JP2009541532A - Lactam polymer derivatives - Google Patents

Abstract

A cross-linked lactam polymer is disclosed.
A lactam polymer having pendant acrylate groups is crosslinked by a Michael addition acrylate reactant. Cross-linked lactam polymers are useful for medical and drug applications. Further disclosed is a process for preparing hydroxyl functional lactam polymer derivatives.
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Description

Disclosure details

(Field of the Invention)
The present invention relates to lactam polymer derivatives, such as hydroxyl functional lactam polymers and their derivatives, and crosslinked lactam polymers. More particularly, the present invention relates to crosslinked polymers derived from lactam polymers functionalized with pendant acrylate groups, and methods for making and using the crosslinked polymers. The invention further relates to a process for the production of hydroxyl functional lactam polymer derivatives.

BACKGROUND OF THE INVENTION
Degradable crosslinked polymer networks are used in many biotechnology applications and medicines such as drug delivery, tissue engineering, implantable devices and in-situ gelling materials. Important in application. The presence of degradable linkages eliminates the need for long-term biocompatibility of the implanted polymer or the surgical retrieval of the implanted polymer. Degradable networks are advantageous in tissue engineering, which requires a temporary scaffold for structural support, cell attachment and growth.

  Poly (N-vinyl-2-pyrrolidone), also known as polyvinylpyrrolidone, PVP, Povidone or Plasdone, can be used, for example, aerosol hair sprays, adhesives, lithographic printing solutions, pigment dispersions It is a water-soluble lactam polymer that is used commercially in products such as the body, drug formulations, cleansing formulations and cosmetic formulations. General classification systems for lactam polymers, including PVP, are described, for example, in Robinson, B. et al. V. “PVP: A Critical Review of the Kinetics and Toxicology of Polyvinylpyrrolidone (Povidone) (1990)” (1990); US Pat. No. 3,153,640 No. 2,927,913, US Pat. No. 3,532,679; and British Patent No. 811,135. PVP has been widely used in pharmaceuticals since 1939. PVP was first used in medicine during World War II, when a 3.5% solution of PVP was infused into patients as a synthetic plasma expander. The toxicity of PVP has been extensively studied in various species, including humans and other primates, but is very low. PVP has also found use as an internal wetting agent when wearing contact lenses.

  The preparation of functional lactam polymers having pendant acrylate groups is described in US 20060069235 ("'235"). The '235 publication generally describes first treating a lactam polymer with a reducing agent to form a lactam polymer functionalized with hydroxyl groups. The hydroxyl functional lactam polymer was then further functionalized with a hydroxyl reactive compound containing an acrylate group to form an acrylate functional lactam polymer. More specifically, the lactam polymer was dissolved in a protic solvent using a reducing agent and then heated between 40 ° C. and 90 ° C. for 2 days or less. After purification by precipitation, the resulting hydroxyl functional lactam polymer was then further functionalized with a hydroxyl reactive compound containing an acrylate group such as, for example, acryloyl chloride. In the case of acryloyl chloride, the acrylate functional lactam polymer was prepared by acryloylation of the hydroxyl groups on the hydroxyl functional lactam polymer in an inert organic solvent containing an acid scavenger. . The hydrochloride salt was removed by filtration and the polymer was recovered by removing the solvent by rotary evaporation. Finally, the acrylate functional lactam polymer was purified by precipitation.

  The '235 publication also describes the preparation of cross-linked polymer hydrogels from acrylate functional lactam polymers. The cross-linking reaction was achieved by free radical polymerization. The free radical polymerization was initiated by using a thermal polymerization initiator and heat, or by using a photoinitiator and ultraviolet or visible light. According to the reaction kinetics of free radical polymerization, usually high molecular weight polymer chains are formed as a result. High molecular weight polymers may be useful for some applications such as contact lenses, for example, but high molecular weight polymer chains produced by free radical polymerization are not beneficial for some biomedical applications It may be. The resulting polymer cannot be easily eliminated from the body due to its large hydrodynamic volume. For example, free radical polymerization of acrylate functional lactam polymers results in a crosslinked network containing polyacrylate segments covalently bonded to the modified lactam polymer. The crosslinked network, when hydrolyzed, provides a lactam polymer with a known molecular weight range (same molecular weight as that of the starting lactam polymer). However, polyacrylic acid of various molecular weights including high molecular weight is conceivable. The molecular weight of these chains is hardly controlled without the addition of additional complication of chain transfer agents. Furthermore, in a photopolymerizable polymer, the maximum cure depth that can be reached is limited to several millimeters due to light attenuation by the polymerization initiator. Thus, photopolymerizable polymers cannot be applied to biomedical applications where the polymer or device requires a thickness of only a few millimeters.

  For example, in some biomedical applications, such as implantable biodegradable medical devices or in situ polymerizable medical devices, free-radical chemistry is used to crosslink functional lactam polymers. It would be desirable to crosslink lactam polymers using alternative chemistries in view of deficiencies in doing so.

  Not only consider long-term use of PVP (polyvinylpyrrolidone) in biomedical applications, but also have reactive moieties along the polymer backbone that can react to form new polymers with the desired properties An improved method for producing hydroxyl functional polyvinyl pyrrolidone in which the hydroxyl moieties are randomly distributed throughout the polyvinyl pyrrolidone backbone, also taking into account the advantages associated with PVP derivatives (eg, hydroxyl functional polyvinyl pyrrolidone) It would be beneficial to have

[Summary of the Invention]
The present invention is a cross-linked lactam polymer. The crosslinked lactam polymer comprises a reaction product of a) a lactam polymer functionalized with pendant acrylate groups and b) a Michael addition acrylate reactant.

  The crosslinked lactam polymers of the present invention are particularly useful for medical and drug applications. For example, the polymers can be used for tissue augmentation, bioactive agent delivery, hard tissue repair, hemostasis, adhesion prevention, tissue engineering applications, medical device coatings, adhesives, sealants, and the like.

  The present invention is also directed to a method of synthesizing derivatives of hydroxyl functional lactam polymers or copolymers as described in the claims.

Detailed Description of the Invention
Those skilled in the art will be able to utilize the invention to its fullest extent based on the description herein. The specific embodiments described below are merely exemplary and should not be construed as limiting the remaining disclosure in any way.

  Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In addition, all publications, patent application specifications, patent specifications, and other references mentioned herein are incorporated by reference in their entirety. Unless otherwise specified, all percentages used herein are by weight. Furthermore, all ranges described herein are meant to include any combination of numerical values between the two endpoints, including those numerical values.

In one embodiment, lactam polymers functionalized with pendant acrylate groups can be prepared according to the method described in the '235 publication. These functional lactam polymers contain repeating units derived from substituted and unsubstituted lactam monomers in the polymer backbone. A proportion of these lactam repeat units are initially converted to secondary or tertiary hydroxyalkylamines and then converted to acrylates. The acrylate is randomly distributed throughout the polymer backbone. Suitable lactam monomers include, but are not limited to, substituted and unsubstituted 4-7 membered lactam rings. Suitable substituents include, but are not limited to, C _1-3 alkyl groups and aryl groups. Examples of suitable lactam monomers include N-vinyl lactams such as N-vinyl-2-pyrrolidinone, N-vinyl-2-piperidone, N-vinyl-ε-caprolactam, N-vinyl-3-methyl-2 -Pyrrolidone, N-vinyl-3-methyl-2-piperidone, N-vinyl-3-methyl-2-caprolactam, N-vinyl-4-methyl-2-pyrrolidone, N-vinyl-4-methyl-2-caprolactam N-vinyl-5-methyl-2-pyrrolidone, N-vinyl-5-methyl-2-piperidone, N-vinyl-5,5-dimethyl-2-pyrrolidone, N-vinyl-3,3,5-trimethyl -2-pyrrolidone, N-vinyl-5-methyl-5-ethyl-2-pyrrolidone, N-vinyl-3,4,5-trimethyl-3-ethyl-2-pyrrolidone, N-vinyl-6-methyl Lu-2-piperidone, N-vinyl-6-ethyl-2-piperidone, N-vinyl-3,5-dimethyl-2-piperidone, N-vinyl-4,4-dimethyl-2-piperidone, N-vinyl- 7-methyl-2-caprolactam, N-vinyl-7-ethyl-2-caprolactam, N-vinyl-3,5-dimethyl-2-caprolactam, N-vinyl-4,6-dimethyl-2-caprolactam, N- Vinyl-3,5,7-trimethyl-2-caprolactam, N-vinylmaleimide, N-vinylsuccinimide, and mixtures thereof and the like are included.

  In one embodiment, the lactam monomer is a substituted and unsubstituted 4-6 membered lactam ring. Suitable lactam monomers include N-vinyl-2-pyrrolidinone, N-vinyl-2-piperidone, N-vinyl-ε-caprolactam, N-vinylsuccinimide, N-vinyl-3-methyl-2-pyrrolidone, and N -Vinyl-4-methyl-2-pyrrolidone. In one embodiment, the lactam monomer is an unsubstituted 4-6 membered lactam ring. In another embodiment, the lactam monomer is a repeating unit derived from N-vinyl-2-pyrrolidinone, N-vinyl-2-piperidone, N-vinyl-ε-caprolactam, and N-vinylsuccinimide. In yet another embodiment, the lactam monomer is derived from N-vinyl-2-pyrrolidinone.

  The lactam polymer may contain a repeating unit derived from a non-lactam monomer in addition to the lactam monomer. Suitable non-lactam monomers are methyl methacrylate, methacrylic acid, styrene, butadiene, acrylonitrile, 2-hydroxyethyl methacrylate, acrylic acid, methyl acrylate, methyl methacrylate, vinyl acetate, N, N-dimethylacrylamide, N- Including, but not limited to, isopropylacrylamide, poly (ethylene glycol) monomethacrylate, combinations thereof, and the like. In one embodiment, the non-lactam monomer is methacrylic acid, acrylic acid, acetonitrile, and combinations thereof. In one embodiment, the functional lactam polymer used to prepare the crosslinked lactam polymer has at least about 10% lactam repeat units, ie, at least about 30% lactam repeat units, or Contains at least about 50% lactam repeat units. As used herein, “functionalized lactam polymer” shall mean lactam polymers having functional groups such as, for example, hydroxyl groups or acrylates.

  In another embodiment, a hydroxyl functional lactam polymer can be produced by first dissolving a lactam polymer in an effective amount of polyol in the presence of an effective amount of a metal catalyst. The polyol also acts as a solvent. As used herein, an “effective amount” of polyol is at least the amount of polyol required to substantially dissolve the lactam polymer, and is about 10 weight based on the total weight of all components in the reaction mixture. % To about 99% by weight, ie, for example, in the range of between about 40% to about 90% by weight. The metal catalyst can be added to the lactam polymer before, after, or simultaneously with the addition of the metal catalyst to the lactam polymer.

