The present invention provides curable materials, medical devices incorporating such materials, wherein the curable materials are capable of releasing hydrolyzable leaving agents upon hydrolysis that can form agents (e.g., pharmaceutically active agents), and methods of making and using such materials and devices.

Description of the Invention

SUMMARY OF THE INVENTION

The present invention provides curable materials (preferably biocompatible materials) that are capable of releasing hydrolyzable leaving groups upon hydrolysis. The curable materials can include monomers, oligomers, polymers, or mixtures thereof. Such monomers, oligomers, and polymers are referred to herein as prepolymers (i.e., a material capable of forming a polymer or further polymerizing and/or crosslinking). The prepolymer includes at least one hydrolyzable group bonded to at least one silicon atom.

Significantly, upon contact with an aqueous bodily fluid the prepolymer is hydrolyzed thereby releasing a leaving group, which is preferably a biocompatible material and more preferably a biologically active agent, and a silanol-containing reactive intermediate, which is subsequently cured (i.e., polymerized and/or crosslinked) upon condensation. Thus, the prepolymer is capable of releasing a biologically active agent and curing in situ (i.e., in the body of a subject).

Preferably, the hydrolyzable leaving group forms a biocompatible compound (i.e., the hydrolyzed leaving group) upon hydrolysis of the prepolymer and release of the hydrolyzed group. Alternatively and more preferably, the hydrolyzable leaving group forms a pharmaceutically active agent (i.e., the hydrolyzed leaving group) upon hydrolysis of the prepolymer and release of the hydrolyzed group.

Upon release of the hydrolyzable leaving group, the prepolymer forms a curable intermediate (i.e., a polymerizable and/or crosslinkable intermediate). The curable intermediate is preferably biocompatible and forms a biocompatible polymer upon condensation, preferably in the body of a subject.

Preferably, hydrolyzed leaving group is a pharmaceutically active agent. It preferably includes one or more hydroxyl groups (e.g., an alcohol or phenol), carboxylic acid groups, amine groups (e.g., a primary or secondary amine), urea groups, carbamate groups, amide groups, urethane groups, hemiacetal groups, hemiketal groups, or combinations thereof (e.g., amino acids, vicinal diols, hydroxy acids). Specific examples of pharmaceutically active agents include those selected from the group consisting of salicylic acid, fenbufen, cortisone, ibuprofen, diflunisal, sulindac, difluprednate, prednisone, medrysone, acematacin, indomethacin, meloxicam, camptothecin, benoxinate, benzocaine, procaine, ciprofloxacin, norfloxacin, clofoctol, and combinations thereof.

In one embodiment, the present invention provides an implantable medical device that includes a curable material that includes one or more prepolymers, which can be in the form of monomers, oligomers, polymers, or mixtures thereof. The prepolymer includes at least one silicon atom (per molecule) and at least one hydrolyzable leaving group bonded to at least one silicon atom (per molecule).

In another embodiment, the present invention provides a curable (preferably biocompatible) material that includes one or more prepolymers that include at least one silicon atom and at least one hydrolyzable leaving group bonded to at least one silicon atom, wherein the hydrolyzable leaving group forms a pharmaceutically active agent upon hydrolysis of the prepolymer and release of the hydrolyzable leaving group.

The prepolymer can include a wide variety of ratios of silicon atoms to hydrolyzable groups. For example, the prepolymer can include one or more silicon atoms per one hydrolyzable group, wherein the hydrolyzable group can be a terminal group bonded to the silicon atom. Alternatively, the prepolymer can include one silicon atom per one or two hydrolyzable groups or per one to three hydrolyzable groups. Alternatively, the prepolymer can include two silicon atoms per one hydrolyzable group, wherein the hydrolyzable group can be bonded to the two silicon atoms to form a linear polymer or a ring. Alternatively, the prepolymer can include one or more silicon-bonded hydrolyzable leaving groups pendant from a polymeric chain.

