The present invention includes photocurable, liquid polymers incorporating coumarin ester endgroups into their molecular structure, which polymers are crosslinked upon irradiation with ultraviolet light by photochemically allowed [2+2] cycloaddition reactions among the chain ends, and which crosslinked polymers are useful in the preparation of medical devices, tissue engineering scaffolds, drug delivery systems and, in particular, in vivo preparation of implants in an open surgical procedure or laproscopically.

SUMMARY OF THE INVENTION

The present invention is directed to photocurable, fluid prepolymers comprising a polymer prepared from at least one lactone monomer selected from the group consisting of ε-caprolactone, trimethylene carbonate, glycolide, L-lactide, D-lactide, DL-lactide, p-dioxanone, 5,5-dimethyl-1,3-dioxan-2-one, 1,4-dioxepan-2-one and 1,5-dioxepan-2-one, said prepolymer being a liquid at 65° C. or at a lower temperature and comprising coumarin ester endgroups, wherein the inherent viscosity of the polymer is between about 0.05 dL/g and about 0.8 dL/g as determined in a 0.1 g/dL solution of hexafluoroisoproanol at 25° C., and wherein the polymer is crosslinked upon irradiation with ultraviolet light, and to polymeric networks, microparticles and medical devices, each formed by irradiating fluid prepolymers of the present invention. The present invention also is directed to methods of modifying a surface of a substrate, to methods of forming medical implants and to methods of repairing bony defects, each method utilizing the fluid prepolymers of the present invention. Photocuring of the fluid prepolymers can be conducted manually, for example, in an operating room by first applying the fluid prepolymer to the desired site and then irradiating the liquid with an ultraviolet light source effective to crosslink the polymer. Alternately, photocuring can be conducted automatically using a computerized instrument, e.g. a stereolithography apparatus, to make medical devices.

DETAILED DESCRIPTION OF THE INVENTION

The ring opening polymerization of lactone monomers has been widely studied, and the resulting aliphatic polyesters have been melt processed by extrusion and injection molding into many commercial medical devices such as sutures, suture anchors, ribbons, plates, pins, screws, rods, and staples. The most common monomers are glycolide, L-lactide, DL-lactide, p-dioxanone, 5,5-dimethyl-1,3-dioxan-2-one, trimethylene carbonate and ε-caprolactone, and, except for poly(trimethylene carbonate) which is amorphous and above its glass transition temperature at 37° C., all of the resulting homopolymers are materials with useful physical, mechanical and biological properties. Nonetheless, there are many manufacturing processes and medical applications in which these thermoplastic polymers can not be employed because of their high viscosity, solubility or insolubility, thermal instability, crystallization kinetics, and phase separation phenomena. For these reasons and others, in the field of commodity plastics, thermosetting resins were developed. Thermosetting resins usually are prepared from low molecular weight compounds that react when mixed together or exposed to a stimulus such as heat, light, the addition of a catalyst or an initiator. Thermosetting resins typically are not melt processed, but rather are used at ambient or near ambient temperatures. The components of a thermosetting system react to form a polymeric network that exhibits excellent mechanical properties. In fact, there is excellent control of those properties by varying the type and amount of the components. In the present invention, liquid absorbable polymers made by the ring opening polymerization of lactone monomers are transformed into photocurable, thermosetting materials by an endcapping reaction that converts the hydroxyl endgroups into coumarin ester endgroups which are capable of undergoing a [2+2] cycloaddition dimerization reaction.

As disclosed in U.S. Pat. Nos. 5,411,554, 5,599,852, 5,631,015, 5,653,992, 5,728,752, and 5,824,333, low molecular weight polyesters are synthesized in the same manner as high molecular weight polymers from their corresponding lactone monomers. To illustrate this, the chemical equation describing the synthesis of a liquid poly[ε-caprolactone-co-trimethylene carbonate] is shown below. R(OH)_n represents a generic polyol as the initiator, Sn(oct)₂ represents tin (II) 2-ethyl-hexanonate as the Lewis acid catalyst, and P(OH)_n represents the liquid absorbable polymer.