  Suitable polyols are 1,3-propanediol, 1,4-butanediol, 1,5-pentanediol, 1,6-hexanediol, 1,8-octanediol, 1,12-dodecanediol, ethylene glycol, Diethylene glycol, triethylene glycol, tetraethylene glycol, pentaethylene glycol, hexaethylene glycol, heptaethylene glycol, and poly (ethylene glycol), glycerin, erythritol, pentaerythritol, ethoxylated pentaerythritol, dipentaerythritol, xylitol, ribitol, sorbitol , Trimethylolpropane, 1,2,6-hexanetriol, 1,2,4-butanetriol, and combinations thereof. In one embodiment, the polyol is ethylene glycol, glycerin, or a mixture thereof.

  As used herein, an “effective amount” of a metal catalyst is at least the amount of metal catalyst required to promote the reaction between the lactam and the polyol to the desired rate, Based on the ratio of moles of polymer to moles of catalyst, [from about 100 to about 10,000 moles of lactam polymer]: [about 1 mole of catalyst], for example, [about 1000 to about 5000 moles of lactam polymer] : [About 1 mol of catalyst].

  Suitable metal catalysts include tin catalysts, aluminum catalysts such as aluminum isopropoxide, calcium catalysts such as calcium acetylacetonate, manganese catalysts such as manganese chloride, lanthanide catalysts such as yttrium isopropoxide, antimony trioxide or antimony trihalide Antimony catalysts such as (antimony trihalides), zinc catalysts such as zinc lactate, and tin catalysts such as tin alkanoate, tin alkoxide, tin oxide, tin halides and tin carbonates, and Including, but not limited to, mixtures thereof. Suitable tin catalysts include stannous octoate [tin (II) 2-ethyl-hexanonate], dibutyltin oxide, tin (II) chloride, and the like And mixtures thereof, but are not limited thereto. In one embodiment, the tin catalyst is stannous octylate.

  Thus, the reaction may be performed at any temperature at which the selected solvent is in a liquid state. Suitable temperatures include temperatures between about 20 ° C. and about 150 ° C., ie, for example, temperatures between about 40 ° C. and about 110 ° C. The pressure is not critical and ambient pressure can be used. One skilled in the art will readily recognize that the reaction time will vary depending on, for example, the type and amount of catalyst selected, the type and amount of polyol selected, and the temperature selected. However, suitable reaction times can include up to about 5 days, i.e., for example, from about 1 to 2 days.

  In one embodiment, the resulting hydroxyl functional lactam polymer product is in an amount of about 1 mol% to about 99 mol%, based on the total molar content of lactam groups in the lactam polymer, i.e. For example, it has hydroxyl groups along its polymer backbone in an amount of about 1 mol% to about 20 mol%. For example, a hydroxyl functional lactam polymer having a number average molecular weight of 100,000 and containing about 5 mol% hydroxyl groups is an average of 900 monomeric lactam repeat units per average unit. About 45 hydroxyl groups.

  The resulting hydroxyl functional lactam polymer can then be further reacted with a hydroxyl reactive compound containing at least one acrylate group to form an acrylate functional lactam polymer. Details of the conditions for this reaction are disclosed in, for example, the '235 publication. For example, Example 6 of the '235 publication describes acryloylating hydroxyl groups on hydroxyl functional lactam polymers. Further, Example 7 of the '235 publication describes reacting hydroxyl groups on a hydroxyl functional lactam polymer with 2-isocyanatoethyl methacrylate to form an acrylate functional lactam polymer. .

In one embodiment, the acrylate functional lactam polymer has a number average molecular weight of at least about 1.66 × 10 ⁻²¹ g (about 1000 Daltons). In another embodiment, the number average molecular weight of the acrylate functional lactam polymer is greater than about 3.32 × 10 ⁻²¹ g (about 2000 Daltons). In yet another embodiment, the acrylate functional lactam polymer has a number average molecular weight of about 3.32 × 10 ⁻²¹ g (about 2000 Daltons) to about 4.98 × 10 ⁻¹⁹ g (about 300000 Daltons), That is, for example, between about 3.32 × 10 ⁻²¹ g (about 2000 Daltons) and about 1.66 × 10 ⁻¹⁹ g (about 100,000 Daltons), or about 3.32 × 10 ⁻²¹ g (about 2000 Daltons). ) To about 6.64 × 10 ⁻²⁰ g (about 40,000 daltons).

  In one embodiment, the acrylate functional lactam polymer can be crosslinked by reaction with a Michael addition acrylate reactant. Michael addition acrylate reactants may be difunctional or multifunctional and are described in Lutolf, M .; P. Et al: 12 (6) J. A. Bioconjugate Chem., Page 1051 (2001), US Pat. No. 6,958,212, and Smith, M. et al. B. March, J.A. : "March's Advanced Organic Chemistry Reactions, Mechanisms, and Structure", pages 1022 to 1024 (5th edition, 2001). For example, Lutolf, M.M. P. : Hubbell, J.H. A. , 4 (3) Biomacromolecules, 713 (2003), Rutorf, M. et al. P. Et al .: 12 (6) Bioconjugate Chem., Page 1051 (2001), Vernon, B. et al. 64A J Biomed Mater Res Part A page 447 (2003) [Chemicals by Michael addition of polyfunctional thiol-containing compounds with end-functional polymers containing unsaturated groups (eg, polyethylene glycol diacrylate)] See also the preparation of chemically cross-linkable degradable hydrogels].

In one embodiment, the Michael addition acrylate reactant is an acrylate reactive thiol. Suitable acrylate-reactive thiols include proteins containing cysteine residues, albumin, glutathione, 3,6-dioxa-1,8-octanedithiol [TCI America, Portland, Oreg.], Oligo (oxyethylene) Dithiol, pentaerythritol poly (ethylene glycol) ether tetra-sulfhydryl, sorbitol poly (ethylene glycol) ether hexa-sulfhydryl [preferred molecular weight is in the range of about 5,000 to 20,000, SunBio Inc. Inc.), California Olinda (Orinda)], dimercaptosuccinic acid [Epokemi Company Limited (Epochem Co. Ltd.), Shanghai, China], dihydrolipoic acid _{[HOOC- (CH 2) 4 -CH} (SH) - CH ₂ -CH ₂ H, Jeronoba Research Incorporated Ray Incorporated (Gernova Research Inc.), Nevada Reno (Reno)], dithiothreitol _{(dithiothreitol) [HS-CH 2} -CH (OH) -CH (OH) -CH 2 SH Sigma Aldrich Co. (Milwaukee, Wis.)], Trimethylolpropane tris (3-mercaptopropionate) (Sigma Aldrich Company, Wisconsin) Milwaukee State), pentaerythritol tetrathioglycolate, pentaerythritol tetra (3-mercaptopropionate), dipentaerythritol hexakis (thioglycolate) taerythritol hexakis (thioglycolate) (DPHTG) [Austin Chemicals, Buffalo Grove, Ill.], and ethoxylated pentaerythritol (PP150) tetrakis (3-mercaptopropionate) (PP150) ) tetrakis (3-mercapto propionate)) [Austin Chemicals, Buffalo Grove, Illinois], and mixtures thereof. In one embodiment, the acrylate reactive thiol is pentaerythritol tetrathioglycolate, pentaerythritol tetra (3-mercaptopropionate), dipentaerythritol hexakis (thioglycolate) (DPHTG) (Austin Chemicals, Illinois). Buffalo Grove), and ethoxylated pentaerythritol (PP150) tetrakis (3-mercaptopropionate) (Austin Chemicals, Buffalo Grove, Ill.). The most preferred acrylate reactive thiol is ethoxylated pentaerythritol (PP150) tetrakis (3-mercaptopropionate) (Austin Chemicals, Buffalo Grove, Ill.).

  Alternative Michael addition acrylate reactants are also suitable, such as amines, enamines, nitriles, imidazoles and derivatives thereof, acetoacetates, ketones, enolates, dithiocarbamate anions, nitroalkanes, and Those skilled in the art will recognize that, including, but not limited to, mixtures thereof.

  The cross-linked acrylate functional lactam polymers of the present invention can be used in a Michael addition acrylate reaction in a basic aqueous medium at a temperature between about room temperature and about 60 ° C., for example, between about 25 ° C. and about 40 ° C. Can be prepared by dispersing the acrylate functional lactam polymer in the presence of the product. The pH of the basic aqueous medium is greater than about 7, i.e., for example, in the range of about 7.5 to about 11, i.e., in the range of about 8 to about 10.5, or about 8.5 to about 10.5. Should be a range. The pH of the base is provided by adding an organic or inorganic base and / or by including an amount of buffer system that provides the desired range of pH. Other chemical synthesis modifiers (eg, catalysts, activators, polymerization initiators, temperature, or other stimuli) can be utilized to achieve reactivity. Various biocompatible solvents may be incorporated, if necessary, in an amount 0.2 to 100 (weight) times the co-reactants. These biocompatible solvents are dimethyl sulfoxide, N-methyl-2-pyrrolidone, glycerin, triacetin, propylene glycol, water, TWEEN (polysorbate) [ICI Americas Inc., New Jersey Including but not limited to State Bridgewater, poly (ethylene glycol), and combinations thereof

  In one embodiment, the reaction conditions of the crosslinked polymer are such that the acrylate functional lactam polymer is Michael at a temperature of about 25 ° C. to about 40 ° C. in an aqueous basic medium having a pH of about 8.5 to about 10. It is a condition to be mixed with the addition type acrylate reactant.

  The use of molar equivalents of the above reactants may be desirable and may be essential in some cases. In some cases, excess molar reactants can be added to compensate for side reactions such as those resulting from hydrolysis of the ester moiety.

  It is also appropriate to prepare the crosslinked polymers of the present invention in an organic solvent, especially if the reactants are solid, not readily soluble in water, and not water dispersible. Aqueous solutions, organic solvents, poly (ethylene glycol), or aqueous organic mixtures can also be added to improve the reaction rate or to adjust the viscosity of a given formulation.

  In another embodiment, the hydroxyl functional lactam polymer can be further reacted with an effective amount of a hydroxyl reactive compound or polymerizing agent under conditions sufficient to form a hydroxyl polymer derivative. Such hydroxyl polymer derivatives are useful, for example, as bioadhesive materials or sealants for biomedical applications. As used herein, “an effective amount of a hydroxyl-reactive compound or polymerizing agent” shall mean at least an amount corresponding to the moles of hydroxyl groups in the hydroxyl-functional lactam polymer, The excess may be up to about 10 times.

  In one embodiment, the hydroxyl-reactive compound contains at least one additional reactive moiety. This type of hydroxyl-reactive compound is useful when it is desirable to result in hydroxyl polymer derivative crosslinks when exposed to water, biological tissue or other reactive compounds. is there. Suitable hydroxyl reactive compounds are selected from the group consisting of carbamate, acyl chloride, sulfonyl chloride, isothiocyanate, cyanoacrylate, oxirane, imine, thiocarbonate, thiol, aldehyde, aziridine, azide, and mixtures thereof. Additional reactive moieties may be included.

  Examples of suitable hydroxyl reactive compounds include, but are not limited to, acrylol chloride, 2-isocyanatoethyl methacrylate, epichlorohydrin, maleic anhydride, glutamic acid, mercaptopropionic acid, and mixtures thereof. It is not limited.

