sub.2).sub.8—CH.sub.3).
Example 4
Synthesis of DMAPMAC.SUB.12
[0217] 75 mL (309.8 mmol) of 1-Bromododecane was added to a 1 L round bottom flask. 210 mL of acetonitrile and 110 mL of chloroform was added to the flask which was purged with argon for 10 minutes. 50 mL (276.1 mmol) of N-[3-(Dimethylamino)propyl]methacrylamide was added to the reaction. The reaction was placed at 40-45° C. with argon purging for 20 hours. ˜½ of the solvent was rotary evaporated off. The solution was poured into 1.8 L of diethyl ether and placed at −15° C. for 4 hours. The precipitate was decanted off and placed under vacuum overnight. The precipitate was dissolved in 100 mL of chloroform and poured into 3.8 L of diethyl ether. The solution was placed at −15° C. for 6 hours. The precipitate was suction filtered and placed under vacuum until dry. 78.61 g of pure material was obtained.
.sup.1H NMR (400 MHz, DMSO/TMS): δ8.08; (s, 1H, CH.sub.2═C(CH.sub.3)—CONH—), 5.68; (s, 1H, CH.sub.2═C(CH.sub.3)—CONH—), 5.33; (s, 1H, CH.sub.2═C(CH.sub.3)—CONH—), 3.25; (m, 4H, —CONH—CH.sub.2—CH.sub.2—CH.sub.2—N.sup.+(CH.sub.3).sub.2—CH.sub.2—), 3.16; (m, 2H, —CONH—CH.sub.2—CH.sub.2—CH.sub.2—N.sup.+(CH.sub.3).sub.2—CH.sub.2—), 2.99; (s, 6H, —CONH—CH.sub.2—CH.sub.2—CH.sub.2—N.sup.+(CH.sub.3).sub.2—CH.sub.2—), 1.85; (s, 5H, CH.sub.2═C(CH.sub.3)—CONH—CH.sub.2—CH.sub.2—CH.sub.2—N.sup.+(CH.sub.3).sub.2—CH.sub.2—CH.sub.2—), 1.60; (s, 2H, CH.sub.2═C(CH.sub.3)—CONH—CH.sub.2—CH.sub.2—CH.sub.2—N.sup.+(CH.sub.3).sub.2—), 1.23; (m, 18H, —N.sup.+(CH.sub.3).sub.2—CH.sub.2—CH.sub.2—(CH.sub.2).sub.9—CH.sub.3), 0.85; (m, 3H, —N.sup.+(CH.sub.3).sub.2—CH.sub.2—CH.sub.2—(CH.sub.2).sub.9—CH.sub.3).
Example 5
Synthesis of VAMA
[0218] 14.44 g (172 mmol) of sodium bicarbonate and 50.1 g (94.7 mmol) of sodium tetraborate was added to a 1000 mL round bottom flask. 360 mL of nanopure water was added to the round bottom flask which was purged with nitrogen while heating at 50° C. Heating and stirring allowed for the complete dissolution of sodium bicarbonate and sodium tetraborate. The mixture was removed from the heat source and 18.04 g (95.1 mmol) of vanillylamine hydrochloride was added and stirred until dissolved. 100 mL of 1N sodium hydroxide was added to the reaction mixture. 17 mL (160.2 mmol) of methacrylic anhydride was dissolved in 90 mL of THF and added to the solution. The reaction was stirred for 21 hours under argon. 31 mL of concentrated HCl was added to adjust the pH to ˜2. The reaction was stirred for ˜6 hours. Three extractions with a total of 900 mL of ethyl acetate were performed followed by gravity filtration. 600 mL of ethyl acetate was rotary evaporated off. The remaining solution was added to 3.6 L of MTBE and placed at −15° C. for 24 hours. The precipitate was suction filtered off and placed under vacuum until dry. 9.69 g of pure material was obtained.