The molar ratio of the sum of the monomers in a reaction to the amount of initiator added controls the molecular weight of the resulting polymer. Consequently, the synthesis of low molecular weight, liquid absorbable polymers involves adding more initiator to the reaction than when high molecular weight materials are desired, barring any thermodynamic problems caused by a high concentration of chain ends. Branched liquid absorbable polymers can also be prepared by using multifunctional initiators such as trimethylolpropane, pentaerythritol, branched poly(ethylene glycol)s, oligomeric poly(2-hydroxyethyl methacrylate, poly(vinyl alcohol), poly(vinyl alcohol-co-vinyl acetate), or any other polyol. In fact, these multifunctional initiators can be used in conjunction with diols like ethylene glycol, 1,2-propylene glycol, 1,3-propanediol, diethylene glycol, linear poly(ethylene glycol)s, linear poly(propylene glycol)s, and linear poly(ethylene glycol-co-propylene glycol)s. Liquid absorbable polymers can be segmented block copolymers by adding different lactone monomers or different mixtures of lactone monomers sequentially to the reaction. Two or more unique liquid absorbable polymers can be mixed together and used to tailor the mixture's physical properties.

For the purposes of this invention, liquid absorbable polymer will mean any linear or branched polymer or mixture of polymers, of any possible microstructure (statistically random or segmented block), prepared from at least one lactone monomer which is a fluid at 65° C. or lower.

These liquid absorbable polymers are converted into a photocurable, thermosetting resin by converting the hydroxyl endgroups by any conceived synthetic route into a coumarin derivative. Although there are many possible endcapping reagents that could be prepared to accomplish this functionalization of the liquid absorbable polymer, the preferred endcapping agent is 7-chlorocarbonylmethoxycoumarin. The preferred synthesis of 7-chlorocarbonylmethoxycoumarin, as well as the endcapping reaction with a liquid absorbable copolymer.

The endcapping reaction does not alter the physical state of the liquid absorbable polymer (still fluid at 65° C.) thereby providing an easy to use liquid that can be injected, pumped, spread, sprayed, or dissolved as required by the manufacturing process. When these coumarin ester endcapped, liquid absorbable polymers are irradiated with ultraviolet light, the coumarin endgroups undergo a photochemically allowed, [2+2] cycloaddition dimerization reaction as depicted below.

This cycloadditon reaction covalently bonds two polymers together. For a linear (difunctional) liquid absorbable polymer, the result is an increase in the molecular weight of the material. In the case when a blend of at least two compositionally different, linear, coumarin ester endcapped, liquid polymers are used, the result is the formation of a linear segmented block copolymer. For a branched (multifunctional>2) liquid absorbable polymer, the result is the formation of a polymeric network. In contrast to many other kinds of crosslinking chemistry, the coumarin dimerization reaction requires no additives, catalysts, intiators, or sensitizers which makes the system more elegant as well as safer when used in vivo.

Therefore, the present invention describes a fluid prepolymer comprising a polymer prepared from at least one lactone monomer selected from the group consisting of ε-caprolactone, trimethylene carbonate, glycolide, L-lactide, D-lactide, DL-lactide, p-dioxanone, 5,5-dimethyl-1,3-dioxan-2-one, 1,4-dioxepan-2-one and 1,5-dioxepan-2-one, said prepolymer being a liquid at 65° C. or at a lower temperature and comprising coumarin ester endgroups, wherein the inherent viscosity of the polymer is between about 0.05 dL/g and about 0.8 dL/g as determined in a 0.1 g/dL solution of hexafluoroisoproanol at 25° C., that reacts upon exposure to ultraviolet light to form a polymeric network or a segmented block copolymer depending on the overall functionality and photoconversion. The photocuring can be carried out manually, for example, in an operating room by first applying the fluid prepolymer to the desired site and then irradiating the liquid with an ultraviolet light source, or can be carried out automatically using a computerized instrument such as a stereolithography apparatus to make medical device prototypes.

In another embodiment of the present invention, a method of surface modification is disclosed comprising forming a film of the fluid prepolymer, said prepolymer comprising a polymer prepared from at least one of lactone monomer selected from the group consisting of ε-caprolactone, trimethylene carbonate, glycolide, L-lactide, D-lactide, DL-lactide, p-dioxanone, 5,5-dimethyl-1,3-dioxan-2-one, 1,4-dioxepan-2-one and 1,5-dioxepan-2-one, said prepolymer being a liquid at 65° C. or at a lower temperature and comprising coumarin ester endgroups, wherein the inherent viscosity of the polymer is between about 0.05 dL/g and about 0.8 dL/g as determined in a 0.1 g/dL solution of hexafluoroisoproanol at 25° C., on the substrate and irradiating the film with ultraviolet light effective to form a crosslinked coating. Such a coating on a medical device can be employed to modify the surface properties of the implant, thereby controlling the cellular interactions and modifying the absorption profile of absorbable devices. A template may be used to direct the ultraviolet light to only certain areas of the coated substrate. In this way, a surface architecture can be formed on the substrate akin to the photoresists of the electronics industry.