  In one embodiment, the hydroxyl functional lactam polymer is dissolved in an effective amount of an anhydrous solvent to prevent side reactions of the reactive moieties prior to adding the hydroxyl reactive compound or polymerizer to the polymer. be able to. As used herein, “an effective amount of anhydrous solvent” is intended to mean at least the amount necessary to substantially dissolve the hydroxyl functional lactam polymer, and to the weight of the hydroxyl functional lactam polymer. Based on, it may be in an amount of about 10% to about 99% by weight, ie, for example, an amount between about 40% to about 90% by weight. Examples of suitable anhydrous solvents are 1,4-dioxane, N, N-dimethylacetamide (DMAC), N, N-dimethylformamide (DMF), methyl sulfoxide (DMSO), N-methylpyrrolidone (NMP), and Including, but not limited to, mixtures thereof.

  For example, a hydroxyl functional lactam polymer is dissolved in an effective amount of anhydrous 1,4-dioxane followed by 2,2,3,3,4,4,5,5-octafluorohexamethylene-1,6- It can react with 2 equivalents of diisocyanates such as diisocyanates to form hydroxyl polymer derivatives with pendant isocyanate groups. Hydroxyl polymer derivatives having pendant isocyanate groups are then crosslinked network when contacted with water, biological tissue, or other reactive compounds (eg, amines, thiols, hydroxyl group-containing compounds, and the like). ) Will form.

  Suitable hydroxyl-reactive compounds having reactive moieties include diisocyanates such as 2,2,3,3,4,4,5,5-octafluorohexamethylene-1,6-diisocyanate, hexamethylene diisocyanate (HMDI). ) 2,2,3,4,4-hexafluoropentamethylene-1,5-diisocyanate, tolylene-2,4-diisocyanate (TDI), isophorone diisocyanate (IPDI), p-phenylene diisocyanate, lysine diisocyanate ( LDI), lysine triisocyanate (LTI), and combinations thereof, and the like.

  In another embodiment, the hydroxyl functional lactam polymer can be further reacted with an effective amount of a polymerizing agent comprising at least one polymerizable group under sufficient conditions to form a hydroxyl polymer derivative. . As used herein, “polymerizable groups” shall mean any moiety capable of undergoing anionic, cationic or free radical polymerization.

Suitable free radical polymerizable groups include acrylate, styryl, vinyl, vinyl ether, C _1-6 alkyl acrylate, acrylamide, C _1-6 alkyl acrylamide, N-vinyl lactam, N-vinyl amide, C _2-12 alkenyl, C _{2-12 alkenylphenyl, C 2-12} alkenyl _{naphthyl, C 2 to 6} alkenyl phenyl _{C 1 to 6} alkyl, or encompass a copolymer thereof or a mixture, but not limited to.

  Suitable polymerizing agents containing at least one cation reactive group include, but are not limited to, vinyl ethers, 1,1-dialkyl olefins, epoxide groups, mixtures thereof, and the like.

  Suitable polymerizing agents containing at least one anion reactive group include, but are not limited to, acrylate, methacrylate, styryl, epoxide groups, mixtures thereof, and the like.

  In one embodiment, the polymerizing agent is selected from the group consisting of methacrylates, acrylates, methacrylamides, acrylamides, and copolymers and mixtures thereof.

  In one embodiment, the polymerization agent may be a photopolymerization agent. The photopolymerization agent is acryloyl chloride, methacryloyl chloride, methacrylic anhydride, methacrylic acid, acrylic acid, 3-isopropenyl-α, α-dimethylbenzyl isocyanate, 2-isocyanatoethyl methacrylate, or a copolymer thereof. Including but not limited to mixtures.

  In one embodiment, the hydroxyl-functional lactam polymer is a polymeric prodrug that can be further reacted with an effective amount of a hydroxyl-reactive bioactive agent under sufficient conditions to be used as an implantable device ( polymeric prodrugs). The bioactive substance can be released from the polymer prodrug when the hydroxyl polymer derivative-bioactive substance binding site is hydrolytically cleaved. In one embodiment, the polymeric prodrug contains a bioactive substance that is covalently bonded to the hydroxyl polymer derivative via a spacer group, and further connects the spacer group to the bioactive substance. The bioactive substance is released from the macromolecular prodrug when the bond or the bond linking the hydroxyl polymer derivative to the bioactive substance, or both, are hydrolyzed. It is possible. As described above, when the bioactive substance is covalently bound, the bioactive substance can be controlled and released by hydrolysis under physiological conditions.

  Suitable hydroxyl-reactive bioactive substances include any bioactive substance that can be linked to, dispersed in, or coated on a hydroxyl polymer derivative. Are also included. Thus, any bioactive substance that can react with hydroxyl groups on the hydroxyl polymer derivative to form a covalent bond without undergoing substantial degradation or side reactions can be used. Examples of suitable hydroxyl-reactive bioactive substances are those of the following drug classes: angiotensin converting enzyme inhibitors, antianginal drugs, antiarrhythmic drugs, antiasthma drugs, anti-cholesterolemics, anticholesterolics Anticonvulsants, antidepressants, anti-diarrheal preparations, antihistamines, antihypertensives, anti-infectives, anti-inflammatory agents, anti-lipid agents, antiepileptics, antiemetics, anti-stroke agents, antithyroid agents Antitumor drugs, antitussive drugs, antiuric acid drugs, antiviral drugs, acne drugs, alkaloids, amino acid preparations, anabolic agents, analgesics, anesthetics, angiogenesis inhibitors, antacids, antiarthritis drugs, antibiotics Anticoagulant, antiemetic, antiobesity, antiparasitic, antipsychotic, antipyretic, antispasmodic, antithrombotic, anxiolytic, appetite stimulant, appetite suppressant, beta-blocker, bronchodilator, heart Vascular agonist, cerebral dilator, chelating agent, cholecyst Kinin antagonists, chemotherapeutic drugs, cognition activators, contraceptives, coronary dilators, antitussives, decongestants, deodorizers, skin drugs, diabetes drugs, diuretics, emollients, enzymes, red blood cells Generating agents, expectorants, pregnancy promoters, bactericides, gastrointestinal drugs, growth regulators, hormone supplements, antihyperglycemic agents, hypnotics, hypoglycemic agents, laxatives, migraine treatments, mineral supplements, mucolysis Drugs, narcotics, neuroleptics, neuromuscular drugs, non-steroidal anti-inflammatory drugs, nutritional additives, peripheral vasodilators, prostaglandins, psychotropic drugs, renin inhibitors , Respiratory stimulants, steroids, stimulants, sympathetic blockers, thyroid preparations, tranquilizers, uterine relaxants, vaginal preparations, vasoconstrictors, vasodilators, dizziness drugs (v ertigo agents), vitamins, and wound healing agents.

  Suitable reaction conditions include using an effective amount of a solvent that is co-miscible with the hydroxyl-functional lactam polymer and the hydroxyl-reactive bioactive agent. As used herein, an “effective amount” of such a solvent shall mean at least the amount in which the hydroxyl polymer and bioactive agent are dissolved, and is about 10 based on the total weight of all components in the reaction mixture. It may range from wt% to about 99 wt%, i.e., for example, between about 40 wt% and about 90 wt%. Examples of such suitable solvents are water, N, N-dimethylacetamide (DMAC), N, N-dimethylformamide (DMF), 1,4-dioxane, methyl sulfoxide (DMSO), N-methylpyrrolidone ( NMP), combinations thereof, and the like, but not limited to.

  The reaction is a temperature that effectively accelerates the reaction rate without significantly modifying the biological activity of the drug, for example, the type and amount of the selected hydroxyl-reactive bioactive substance, selection Those skilled in the art will appreciate that they should proceed at temperatures typically ranging from about 0 ° C. to about 100 ° C., although they may be affected by the type and amount of the hydroxyl polymer derivative produced and the like. Would be easily recognized. The electrophilic addition reaction or nucleophilic substitution reaction between the lactam-OH hydroxyl group and the physiologically active substance results in the formation of a polymeric prodrug.

  Crosslinked polymers produced by the present invention are formed in various physical forms [eg, liquids, waxes, solids, semisolids, gels such as hydrogels, elastic solids, viscoelastic solids (such as gelatin), gel microparticles Or viscoelastic liquids that are considerably more viscous than any of the reactants when mixed together. The term “gel” refers to the state of matter between a liquid and a solid. Thus, a “gel” is a part of the properties of a liquid (ie, the shape is elastic and deformable) and the properties of a solid (ie, the shape is three-dimensional on a two-dimensional surface. Part of which is sufficiently discrete to hold. Preferred physical forms are elastic solids or viscoelastic solids.

  These crosslinked polymers can be used in a variety of different drug and medical applications. In general, the polymers described herein may be configured for use in any medical or drug application in which the polymer is currently used. For example, the polymers of the invention can be used in tissue augmentation (ie, fillers in soft tissue repair), in hard tissue repair (eg, bone replacement materials), as tissue sealants and tissue adhesive materials, in preventing tissue adhesion (adhesion prevention). It is useful as a hemostatic agent in the provision of surface modifications, in tissue engineering applications, intraocular lenses, contact lenses, medical device coatings, and in drug / cell / gene delivery applications. One skilled in the art having the benefit of this disclosure will be able to determine the appropriate administration of the polymer composition of this invention.

  In one embodiment, the reactions of the present invention occur in-situ, that is, they occur at a local site, such as on a living animal or human organ or tissue. Means. In another embodiment, the reactions do not release heat of polymerization that raises the local temperature to a temperature above 60 ° C. In yet another embodiment, any reaction that causes gelation occurs within 30 minutes, yet in another embodiment, within 15 minutes, and in yet another embodiment, within 5 minutes. . Such polymers of the present invention form gels that have sufficient adhesive and cohesive strength to be securely fixed in place. It should be understood that for some applications, adhesive strength, bond strength and gelation are not prerequisites.

  With respect to the reactions of the present invention that occur in situ, the reactants utilized in the present invention are typically delivered to the administration site such that the reactants first contact the administration site or just prior to each other. Thus, in one embodiment, the reactants of the present invention are delivered to the site of administration using a device that allows the components to be delivered separately. Such delivery systems typically have individual compartments for holding the reactants separately, for example, with a single or multihead device carrying pastes, sprays, liquids or solids. I have. The reactants of the present invention can be administered using, for example, a syringe and needle, or various devices. The reactants are devices containing the reactants, the outlet for the reactants, a discharger for releasing the reactants, and for administering the reactants into an animal or human. It is also envisioned that the device can be provided in the form of a kit having a device having a hollow tubular member that fits snugly into the outlet.

  Alternatively, the reactants can be conveyed separately using any kind of controllable extrusion system, or the reactants can be in the form of separate pastes, liquids or dry powders, It can be transported manually and then mixed together manually at the administration site. Many devices configured to carry multi-component compositions are well known in the art and can also be used to practice the present invention.

  Alternatively, the reactants of the present invention can be prepared in an inert form as a liquid or powder. Such reactants are then supplied in premixed form and then activated by using an activator after use at the administration site or just prior to use at the administration site. Is possible. In one embodiment, the activator is a buffer solution that activates the formation of the crosslinked polymer once mixed with the activator.