.sup.1H NMR (400 MHz, DMSO/TMS): δ8.8; (s, 1H, —C.sub.6H.sub.3—(OH)), 8.34; (s, 1H, —CH.sub.2—C(CH.sub.3)—CONH—CH.sub.2—), 6.82; (s, 1H, —C.sub.6H.sub.3—), 6.68; (d, 1H, —C.sub.6H.sub.3—), 6.63; (d, 1H, —C.sub.6H.sub.3—), 5.67; (s, 1H, CH.sub.2═C(CH.sub.3)—CONH—), 5.33; (s, 1H, CH.sub.2═C(CH.sub.3)—CONH—), 4.20; (d, 2H, —CH.sub.2—NHCO—), 3.72; (s, 3H, —C.sub.6H.sub.3—(OCH.sub.3)), 1.86; (s, 3H, CH.sub.2═C(CH.sub.3)—CONH—).
Example 6
Synthesis of 3,5-DM-4-HPEAMA
[0219] 0.545 g (6.49 mmol) of sodium bicarbonate and 1.39 g (3.57 mmol) of sodium tetraborate was added to a round bottom flask. 15 mL of nanopure water was added to the round bottom flask which was purged with nitrogen while heating at 50° C. Heating and stirring allowed for the complete dissolution of sodium bicarbonate and sodium tetraborate. The mixture was removed from the heat source and 800 mg (3.42 mmol) of 3,5-dimethoxy-4-hydroxyphenethylamine hydrochloride was added and stirred until dissolved. 0.3 mL of 10N sodium hydroxide was added to the reaction mixture. 0.800 mL (5.37 mmol) of methacrylic anhydride was dissolved in 3.25 mL of THF and added to the solution. The reaction was stirred for 16 hours under argon. 1.5 mL of concentrated HCl was added to adjust the pH to ˜0. The reaction was stirred for ˜2 hours. The insoluble material was suction filtered. Two extractions with a total of 100 mL of ethyl acetate were performed. The insoluble material was dissolved into the ethyl acetate extract and washed 3 times with a total of 150 mL of nanopure water. The ethyl acetate fraction was rotary evaporated off. The resulting material was dissolved in 100 mL of acetone, followed by rotary evaporation of the acetone. The material was placed under vacuum to dry for 4 hours. The material was dissolved in 25 mL of methanol and poured into 900 mL of nanopure water. The material was placed at −15° C. for ˜2 hours. No precipitate was observed so the solution was frozen and placed on the freeze drier. The material was dissolved in 20 mL of ethyl acetate with slight heating and placed in the freezer for 1 hour. The resulting precipitate was placed under vacuum until dry. 151 mg of pure material was obtained.
.sup.1H NMR (400 MHz, DMSO/TMS): δ8.07; (s, 1H, —C.sub.6H.sub.2—(OH)), 7.93; (s, 1H, —CH.sub.2—C(CH.sub.3)—CONH—CH.sub.2—), 6.42; (s, 2H, —C.sub.6H.sub.2—), 5.60; (s, 1H, CH.sub.2═C(CH.sub.3)—CONH—), 5.29; (s, 1H, CH.sub.2═C(CH.sub.3)—CONH—), 3.71; (s, 6H, —C.sub.6H.sub.3—(OCH.sub.3).sub.2), 3.27; (m, 2H, —CH.sub.2—CH.sub.2—NH—CO—), 2.64; (t, 2H, —CH.sub.2—CH.sub.2—NH—CO—), 1.86; (s, 3H, CH.sub.2═C(CH.sub.3)—CONH—).