In certain embodiments, the prepolymer is a polymer and further includes a poly(alkylene oxide) segment, a polysiloxane segment, a polyester segment, a poly(vinyl pyrrolidone) segment, a polyacrylate segment, a polymethacrylate segment, a polycarbonate segment, a hydrocarbon segment, a polycarbosilane segment, a fluoropolymeric segment, a polyoxazoline segment, or mixtures or copolymers thereof.

In certain embodiments, the hydrolyzable leaving group forms a biocompatible compound upon hydrolysis of the prepolymer and release of the hydrolyzable leaving group. In other embodiments, the hydrolyzable leaving group forms a pharmaceutically active agent upon hydrolysis of the prepolymer and release of the hydrolyzable leaving group.

In certain embodiments, a curable intermediate is formed upon hydrolysis of the prepolymer and release of the hydrolyzable leaving group. This curable intermediate typically and preferably forms a biocompatible polymer upon condensation in the body of a subject. Preferably, the curable intermediate includes at least two silanol groups.

The prepolymer can be formed by polymerizing a polymerizable monomer that includes at least one silicon atom and at least one hydrolyzable leaving group bonded to at least one silicon atom. The polymerizable monomer can be formed by reacting a pharmaceutically active agent and a silicon-containing starting material of the formula SiX.sub.xR.sub.y wherein: each X is independently a halogen, pseudohalogen, alkoxy, or acetoxy; each R is independently hydrogen or an organic group; and x=0-4, y=0-4, and x+y=4. The polymerizing reaction can be, for example, a hydrosilylation reaction or an alkene metathesis reaction.

Alternatively, the polymerizable monomer can be formed by reacting a pharmaceutically active agent and a silicon starting material of the formula X.sub.x'R.sub.y'Si--R.sup.1--SiX.sub.x'R.sub.y' wherein: each X is independently a halogen or pseudohalogen; each R is independently hydrogen or an organic group; R.sup.1 is an alkylene, a divalent siloxane, a divalent oligo- or poly-alkylene oxide, a divalent carbosilane; and x'=0-3, y'=0-3, and x'+y'=3. Alternatively, this same silicon starting material can be used to make the prepolymer per se.

Alternatively, the prepolymer can be formed directly by reacting a pharmaceutically active agent and a silicon-containing polymer.

As used herein, a "biocompatible" material or compound may be defined as a material or compound that is substantially insoluble in body fluids and tissues and that is designed and constructed to be placed in or onto the body or to contact fluid or tissue of the body. Ideally, a biocompatible material or compound will not induce undesirable reactions in the body such as blood clotting, tissue death, tumor formation, allergic reaction, foreign body reaction (rejection) or inflammatory reaction; will have the physical properties such as strength, elasticity, permeability and flexibility required to function for the intended purpose; can be purified, fabricated and sterilized easily; and will substantially maintain its physical properties and function during the time that it remains implanted in or in contact with the body.

As used herein, a "medical device" may be defined as a device that has surfaces that contact tissue, bone, blood or other bodily fluids in the course of their operation, which fluids are subsequently used in patients. This can include, for example, extracorporeal devices for use in surgery such as blood oxygenators, blood pumps, blood sensors, tubing used to carry blood and the like which contact blood which is then returned to the patient. This can also include endoprostheses implanted in blood contact in a human or animal body such as vascular grafts, stents, pacemaker leads, heart valves, and the like, that are implanted in blood vessels or in the heart. This can also include devices for temporary intravascular use such as catheters, guide wires, and the like which are placed into the blood vessels or the heart for purposes of monitoring or repair. Preferably, medical devices of the present invention are implantable medical devices (i.e., those that are implanted into a body and remain in the body for an extended period (e.g., greater than 28 days)).

As used herein, the terms "pharmaceutically active agent," "biologically active agent," and "active agent," are used interchangeably and include pharmacologically active substances that produce a local or systemic effect in an animal. The terms thus mean any substance intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease or in the enhancement of desirable physical or mental development and conditions in a subject.

The term "subject" used herein is taken to include humans, sheep, horses, cattle, pigs, dogs, cats, rats, mice, birds, reptiles, fish, insects, arachnids, protists (e.g., protozoa), and prokaryotic bacteria. Preferably, the subject is a human or other mammal.