  In another embodiment, for applications where the crosslinked polymer obtained from the reactants of the present invention need not be transported to a site and is formed in situ, the crosslinked polymer is pre-prepared. It can take the form of various liquids or solids depending on the application of interest as previously described herein.

  Optional materials can be added to one or more of the reactants to be incorporated into the resulting crosslinked polymer of the present invention, or can be administered separately. Optional materials include, but are not limited to, visualizing agents such as colorants, diluents, odorants, carriers, excipients, stabilizers, formulation enhancers, or the like. Not.

  The reactants (and thus the crosslinked polymer of the present invention) can further contain a visualization agent to improve their visibility during the surgical procedure. Visualizing agents are various colored substances or dyes suitable for use in implantable medical devices, such as, for example, Food Drug & Cosmetic (FD & C) dye numbers 3 and 6, eosin, methylene blue , Indocyanine green, or dyes commonly found in synthetic surgical sutures. In one embodiment, the visualization agent is green, blue or violet. The visualization agent may or may not be incorporated into the polymer. In one embodiment, the visualization agent does not have a functional group that can react with the reactants of the present invention.

  For example, fluorescent compounds [e.g. fluorescein, eosin, green or yellow fluorescent dye under visible light], X-ray contrast agents (e.g. iodine compounds) for obtaining visibility under X-ray imaging devices, ultra Additional visualization agents such as sonic contrast agents or magnetic resonance imaging (MRI) contrast agents (eg, gadolinium-containing compounds) can be used.

  The visualization agent can be used in small amounts, in one embodiment less than 1% (weight / volume), in another embodiment less than 0.01% (weight / volume) and yet another implementation. In form, it can be used at less than 0.001% (weight / volume).

  The following examples serve to further illustrate the present invention and should not be construed to limit the scope of the invention. The scope of the invention is limited by the claims. In these examples, the amounts are by weight unless otherwise specified.

Example Example 1
Synthesis of hydroxyl functional polyvinyl pyrrolidone (PVP-OH) 143 g (1.29 mol) of polyvinyl pyrrolidone [K25, molecular weight = about 30,000, Fluka, Milwaukee, Wis.] Was added to a mechanical stirrer. Dissolved in 888 g of triethylene glycol (Aldrich, Milwaukee, Wis.) In a 4 liter beaker equipped. To the PVP solution, 48.7 g (1.29 mol) of sodium borohydride [VenPure AF granules, 98 +%, Aldrich, Milwaukee, Wis.] Was added over 1 hour at room temperature. Substantial bubbling was observed. The reaction was heated to 110 ° C. and stirred for 5 hours. To the hot reaction mixture, 500 mL of distilled water was added. The polymer is dialyzed against distilled water for 5 days using a 1000 molecular weight cut-off dialysis membrane (cellulose, Spectum Laboratories, Rancho Dominguez, CA), then 2 Dialyzed against 2-propanol for one day. The polymer was precipitated in hexane: isopropyl ether (50:50 volume / volume) to yield a white solid having a number average molecular weight of 8,000 and a weight average molecular weight of 24,500 [gel permeation chromatograph, hexafluoro Use isopropanol (HFIP) and poly (2-vinylpyridine) standards]. Hydroxyl number (OH #) was determined by titration [OH # = 53.4 mg potassium hydroxide / g sample, hydroxyl group equivalent (EW) = 1050 g / mol].

Synthesis of Acrylate Functional Polyvinylpyrrolidone (PVP-Acrylate) 4.5 g of the PVP-OH (monomer unit = 41 mmol, OH = 4.3 mmol) was added to a 500 mL 2 equipped with nitrogen inlet, rubber septum and magnetic stir bar. Dissolve in 250 mL of anhydrous N, N-dimethylacetamide in a cervical round bottom flask. 0.39 g (4.3 mmol) of acryloyl chloride (Aldrich, Milwaukee, Wis.) And 10 mg of catechol (Aldrich, Milwaukee, Wis.) Were added to the polymer solution. 1.3 g (13 mmol) of triethylamine (Fluka, Milwaukee, Wis.) Was added and the reaction mixture was then stirred at 70 ° C. for 6 hours. The polymer solution was filtered to remove the hydrochloride and then precipitated three times with isopropyl ether to yield a solid polymer containing about 3 mol% acrylate groups. This was confirmed by ¹ H NMR spectroscopy shown in FIG. ¹ H NMR (CDCl ₃ ) δ = 6.41 to 6.29 (bm, 1H, acrylate vinyl), 6.13 to 6.01 (bm, 1H, acrylate vinyl), 5.85 to 5.66 (bm , 1H, acrylate vinyl), 4.18 to 3.44 (bm, 1H, PVP methine proton), 3.43 to 3.01 (bm, 2H, PVP), 2.49 to 1.28 (bm, 6H) , PVP).

Synthesis of First Crosslinked Polymer 451 mg of PVP-acrylate was dissolved in 3.24 g of borate buffer solution (pH = 9.0, Fluka, Milwaukee, Wis.) In a 20 mL glass scintillation vial. It was. Ethoxylated pentaerythritol (PP150) tetrakis (3-mercaptopropionate) [average molecular weight = 1201.5, FAO Austin Chemical Company Inc., Benseville, Ill.] 67 mg (55.8 μmol) was added to the reaction mixture at room temperature. The reaction mixture gelled within 1 minute to form a crosslinked hydrogel.

Synthesis of Second Crosslinked Polymer 0.71 g of PVP-acrylate was dissolved in 1.6 g of borate buffer solution (pH = 9.0, Fluka, Milwaukee, Wis.) In a 5 mL glass vial. 69 mg (57.4 micromoles) of ethoxylated pentaerythritol (PP150) tetrakis (3-mercaptopropionate) [average molecular weight = 1201.5, FAO Austin Chemical Company, Inc., Bensevire, IL] It was added to the reaction mixture at room temperature and shaken with a vortex stirrer. The reaction mixture gelled within 24 hours to form a crosslinked hydrogel.

Synthesis of Third Crosslinked Polymer 0.33 g of PVP-acrylate was dissolved in 321 mg of borate buffer solution (pH = 9.0, Fluka, Milwaukee, Wis.) In a 5 mL glass vial. Ethoxylated pentaerythritol (PP150) tetrakis (3-mercaptopropionate) (average molecular weight = 1201.5) 93 mg (77.6 μmol) was added to the reaction mixture at room temperature and shaken with a vortex stirrer. The reaction mixture gelled within 2 hours to form a crosslinked hydrogel.

Synthesis of Fourth Crosslinked Polymer 0.82 g PVP-acrylate from Example 1b was dissolved in 2.8 g borate buffer solution (pH = 9.0, Fluka, Milwaukee, Wis.) In a 5 mL glass vial. I let you. 173 mg (144 μmol) of ethoxylated pentaerythritol (PP150) tetrakis (3-mercaptopropionate) (average molecular weight = 1201.5) was added to the reaction mixture at room temperature and shaken with a vortex stirrer. The reaction mixture gelled overnight to form a crosslinked hydrogel.

Example 2
Synthesis of hydroxyl functional polyvinylpyrrolidone (PVP-OH) 100 g (0.90 mmol) of polyvinylpyrrolidone [K30, average molecular weight = about 40,000, Fluka, Milwaukee, Wis.] In a 4 liter beaker equipped with mechanical stirring In 700 mL of 2-propanol [Aldrich, Milwaukee, Wis.]. To the PVP (polyvinylpyrrolidone) solution was added 34 g (0.90 mol) of sodium borohydride [Venpure AF granules, 98 +%, Aldrich, Milwaukee, Wis.] Over 1 hour at room temperature. Substantial bubbling was observed. The reaction was heated to 50 ° C. and stirred for 16 hours. To the reaction mixture, 500 mL of distilled water was added. The polymer is dialyzed against distilled water for 7 days and dialyzed against methyl alcohol for 2 days using a 1000 molecular weight cut-off dialysis membrane (cellulose, Spectrum Laboratories, Rancho Domingas, CA). Dialyzed against 2-propanol for one day. The polymer was precipitated in isopropyl ether: acetone (50:50 vol / vol) and white solid with OH # = KOH 20.5 mg / g sample and hydroxyl group equivalent (EW) = 2,700 g / mol Produced.

Synthesis of Acrylate Functional Polyvinylpyrrolidone (PVP-Acrylate) 25.2 g of PVP-OH (monomer unit = 227 mmol, OH = 9.3 mmol) was added to a 500 mL 2 equipped with nitrogen inlet, rubber septum and magnetic stir bar. Dissolved in 308 g of anhydrous 1,4-dioxane (Aldrich, Milwaukee, Wis.) In a cervical round bottom flask. 1.67 g (18.4 mmol) acryloyl chloride and 20 mg hydroquinone (Aldrich, Milwaukee, Wis.) Were added to the polymer solution. 5.60 g (55.3 mmol) of triethylamine was added and the reaction mixture was then stirred at 70 ° C. for 6 hours. The polymer solution was filtered to remove the hydrochloride and then precipitated three times with isopropyl ether to yield a solid polymer containing about 0.2-0.3 mol% acrylate groups. This was confirmed by ¹ H NMR spectroscopy. ¹ H NMR (CDCl ₃ ) δ = 6.75 to 5.65 (bm, 3H, acrylate vinyl), 4.21 to 3.44 (bm, 1H, PVP methine proton), 3.43 to 2.80 ( bm, 2H, PVP), 2.65 to 0.60 (bm, 6H, PVP).

Synthesis of Crosslinked Polymer 2.54 g of PVP-acrylate was dissolved in 4.43 g of borate buffer solution (pH = 9.0, Fluka, Milwaukee, Wis.) In a 20 mL glass scintillation vial. Ethoxylated pentaerythritol (PP150) tetrakis (3-mercaptopropionate) (average molecular weight = 1201.5) 323 mg (269 μmol) was added to the reaction mixture at room temperature. The reaction mixture gelled within 24 hours at room temperature to form a crosslinked hydrogel.

Synthesis of Crosslinked Polymers Containing Pemirolast (Mast Cell Stabilizer) A borate buffer solution (pH = 9.0, Fluka, Wisconsin) in 2.0 mL PVP-acrylate in a 20 mL glass scintillation vial Milwaukee) 3.1 g, propylene glycol (Aldrich, Milwaukee, Wis.) 2.0 g, and N-methyl-2-pyrrolidone (Aldrich, Milwaukee, Wis.) 1.8 g. To the reaction mixture at room temperature, pemirolast (mast cell stabilizer) [Dipharma SpA, Italy, Milan] 109 mg (475 mmol), and ethoxylated pentaerythritol (PP150) tetrakis (3- Mercaptopropionate) (PP150-TMP) (average molecular weight = 1201.5) 501 mg (417 micromol) was added. The reaction mixture was shaken for 2 minutes using a vortex mixer and then poured into a 70 mm diameter aluminum dish. The membrane gelled within 30 minutes at room temperature.