In another embodiment of the present invention, a fluid prepolymer comprising a polymer prepared from at least one lactone monomer selected from the group consisting of ε-caprolactone, trimethylene carbonate, glycolide, L-lactide, D-lactide, DL-lactide, p-dioxanone, 5,5-dimethyl-1,3-dioxan-2-one, 1,4-dioxepan-2-one, and 1,5-dioxepan-2-one, said prepolymer being a liquid at 65° C. or at a lower temperature and comprising coumarin ester endgroups, wherein the inherent viscosity of the polymer is between about 0.05 dL/g and about 0.8 dL/g as determined in a 0.1 g/dL solution of hexafluoroisoproanol at 25° C., that reacts upon exposure to ultraviolet light to form a polymeric network, and at least one bioactive compound, is disclosed for the sustained release of the entrapped drugs. Medical devices such as stents and catheters coated in this fashion become bioactive medical devices with a drug delivery component in addition to any surface modifications mentioned previously. Drug containing microparticles also can be formed by irradiating droplets of the fluid prepolymer comprising dissolved or suspended drugs and other biologically active substances.

The variety of different therapeutic agents that may be used in conjunction with the coumarin ester endcapped, liquid polymers of the invention is vast. In general, therapeutic agents which may be administered via the pharmaceutical compositions and coatings of the invention include, without limitation, anti-infectives such as antibiotics and antiviral agents, analgesics and analgesic combinations, anorexics, antihelmintics, antiarthritics, antiasthmatic agents, anticonvulsants, antidepressants, antidiuretic agents, antidiarrheals, antihistanimes, anti-inflammatory agents, antimigraine preparations, antinauseants, antineoplastics, antiparkinsonism drugs, antipruritics, antipsychotics, antipyretics, antispasmodics, anticholinergics, sympathomimetices, xanthine derivatives, cardiovascular preparations including calcium channel blockers and beta-blockers such as pindolol and antiarrhymics, antihpertensives, diuretics, vasodilators including general coronary, peripheral and cerebral, central nervous system stimulants, cough and cold preparations, including decongestants, hormones such as estradiol and other steroids including corticosteroids, hypnotics, immunosuppressives, muscle relaxants, parasympatholytics, psychostimulants, sedatives, and tranquilizers, and naturally derived or genetically engineered proteins, polysaccharides, glycoproteins, or lipoproteins. Suitable pharmaceuticals for parenteral administration are well known as is exemplified by the Handbook on Injectable Drugs, 6^th edition, by Lawrence A Trissel, American Society of Hospital Pharmacists, Bethesda, Md., 1990 (hereby incorporated by reference).

Parenteral administration of a drug formulation of the invention can be affected by the injection of the mixture of drug and coumarin ester endcapped, liquid polymer and then photocured in situ, or by the injection of suspended, drug filled microparticles made by dissolving or mixing the drug in the coumarin ester endcapped, liquid polymer, dispersing this mixture to form small droplets, irradiating those droplets to form a crosslinked network, thereby entrapping the drug in the polymeric matrix, suspending these particles in a suitable fluid as a carrier, and then injecting that suspension into the body.

Parenteral formulations of the copolymers may be formulated by mixing one or more therapeutic agents with the liquid copolymer. The therapeutic agent may be present as a liquid, a finely divided solid, or any other appropriate physical form. Drug excipients and stabilizers may also be added to the mixture of liquid absorbable polymer and bioactive compound to produce a therapeutic product with sufficient shelf life to be safe and sold commercially.

Similar formulations can also be used in oral drug delivery formulations. In this case, the drug filled particles or solid form is placed in a capsule or is coated with a suitable barrier layer to pass through the stomach and into the intestine. Sometimes, the capsule or coating may not be necessary or desirable.

The amount of therapeutic agent will be dependent upon the particular drug employed and the medical condition being treated. Typically, the amount of drug represents about 0.001% to about 75%, more typically from about 0.001% to about 50%, and most typically from about 0.001% to about 25% by weight of the total composition.

The quantity and type of copolymers incorporated into the parenteral formulation will vary depending on the release profile desired and the amount of drug employed. For a more viscous composition, generally a higher molecular weight polymer is used. If a less viscous composition is desired, a lower molecular weight polymer can be employed. The product may contain blends of liquid copolymers to provide the desired release profile or consistency to a given formulation. In fact, the molecular weight and its distribution of the coumarin ester endcapped, liquid absorbable polymer also determines the crosslink density of the resulting polymeric network, because the individual polymer chains are simply bonded together at their ends by [2+2] cycloaddition reactions without any side reactions. The higher the initial molecular weight of the coumarin ester endcapped, liquid polymer, the longer the segment length (the number of bonds between crosslinks) of the resulting polymeric network, the lower the crosslink density. Many physical and mechanical properties like stiffness and elasticity depend on the crosslink density of the network and can be tailored by choosing the chemical composition and molecular weight the precursor liquid polymer to match the desired properties.

