WO2008033533A2

WO2008033533A2 - Composite drug delivery system

Info

Publication number: WO2008033533A2
Application number: PCT/US2007/020059
Authority: WO
Inventors: David M. Gravett; Shalaby W. Shalaby; Dechi Guan; Philip M. Toleikis; Larry Murphy; Kenneth Bruce Ii Thurmond
Original assignee: Angiotech Pharmaceuticals, Inc.
Priority date: 2006-09-15
Filing date: 2007-09-14
Publication date: 2008-03-20
Also published as: WO2008033533A3

Abstract

A present invention provides composite drug delivery systems and methods for maintaining or improving a integrity of body passageways (i.e., for example, blood vessels) following surgery, such as at a graft site, or injury. Delivery systems including one or more bioactive agents and a polymer matrix, reinforced by a fibrous construct are described. The fibrous constructs provide a predictable rate of degradation and therapeutic agent release based upon surface area and density relationships. Representative examples of bioactive agents include microtubule stabilizing agents (i.e., for example, paclitaxel), anti-angiogenic factors, inhibitors of smooth muscle cell growth or proliferation, non-steroidal anti-inflammatory drugs, and some factors useful preventing and/or reducing a proliferative biological response that may obstruct or hinder a optimal functioning of a passageway or cavity.

Description

Composite Drug Delivery System

Field Of The Invention

The present invention relates generally to a composite drug delivery system and methods for improving and maintaining the integrity of body passageways or cavities following surgery or injury, and more specifically, to composite drug delivery systems that include therapeutic agents which may be delivered to body passageways or cavities for the purpose of preventing and/or reducing a proliferative biological response that may obstruct or hinder the optimal functioning of a passageway or cavity. The device comprises fibrous constructs that provide a predictable rate of degradation and therapeutic agent release based upon surface area and density relationships. '

Background Of The invention

Each year, thousands of people lose the ability to deliver sufficient blood to various limbs of the body. When blood vessels do fail, natural or artificial grafts may be used to restore vessel function. For example, in patients who must undergo chronic injections or puncturing of blood vessels, the insulted blood vessel(s) may ultimately die. This may occur in patients suffering from end-stage renal failure, who may require hemodialysis and multiple injections or punctures. Many artificial grafts, such as those made from expanded polytetrafluoroethylene (ePTFE) or poly(ethylene terephthalate), have been designed to act, and have been used, as replacement blood conduits. Hence, needles or some medical devices may be repeatedly used on an on-going basis to penetrate a graft without causing the death of the blood vessel.

Although these grafts have been used successfully for many years, many fail for a variety of reasons. For example, thrombus formation may arise from reduced blood flow due to intimal hyperplasia, which occurs at a venous anastomosis (i.e., for example, at a blood vessel-graft attachment site). A thrombus arising from intimal hyperplasia may result in graft occlusion and graft failure. Factors thought to contribute to the occurrence of intimal hyperplasia include, for example, changes in blood flow hemodynamics along with damage to the vessel endothelium, compliance differences between a graft and a blood vessel, and changes in blood vessel stress. The development of intimal hyperplasia arising from an arteriole-venous bypass graft placement is only one of many examples whereby intimal hyperplasia may occur following device placement.

To increase the potency of these devices, a method for reducing the degree of intimal hyperplasia is required. In this regard, several systemic pharmacotherapies have been tried. For example, pharmacotherapeutic regimes have included systemic anti-platelet therapies, such as aspirin and heparin. While these treatments have demonstrated some degree of efficacy in reducing intimal hyperplasia in animal models, no efficacy has been demonstrated in clinical studies. Methods of local drug delivery to the inside of a vessel have also failed to produce efficacy in a clinic.

What is needed in the art is a drug delivery device capable of predictable high efficiency loading and drug elution profiles.

Summary Of The Invention The present invention relates generally to composite drug delivery systems and methods for improving or maintaining the integrity of body passageways or cavities following surgery or injury. The composite drug delivery systems include one or more therapeutic agents and may be delivered to the external walls of body passageways or cavities for the purpose of preventing and/or reducing a proliferative biological response that may obstruct or hinder the optimal functioning of a passageway or cavity. The device comprises fibrous constructs that provide a predictable rate of degradation and therapeutic agent release based upon surface area and density relationships.