In Vitro Release from Crosslinked Polymer of Pemirolast PP150-TMP was added to the reaction mixture as described above, and after 6.5 hours, a portion of the crosslinked membrane (7.58 g, thickness 2. 5 mm) was placed in 370 mL of phosphate buffer (pH = 7.4, Sigma-Aldrich, Milwaukee, Wis.). An aliquot of 2.5 mL was removed at each time point and replaced with 2.5 mL of fresh buffer. The release of pemirolast was quantified by UV / VIS spectroscopy (λ _max = 256 nm). Table 1 shows the corresponding release profile.

Synthesis of cross-linked polymer containing lidocaine 3.0 g of borate buffer solution (pH = 9.0, Fluka, Milwaukee, Wis.) In 1.44 g of PVP-acrylate in a 20 mL glass scintillation vial, Dissolved in 1.4 g glycerin (Aldrich, Milwaukee, Wis.), 0.46 g propylene glycol, and 2.1 g N-methyl-2-pyrrolidone. To the reaction mixture at room temperature, 251 mg (1.07 mmol) lidocaine (Sigma, Milwaukee, WI), and 329 mg (average molecular weight = 1201.5) ethoxylated pentaerythritol (PP150) tetrakis (3-mercaptopropionate) ( 274 micromol) was added. The reaction mixture was shaken for 2 minutes using a vortex mixer and then poured into a 70 mm diameter aluminum dish. The thick film gelled within 30 minutes at room temperature.

Release of Lidocaine from Crosslinked Polymer In vitro PP150-TMP was added to the reaction mixture described above 3.1 hours later, a portion of the crosslinked membrane (0.98 g, thickness 2.5 mm) was phosphoric acid. It was placed in 20.0 mL of buffer (pH = 7.4, Sigma-Aldrich, Milwaukee, Wis.). An aliquot of 2.5 mL was removed at each time point and replaced with 2.5 mL of fresh buffer. Lidocaine release was quantified by ultraviolet / visible spectroscopy (λ _max = 262 nm). Table 2 shows the corresponding release profile.

Example 3
Synthesis of hydroxyl functional polyvinylpyrrolidone (PVP-OH) Polyvinylpyrrolidone [K15, average molecular weight = about 10,000, Fluka, Milwaukee, Wis. And dissolved in 3 liters of distilled water. To the PVP solution, 360 g (9.5 mol) of sodium borohydride (powder, 98 +%, Aldrich, Milwaukee, Wis.) Was slowly added over 3 hours at room temperature. Substantial bubbling was observed. The reaction was heated to 70 ° C. and stirred for 24 hours. Concentrated hydrochloric acid [Fisher Scientific, Pittsburg, PA] was added to reduce the pH from 11 to 7. The polymer was dialyzed against distilled water for 10 days using a 500 molecular weight cut-off dialysis membrane (cellulose, Spectrum Laboratories, Rancho Domingas, CA). Water was removed by rotary evaporation to yield a white solid with OH # = KOH 33.3 mg / g sample and hydroxyl group equivalent (EW) = 1,680 g / mol.

Synthesis of Acrylate Functional Polyvinylpyrrolidone (PVP-Acrylate) 32.3 g of PVP-OH (monomer unit = 291 mmol, OH = 19 mmol) was added to a 500 mL Nikakumaru equipped with a nitrogen inlet, a rubber partition and a magnetic stir bar Dissolved in 400 mL anhydrous N, N-dimethylformamide (Aldrich, Milwaukee, Wis.) And 10 mL anhydrous pyridine (Aldrich, Milwaukee, Wis.) In a bottom flask. 3.48 g (38.4 mmol) acryloyl chloride, 100 mg (0.82 mmol) 4- (dimethylamino) pyridine (Aldrich, Milwaukee, Wis.) And 20 mg hydroquinone were added to the polymer solution. The reaction mixture was then stirred at 100 ° C. for 1 hour. The polymer solution was filtered to remove the hydrochloride and then precipitated three times with isopropyl ether to yield a solid polymer containing about 4-5 mol% acrylate groups. This was confirmed by ¹ H NMR spectroscopy. ¹ H NMR (D ₂ O) δ = 6.39 to 6.21 (bm, 1H, acrylate vinyl), 6.18 to 5.96 (bm, 1H, acrylate vinyl), 5.95 to 5.82 ( bm, 1H, acrylate vinyl), 4.01-3.42 (bm, 1H, PVP methine proton), 3.41-2.95 (bm, 2H, PVP), 2.50-1.10 (bm, 6H, PVP).

Synthesis of Crosslinked Polymer 2.29 g of PVP-acrylate was dissolved in 3.17 g of borate buffer solution (pH = 9.0) in a 20 mL glass scintillation vial. 650 mg (541 μmol) of ethoxylated pentaerythritol (PP150) tetrakis (3-mercaptopropionate) (average molecular weight = 1201.5) was added to the reaction mixture at room temperature. The reaction mixture was vortexed for 2 minutes at room temperature and then poured between two parallel plates (diameter = 40 mm). Rheological data was obtained with a Rheometrics RDA-II rheometer (Rheometer) using a single point dynamic time sweep test. The reaction mixture gelled within 24 hours at room temperature to form a crosslinked hydrogel.

Example 4
Synthesis of acrylate-functional polyvinylpyrrolidone (PVP-acrylate) 6.7 g of PVP-OH from Example 3 (monomer units = 60 mmol, OH = 4 mmol) were equipped with a nitrogen inlet, a rubber septum and a magnetic stir bar. Dissolved in 400 mL anhydrous 1,4-dioxane in a 500 mL two-necked round bottom flask. 1.1 g (12 mmol) of acryloyl chloride and 3.6 g of triethylamine were added dropwise in this order. 100 mg of hydroquinone was added to the polymer solution and the reaction mixture was then stirred at 55 ° C. for 6 hours. The polymer solution is filtered to remove the hydrochloride and then precipitated three times with isopropyl ether: hexane (50:50 vol / vol) to yield a solid polymer containing about 5-6 mol% acrylate groups. It was. This was confirmed by ¹ H NMR spectroscopy. ¹ H NMR (D ₂ O) δ = 6.39 to 6.21 (bm, 1H, acrylate vinyl), 6.18 to 5.96 (bm, 1H, acrylate vinyl), 5.95 to 5.82 ( bm, 1H, acrylate vinyl), 4.01-3.42 (bm, 1H, PVP methine proton), 3.41-2.95 (bm, 2H, PVP), 2.50-1.10 (bm, 6H, PVP).

Synthesis of cross-linked polymer 1.0 g of PVP-acrylate was dissolved in 2 g of borate buffer solution (pH = 10.0) in a 2 dram glass vial and 2 g of N-methyl-2-pyrrolidone. . 133 mg (111 μmol) of ethoxylated pentaerythritol (PP150) tetrakis (3-mercaptopropionate) (average molecular weight = 1201.5) was added to the reaction mixture at ambient temperature. The reaction mixture gelled within 30 minutes at ambient temperature to form a crosslinked hydrogel.

Example 5
Synthesis of hydroxyl functional polyvinyl pyrrolidone (PVP-OH) using glycerin and tin octoate 58 g (521.9 mmol) of polyvinyl pyrrolidone (K90, Fluka, Milwaukee, Wis.) Were equipped with a mechanical stirrer. In 619 g (6,721 mmol) glycerin (Aldrich, Milwaukee, Wis.) In a 4 liter beaker. 400 μL of a 0.33 molar solution of tin octoate in toluene was then added to the PVP solution. The solution was then heated to 110 ° C. and then stirred at ambient pressure for 90 hours. Then 500 mL of isopropanol was added to the reaction mixture to dilute the concentrated solution. The PVP-OH polymer is precipitated in acetone, then 7 days using 100 molecular weight cut-off dialysis membrane (cellulose, Spectrum Laboratories, Rancho Domingas, CA) for 2 days against distilled water. Dialyzed sequentially against water / isopropanol and against water / methanol for 1 day. The polymer was finally precipitated one more time in acetone to give a white solid with OH # = KOH 70 mg / g sample and hydroxyl group equivalent (EW) = 801.4 g / mol. The hydroxyl functional PVP was characterized by ¹ H NMR spectroscopy.

Example 6
Synthesis of hydroxyl functional polyvinylpyrrolidone (PVP-OH) using ethylene glycol and tin octoate 53.6 g (483 mmol) of polyvinylpyrrolidone (K90, Fluka, Milwaukee, Wis.) In 4 liters equipped with a mechanical stirrer Dissolved in 712 g (11,471 mmol) of ethylene glycol (Aldrich, Milwaukee, Wis.) In a beaker. Then 500 μL of a 0.33 molar solution of tin octoate in toluene was added to the PVP solution. The solution was then heated to 95 ° C. and then stirred for 24 hours. The PVP-OH polymer is purified by repeated washing in a hexane: acetone (50:50 volume / volume) mixture, then recovered by centrifugation and then dried under vacuum at ambient temperature, A white solid was produced having OH # = KOH 107 mg / g sample, and hydroxyl group equivalent (EW) = 520.4 g / mol. The hydroxyl functional PVP was characterized by ¹ H NMR spectroscopy using deuterated dimethylformamide.

Example 7
Synthesis of hydroxyl functional polyvinylpyrrolidone (PVP-OH) using ethylene glycol and tin octoate 53.6 g (482.3 mmol) of polyvinylpyrrolidone (K15, Fluka, Milwaukee, Wis.) Were equipped with a mechanical stirrer. Dissolved in excess ethylene glycol (Aldrich, Milwaukee, Wis.) In a 4 liter beaker. Then 500 μL of a 0.33 molar solution of tin octoate in toluene was added to the PVP solution. The solution was then heated to 100 ° C. and then stirred for 24 hours. The PVP-OH polymer was purified by dialysis against distilled water for 7 days using a 1000 molecular weight cut-off dialysis membrane (cellulose, Spectrum Laboratories, Rancho Domingas, CA). The hydroxyl functional PVP was characterized by ¹ H NMR spectroscopy using deuterated chloroform.

Example 8
Synthesis of hydroxyl functional polyvinylpyrrolidone (PVP-OH) using ethylene glycol and tin octoate 100 g (899.8 mmol) of polyvinylpyrrolidone (K25, Fluka, Milwaukee, Wis.) Was added to a 4 liter equipped with mechanical stirrer. Dissolved in 791 g (12,744 mmol) of ethylene glycol (Aldrich, Milwaukee, Wis.) In a beaker. 2 mL of a 0.33 molar solution of tin octoate in toluene was then added to the PVP solution. The mixture was then heated to 125 ° C. and then stirred for 72 hours. The polymer was sequentially precipitated in a few liters of isopropyl ether, acetone and hexane. The PVP-OH polymer is finally dried in a vacuum oven at ambient temperature to yield a dark solid with OH # = KOH 41.8 mg / g sample and hydroxyl group equivalent (EW) = 1300 g / mol It was. The hydroxyl functional PVP was characterized by ¹ H NMR spectroscopy.