Individual formulations of drugs and coumarin ester endcapped, liquid absorbable polymers may be tested in appropriate in vitro and in vivo models to achieve the desired drug release profiles. For example, a drug could be formulated with the coumarin ester endcapped, liquid absorbable polymer, photocured into a coating or particles, and implanted into an animal. The drug release profile could then be monitored by appropriate means such as by taking blood samples at specific times and assaying those samples for drug concentration. Following this or similar procedures, those skilled in the art will be able to formulate a variety of sustained release parenteral formulations.

In another embodiment of the present invention, a method of forming medical implants by irradiating the fluid prepolymer, comprising a polymer prepared from at least one lactone monomer selected from the group consisting of ε-caprolactone, trimethylene carbonate, glycolide, L-lactide, D-lactide, DL-lactide, p-dioxanone, 5,5-dimethyl-1,3-dioxan-2-one, 1,4-dioxepan-2-on and 1,5-dioxepan-2-one, said prepolymer being a liquid at 65° C. or at a lower temperature and comprising coumarin ester endgroups, wherein the inherent viscosity of the polymer is between about 0.05 dL/g and about 0.8 dL/g as determined in a 0.1 g/dL solution of hexafluoroisoproanol at 25° C., in vivo is provided. In this way, polymeric networks with custom shapes are formed during surgery to prevent adhesions, to bulk tissue, or to fill tissue defects. Since the fluid prepolymer is a liquid, it can be applied to the surgical site by injection and subsequently cured by exposure to ultraviolet radiation. This series of steps may be conducted laproscopically through an appropriately design applier comprising an injection system and fiber optic light source, or more conveniently, in an open procedure with a syringe and light source.

In another embodiment of the present invention, a fluid prepolymer comprising a polymer prepared from at least one lactone monomer selected from the group consisting of ε-caprolactone, trimethylene carbonate, glycolide, L-lactide, D-lactide, DL-lactide, p-dioxanone, 5,5-dimethyl-1,3-dioxan-2-one, 1,4-dioxepan-2-one and 1,5-dioxepan-2-one, said prepolymer being a liquid at 65° C. or at -a lower temperature and comprising coumarin ester endgroups, wherein the inherent viscosity of the polymer is between about 0.05 dL/g and about 0.8 dL/g as determined in a 0.1 g/dL solution of hexafluoroisoproanol at 25° C., and at least one inorganic compound, is disclosed for use as a bone filler. The number of inorganic compounds that can be used is large. The following inorganic compounds are widely used in biomedical applications and can be incorporated as components of the bone filler of this invention: alpha-tricalcium phosphate, beta-tricalcium phosphate, calcium carbonate, barium carbonate, calcium sulfate, barium sulfate, and hydroxyapatite. In this application, the ceramic or glass filled prepolymer is placed in a boney defect with or without bone fragments from the patient and then irradiated to form a temporary defect filler that will not flow out of the desired surgical site. Drugs and growth factors may also be incorporated into the formulation of fluid prepolymer and inorganic compound.
 

Claim 1 of 2 Claims

1. A method of repairing bony defects, comprising:

filling empty spaces within a bone during an operation with a fluid prepolymer comprising a polymer prepared from at least one lactone monomer selected from the group consisting of ε- caprolactone, trimethylene carbonate, glycolide, L-lactide, D-lactide, DL-lactide, p- dioxanone, 5,5-dimethyl-1,3-dioxan-2-one, 1,4-dioxepan-2-one and 1,5-dioxepan-2-one, said prepolymer being a liquid at 65° C. or at a lower temperature and comprising coumarin ester endgroups, wherein the polymer further comprises at least one inorganic compound selected from the group consisting of alpha-tricalcium phosphate, beta-tricalcium phosphate, calcium carbonate, barium carbonate, calcium sulfate, barium sulfate and hydroxyapatite, and wherein the inherent viscosity of the polymer is between about 0.05 dL/g and about 0.8 dL/g as determined in a 0.1 g/dL solution of hexafluoroisoproanol at 25° C.; and then irradiating said fluid prepolymer in vivo, thereby forming a polymeric network in vivo.
 

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