In one embodiment, the present invention contemplates a device, comprising: a) a fabric having a density of about 2.5 mg/cm² to about 5.0 mg/cm²; b) a matrix coating said fabric, wherein said coating comprises a polyether-polyester copolymer; and c) a therapeutic agent within said matrix, wherein said matrix is capable of releasing about 85% of said therapeutic agent in about 7 days. In one embodiment, the fabric comprises a polymer fiber with a molar ratio of glycolide:L-lactide ranging between about 97:3 to about 85:15. In one embodiment, the device releases about 40% to about 60% of said therapeutic agent in about 7 days. In one embodiment, the device releases about 50% to about 80% of said therapeutic agent in about 7 days. In one embodiment, the device releases about 25% to about 55% of said therapeutic agent within 24 hours. In one embodiment, the fabric comprises a density of about 3.0-3.5 mg/cm². In one embodiment, the fiber comprises a denier of about 80 to 100 grams. In one embodiment, the fiber has a denier of about 70 to 90 grams. In one embodiment, the fiber comprises a plurality of filaments, wherein said filaments have diameters of about 10-30 microns. In one embodiment, the filaments have diameters of about 15-25 microns. In one embodiment, the fabric comprises a stitch count of about 5 to about 25 stitches/cm. In one embodiment, the fabric comprises a stitch count of about 30 to about 100 stitches/cm. In one embodiment, the matrix is about 10 mg to about 25 mg. In one embodiment, the matrix is about 10 mg about 15 mg. In one embodiment, the matrix is about 15 to about 25 mg. In one embodiment, the therapeutic agent is about 0.3 mg to about 2.2 mg. In one embodiment, the therapeutic agent is about 1.25 mg to about 2.0 mg. In one embodiment, the therapeutic agent is about 0.13 mg/cm² to about 0.20 mg/cm². In one embodiment, the therapeutic agent is about 0.06 mg/cm² to about 0.1 mg/cm². In one embodiment, the fiber comprises a tenacity of about 3 g/denier to 6 g/denier. In one embodiment, the fiber comprises an elongation of about 10% to about 50%. In one embodiment, the fiber comprises a melting temperature of about 200-225 ⁰C. In one embodiment, the fiber comprises at least one filament having a diameter of about 8 to 25 microns. In one embodiment, the polyether-polyester copolymer comprises a weight average molecular weight of at least 3 kDa. In one embodiment, the polyether-polyester copolymer comprises a molecular weight of about 6000 Da to about 9000 Da. In one embodiment, the polyether-polyester copolymer comprises a molecular weight of about 6000 Da to about 7000 Da. In one embodiment, the polyether-polyester copolymer comprises a molecular weight of about 7000 Da to about 9000 Da. In one embodiment, the matrix and said fabric comprise a weight ratio of about 90/10 to about 70/30. In one embodiment, the weight ratio comprises about 70/30 to about 50/50. In one embodiment, the weight ratio comprises about 50/50 to about 30/70. In one embodiment, the weight ratio comprises about 30/70 to about 10/90. In one embodiment, the polyether copolymer is a polyether glycol. In one embodiment, the polyether glycol is a polyethylene glycol. In one embodiment, the polyethylene glycol is polyethylene glycol monomethyl ether. In one embodiment, the polyether glycol is selected from the group consisting of a polypropylene glycol, a copolymer of ethylene and propylene oxide, a copolymer of polyethylene glycol, and a polypropylene glycol. In one embodiment, the polyester copolymer comprises at least one monomer selected from the group consisting of glycolide, L-lactide, D,L-lactide, ε-caprolactone, trimethylene carbonate, p-dioxanone, and morpholinedione. In one embodiment, the polyether-polyester copolymer comprises at least one monomer residue selected from the group consisting of glycolide, L-lactide, D, L-lactide, and meso-lactide. In one embodiment, the matrix further comprises a graft copolymer selected from the group consisting of a polyethylene glycol monomethyl ether, glycolide monomers, and lactide monomers. In one embodiment, the therapeutic agent comprises paclitaxel or an analogue or derivative thereof. In one embodiment, the therapeutic agent is paclitaxel. In one embodiment, the therapeutic agent is selected from the group consisting of sirolimus, everolimus, tacrolimus, an analogue and a derivative thereof. In one embodiment, the device is less than 500 microns thick. In one embodiment, the device is about 100 microns to about 400 microns thick. In one embodiment, the device degrades over a period of about 60 days to about 120 days in vivo. In one embodiment, the device degrades over a period of about 60 days to about 90 days in vivo. In one embodiment, the fabric is knitted, hi one embodiment, the knitted fabric has a surface area ranging from about 3000 to about 10,000 mm². In one embodiment, the surface area ranges from about 3500 to about 5000 mm². In one embodiment, the surface area ranges from about 7000 to about 9000 mm². In one embodiment, the matrix comprises about 80% to about 95% by weight of said polyether- polyester copolymer and about 5% to about 20% of said therapeutic agent. In one embodiment, the matrix comprises about 80% to about 90% by weight of said polyether- polyester copolymer and about 10% to about 20% of said therapeutic agent. In one embodiment, the matrix comprises about 85% to about 90% by weight of said polyether- polyester copolymer and about 10% to about 15% of said therapeutic agent. In one embodiment, the matrix comprises about 85% to about 95% by weight of said polyether- polyester copolymer and about 5-15% of said therapeutic agent. In one embodiment, the matrix comprises about 90% to about 95% by weight of said polyether-polyester copolymer and about 5% to about 10% of said therapeutic agent. In one embodiment, the present invention contemplates a composite material providing in vivo delivery of a bioactive agent, comprising: (a) a fibrous construct, wherein a fibrous construct comprises one or more polymer fibers; (b) a polymer matrix, comprising an amphiphilic, amorphous polymer, wherein a matrix is reinforced by a fibrous construct; and (c) at least one bioactive agent, wherein the composite material is biodegradable and provides for the controlled release of at least one bioactive agent. In one embodiment, the fibrous construct may further comprise a knitted fabric. In one embodiment, the knitted fabric comprises a density of less than 15 mg/cm². In some embodiments, the knitted fabric comprises a density of about 2.5 mg/cm² to about 5.0 mg/cm². In one embodiment, the fibrous construct may further comprise one or more polymer fibers. In one embodiment, the polymer fiber may further comprise a plurality of filaments. In one embodiment, the plurality of filaments may have an average diameter of about 10 microns to about 20 microns. In one embodiment, the one or more polymer fibers may have a melting temperature (i.e., for example, 205 ⁰C to about 220 ⁰C). In one embodiment, the one or more polymer fibers may have a yarn denier of about 80 to about 100. In one embodiment, the one or more polymer fibers may have a yarn tenacity of about 3 g/denier to about 6 g/denier. In one embodiment, the one or more polymer fibers may have an elongation of about 20 to 50%. In one embodiment, the one or more polymer fibers may comprise a plurality of cyclic monomer residues (i.e., for example, glycolide, L- lactide, ε-caprolactone, trimethylene carbonate, p-dioxanone, or morpholinedione residues). In one embodiment, the one or more polymer fibers may further comprise a plurality of glycolide and L-lactide residues. In one embodiment, the molar ratio of glycolide residues may be greater than about 80 or about 95. In one embodiment, the weight ratio of a polymer matrix to a reinforcing fibrous construct may be between about 90/10 and about 10/90; or about 90/10 and about 70/30; or about 70/30 and about 50/50; or about 50/50 and about 30/70; or about 30/70 and about 10/90. In one embodiment, the composite material may be absorbable in vivo (i.e., for example, bioabsorbable) and may have a thickness of less than 500 microns or about 100 microns to about 400 microns. In certain embodiments, the composite material may be in the form of a perivascular wrap, thereby preventing vascular stenosis, hi one embodiment, the polymer matrix may further comprise an amphophilic, amorphous polymer, including, but not limited to, a polyether- polyester copolymer; or a polymer having at least one residue selected from the group comprising a glycolide, a L-lactide, an ε-caprolactone, a trimethylene carbonate, a p- dioxanone, and a morpholinedione; or a polymer having a plurality of alkylene oxide residues. In one embodiment, the polyether may comprise a terminal alkyl moiety, such as a methyl moiety. In one embodiment, the alkylene oxide residues may comprise residues of ethylene glycol. In one embodiment, the amphophilic, amorphous polymer may have a weight average molecular weight of greater than 3 kDa; or of about 3 kDa to about 9 kDa. In one embodiment, the bioactive agent may include, but is not limited to, paclitaxel or a paclitaxel analogue or derivative; sirolimus or a sirolimus derivative including, but not limited to, everolimus or tacrolimus. In one embodiment, the bioactive agent may be present in a matrix at a concentration of 0.005 mg or greater per cm² of a fabric.