Example 9
Synthesis of PVP-acrylate using PVP-OH from Example 8 28.9 g of polyvinylpyrrolidone (K25) -ethylene glycol adduct (equivalent = 1300) prepared according to the method described in Example 8. 2 mmol) was dissolved in 300 g of 1,4-dioxane in a 2 liter round bottom flask equipped with a mechanical stirrer at ambient temperature and pressure. To the reaction mixture was then added 50 mg of hydroquinone (Aldrich, Milwaukee, Wis.). To the reaction mixture was then added 4 g (44.5 mmol) acryloyl chloride, followed by 13.5 g (133.4 mmol) triethylamine. The mixture was then heated at 50 ° C. for 20 hours and then stirred at room temperature for 7 days. After removal of triethylammonium salt from the mixture by centrifugation, use Rotavator R-144 and Waterbath B-481 [Buchi Corporation, New Castle, Del.] The dioxane solvent was then removed from the mixture by rotoevaporation under vacuum with an aspirator. The temperature was raised very slowly from room temperature to about 50 ° C. The resulting polymer was then dissolved in methanol and then precipitated into a 50:50 volume: volume solution of isopropyl ether: acetone to yield a slightly brownish polymer. The resulting polymer was found to have 3.8 to 4.7 mol% acrylate groups. This was determined by ¹ H NMR spectroscopy.

Example 10
Synthesis of hydroxyl functional polyvinylpyrrolidone (PVP-OH) using glycerin and tin octoate 100 g (899.8 mmol) of polyvinylpyrrolidone (K25, Fluka, Milwaukee, Wis.) Was added to a 4 liter beaker equipped with a mechanical stirrer. In glycerin (Aldrich, Milwaukee, Wis.) In 631.5 g (6856.7 mmol). 2 mL of a 0.33 molar solution of tin octoate in toluene was then added to the PVP solution. The solution was then heated to 100 ° C. and stirred for 16 hours. The PVP-OH polymer was sequentially precipitated in several liters each of isopropyl ether, acetone and hexane. The PVP-OH polymer was finally purified by dialysis against distilled water for 7 days using a 1000 molecular weight cut-off dialysis membrane (cellulose, Spectrum Laboratories, Rancho Domingas, CA). The polymer was finally precipitated one more time in acetone to give a white solid with OH # = KOH 70 mg / g sample and hydroxyl group equivalent (EW) = 801.4 g / mol.

Example 11
Synthesis of methacrylate-functional polyvinylpyrrolidone (PVP-methacrylate) using PVP-OH from Example 10 1 g of PVP-OH from Example 10 above (monomer unit = 9.0 mmol, OH = 1.3) Millimoles) was dissolved in 10 mL of anhydrous N, N-dimethylformamide (Aldrich, Milwaukee, Wis.) In a 20 mL vial equipped with a nitrogen inlet, rubber septum and magnetic stir bar. 0.19 g (1.3 mmol) of isocyanatoethyl methacrylate (Aldrich, Milwaukee, Wis.) And a drop of tin octanoate solution as catalyst were added to the polymer solution. The solution was then stirred for 24 hours at room temperature. The polymer solution was then precipitated three times with a 50:50 mixture of hexane: isopropyl ether to yield a solid polymer containing about 1.3 mol% of methacrylate groups. This was confirmed by ¹ H NMR spectroscopy using deuterated dimethylformamide.

Example 12
Synthesis of acrylate-functional polyvinylpyrrolidone (PVP-acrylate) using PVP-OH from Example 10 1 g of PVP-OH from Example 10 above (monomer unit = 9.0 mmol, OH = 1.3) 1 ml of anhydrous N, N-dimethylformamide (Aldrich, Milwaukee, Wis.) In a 20 mL vial equipped with a nitrogen inlet, rubber septum and magnetic stir bar, and anhydrous triethylamine (Aldrich, Milwaukee, Wis.). Dissolved in 1 g (3.9 mmol). 0.112 g (1.3 mmol) of acryloyl chloride (Aldrich, Milwaukee, Wis.) And 20 mg of hydroquinone were added to the polymer solution. The reaction mixture was then stirred for 24 hours at room temperature. The mixture was filtered to remove the hydrochloride and then precipitated three times with a 50:50 mixture of hexane: isopropyl ether to give an oily polymer containing about 2-3 mol% of acrylate groups. This was confirmed by ¹ H NMR spectroscopy using deuterated dimethylformamide.

Example 13
Synthesis of methacrylate-functional polyvinylpyrrolidone (PVP-isopropenyl) using PVP-OH from Example 10 1 g PVP-OH from Example 10 above (monomer unit = 9.0 mmol, OH = 1. 3 mmol) was dissolved in 10 mL of anhydrous N, N-dimethylformamide (Aldrich, Milwaukee, WI) in a 20 mL vial equipped with a nitrogen inlet, rubber septum and magnetic stir bar. 0.26 g (1.3 mmol) 3-isopropenyl-α, α-dimethylbenzyl isocyanate (Aldrich, Milwaukee, Wis.) And a drop of tin octanoate solution as catalyst are added to the polymer solution. Added. The solution was then stirred for 24 hours at room temperature. The PVP-isopropenyl polymer was then precipitated three times with a 50:50 mixture of hexane: isopropyl ether to yield a solid polymer.

Example 14
Synthesis of crosslinked polyurethane using PVP-OH from Example 10 and bis (4-isocyanatocyclohexyl) methane (HMDI) 1 g of PVP-OH from Example 10 above (monomer units = 9.0 mmol) OH = 1.3 mmol) was dissolved in 10 mL of anhydrous N, N-dimethylformamide (Aldrich, Milwaukee, Wis.) In a 20 mL vial equipped with a nitrogen inlet, rubber septum and magnetic stir bar. To the polymer solution was added 1.1 g (3.9 mmol) of anhydrous bis (4-isocyanatocyclohexyl) methane (HMDI) (Aldrich, Milwaukee, Wis.). The solution was then stirred for about 2 hours at room temperature to form a crosslinked polymer gel.

Example 15
Preparation of contact lenses using PVP-methacrylate from Example 11 In a 20 mL amber vial, 30 parts by weight of methyldi (trimethylsiloxy) silylpropylglycerol methacrylate (SIMAA) and monomethacryloxypropyl terminated polydimethylsiloxane ( Molecular weight = 800 to 1000) (mPDMS) 22 parts by weight, N, N-dimethylacrylamide (DMA) 31 parts by weight, 2-hydroxyethyl methacrylate (HEMA) 8.5 parts by weight, ethylene glycol dimethacrylate (EGDMA) 0.75 part by weight, 2- (2′-hydroxy-5-methacrylyloxyethylphenyl) -2H-benzotriazole (2- (2′-hydroxy-5-methacrylyloxyethylphenyl) -2H-benzotriazole) [norblock ( Norblock) 7966] 1.5 layers Parts, bis (2,6-dimethoxybenzoyl) -2,4,4-trimethylpentylphosphine oxide (CGI819) 0.23 parts by weight, tert-amyl alcohol (TAA) 29 parts by weight, PVP polyvinylpyrrolidone (molecular weight = 2,500) 11 parts by weight and 4.3 parts by weight of PVP-methacrylate from Example 11 were combined to make a reaction mixture. Diluted PVP (molecular weight = 2500) accounted for 7.8% of the mass of the complete reaction mixture. The resulting reaction mixture was a clear and homogeneous solution. A polypropylene contact lens mold was filled, closed, and then irradiated with a total of 4 mW / cm ² of visible light at 47 ° C. for 20 minutes. The mold was opened and the lens was released into isopropanol (IPA) and then transferred into deionized water. The lens was transparent.