The terms "comprises" and variations thereof do not have a limiting meaning where these terms appear in the description and claims.

As used herein, "a," "an," "the," "at least one," and "one or more" are used interchangeably.

Also herein, the recitations of numerical ranges by endpoints include all numbers subsumed within that range (e.g., 1 to 5 includes 1, 1.5, 2, 2.75, 3, 3.80, 4, 5, etc.).

DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS

The present invention provides curable materials (preferably biocompatible materials) that are capable of releasing hydrolyzable leaving groups (preferably, biologically active agents) upon hydrolysis. The curable material includes one or more prepolymers that include at least one hydrolyzable group bonded to silicon. The prepolymers may include polymers, monomers, oligomers, or mixtures thereof. The curable materials are referred to herein as "curable" because they form intermediates that are curable (which can occur through polymerization, crosslinking, or both). These intermediates are the molecules remaining after hydrolysis of the prepolymer and release of the hydrolyzable leaving group. The curable intermediate is also preferably biocompatible. Upon condensation of the intermediate, a biocompatible polymer is formed, preferably in the body of a subject. Preferably, the curable intermediate includes at least two silanol groups, which are capable of undergoing condensation.

Significantly, in preferred embodiments, upon contact with an aqueous bodily fluid the curable material is hydrolyzed, thereby cleaving the bond or bonds between the hydrolyzable group(s) and silicon atom(s) and forming biologically active agent(s) and silanol-containing reactive intermediate(s), which can subsequently cure (i.e., polymerize and/or crosslink) upon condensation. Thus, a preferred curable material of the present invention is capable of releasing a biologically active agent and polymerizing in situ.

It has been discovered that incorporation of a biologically active agent into a polymeric matrix provides a polymer-bound active agent adduct composition that can be applied with specificity to a biological site of interest. Site specific application of the polymer-bound adduct composition enhances the selectivity of action of the active agent. If active agents attached to the polymer are necessarily localized, then the effect of the release of the active agents will be concentrated in the tissues with which they are in contact.

The curable materials of the present invention are capable of releasing such biologically active agents, or other hydrolyzable leaving groups, ispontaneously upon contacting an aqueous environment. That is, they do not require activation through a redox reaction or electron transfer reaction such as is required for glyceryl trinitrate and sodium nitroprusside. Preferably, the active agents, or other hydrolyzable leaving groups, are released under physiological conditions.

Although it is preferred that the hydrolyzable leaving group forms a biocompatible compound (i.e., the hydrolyzed leaving group) upon hydrolysis of the prepolymer and release of the hydrolyzed group, it is not a requirement that such released compound be biocompatible.

In some embodiments, it may be advantageous to release molecules other than pharmaceutically active molecules. In these embodiments, a prepolymer may be designed such that the molecule released has minimal physiological effect, as an alternative to pharmaceutically active molecules. Such molecules include amino acids, alditols, synthetic polyols (such as pentaerythritol), carbohydrates, alcohols, fatty acids, vitamins, aspartame, glyceraldehydes, and the like. For example, the dosage of a pharmaceutically active agent could be controlled by synthesizing the prepolymer from starting materials that are derived from both the desired active agent and from other molecules that can undergo hydrolysis, but have minimal physiological effect. In other embodiments, it may be desirable to release only a small molecule (preferably less than 1000 grams per mole (g/mol), and more preferably less than 200 g/mol) from the prepolymer that is not pharmaceutically active. For example, if it is desirable that the prepolymer show low shrinkage as it cures, use of such a small molecule may facilitate this goal.

Alternatively and more preferably, the hydrolyzable leaving group forms a pharmaceutically active agent (i.e., the hydrolyzed leaving group) upon hydrolysis of the prepolymer and release of the hydrolyzed group.

The active agents that can be delivered according to the present invention include inorganic and organic drugs, without limitation, and include drugs that act on the peripheral nerves, adrenergic receptors, cholinergic receptors, nervous system, skeletal muscles, cardiovascular system, smooth muscles, blood circulatory system, synaptic sites, neuro-effector junctional sites, endocrine system, hormone systems, immunological system, reproductive system, skeletal system, autocoid systems, alimentary and excretory systems (including urological systems), histamine systems, and the like. Such conditions, as well as others, can be advantageously treated using the materials of the present invention.

For example, currently used injectable agents in the treatment of female stress urinary incontinence include polytetrafluoroethylene, autologous fat, collagen, silicone microparticles, silicone microballoons, and pyrolytic carbon. All of these materials have drawbacks, such as particle migration or decreased efficacy over time. None of them is more than about 70% effective over long time periods. There exists a need for better injectable materials that are not particulate (to prevent migration) and that maintain their physical properties and effectiveness for longer periods. Polymers have also been injected near the lower esophageal sphincter to mitigate gastroesophageal reflux disease. Current approaches include injecting a solid prosthesis fabricated from a dehydrated hydrophilic polymer and injecting poly(vinyl alcohol) which has been dissolved in dimethylsulfoxide. In both of these applications, releasing a pharmaceutically active agent as the injected polymer cures may improve patient outcomes or recovery.

The active agents that can be delivered using the materials of the present invention include, but are not limited to, anticonvulsants, analgesics, antiparkinsons, antiinflammatories (e.g., ibuprofen, fenbufen, cortisone, and the like), calcium antagonists, anesthetics (e.g., benoxinate, benzocaine, procaine, and the like), antibiotics (e.g., ciprofloxacin, norfloxacin, clofoctol, and the like), antimalarials, antiparasitics, antihypertensives, antihistamines, antipyretics, alpha-adrenergic agonists, alpha-blockers, biocides, bactericides, bronchial dilators, beta-adrenergic blocking drugs, contraceptives, cardiovascular drugs, calcium channel inhibitors, depressants, diagnostics, diuretics, electrolytes, enzymes, hypnotics, hormones, hypoglycemics, hyperglycemics, muscle contractants, muscle relaxants, neoplastics, glycoproteins, nucleoproteins, lipoproteins, ophthalmics, psychic energizers, sedatives, steroids sympathomimetics, parasympathomimetics, tranquilizers, urinary tract drugs, vaccines, vaginal drugs, vitamins, collagen, hyaluronic acid, nonsteroidal anti-inflammatory drugs, angiotensin converting enzymes, polynucleotides, polypeptides, polysaccharides, and the like.

Preferably, a pharmaceutically active agent (or other hydrolyzed, i.e., released, leaving group) includes one or more active hydrogen atoms. These can be present in one or more hydroxyl groups (e.g., an alcohol or phenol), carboxylic acid groups, amine groups (e.g., a primary or secondary amine), urea groups, carbamate groups, amide groups, urethane groups, hemiacetal groups, hemiketal groups, or combinations thereof (e.g., amino acids, vicinal diols, hydroxy acids).

Exemplary active agents include, but are not limited to, salicylic acid, fenbufen, cortisone, ibuprofen, diflunisal, sulindac, difluprednate, prednisone, medrysone, acematacin, indomethacin, meloxicam, camptothecin, benoxinate, benzocaine, procaine, ciprofloxacin, norfloxacin, clofoctol, and combinations thereof. Preferred active agents are salicylic acid, fenbufen, cortisone, ibuprofen, diflunisal, and sulindac, which are shown below. Any one prepolymer can include two or more different active agents -- see Original Patent.

In addition to silicon and at least one hydrolyzable group bonded to silicon, certain exemplary curable materials are polymeric (although they may also be oligomeric and monomeric). If the prepolymers are polymeric, they preferably further include a polymeric segment such as a poly(alkylene oxide) segment, a polysiloxane segment, a polyester segment, a poly(vinyl pyrrolidone) segment, a polyacrylate segment, a polymethacrylate segment, a polycarbonate segment, a hydrocarbon segment, a polycarbosilane segment, a fluoropolymeric segment, a polyoxazoline segment, or mixtures or copolymers thereof. Such segments typically form a polymer backbone. Preferred such polymer backbones include a polysiloxane segment, a poly(alkylene oxide) segment, a hydrocarbon segment, a polycarbosilane segment, or mixtures or copolymers thereof. Combination of different polymeric segments can be included in any one prepolymer.

The following structures are representations of compounds wherein the arcs or wavy lines represent a polymer backbone (i.e., the polymer segments listed above), M represents the hydrolyzable leaving group (e.g., a group derived from the desired active agent to be delivered), and R represents nonreactive organic groups, such as methyl. Preferred R groups include up to 20 carbon atoms and may optionally include oxygen atoms in the chain as in oligo(alkylene oxides).

In certain embodiments, the curable material includes a prepolymer that includes one or more silicon atoms per one hydrolyzable group. Such hydrolyzable group can be a terminal group bonded to the silicon atom, although this is not a requirement. Examples of such a material are represented by the following four structures -- see Original Patent.

In structure I, the prepolymer is linear and would yield a linear polymer upon hydrolysis and condensation.

In structure II, the prepolymer is shown with the pharmaceutically active agent salicylic acid as M. Upon hydrolysis and condensation, this prepolymer would generate a comb or brush polymer. For example, the backbone of the comb polymer would be a polysiloxane, and the teeth of the comb polymer would be formed by the polymer tail shown as the wavy line, which could be poly(ethylene oxide), for example.

In structure III, the prepolymer would generate a denser comb upon hydrolysis and condensation due to the presence of two tails per silicon atom.

In structure IV, the prepolymer would form a comb polymer that has a polysiloxane backbone. The teeth of the comb would correspond to the polymeric segment represented by the wavy line.

In certain embodiments, the curable material includes a prepolymer that includes one silicon atom per one or two hydrolyzable groups. Examples of such a material is represented by the following two structures -- see Original Patent.

In structure V, the prepolymer would yield a crosslinked polymer with free chain ends upon hydrolysis and condensation.

In structure VI, the prepolymer would yield a crosslinked polymer with no free chain ends upon hydrolysis and condensation.

In certain embodiments, the curable material includes a prepolymer that includes one silicon atom per one to three hydrolyzable groups. Examples of such a material is represented by the following two structures -- see Original Patent.

In structure VII, the prepolymer would yield a crosslinked polymer upon hydrolysis and condensation. The M's could be separate moieties or they could represent a multi-functional (e.g., di- or tri-functional) hydrolyzable leaving group.

In structure VIII, the prepolymer is star-shaped. The M's could be separate moieties or they could represent a multi-functional (e.g., di- or tri-functional) hydrolyzable leaving group.

In certain embodiments, the curable material includes a prepolymer that includes one hydrolyzable group bonded to two silicon atoms. Examples of such a material are represented by the following two structures -- see Original Patent.

In structure IX, the hydrolyzable group is bonded to the two silicon atoms to form a linear polymer. The prepolymer would yield a linear polymer upon hydrolysis and condensation with the M's being replaced by oxygen atoms.

In structure X, the hydrolyzable group is bonded to two silicon atoms to form a ring. The prepolymer would yield a linear polymer upon hydrolysis and condensation with the backbone segments joined by tetramethyldisiloxane moieties.

In certain embodiments, the curable material includes a prepolymer that includes one or more silicon-bonded hydrolyzable groups pendant from the main chain of a polymer. An example of such a material is represented by the structure shown in the following reaction scheme -- see Original Patent.

Prepolymers of the present invention can be made in a number of ways. For example, in certain embodiments, the prepolymer can be formed by polymerizing a polymerizable monomer comprising silicon and a hydrolyzable leaving group. The polymerizable monomers include at least one polymerizable group attached to the silicon. Examples of polymerizable groups include ethylenically unsaturated groups (e.g., --CH.dbd.CH.sub.2, (meth)acrylates, --CH.sub.2CH.sub.2CH.sub.2CH.dbd.CH.sub.2) and active hydrogen atoms.

Examples of polymerizable monomers include those shown below with a salicylic acid (Compounds 1-5), fenbufen (Compound 6), or benzocaine (Compounds 7 and 8) precursors as the hydrolyzable leaving group -- see Original Patent.

Polymerizable monomers can be formed by reacting a pharmaceutically active agent and a silicon-containing starting material. Typically, at least one silicon-containing starting material is reacted with at least one pharmaceutically active agent (preferably with at least one active hydrogen atom) to form the polymerizable monomer.