In one embodiment, the present invention contemplates a composite drug delivery system comprising an absorbable, biodegradable composite, wherein the composite comprises a flat textile fabric of less than 500 microns in thickness thereby controlling a release of at least one bioactive agent from an amphiphilic, amorphous matrix, wherein the matrix is reinforced by at least one fibrous construct. In one embodiment, the amphiphilic matrix may comprise a polyether-ester. In one embodiment, the polyether-ester may comprise a polyethylene glycol grafted with at least one cyclic monomer selected from the group comprising glycolide, L-lactide, ε-caprolactone, trimethylene carbonate, p- dioxanone, and a morpholinedione. In some embodiments, the polyether-ester comprises a polyethylene glycol monomethyl ether grafted with at least one cyclic monomer such as glycolide, L-lactide, ε-caprolactone, trimethylene carbonate, p-dioxanone, and a morpholinedione. In one embodiment, the weight ratio of the matrix to the reinforcing fibrous construct is between about 90/10 and 10/90. In one embodiment, the matrix may be reinforced with knitted fabric having a density of less than 15 mg/cm². In some embodiments, the density of a knitted fabric be approximately 2.5-5.0 mg/cm.² In one embodiment, the matrix may comprise a multifilament yarn made of a high glycolide polymer. In one embodiment, the fabric may comprise a multifilament yarn made of about 95/5 glycolide/L-lactide copolymer. In some embodiments, the yam may have a yarn denier of about 60 to 100, a yarn tenacity of about 3 to 6 g/denier, an elongation of about 10 to 50% (in some cases, 20 to 50% elongation may be desirable) and a melting temperature of about 205-220 ⁰C, wherein a single filament of a multifilament yarn has diameter of about 10 to 30 microns. In one embodiment, the present invention contemplates an absorbable, biodegradable composite flat textile fabric that comprises a bioactive agent including, but not limited to, paclitaxel. In one embodiment, tje matrix is amphiphilic and comprises the paclitaxel at a concentration equivalent to more than 0.005 mg/cm² of a matrix.