Embodiment
(1) In the crosslinked lactam polymer,
A) a reaction product, a) a lactam polymer having pendant acrylate groups, and
b) Michael addition-type reactant,
Reaction products of
A cross-linked lactam polymer.
(2) In the crosslinked lactam polymer according to Embodiment 1,
The lactam polymer includes N-vinyl-2-pyrrolidinone, N-vinyl-2-piperidone, N-vinyl-ε-caprolactam, N-vinyl-3-methyl-2-pyrrolidone, N-vinyl-3-methyl- 2-piperidone, N-vinyl-3-methyl-2-caprolactam, N-vinyl-4-methyl-2-pyrrolidone, N-vinyl-4-methyl-2-caprolactam, N-vinyl-5-methyl-2- Pyrrolidone, N-vinyl-5-methyl-2-piperidone, N-vinyl-5,5-dimethyl-2-pyrrolidone, N-vinyl-3,3,5-trimethyl-2-pyrrolidone, N-vinyl-5 Methyl-5-ethyl-2-pyrrolidone, N-vinyl-3,4,5-trimethyl-3-ethyl-2-pyrrolidone, N-vinyl-6-methyl-2-piperidone, N-vinyl-6 Ethyl-2-piperidone, N-vinyl-3,5-dimethyl-2-piperidone, N-vinyl-4,4-dimethyl-2-piperidone, N-vinyl-7-methyl-2-caprolactam, N-vinyl- 7-ethyl-2-caprolactam, N-vinyl-3,5-dimethyl-2-caprolactam, N-vinyl-4,6-dimethyl-2-caprolactam, N-vinyl-3,5,7-trimethyl-2- A crosslinked lactam polymer comprising repeating units derived from a lactam monomer selected from the group consisting of caprolactam, N-vinylmaleimide, N-vinylsuccinimide, and combinations thereof.
(3) In the crosslinked lactam polymer according to Embodiment 2,
The lactam polymers include N-vinyl-2-pyrrolidinone, N-vinyl-2-piperidone, N-vinyl-ε-caprolactam, N-vinylsuccinimide, N-vinyl-3-methyl-2-pyrrolidone, and N- A cross-linked lactam polymer comprising repeating units derived from a lactam monomer selected from the group consisting of vinyl-4-methyl-2-pyrrolidone and combinations thereof.
(4) In the crosslinked lactam polymer according to Embodiment 3,
The lactam polymer is a lactam monomer selected from the group consisting of N-vinyl-2-pyrrolidinone, N-vinyl-2-piperidone, N-vinyl-ε-caprolactam, and N-vinylsuccinimide, and combinations thereof. A crosslinked lactam polymer containing repeating units derived from
(5) In the crosslinked lactam polymer according to the fourth embodiment,
The lactam polymer is a crosslinked lactam polymer containing a repeating unit derived from N-vinyl-2-pyrrolidinone.
(6) In the crosslinked lactam polymer according to Embodiment 2,
The Michael addition type reaction product is a protein having a cysteine residue, albumin, glutathione, 3,6-dioxa-1,8-octanedithiol, oligo (oxyethylene) dithiol, pentaerythritol poly (ethylene glycol) ether tetra-sulfhydryl Sorbitol poly (ethylene glycol) ether hexa-sulfhydryl, dimercaptosuccinic acid, dihydrolipoic acid, dithiothreitol, trimethylolpropane tris (3-mercaptopropionate), pentaerythritol tetrathioglycolate, pentaerythritol tetra (3- Mercaptopropionate), dipentaerythritol hexakis (thioglycolate), and ethoxylated pentaerythritol (PP150) tetrakis (3- Le mercaptopropionate), and selected from the group consisting of an acrylate reactive thiol, crosslinked lactam polymer.
(7) In the crosslinked lactam polymer according to Embodiment 3,
The Michael addition type reactants include pentaerythritol tetrathioglycolate, pentaerythritol tetra (3-mercaptopropionate), dipentaerythritol hexakis (thioglycolate), and ethoxylated pentaerythritol (PP150) tetrakis (3-mercapto). Cross-linked lactam polymers that are acrylate-reactive thiols selected from the group consisting of propionates) and combinations thereof.
(8) In the crosslinked lactam polymer according to Embodiment 4,
The Michael addition type reactants include pentaerythritol tetrathioglycolate, pentaerythritol tetra (3-mercaptopropionate), dipentaerythritol hexakis (thioglycolate), and ethoxylated pentaerythritol (PP150) tetrakis (3-mercapto). Cross-linked lactam polymers that are acrylate-reactive thiols selected from the group consisting of propionates) and combinations thereof.
(9) In the crosslinked lactam polymer according to Embodiment 5,
The Michael addition reactant is a cross-linked lactam polymer, which is ethoxylated pentaerythritol (PP150) tetrakis (3-mercaptopropionate).
(10) In the crosslinked lactam polymer according to Embodiment 6,
The lactam polymers are methyl methacrylate, methacrylic acid, styrene, butadiene, acrylonitrile, 2-hydroxyethyl methacrylate, acrylic acid, methyl acrylate, methyl methacrylate, vinyl acetate, N, N-dimethylacrylamide, N-isopropylacrylamide. And a cross-linked lactam polymer further comprising repeat units from non-lactam monomers selected from the group consisting of, and poly (ethylene glycol) monomethacrylate, and combinations thereof.
(11) In the crosslinked lactam polymer according to Embodiment 7,
The lactam polymer is a crosslinked lactam polymer further comprising a repeating unit from a non-lactam monomer selected from the group consisting of methacrylic acid, acrylic acid, acetonitrile, and combinations thereof.
(12) In the crosslinked lactam polymer as described in Embodiment 8,
The lactam polymer is a crosslinked lactam polymer further comprising a repeating unit from a non-lactam monomer selected from the group consisting of methacrylic acid, acrylic acid, acetonitrile, and combinations thereof.
(13) In the crosslinked lactam polymer according to Embodiment 9,
The lactam polymer is a crosslinked lactam polymer further comprising a repeating unit from a non-lactam monomer selected from the group consisting of methacrylic acid, acrylic acid, acetonitrile, and combinations thereof.
(14) In the method,
Reacting at least one lactam polymer with a polyol in the presence of a metal catalyst to form a hydroxyl-functional lactam polymer;
Including a method.
(15) In the method according to the fourteenth embodiment,
The polyol is 1,3-propanediol, 1,4-butanediol, 1,5-pentanediol, 1,6-hexanediol, 1,8-octanediol, 1,12-dodecanediol, ethylene glycol, diethylene glycol. , Triethylene glycol, tetraethylene glycol, pentaethylene glycol, hexaethylene glycol, heptaethylene glycol, and poly (ethylene glycol), glycerin, erythritol, pentaerythritol, ethoxylated pentaerythritol, dipentaerythritol, xylitol, ribitol, sorbitol, A process selected from the group consisting of trimethylolpropane, 1,2,6-hexanetriol, and 1,2,4-butanetriol, and mixtures thereof.
(16) In the method according to the fifteenth embodiment,
The method wherein the polyol is selected from the group consisting of ethylene glycol, glycerin, and mixtures thereof.
(17) In the method according to the fourteenth embodiment,
The process wherein the polyol is present in an amount of about 10 wt% to about 99 wt%, based on the total weight of the polyol and lactam polymer.
(18) In the method according to the fourteenth embodiment,
The process wherein the polyol is present in an amount of about 40 wt% to about 90 wt%, based on the total weight of the polyol and lactam polymer.
(19) In the method according to the fourteenth embodiment,
The method wherein the metal catalyst is selected from the group consisting of an aluminum catalyst, a calcium catalyst, a manganese catalyst, a lanthanide catalyst, an antimony catalyst, a zinc catalyst, a tin catalyst, and mixtures thereof.
(20) In the method described in Embodiment 19,
The method, wherein the tin catalyst is selected from the group consisting of stannous octylate, dibutyltin oxide, tin (II) chloride, and mixtures thereof.
(21) In the method described in Embodiment 20,
The method, wherein the tin catalyst is stannous octylate and is present in an amount of about 9 mol% to about 50 mol%, based on the total moles of lactam groups in the lactam polymer.
(22) In the method according to the fourteenth embodiment,
The method wherein the metal catalyst is present in an amount such that the molar ratio of [lactam polymer] to [catalyst] is from about 100 to 1 to about 10,000 to 1.
(23) In the method according to the fourteenth embodiment,
The process wherein the metal catalyst is present in an amount such that the molar ratio of [lactam polymer] to [catalyst] is from about 1000 to 1 to about 5000 to 1.
(24) In the method according to the fourteenth embodiment,
A process carried out at a temperature between about 20 ° C and about 150 ° C.
(25) In the method according to the fourteenth embodiment,
The method is carried out at a temperature between about 40 ° C and about 110 ° C.
(26) In the method according to the fourteenth embodiment,
The method is performed for a time not exceeding about 5 days.
(27) In the method according to the fourteenth embodiment,
The method is performed for about 24 hours to about 48 hours.
(28) In the method according to the fourteenth embodiment,
The method wherein the lactam polymer comprises at least about 10 mole percent of repeating units derived from at least one lactam group based on the total molar amount of the lactam polymer.
(29) In the method according to the fourteenth embodiment,
The method wherein the lactam polymer comprises at least about 30 mole percent of repeating units derived from at least one lactam group based on the total molar amount of the lactam polymer.
(30) In the method according to the fourteenth embodiment,
The method wherein the lactam polymer comprises at least about 50 mole percent repeat units derived from at least one lactam group based on the total molar amount of the lactam polymer.
(31) In the method described in embodiment 28,
The method wherein the at least one lactam group is selected from the group consisting of a substituted 4-7 membered lactam ring, an unsubstituted 4-7 membered lactam ring, and combinations thereof.
(32) In the method described in embodiment 28,
The method wherein the at least one lactam group is an unsubstituted 4-6 membered lactam ring.
(33) In the method described in embodiment 28,
The at least one lactam polymer may be N-vinyl-2-pyrrolidone, N-vinyl-2-piperidone, N-vinyl-2-caprolactam, N-vinyl-3-methyl-2-pyrrolidone, N-vinyl. -3-methyl-2-piperidone, N-vinyl-3-methyl-2-caprolactam, N-vinyl-4-methyl-2-pyrrolidone, N-vinyl-4-methyl-2-caprolactam, N-vinyl-5 -Methyl-2-pyrrolidone, N-vinyl-5-methyl-2-piperidone, N-vinyl-5,5-dimethyl-2-pyrrolidone, N-vinyl-3,3,5-trimethyl-2-pyrrolidone, N -Vinyl-5-methyl-5-ethyl-2-pyrrolidone, N-vinyl-3,4,5-trimethyl-3-ethyl-2-pyrrolidone, N-vinyl-6-methyl-2-piperide N-vinyl-6-ethyl-2-piperidone, N-vinyl-3,5-dimethyl-2-piperidone, N-vinyl-4,4-dimethyl-2-piperidone, N-vinyl-7-methyl-2 -Caprolactam, N-vinyl-7-ethyl-2-caprolactam, N-vinyl-3,5-dimethyl-2-caprolactam, N-vinyl-4,6-dimethyl-2-caprolactam, N-vinyl-3,5 , 7-trimethyl-2-caprolactam, N-vinylmaleimide, vinylsuccinimide, and a lactam monomer selected from the group consisting of combinations thereof.
(34) In the method according to embodiment 28,
The method wherein the at least one lactam polymer contains an N-vinyl-2-pyrrolidone monomer.
(35) In the method according to embodiment 28,
The method wherein the lactam polymer further comprises repeating units derived from at least one non-lactam monomer.
(36) In the method described in embodiment 35,
The at least one non-lactam monomer is methyl methacrylate, methacrylic acid, styrene, butadiene, acrylonitrile, 2-hydroxyethyl methacrylate, acrylic acid, methyl acrylate, methyl methacrylate, vinyl acetate, N, N-dimethyl. A method selected from the group consisting of acrylamide, N-isopropylacrylamide, and polyethylene glycol monomethacrylate, and combinations thereof.
(37) In the method described in embodiment 35,
The method wherein the at least one non-lactam monomer is selected from the group consisting of methacrylic acid, acrylic acid, acetonitrile, and mixtures thereof.
(38) In the method according to the fourteenth embodiment,
Reacting the hydroxyl functional lactam polymer with a hydroxyl reactive compound containing at least one acrylate group to form an acrylate functional lactam polymer;
The method further comprising:
(39) In the method described in embodiment 38,
Reacting the acrylate functional lactam polymer with a Michael addition acrylate reactant to form a crosslinked lactam polymer;
The method further comprising:
(40) In the method according to the fourteenth embodiment,
Reacting the hydroxyl functional lactam polymer with a hydroxyl reactive compound to form a hydroxyl polymer derivative;
The method further comprising:
(41) In the method according to the fourteenth embodiment,
Reacting the hydroxyl functional lactam polymer with a polymerizing agent to form a hydroxyl polymer derivative;
The method further comprising:
(42) In the method according to the fourteenth embodiment,
Reacting the hydroxyl functional lactam polymer with a hydroxyl reactive bioactive agent to form a polymeric prodrug;
The method further comprising:

Claims (42)