A preferred silicon-containing starting material is of the formula SiX.sub.xR.sub.y wherein: each X is independently a halogen (preferably, chlorine), pseudohalogen (preferably, nitrile), alkoxy (preferably, a C1-C20 alkoxy, and more preferably, methoxy or ethoxy), or acetoxy (preferably, C1-C20 acetoxy, and more preferably, acetyloxy)); each R is independently hydrogen or an organic group; and x=0-4, y=0-4, and x+y=4. Preferably, each R is independently hydrogen, an alkyl (preferably, C1-C20 alkyl, and more preferably, C1-C10 alkyl), an alkenyl (preferably, C3-C20 alkenyl in which at least one double bond is within six carbons from the terminus, and more preferably, vinyl), a vinyl ether (e.g., --CH.sub.2CH.sub.2--O--CH.dbd.CH.sub.2), an allyl (e.g., --CH.sub.2CH.dbd.CH.sub.2), an allyl ether (e.g., --CH.sub.2CH.sub.2OCH.sub.2CH.dbd.CH.sub.2), an alkynyl (e.g., ethynyl, --C.ident.--CH), a (meth)acrylate (e.g., CH.sub.2.dbd.C(CH.sub.3)CO.sub.2CH.sub.2CH.sub.2--), or an acrylamide (e.g., CH.sub.2.dbd.CHCON(CH.sub.3)CH.sub.2CH.sub.2--). Examples of silicon-containing starting materials include SiCl.sub.2(CH.sub.3)(CH.dbd.CH.sub.2), SiCl.sub.2(CH.dbd.CH.sub.2).sub.2, SiCl.sub.2H.sub.2, SiCl.sub.2H(CH.sub.3), SiCl(CH.sub.3).sub.2(CH.dbd.CH.sub.2), SiClH(CH.sub.3).sub.2, SiCl.sub.4, SiCl.sub.3(CH.sub.3), and SiCl(CH.sub.3)(CH.dbd.CH.sub.2).sub.2.

The polymerizable monomers can be reacted with other polymerizable monomers to form prepolymers of the present invention. A wide variety of monomers that do not include silicon can be used. Examples include vinyltelechelic poly(ethylene glycol) or poly(propylene glycol), 1,5-hexadiene, and 1,7-octadiene. They can also be reacted with monomers that do contain silicon atoms, such as dimethyldivinylsilane, trimethylsilane, trimethylvinylsilane, and the following compound (Compound 9 in the Examples Section) -- see Original Patent.

The polymerization reaction can involve a variety of mechanisms including hydrosilylation, alkene metathesis, vinyl radical polymerization, ring opening polymerization, ionic polymerization (including anionic polymerization).

Exemplary reaction schemes for forming prepolymers by initially reacting a silicon-containing starting material with a pharmaceutically active agent are shown below -- see Original Patent.

Alternatively, the same reactive prepolymer may be synthesized by the route shown below -- see Original Patent.

Exemplary reaction schemes for forming prepolymers by directly reacting a silicon-containing starting material with a pharmaceutically active agent are shown below -- see Original Patent.

Prepolymers of the present invention can be used in various combinations for various applications. They can be used as tissue-bulking agents in urological applications for bulking the urinary sphincter to prevent stress incontinence or in gastrological applications for bulking of the lower esophageal sphincter to prevent gastroesophageal reflux disease. They can be used for replacements for nucleus pulposis or repair of annulus in intervertebral disc repair procedures. They can be used as tissue adhesives or sealants. They can be used as surgical void fillers, for example, in reconstructive or cosmetic surgery (e.g., for filling a void after tumor removal). They can be used to repair aneurysms, hemorrhagic stroke or other conditions precipitated by failure of a blood vessel. They can be used as an antiadhesion agent. They can be used in a wide variety of other applications in which a material is needed that will increase strength and/or modulus after implantation.