In one embodiment, the present invention contemplates a method for making composite materials as described herein. In one embodiment, the method comprises producing an absorbable, biodegradable composite. In one embodiment, the method comprises an absorbable, biodegradable composite material for predictably controlling the release of at least one bioactive agent from the matrix reinforced with at least one fibrous construct type. In one embodiment, the present invention contemplates a method for making an absorbable, biodegradable composite comprising (a) providing a biodegradable fibrous construct and (b) contacting a fibrous construct with a biodegradable, amphiphilic, amorphous polymer composition that further comprises a bioactive agent. In one embodiment, the amphiphilic, amorphous polymer composition is reinforced with a fibrous construct. In one embodiment, the composite predictably controls the release of at least one bioactive agent. In one embodiment, the fibrous construct may be formed by weaving or knitting and may be a flat textile fabric. In one embodiment, the biodegradable, amphiphilic, amorphous polymer composition may be in a viscous or a liquid form. In one embodiment, the fibrous construct may be coated (i.e., for example, for example, by painting, dipping, spin-casting, or spraying). In one embodiment, the composite is formed into a wrap (i.e., for example, a perivascular wrap). In one embodiment, the biodegradable, amphiphilic, amorphous polymer composition is in a form of a solid. In one embodiment, the biodegradable, amphiphilic amorphous polymer composition is in a form of a liquid. In one embodiment, the polymer composition may include, but not limited to, paclitaxel or an analogue or derivative thereof or another therapeutic agent, such as rapamycin, actinomycin, 17-β-estradiol, a statin selected from the group comprising lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, and cervistatin, or an anthracycline selected from the group comprising doxorubicin, daunorubicin, idarubicin, epirubicin, pirarubicin, zorubicin, carubicin, or an analogue or derivative thereof. In one embodiment, the present invention contemplates an absorbable, biodegradable composite comprising a flat textile fabric of less than 500 microns in thickness for a controlled release of at least one bioactive agent from an amphiphilic, amorphous polymer matrix reinforced with at least one fibrous construct type. In one embodiment, the amphiphilic matrix comprises a polyether-ester comprising a polyethylene glycol grafted with at least one cyclic monomer selected from a group consisting of glycolide, /-lactide, ε-caprolactone, trimethylene carbonate, p-dioxanone, and a morpholinedione. In one embodiment, the amphiphilic matrix comprises a polyether glycol selected from the group consisting of polyethylene glycol, polypropylene glycol, random copolymers of ethylene and propylene oxide and block copolymers of polyethylene glycol and polypropylene glycol. In one embodiment, the amphiphilic matrix comprising a polyether-ester comprises a polyethylene glycol monomethyl ether grafted with at least one cyclic monomer selected from a group consisting of glycolide, L-lactide, ε-caprolactone, trimethylene carbonate, p-dioxanone, and a morpholinedione. In one embodiment, the amphiphilic matrix comprises paclitaxel at a concentration of more than 0.005 mg/cm² of the fabric. In one embodiment, the amphiphilic matrix comprises a polyether-ester having a weight average molecular weight exceeding 3 kDa. In one embodiment, the matrix is reinforced with a knitted fabric having a density of 2.5-5.0 mg/cm², wherein a knitted fabric comprises a crystalline multifilament yarn made of a high glycolide polymer. In one embodiment, the crystalline multifilament yam is made of about 95/5 glycolide/L-lactide copolymer, wherein the yarn has a yarn denier of about 80 to 100, a yarn tenacity of about 3 to 6 g/denier, an elongation of about 20 to 50%, and a melting temperature of about 200- 225 ⁰C₃ wherein a single filament of a multifilament yarn has diameter of about 10 to 20 microns. In one embodiment, the melting temperature is about 205-220 ⁰C. In one embodiment, the fabric comprises a form of an epivascular (perivascular) wrap for preventing vascular stenosis. In one embodiment, the weight ratio of a matrix to a reinforcing fibrous construct is between about 90/10 and 10/90.

In one embodiment, the present invention contemplates a method for improving or maintaining the integrity of a body passageway lumen or cavity, comprising applying to an external portion of a body passageway or cavity an absorbable, biodegradable composite, flat textile fabric.

In one embodiment, the present invention contemplates a method for treating or preventing intimal hyperplasia, comprising delivering to an anastomotic site an absorbable, biodegradable composite, flat textile fabric, hi one embodiment, the anastomotic site is selected from a group consisting of a venous anastomosis, an arterial anastomosis, an arteriovenous fistula, and an arteriovenous graft. In one embodiment, the device is applied to an external portion of an anastomotic site.

In one embodiment, the present invention contemplates a method of producing an absorbable, biodegradable composite material, comprising: (a) providing a biodegradable fibrous construct; and (b) contacting a fibrous construct with a biodegradable, amphiphilic, amorphous polymer composition that comprises a bioactive agent, wherein a method provides an absorbable, biodegradable composite material, wherein a amphiphilic, amorphous polymer composition is reinforced with a fibrous construct, wherein a composite material provides for a predictably controlled release of at least one bioactive agent. In one embodiment, the fibrous construct is formed by weaving or knitting, hi one embodiment, the biodegradable, amphiphilic, amorphous polymer composition is in an amorphous solid or viscous liquid form, hi one embodiment, the composite is a flat textile fabric. In one embodiment, the fibrous construct is coated by painting, dipping, spin casting, or spraying, hi one embodiment, the composite is capable of being formed into a wrap. In one embodiment, the therapeutic agent is paclitaxel or a paclitaxel analogue or derivative, hi one embodiment, the therapeutic agent is rapamycin or a rapamycin analogue or derivative. In one embodiment, the therapeutic agent is actinomycin, 17-β- estradiol, a statin selected from lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, and cervistatin, or an anthracycline selected from doxorubicin, daunorubicin, idarubicin, epirubicin, pirarubicin, zorubicin, and carubicin. In one embodiment, the present invention contemplates an absorbable, biodegradable composite material for in vivo delivery of a bioactive agent, comprising: (a) a biodegradable fibrous construct, wherein a fibrous construct comprises one or more polymer fibers; (b) a polymer matrix, comprising an amphophilic, amorphous polymer, wherein a matrix is reinforced by a fibrous construct; and (c) at least one bioactive agent, wherein a composite material is absorbable and biodegradable and provides for a controlled release of a at least one bioactive agent. In one embodiment, the fibrous construct comprises knitted fabric. In one embodiment, the knitted fabric has a density of about 2.5 mg/cm² to about 5.0 mg/cm². In one embodiment, the one or more polymer fibers comprise a plurality of filaments. In one embodiment, the filament has an average diameter of about 8 microns to about 25 microns, m one embodiment, the filament has an average diameter of about 10 microns to about 20 microns. In one embodiment, the one or more polymer fibers have a melting temperature. In one embodiment, the one or more polymer fibers have a melting temperature of about 200 ⁰C to about 225 ⁰C. In one embodiment, the one or more polymer fibers have a yarn denier of about 80 to about 100. In one embodiment, the one or more polymer fibers have a yarn tenacity of about 3 g/denier to about 6 g/denier. In one embodiment, the one or more polymer fibers have an elongation of about 10 to 50%. In one embodiment, the one or more polymer fibers comprise a plurality of cyclic monomer residues selected from glycolide, L-lactide, ε- caprolactone, trimethylene carbonate, p-dioxanone, and morpholinedione residues. In one embodiment, the polymer fiber comprises a plurality of glycolide and L-lactide residues. In one embodiment, the copolymer has a molar ratio of glycolide residues to L-lactide residues that is greater than about 80 to about 20. In one embodiment, the copolymer has about a 95:5 molar ratio of glycolide to L-lactide residues. In one embodiment, the weight ratio of a matrix to a reinforcing fibrous construct is between about 90/10 and about 10/90. In one embodiment, the weight ratio of a matrix to a reinforcing fibrous construct is between about 90/10 and about 70/30. In one embodiment, the weight ratio of a matrix to a reinforcing fibrous construct is between about 70/30 and about 50/50. In one embodiment, the weight ratio of a matrix to a reinforcing fibrous construct is between about 50/50 and about 30/70. In one embodiment, the weight ratio of a matrix to a reinforcing fibrous construct is between about 30/70 and about 10/90. In one embodiment, the polymer matrix comprises a polyether-polyester copolymer. In one embodiment, the fiber comprises a segmented or block copolymer derived from at least one monomer selected from the group consisting of glycolide, L-lactide, D, L-lactide, meso-lactide, ε-caprolactone, trimethylene carbonate, p-dioxanone, and a morpholinedione monomer. In one embodiment, the polymer matrix comprises a plurality of alkylene oxide residues. In one embodiment, the polyether comprises a terminal alkyl moiety. In one embodiment, the alkyl moiety is a methyl group. In one embodiment, the alkylene oxide residues comprise residues of ethylene glycol. In one embodiment, the amphiphilic, amorphous polymer has a weight average molecular weight greater than 3 kDa. In one embodiment, the amphiphilic, amorphous polymer has a weight average molecular weight of about 3 kDa to about 9 kDa. In one embodiment, the bioactive agent is paclitaxel, a paclitaxel analogue or derivative, sirolimus, everolimus, or tacrolimus. In one embodiment, the bioactive agent is present in a matrix at a concentration of 0.005 mg or greater per cm² of a material. In one embodiment, the system is absorbable in vivo. In one embodiment, the material has thickness of less than 500 microns. In one embodiment, the material has a thickness of about 100 microns to about 400 microns. In one embodiment, the material is in a form of a perivascular wrap for preventing vascular stenosis. In one embodiment, the material degrades via hydrolysis. In one embodiment, the material degrades over a period of about 60 days to about 120 days. In one embodiment, the material degrades over a period of about 60 days to about 90 days. In one embodiment, the material comprises about 0.6 mg to about 2.2 mg of paclitaxel.

In one embodiment, the present invention contemplates a kit comprising a composite drug delivery device and a therapeutic agent. In one embodiment, the device is placed in a first container. In one embodiment the therapeutic is placed in a second container. In one embodiment, the device is layer with the therapeutic agent and is placed in the same container. In one embodiment, the kit further comprises instructions. In one embodiment, the instructions provide information comprising the relative amounts of excipient ingredients or diluent. In one embodiment, the kit is sterile. In one embodiment, the kit containers are water resistant. In one embodiment, the kit container further comprise a dessicant. In one embodiment, the kit container is opaque. In one embodiment, the kit container further comprises an inert gas. In one embodiment, the kit further comprises a vascular graft. In one embodiment, the vascular graft comprises ePTFE. In one embodiment, the therapeutic agent comprises an anti-proliferative drug. In one embodiment, the therapeutic agent comprises an immunosupressive drug. In one embodiment, the instructions provide a method for using the kit for an A-A peripheral bypass grafting procedure. In one embodiment, the vascular graft comprises an A-A peripheral bypass graft. In one embodiment, the instructions provide a method for using the kit for an A-V hemodialysis access procedure. In one embodiment, the vascular graft comprises an A-V hemodialysis access graft.

The present invention also contemplates methods for using a composite materials described herein.

In one embodiment, the present invention contemplates a method for improving or maintaining a body passageway lumen or cavity integrity, comprising delivering to an external portion of a body passageway or cavity a absorbable, biodegradable composite, flat textile fabric described herein.

In one embodiment, the present invention contemplates a method for treating or preventing intimal hyperplasia, comprising delivering to an anastomotic site an absorbable, biodegradable composite, flat textile fabric described herein. In one embodiment, the anastomotic site may be a venous anastomosis, an arterial anastomosis, an arteriovenous fistula, or an arteriovenous graft. In one embodiment, the composite may be delivered to an external portion of the anastomotic site.

In one embodiment, the present invention contemplates a method for delivering a composite material to an external portion of a body passageway or cavity to improve or maintain the body passageway lumen or cavity and may be used to treat a variety of medical conditions. In one embodiment, the composite material may be delivered to an anastomotic site (i.e., for example, venous anastomosis, an arterial anastomosis, an arteriovenous fistula, or an arteriovenous graft) to inhibit fibrosis.

In one embodiment, the present invention contemplates a method for adapting a composite material to contain and/or release an agent that inhibits one or more of the four general components of a process of fibrosis (i.e., for example, scarring), including, but not limited to, formation of new blood vessels (angiogenesis), migration and proliferation of connective tissue cells (such as fibroblasts or smooth muscle cells), deposition of extracellular matrix (ECM), and remodeling (maturation and organization of a fibrous tissue).

In one embodiment, the present invention contemplates a method for using a composite material to reduce formation of intimal hyperplasia at an anastomotic site. In some methods, the composite materials are used for treating or preventing: i) iatrogenic complications of arterial and venous catheterization; ii) complications of vascular dissection; iii) complications of gastrointestinal passageway rupture and dissection; iv) restonotic complications associated with vascular surgery; or v) intimal hyperplasia.

In one embodiment, the present invention contemplates a method for using a composite material as a drug delivery system. In certain embodiments, the system may be delivered to an external portion of an arterial anastomosis {i.e., for example, arterial bypass) site. In one embodiment, the system may be wrapped about an external surface of a blood vessel {i.e., for example, a perivascular wrap). In certain embodiments, the absorbable/biodegradable composite flat textile fabric is in a form of an epivascular wrap for preventing vascular stenosis.

These, and other, embodiments of the present invention will become evident upon reference to the following detailed description and attached drawings.

Brief Description Of The Drawings

Figure 1 is an illustrative cartoon that shows a heart with a bypass graft.

Figure 2 is a representative picture that shows expanded polytetrafluoroethylene (ePTFE) vascular grafts. Figure 3 is a representative picture that shows an uninjured carotid artery from a rat balloon injury model.

Figure 4 is a representative picture that shows an injured carotid artery from a rat balloon injury model. Figure 5 is a representative picture that shows a paclitaxel-loaded composite system treated carotid artery in a rat balloon injury model (345 μg paclitaxel in a 50:50 PLG coating on a 10:90 PLG substrate).

Figure 6 is an illustrative cartoon that shows a schematic drawing of an artery- to- artery graft and showing a placement of a wrap (not to scale).

Figure 7 is an illustrative cartoon that shows a schematic drawing of sectioning plan.

Figure 8 is an exemplary graph that shows an effect of paclitaxel, at different doses, on maximal intimal thickness. Figure 9 is an exemplary graph that shows an effect of paclitaxel, at different doses, on intimal area.

Figure 10 is an exemplary graph that shows an effect of paclitaxel, at different doses, on percent stenosis.

Figure 11 is a representative schematic diagram of an ePTFE Graft and right external jugular vein anastomosis with applied composite system and histological sections.

Figure 12 is a representative schematic diagram of morphometric measurements.

Figure 13 is a representative graph showing average cumulative paclitaxel release (%) from a paclitaxel-loaded fabric as a function of time (days). Diamonds: 0.6 mg paclitaxel-loaded fabric. Squares: 1.3 mg paclitaxel-loaded fabric. Triangles: 2.2 mg paclitaxel-loaded fabric.

Figure 14 is an exemplary graph showing cumulative % release of paclitaxel from coatings prepared with MePEG750-PDLLA having a molecular weight of 5673, 6575, and 6792 Daltons.

Figure 15 is an exemplary graph showing cumulative % release of paclitaxel from coatings prepared with MePEG750-PDLLA having a molecular weight of 5383, 7193, 8576, and 11,927 Daltons. Definitions

"Body passageway" as used herein refers to any of number of passageways, tubes, pipes, tracts, canals, sinuses, or conduits which have an inner lumen and allow the flow of materials within the body. Representative examples of body passageways include, but are not limited to, arteries and veins, lacrimal ducts, a trachea, bronchi, bronchiole, nasal passages (including a sinuses) and some airways, eustachian tubes, external auditory canal, oral cavities, esophagus, stomach, duodenum, small intestine, large intestine, biliary tracts, ureter, bladder, urethra, fallopian tubes, uterus, vagina and some passageways of a female reproductive tract, vas deferens and some passageways of a male reproductive tract, and the ventricular system (cerebrospinal fluid) of a brain and a spinal cord.