In the cross-linked lactam polymer,
A reaction product comprising:
a) a lactam polymer having pendant acrylate groups, and
b) Michael addition-type reactant,
Reaction products of
A cross-linked lactam polymer. The crosslinked lactam polymer according to claim 1, wherein
The lactam polymer includes N-vinyl-2-pyrrolidinone, N-vinyl-2-piperidone, N-vinyl-ε-caprolactam, N-vinyl-3-methyl-2-pyrrolidone, N-vinyl-3-methyl- 2-piperidone, N-vinyl-3-methyl-2-caprolactam, N-vinyl-4-methyl-2-pyrrolidone, N-vinyl-4-methyl-2-caprolactam, N-vinyl-5-methyl-2- Pyrrolidone, N-vinyl-5-methyl-2-piperidone, N-vinyl-5,5-dimethyl-2-pyrrolidone, N-vinyl-3,3,5-trimethyl-2-pyrrolidone, N-vinyl-5 Methyl-5-ethyl-2-pyrrolidone, N-vinyl-3,4,5-trimethyl-3-ethyl-2-pyrrolidone, N-vinyl-6-methyl-2-piperidone, N-vinyl-6 Ethyl-2-piperidone, N-vinyl-3,5-dimethyl-2-piperidone, N-vinyl-4,4-dimethyl-2-piperidone, N-vinyl-7-methyl-2-caprolactam, N-vinyl- 7-ethyl-2-caprolactam, N-vinyl-3,5-dimethyl-2-caprolactam, N-vinyl-4,6-dimethyl-2-caprolactam, N-vinyl-3,5,7-trimethyl-2- A crosslinked lactam polymer comprising repeating units derived from a lactam monomer selected from the group consisting of caprolactam, N-vinylmaleimide, N-vinylsuccinimide, and combinations thereof. The crosslinked lactam polymer according to claim 2,
The lactam polymers include N-vinyl-2-pyrrolidinone, N-vinyl-2-piperidone, N-vinyl-ε-caprolactam, N-vinylsuccinimide, N-vinyl-3-methyl-2-pyrrolidone, and N- A cross-linked lactam polymer comprising repeating units derived from a lactam monomer selected from the group consisting of vinyl-4-methyl-2-pyrrolidone and combinations thereof. In the crosslinked lactam polymer according to claim 3,
The lactam polymer is a lactam monomer selected from the group consisting of N-vinyl-2-pyrrolidinone, N-vinyl-2-piperidone, N-vinyl-ε-caprolactam, and N-vinylsuccinimide, and combinations thereof. A crosslinked lactam polymer containing repeating units derived from In the crosslinked lactam polymer according to claim 4,
The lactam polymer is a crosslinked lactam polymer containing a repeating unit derived from N-vinyl-2-pyrrolidinone. The crosslinked lactam polymer according to claim 2,
The Michael addition type reaction product is a protein having a cysteine residue, albumin, glutathione, 3,6-dioxa-1,8-octanedithiol, oligo (oxyethylene) dithiol, pentaerythritol poly (ethylene glycol) ether tetra-sulfhydryl Sorbitol poly (ethylene glycol) ether hexa-sulfhydryl, dimercaptosuccinic acid, dihydrolipoic acid, dithiothreitol, trimethylolpropane tris (3-mercaptopropionate), pentaerythritol tetrathioglycolate, pentaerythritol tetra (3- Mercaptopropionate), dipentaerythritol hexakis (thioglycolate), and ethoxylated pentaerythritol (PP150) tetrakis (3- Le mercaptopropionate), and selected from the group consisting of an acrylate reactive thiol, crosslinked lactam polymer. In the crosslinked lactam polymer according to claim 3,
The Michael addition type reactants include pentaerythritol tetrathioglycolate, pentaerythritol tetra (3-mercaptopropionate), dipentaerythritol hexakis (thioglycolate), and ethoxylated pentaerythritol (PP150) tetrakis (3-mercapto). Cross-linked lactam polymers that are acrylate-reactive thiols selected from the group consisting of propionates) and combinations thereof. In the crosslinked lactam polymer according to claim 4,
The Michael addition type reactants include pentaerythritol tetrathioglycolate, pentaerythritol tetra (3-mercaptopropionate), dipentaerythritol hexakis (thioglycolate), and ethoxylated pentaerythritol (PP150) tetrakis (3-mercapto). Cross-linked lactam polymers that are acrylate-reactive thiols selected from the group consisting of propionates) and combinations thereof. In the cross-linked lactam polymer according to claim 5,
The Michael addition reactant is a cross-linked lactam polymer, which is ethoxylated pentaerythritol (PP150) tetrakis (3-mercaptopropionate). The crosslinked lactam polymer according to claim 6,
The lactam polymers are methyl methacrylate, methacrylic acid, styrene, butadiene, acrylonitrile, 2-hydroxyethyl methacrylate, acrylic acid, methyl acrylate, methyl methacrylate, vinyl acetate, N, N-dimethylacrylamide, N-isopropylacrylamide. And a cross-linked lactam polymer further comprising repeat units from non-lactam monomers selected from the group consisting of, and poly (ethylene glycol) monomethacrylate, and combinations thereof. In the crosslinked lactam polymer according to claim 7,
The lactam polymer is a crosslinked lactam polymer further comprising a repeating unit from a non-lactam monomer selected from the group consisting of methacrylic acid, acrylic acid, acetonitrile, and combinations thereof. The crosslinked lactam polymer according to claim 8,
The lactam polymer is a crosslinked lactam polymer further comprising a repeating unit from a non-lactam monomer selected from the group consisting of methacrylic acid, acrylic acid, acetonitrile, and combinations thereof. The crosslinked lactam polymer according to claim 9,
The lactam polymer is a crosslinked lactam polymer further comprising a repeating unit from a non-lactam monomer selected from the group consisting of methacrylic acid, acrylic acid, acetonitrile, and combinations thereof. In the method
Reacting at least one lactam polymer with a polyol in the presence of a metal catalyst to form a hydroxyl-functional lactam polymer;
Including a method. 15. The method of claim 14, wherein
The polyol is 1,3-propanediol, 1,4-butanediol, 1,5-pentanediol, 1,6-hexanediol, 1,8-octanediol, 1,12-dodecanediol, ethylene glycol, diethylene glycol. , Triethylene glycol, tetraethylene glycol, pentaethylene glycol, hexaethylene glycol, heptaethylene glycol, and poly (ethylene glycol), glycerin, erythritol, pentaerythritol, ethoxylated pentaerythritol, dipentaerythritol, xylitol, ribitol, sorbitol, A process selected from the group consisting of trimethylolpropane, 1,2,6-hexanetriol, and 1,2,4-butanetriol, and mixtures thereof. The method of claim 15, wherein
The method wherein the polyol is selected from the group consisting of ethylene glycol, glycerin, and mixtures thereof. 15. The method of claim 14, wherein
The process wherein the polyol is present in an amount of about 10 wt% to about 99 wt%, based on the total weight of the polyol and lactam polymer. 15. The method of claim 14, wherein
The process wherein the polyol is present in an amount of about 40 wt% to about 90 wt%, based on the total weight of the polyol and lactam polymer. 15. The method of claim 14, wherein
The method wherein the metal catalyst is selected from the group consisting of an aluminum catalyst, a calcium catalyst, a manganese catalyst, a lanthanide catalyst, an antimony catalyst, a zinc catalyst, a tin catalyst, and mixtures thereof. The method of claim 19, wherein
The method wherein the tin catalyst is selected from the group consisting of stannous octylate, dibutyltin oxide, tin (II) chloride, and mixtures thereof. The method of claim 20, wherein
The method, wherein the tin catalyst is stannous octylate and is present in an amount of about 9 mol% to about 50 mol%, based on the total moles of lactam groups in the lactam polymer. 15. The method of claim 14, wherein
The method wherein the metal catalyst is present in an amount such that the molar ratio of [lactam polymer] to [catalyst] is from about 100 to 1 to about 10,000 to 1. 15. The method of claim 14, wherein
The process wherein the metal catalyst is present in an amount such that the molar ratio of [lactam polymer] to [catalyst] is from about 1000 to 1 to about 5000 to 1. 15. The method of claim 14, wherein
A process carried out at a temperature between about 20 ° C and about 150 ° C. 15. The method of claim 14, wherein
The method is carried out at a temperature between about 40 ° C and about 110 ° C. 15. The method of claim 14, wherein
The method is performed for a time not exceeding about 5 days. 15. The method of claim 14, wherein
The method is performed for about 24 hours to about 48 hours. 15. The method of claim 14, wherein
The method wherein the lactam polymer comprises at least about 10 mole percent of repeating units derived from at least one lactam group based on the total molar amount of the lactam polymer. 15. The method of claim 14, wherein
The method wherein the lactam polymer comprises at least about 30 mole percent of repeating units derived from at least one lactam group based on the total molar amount of the lactam polymer. 15. The method of claim 14, wherein
The method wherein the lactam polymer comprises at least about 50 mole percent repeat units derived from at least one lactam group based on the total molar amount of the lactam polymer. The method of claim 28, wherein
The method wherein the at least one lactam group is selected from the group consisting of a substituted 4-7 membered lactam ring, an unsubstituted 4-7 membered lactam ring, and combinations thereof. The method of claim 28, wherein
The method wherein the at least one lactam group is an unsubstituted 4-6 membered lactam ring. The method of claim 28, wherein
The at least one lactam polymer may be N-vinyl-2-pyrrolidone, N-vinyl-2-piperidone, N-vinyl-2-caprolactam, N-vinyl-3-methyl-2-pyrrolidone, N-vinyl. -3-methyl-2-piperidone, N-vinyl-3-methyl-2-caprolactam, N-vinyl-4-methyl-2-pyrrolidone, N-vinyl-4-methyl-2-caprolactam, N-vinyl-5 -Methyl-2-pyrrolidone, N-vinyl-5-methyl-2-piperidone, N-vinyl-5,5-dimethyl-2-pyrrolidone, N-vinyl-3,3,5-trimethyl-2-pyrrolidone, N -Vinyl-5-methyl-5-ethyl-2-pyrrolidone, N-vinyl-3,4,5-trimethyl-3-ethyl-2-pyrrolidone, N-vinyl-6-methyl-2-piperide N-vinyl-6-ethyl-2-piperidone, N-vinyl-3,5-dimethyl-2-piperidone, N-vinyl-4,4-dimethyl-2-piperidone, N-vinyl-7-methyl-2 -Caprolactam, N-vinyl-7-ethyl-2-caprolactam, N-vinyl-3,5-dimethyl-2-caprolactam, N-vinyl-4,6-dimethyl-2-caprolactam, N-vinyl-3,5 , 7-trimethyl-2-caprolactam, N-vinylmaleimide, vinylsuccinimide, and a lactam monomer selected from the group consisting of combinations thereof. The method of claim 28, wherein
The method wherein the at least one lactam polymer contains an N-vinyl-2-pyrrolidone monomer. The method of claim 28, wherein
The method wherein the lactam polymer further comprises repeating units derived from at least one non-lactam monomer. 36. The method of claim 35, wherein
The at least one non-lactam monomer is methyl methacrylate, methacrylic acid, styrene, butadiene, acrylonitrile, 2-hydroxyethyl methacrylate, acrylic acid, methyl acrylate, methyl methacrylate, vinyl acetate, N, N-dimethyl. A method selected from the group consisting of acrylamide, N-isopropylacrylamide, and polyethylene glycol monomethacrylate, and combinations thereof. 36. The method of claim 35, wherein
The method wherein the at least one non-lactam monomer is selected from the group consisting of methacrylic acid, acrylic acid, acetonitrile, and mixtures thereof. 15. The method of claim 14, wherein
Reacting the hydroxyl functional lactam polymer with a hydroxyl reactive compound containing at least one acrylate group to form an acrylate functional lactam polymer;
The method further comprising: 40. The method of claim 38, wherein
Reacting the acrylate functional lactam polymer with a Michael addition acrylate reactant to form a crosslinked lactam polymer;
The method further comprising: 15. The method of claim 14, wherein
Reacting the hydroxyl functional lactam polymer with a hydroxyl reactive compound to form a hydroxyl polymer derivative;
The method further comprising: 15. The method of claim 14, wherein
Reacting the hydroxyl functional lactam polymer with a polymerizing agent to form a hydroxyl polymer derivative;
The method further comprising: 15. The method of claim 14, wherein
Reacting the hydroxyl functional lactam polymer with a hydroxyl reactive bioactive agent to form a polymeric prodrug;
The method further comprising: