Surgery – Means for introducing or removing material from body for... – Treating material introduced into or removed from body...
Reexamination Certificate
1999-01-28
2001-01-30
Beck, Shrive (Department: 1762)
Surgery
Means for introducing or removing material from body for...
Treating material introduced into or removed from body...
C427S002300, C427S002240, C525S054200, C523S112000
Reexamination Certificate
active
06179817
ABSTRACT:
FIELD OF INVENTION
This invention relates generally to bio-compatible substrate coatings. More particularly, the present invention relates to bio-compatible coating compositions for delivering therapeutic agents in vivo. Methods of enhancing the bio-compatibility of a substrate and of delivering a therapeutic agent in vivo through these coatings, as well as devices incorporating such coatings are also described.
BACKGROUND OF THE INVENTION
It is generally known to provide a substrate, such as a medical device or parts of such a device with bio-active coatings for the purpose of enhancing the bio-compatibility of the device when it is introduced into a mammal, such as a human body. Furthermore, it is generally known that various additives, such as therapeutic agents, can be introduced into as substrate for the purpose of releasing such additives into a mammal, such as a human body.
Endoprostheses used for minimally invasive procedures in body conduits, such as, for example, in blood vessels may be provided with bio-active coatings and may also be provided with a means to releasably incorporate a therapeutic agent. Vascular grafts, stents and graft-stent combinations are specific examples of such endoprostheses. Other useful devices include catheters, guide wires, trocars, introducer sheaths and the like.
A therapeutic agent can be incorporated into a substrate and the substrate can be implanted to provide localized delivery of the therapeutic agent. For example, U.S. Pat. No. 5,651,986 discloses a method for administering a therapeutic agent to inhibit growth of a solid tumor. The delivery of the therapeutic agent is accomplished by implanting a device proximally to the tumor where the agent is encapsulated in a biocompatible matrix on the surface of or throughout the implant. The agent is typically released by diffusion, degradation of the matrix, or a combination thereof.
Delivery of other therapeutic agents, such as taxol, is also possible. For example, U.S. Pat. No. 5,733,925 discloses a delivery system for administering taxol by encapsulating the taxol in a polymer. To encapsulate the taxol, the polymer is dissolved in a halogenated hydrocarbon solvent. The encapsulated taxol is implanted where it can be dispersed by the above-mentioned techniques.
Delivery systems for therapeutic agents can be incorporated into other, medical devices, such as a stent. International Patent Application No. PCT/US96/02125 discloses biodegradable compositions that can coat a stent and can be impregnated with a therapeutic agent. The compositions are polymers derived from the condensation of alpha hydroxycarboxylic acids and related lactones, e.g., polylactides or polyglycolides. To form the coating with a therapeutic agent, the polymer must be dissolved in a halogenated hydrocarbon solvent and the therapeutic agent is then dispersed into the solvent/polymer mixture.
The use of solvents is not limited devices that are by themselves or are incorporated as, delivery system for therapeutic agents. Medical articles or devices coated with hydrophilic coatings have been described in a number of references, some of which are discussed below. These patents all employ the use of solvents and/or the requirement for high temperature curing.
U.S. Pat. No. 4,119,094 discloses a method of coating a substrate with a polyvinylpyrrolidone-polyurethane interpolymer. In this method, a polyisocyanate and a polyurethane in a first solvent, such as, methyl ethyl ketone are applied to a substrate. The first solvent is then evaporated and polyvinylpyrrolidone in a second solvent is applied to the treated substrate. The second solvent is then evaporated.
International Patent Applications Nos. PCT/EP92/00918, PCT/EP92/00919 and PCT/DK92/00132 disclose methods for providing medical devices having polyurethane surfaces with a hydrophilic coating of poly(meth)acrylamide. Before application of the hydrophilic coating to the poly(meth)acrylamide substrate surface, it is treated with a compound having functional groups capable of reacting with the polyurethane and the poly(meth)acrylamide, respectively. This compound is typically a di- or higher isocyanate functionality in an organic solvent.
U.S. Pat. No. 5,272,012 discloses a method for applying a protective, lubricious coating to a surface of a substrate. The coating described by the '012 patent includes aprotective compound, such as a urethane; a slip additive, such as a siloxane; and an optional crosslinking agent, such as a polyfunctional aziridine. The surface of a substrate coated with such a composition, however, is not continuously lubricious. Such a coating contains separate physical domains of lubriciousness interspersed within a protective matrix, rather than a continuous layer of a lubricious agent.
U.S. Pat. No. 5,037,677 discloses a method of interlaminar grafting of continuous, hydrophilic anti-fogging coatings for acrylic intra-ocular lenses. Such a method is accomplished using at least two laminae which are not mutually soluble. For example, the '677 patent describes preparing a solution of a copolymer of ethyl methacrylate, butyl acrylate and hydroxyethyl methacrylate in an ethoxy ethyl acetate organic solvent. To this solution is added a molar excess of polyisocyanate. This solution is applied to a plexiglass substrate which is placed in a vacuum oven, where a prepolymer is formed from the two solutes while the ethoxyethyl acetate solvent is evaporated. A 0.2% sodium hyaluronate solution is then applied to the surface of the plexiglass.
The plexiglass is then returned to an oven wherein the hydroxyl groups of the Na-hyaluronate react with the isocyanate groups in the prepolymer layer. Coatings formed in such a manner as the '677 patent suffer from the drawback that organic solvents and/or other toxic chemicals are used as carriers which, if not completely removed prior to introduction of the substrate into the body, can deleteriously react in vivo to cause inflammation, blood clotting and other undesirable side effects. Thus, in order to avoid the use of such organic solvents, some non-solvent methods have been developed.
For example, EP Pat. Application Nos. 92100787.8 and EP 0496 305 A2 disclose methods for preparing a shaped medical. article with a lubricous coating. In these methods, a coating composition that includes a blend of polyurethane and polyvinylpyrrolidone is co-extruded with a substrate polymer to produce a shaped article having on a surface thereof a layer of the coating composition which becomes lubricous when contacted with water.
U.S. Pat. No. 5,041,100 discloses a method for coating a substrate with a mixture of poly(ethylene oxide) and an aqueous dispersion of a structural plastic material, e.g. polyurethane. As an example, this patent discloses a non-crosslinked admixture of poly(ethylene oxide) and a structural plastic material. This composition provides a hydrophilic character to the substrate which may leach to the surface thereof, or be entrapped adjacent to the surface to provide a hydrophilic, reduced friction character thereto, particularly when hydrated.
The methods in the above-described references suffer from the drawback that inter-polymer networks which physically attach hydrophilic polymers to their substrates often break down upon prolonged turbulent flow or soaking. Furthermore, the hydrophilic species are weakly attached to their substrates and can be easily washed away, thereby rendering the underlying article insufficiently lubricous.
International Pat. Application No. PCT/DK91/00163, co-owned with the present invention, discloses a method of providing a medical instrument with a hydrophilic, low-friction coating. This method includes the steps of (1) forming an inner layer on the substrate from an aqueous polymer emulsion, (2) forming an outer layer on top of the inner layer from an aqueous solution of a water-soluble hydrophilic polymer and (3) curing the two layers simultaneously by heating to a temperature above 100° C.
Although the use of organic solvents is eliminated in this method, high cur
Beck Shrive
Boston Scientific Corporation
Hoffmann & Baron , LLP
Kolb Jennifer
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