Prepolymers of the present invention can be used in injectable compositions. Such injectable materials could be used as tissue bulking agents (e.g., for the treatment of urinary stress incontinence, for the treatment of gastroesophageal reflux disease, or serving to augment a degenerated intervertebral disc), void fillers (e.g., in cosmetic or reconstructive surgery, such as serving as a replacement for the nucleus pulposis), or as an injectable drug delivery matrix.

In some embodiments, no additives would be needed to form an injectable composition. In some embodiments, one or more prepolymers can be combined with a solvent such as dimethylsulfoxide (DMSO), which is a fairly biocompatible solvent. The DMSO diffuses away after injection and the polymer remains in place.

Also, injectable compositions could include crosslinkers (such as triethoxymethylsilane), plasticizers (such as dioctyl phthalate), lipids (soybean oil), poly(ethylene glycol) (with the ends blocked with methyls or similar groups), silicone oil, partially or fully fluorinated hydrocarbons, N-methyl-2-pyrrolidone, or mixtures thereof.

Prepolymers of the present invention can be used in combination with a variety of particulate materials. For example, they can be used with moisture curing ceramic materials (e.g., tricalcium phosphate) for vertebroplasty cements, bone void filling (due to disease such as cancer or due to fracture). They can be used in combination with inorganic materials such as hydroxylapatite to form pastes for use in bone healing, sealing, filling, repair, and replacement. They can be used in combination with polymer microspheres that can be reservoirs for a biologically active agent such as a protein, DNA plasmid, RNA plasmid, antisense agent, etc. Alternatively, they can be used in combination with solid polymer particulate materials, such as polytetrafluoroethylene for forming a composite matrix with greater modulus than that provided by the polymer alone, or imaging particulate materials such as barium sulfate for visualizing material placement using fluoroscopy, for example. They can be combined with fibers, woven or nonwoven fabric for reconstructive surgery, such as the in situ formation of a bone plate or a bone prosthesis.

Curable materials of the present invention can also be applied to a desired site (e.g., a surgical site) using a syringe, catheter, or by hand.

Alternatively, curable materials of the present invention can be coated onto a substrate if desired. A coating mixture of the prepolymer can be prepared using solvents such as toluene, chloroform, tetrahydrofuran, perfluorinated solvents, as well as other organic solvents that can be rendered moisture-free and have no active hydrogens. The coating mixture can be applied to an appropriate substrate such as polymer coated medical wires, stents, prostheses, penile inserts, and the like, by conventional coating application methods. Such methods include, but are not limited to, dipping, spraying, wiping, painting, solvent swelling, and the like. After applying the coating solution to a substrate, the solvent is preferably allowed to evaporate from the coated substrate.

The materials of a suitable substrate include, but are not limited to, polymers, metal, glass, ceramics, composites, and multilayer laminates of these materials. The coating may be applied to metal substrates such as the stainless steel used for guide wires, stents, catheters and other devices. Organic substrates that may be coated with the prepolymers of this invention include, but are not limited to, polyether-polyamide block copolymers, polyethylene terephthalate, polyetherurethane, polyesterurethane, other polyurethanes, natural rubber, rubber latex, synthetic rubbers, polyester-polyether copolymers, polycarbonates, and other organic materials.

Additives that can be combined with the curable material in a composition include, but are not limited to, wetting agents for improving wettability to hydrophobic surfaces, viscosity and flow control agents to adjust the viscosity and thixotropy of the mixture to a desired level, antioxidants to improve oxidative stability of the cured coatings, dyes or pigments to impart color or radiopacity, and air release agents or defoamers, cure catalysts, cure accelerants, plasticizers, solvents, stabilizers (cure inhibitors, pot-life extenders), and adhesion promoters.
 

Claim 1 of 18 Claims

1. An implantable medical device comprising a coating, the coating comprising a curable material comprising a prepolymer comprising at least one silicon atom and at least one hydrolyzable leaving group bonded to at least one silicon atom, the hydrolyzable leaving group being free of acidic hydrogen atoms, wherein upon hydrolysis of the prepolymer, the prepolymer forms a curable intermediate and the hydrolyzable leaving group is released, and wherein the released hydrolyzable leaving group is a salicylic moiety, wherein the implantable medical device is designed to remain in a subject for more than 28 days.
 

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