Example 7
Synthesis of Surphys-095
[0220] Ethylene glycol methyl ether acrylate was passed through Aluminum Oxide to remove any inhibitor present. 19.441 g (59.5 mmol) of DMAEMAC.sub.12, 2.667 g (12.05 mmol) of DMA, 2.605 mL (20.25 mmol) of ethylene glycol methyl ether acrylate (MEA), and 137.6 mg (0.84 mmol) of AIBN were dissolved in 160 mL of DMF. Argon was bubbled through the reaction for 20 minutes. The reaction was then placed at 60-65° C. for 5 hours. The reaction was poured into 1.8 L of diethyl ether and placed at −15° C. for 18 hours. The precipitate was suction filtered off and placed under vacuum for 24 hours. The polymer was then dissolved into 150 mL of methanol and poured into 1.8 L of diethyl ether. This was placed at −15° C. for 18 hours. The precipitate was suction filtered and dried under vacuum for 3 days. The polymer was dissolved in 150 mL of methanol and poured into 1.8 L of diethyl ether and placed at −15° C. for 1 hour. The precipitate was suction filtered and placed under vacuum for 3 days. The polymer was dissolved in 150 mL of methanol and poured into 1.8 L of diethyl ether and placed at −15° C. for 2 hours. The precipitate was suction filtered and placed under vacuum for 5 days. 17.84 g of material was obtained. NMR confirmed <2% monomer was present.
.sup.1H NMR (400 MHz, DMSO/TMS): δ8.66; (s, 2H, —C.sub.6H.sub.3—(OH).sub.2), 8.25-7.25; (s, 1H, —CONH—CH.sub.2—), 6.61; (s, 2H, —C.sub.6H.sub.3—), 6.38; (s, 1H, —C.sub.6H.sub.3—), 5.0-2.75; (multiple broad peaks), 1.70; (s, 2H, —N.sup.+(CH.sub.3).sub.2—CH.sub.2—CH.sub.2—CH.sub.2—), 1.5-0 (multiple broad peaks); Dopamine content based on UV-VIS(DMSO@285 nm): 11.03+/−0.19 Wt %, 0.496+/−0.008 umol DOPA/mg polymer.
Example 8
Synthesis of Surphys-102
[0221] 2-Hydroxyethyl methacrylate (HEMA) was passed through Aluminum Oxide to remove any inhibitor present. 13.085 g (40.0 mmol) of DMAEMAC.sub.12, 1.792g (8.1 mmol) of DMA, 1.635 mL (13.48 mmol) of HEMA, and 94.7 mg (0.58 mmol) of AIBN were dissolved in 110 mL of DMF. Argon was bubbled through the reaction for 20 minutes. The reaction was then placed at 60-65° C. for 5 hours. The reaction was poured into 1.8 L of MTBE and placed at −15° C. for 1 hour. The precipitate was suction filtered off and placed under vacuum overnight. The polymer was then dissolved into 100 mL of methanol and poured into 1.8 L of MTBE. This was placed at −15° C. for 2 hours. The precipitate was suction filtered and dried under vacuum for 2 hours. The polymer was dissolved in 100 mL of methanol and poured into 1.8 L of diethyl ether and placed at −15° C. for 2 hours. The precipitate was suction filtered and placed under vacuum overnight. The polymer was dissolved in 150 mL of methanol and poured into 2.8 L of diethyl ether and placed at −15° C. for 2 hours. The precipitate was suction filtered and placed under vacuum for 4 days. 11.86 g of material was obtained. NMR confirmed <2% monomer was present.
.sup.1H NMR (400 MHz, DMSO/TMS): δ8.67; (s, 1H, —C.sub.6H.sub.3—(OH).sub.2), 8.63; (s, 1H, —C.sub.6H.sub.3—(OH).sub.2), 8.25-7.25; (s, 1H, —CONH—CH.sub.2—), 6.61; (s, 2H, —C.sub.6H.sub.3—), 6.39; (s, 1H, —C.sub.6H.sub.3—), 5.0-2.75; (multiple broad peaks), 1.69; (s, 2H, —N.sup.+(CH.sub.3).sub.2—CH.sub.2—CH.sub.2—CH.sub.2—), 1.5-0 (multiple broad peaks). Dopamine content based on UV-VIS(DMSO@285 nm): 10.02+/−0.06 Wt %, 0.451+/−0.003 umol DOPA/mg polymer.
Example 9
Synthesis of Surphys-103
[0222] 15.16g (44.6 mmol) of DMAPMAC.sub.12, 2.005 g (9.06 mmol) of DMA, 1.542 mL (15 mmol) of N-Hydroxyethyl acrylamide (HEA), and 108.8mg (0.66 mmol) of AIBN were dissolved in 120 mL of DMF. Argon was bubbled through the reaction for 20 minutes. The reaction was then placed at 60-65° C. for 5 hours. The reaction was poured into 2.4 L of diethyl ether and placed at −15° C. for 15 hours. The precipitate was suction filtered off and placed under vacuum for 4 hours. The polymer was then dissolved into 75 mL of methanol and poured into 1.9 L of diethyl ether. This was placed at −15° C. for 1 hour. The precipitate was suction filtered and dried under vacuum overnight. The polymer was dissolved in 75 mL of methanol and poured into 1.9 L of diethyl ether and placed at −15° C. for 90 minutes. The precipitate was suction filtered and placed under vacuum for 5 days. The polymer was dissolved in 75 mL of methanol and poured into 900 mL of diethyl ether and placed at −15° C. for 1 hour. The precipitate was suction filtered and placed under vacuum overnight. 12.71 g of material was obtained. NMR confirmed <2% monomer was present.
.sup.1H NMR (400 MHz, DMSO/TMS): δ8.73; (s, 1H, —C.sub.6H.sub.3—(OH).sub.2), 8.66; (s, 1H, —C.sub.6H.sub.3—(OH).sub.2), 8.25-7.25; (s, 3H, —CONH-CH.sub.2—), 6.61; (s, 2H, —C.sub.6H.sub.3—), 6.38; (s, 1H, —C.sub.6H.sub.3—), 5.0-2.75; (multiple broad peaks), 1.67; (s, 2H, —N.sup.+(CH.sub.3).sub.2—CH.sub.2—CH.sub.2—CH.sub.2—), 1.5-0 (multiple broad peaks). Dopamine content based on UV-VIS(DMSO@285 nm): 9.78+/−0.05 Wt %, 0.44+/−0.002 umol DOPA/mg polymer.
Example 10
Synthesis of Surphys-104
[0223] 20.249 (59.6 mmol) of DMAPMAC.sub.12, 2.663g (12.04 mmol) of DMA, 2.605 mL (20.25 mmol) of ethylene glycol methyl ether acrylate (MEA), and 133 mg (0.81 mmol) of AIBN were dissolved in 160 mL of DMF. Argon was bubbled through the reaction for 20 minutes. The reaction was then placed at 60-65° C. for 5 hours. The reaction was poured into 1.8 L of diethyl ether and placed at −15° C. for 90 minutes. The precipitate was suction filtered off and placed under vacuum for 3 days. The polymer was then dissolved into 150 mL of methanol and poured into 1.8 L of diethyl ether. This was placed at −15° C. for 1 hour. The precipitate was suction filtered and dried under vacuum for 11 days. The polymer was dissolved in 150 mL of methanol and poured into 1.8 L of diethyl ether and placed at −15° C. for 90 minutes. The precipitate was suction filtered and placed under vacuum for 2 days. 18.1 g of material was obtained. NMR confirmed <2% monomer was present.
.sup.1H NMR (400 MHz, DMSO/TMS): δ8.70; (s, 1H, —C.sub.6H.sub.3—(OH).sub.2), 8.63; (s, 1H, —C.sub.6H.sub.3—(OH).sub.2), 8.25-7.25; (s, 2H, —CONH—CH.sub.2—), 6.59; (s, 2H, —C.sub.6H.sub.3—), 6.36; (s, 1H, —C.sub.6H.sub.3—), 5.0-2.75; (multiple broad peaks), 1.64; (s, 2H, —N.sup.+(CH.sub.3).sub.2—CH.sub.2—CH.sub.2—CH.sub.2—), 1.5-0 (multiple broad peaks).
Example 11
Synthesis of Surphys-106
[0224] 9.85 (28.98 mmol) of DMAPMAC.sub.12, 1.30 g (5.88 mmol) of VAMA, 2.605 mL (9.87 mmol) of ethylene glycol methyl ether acrylate (MEA), and 73.5 mg (0.45 mmol) of AIBN were dissolved in 78 mL of DMF. Argon was bubbled through the reaction for 20 minutes. The reaction was then placed at 60-65° C. for 5 hours. The reaction was poured into 900 mL of diethyl ether and placed at −15° C. for 60 minutes. The precipitate was suction filtered off and placed under vacuum overnight. The polymer was then dissolved into 75 mL of methanol and poured into 900 mL of diethyl ether. This was placed at −15° C. for 30 minutes. The precipitate was suction filtered and dried under vacuum for 3 hours. The polymer was dissolved in 75 mL of methanol and poured into 900 mL of diethyl ether and placed at −15° C. for 1 hour. The precipitate was suction filtered and placed under vacuum for 5 days. 7.45 g of material was obtained. NMR confirmed <2% monomer was present.
.sup.1H NMR (400 MHz, DMSO/TMS): δ8.76; (s, 1H, —C.sub.6H.sub.3—(OH)), 8.25-7.25; (s, 2H, —CONH—CH.sub.2—), 6.7; (m, 1H, —C.sub.6H.sub.3—), 6.64; (s, 2H, —C.sub.6H.sub.3—), 5.0-2.75; (multiple broad peaks), 1.67; (s, 2H, —N.sup.+(CH.sub.3).sub.2—CH.sub.2—CH.sub.2—CH.sub.2—), 1.5-0 (multiple broad peaks).
Example 12
Synthesis of Surphys-107
[0225] 0.998 g (2.94 mmol) of DMAPMAC.sub.12, 150 mg (0.54 mmol) of 3,5-DM-4-HPEAMA, 0.128 mL (1 mmol) of ethylene glycol methyl ether acrylate (MEA), and 11 mg (0.07 mmol) of AIBN were dissolved in 8 mL of DMF. Argon was bubbled through the reaction for 20 minutes. The reaction was then placed at 60-65° C. for 5 hours. The reaction was poured into 300 mL of diethyl ether and placed at −15° C. for 30 minutes. The precipitate was suction filtered off and placed under vacuum overnight. The polymer was then dissolved into 23 mL of methanol and poured into 350 mL of diethyl ether. This was placed at −15° C. for 90 minutes. The precipitate was suction filtered and dried under vacuum for 18 hours. The polymer was dissolved in 25 mL of methanol and poured into 350 mL of diethyl ether and placed at −15° C. for 1 hour. The precipitate was suction filtered and placed under vacuum overnight. 500 mg of material was obtained. NMR confirmed <2% monomer was present. .sup.1H NMR (400 MHz, DMSO/TMS): δ8.10; (s, 1H, —C.sub.6H.sub.2—(OH)), 8.0-7.25; (s, 2H, —CONH—CH.sub.2—), 6.41; (m, 2H, —C.sub.6H.sub.2—), 5.0-2.75; (multiple broad peaks), 1.68; (s, 2H, —N.sup.+(CH.sub.3).sub.2—CH.sub.2—CH.sub.2—CH.sub.2—), 1.5-0; (multiple broad peaks).
Example 13
PEG Based Monomers which may be Used in this Application
[0226]
TABLE-US-00001 Monomer Structure Ethylene glycol methyl ether acrylate
Example 14
Neutral Hydrophilic Monomers which may be Used in this Application
[0227]
TABLE-US-00002 Monomer Structure Acrylamide
Example 15
Anionic or Acidic Monomers which may be Used in this Application
[0228]
TABLE-US-00003 Monomer Structure 2-Acrylamido-2-methyl- 1-propanesulfonic acid
Example 16
Cationic or Basic Monomers which may be Used in this Application
[0229]
TABLE-US-00004 Monomer Structure (3-acrylamido- propyl)trimethyl- ammonium
Example17
Hydrophobic Monomers which may be Used in this Application
[0230]
TABLE-US-00005 Monomer Structure 2,2,2-Trifluoroethyl methacrylate
Example 18
PD Monomers which may be Used in this Application
[0231]
TABLE-US-00006 Monomer Structure Vanillylamine methacrylamide
Example 19
Catheter Activation and Coating
[0232] While the procedure focuses on ammonia gas plasma treatment, it is recognized that in lieu of treatment with ammonia plasma, alternative surface treatments may be utilized for adding functional groups to the surface as may be known to those skilled in the art (e.g. gas cluster ion beam, accelerated neutral atom beam, and common wet chemical treatments).
[0233] Prior to plasma treatment, polyurethane samples were cleaned via sequential 10-min sonication in 5% Contrad 70 (Decon Labs Inc., King of Prussia, Pa.) and ultrapure water, and then dried at 55° C. for 4 h. Cleaned samples were placed in a Harrick Plasma Cleaner equipped with a PlasmaFlo gas flow rate controller (Harrick Plasma, Ithaca, N.Y.), then the chamber was pumped down below 100 mTorr and flushed with anhydrous ammonia gas three times.
[0234] A polyurethane catheters were treated with ammonia plasma (Ammonia Gas) for 3 minutes at a pressure of 600 mTorr at a power setting of 29.6 W. A 20 mL solution of S-095 in chloroform (Coating A: 2 mg S-095/mL CHCl.sub.3) (low dose), Coating B: 10 mg S-095/mL CHCl.sub.3) (high dose)) was prepared and poured into a dip tube. Plasma treated catheters were slowly dipped into the dip tube and polymer solution, and held for 1 minute. The catheters were removed from the solution and gently shaken to remove excess solution. The catheters were dried for 4 hours in a fume hood. Separately, a 50 mL crosslinking solution of silver nitrate (AgNO.sub.3) in 18 MOhm deionized water at a concentration of a 0.25 mg/mL was prepared. The catheters were placed in a test tube and filled with the silver nitrate crosslinking solution such that the catheters were fully submerged. The solutions were held for 20 hours, removed from the crosslinking solution, rinsed with three portions of 18 MOhm deionized water, and dried at 55° C. for 4 hours. The catheters were packaged and sterilized prior to implantation.
Example 20
Reduced In Vitro Uropathogen Attachment Assay
[0235]
Example 21
Reduced In Vivo Urinary Infection
[0236]
[0237] While this invention has been described in conjunction with the various exemplary embodiments outlined above, various alternatives, modifications, variations, improvements and/or substantial equivalents, whether known, or that are or may be presently unforeseen, may become apparent to those having at least ordinary skill in the art. Accordingly, the exemplary embodiments according to this invention, as set forth above, are intended to be illustrative not limiting, various changes may be made without departing from the spirit and scope of the invention. Therefore, the invention is intended to embrace all known or later-developed alternatives, modifications, variations, improvements and/or substantial equivalents of these exemplary embodiments.
TABLE-US-00007 TABLE 2 Abbreviations Abbreviation Chemical Description DMA Dopamine methacrylamide VAMA Vanillylamine methacyrlamide DMHPEAMA 3,5-dimethoxy-4-hydroxyphenethylamine methacyrlamide AA Acrylic Acid HEMA Hydroxyethyl methacrylate HEA N-Hydroxyethyl acrylamide MEA Ethylene glycol methyl ester acrylate DMAEMAC.sub.12 2-(dodecyl-dimethylamino)ethyl methacrylate DMAPMAmC.sub.12 3-(dodecyl-dimethylamino)propyl methacrylamide