"Body cavity" as used herein refers to any of number of hollow spaces within the body. Representative examples of cavities include, for example, an abdominal cavity, a buccal cavity, a peritoneal cavity, a pericardial cavity, a pelvic cavity, a perivisceral cavity, a pleural cavity, an inguinal canal, and an uterine cavity. "Therapeutic agent," "bioactive agent," "pharmaceutical agent," "drug," and a like, as used herein, refers to those agents which may mitigate, treat, cure, and/or prevent (i.e., for example, as a prophylactic agent) a given disease or condition. Representative examples of therapeutic agents are discussed in more detail below and include, for example, fibrosis-inhibiting (anti-scarring) agents, such as microtubule stabilizing agents, anti-angiogenic agents, cell cycle inhibitors, antithrombotic agents, antiplatelet agents, antiinflammatory agents as well as cytokines and some factors involved in wound healing or proliferation cascade. Briefly, within the context of the present invention, anti-angiogenic agents should be understood to include any protein, peptide, chemical, or some molecule, which acts to inhibit vascular growth (see, i.e., for example, U.S. Patent Nos. 5,994,341, 5,886,026, and 5,716,981) (all patents herein incorporated by reference).

"Fibrosis," or "scarring," or "fibrotic response" refers to a formation of fibrous (scar) tissue in response to injury or medical intervention. Therapeutic agents which inhibit fibrosis or scarring are referred to herein as "fibrosis-inhibiting agents", "fibrosis- inhibitors", "anti-scarring agents", and a like, wherein these agents inhibit fibrosis through one or more mechanisms including, but not limited to: inhibiting inflammation or an acute inflammatory response, inhibiting migration or proliferation of connective tissue cells (such as fibroblasts, smooth muscle cells, vascular smooth muscle cells), inhibiting angiogenesis, reducing extracellular matrix (ECM) production or promoting ECM breakdown, and/or inhibiting tissue remodeling. Scarring occuring within a confined space (i.e., for example, within a lumen) following surgery or instrumentation (including implantation of a medical device or implant), such that a body passageway (i.e., for example, a blood vessel, a gastrointestinal tract, a respiratory tract, a urinary tract, a female or male reproductive tract, a Eustachian tube etc.) is partially or completely obstructed by scar tissue, is referred to herein as "stenosis" (narrowing). When scarring subsequently occurs to re-occlude a body passageway after it was initially successfully opened by a surgical intervention (such as placement of a medical device or implant), this is referred to as "restenosis."

"Inhibit fibrosis", "reduce fibrosis", "inhibits scarring" and the like are used synonymously to refer to the action of agents or compositions which result in a statistically significant decrease in the formation of fibrous tissue that can be expected to occur in the absence of an agent or composition.

"Host", "person", "subject", "patient" and the like are used synonymously to refer to a living being into which a device or implant of the present invention is implanted. "Implanted" refers to having completely or partially placed a device or implant within a host. A device is partially implanted when some of the device reaches, or extends to the outside of, a host.

"Fiber," "strand," "thread," and "yarn," are used interchangeably herein to refer to an elongate structure formed from multiple filaments or fibrils (i.e., for example, aggregates of single filaments or fibrils). A fiber is characterized by a high ratio of length to diameter (typically 100:1 or greater) and a relatively high tenacity (i.e., strength per unit weight of a fiber, expressed as g/denier). Fibers may be formed by twisting or braiding a plurality of filaments together. Alternatively, fibers may be formed by bundling (i.e., for example, packing) together a plurality of filaments in either an oriented or non-oriented fashion. The filaments may be packed, for example, in a planar fashion (i.e., for example, side by side orientation) to form a flat band of fibers or they may be packed one on top of the other to produce fibers having a stacked configuration. The individual filaments of a fiber may be held together by fusing individual fibers together under the influence of heat and/or pressure or by the presence of an adhesive.

"Filament" or "fibril" refers to an elongate structure characterized by a high ratio of length to diameter (typically 100:1 or greater) and a relatively high tenacity (i.e., strength per unit weight of a filament, expressed as g/denier). Filaments may be composed of one type of material or from several different types of material and may be solid or have a hollow core (which may, optionally, be filled with a substance different from that used to form a sheath of a fiber). Filaments may be formed from natural materials (i.e., for example, cellulose, silk, wool, cotton, and a like) or from synthetic materials (i.e., for example, polymers such as polyamides, polyesters, acrylics, polyolefins). Synthetic filaments may be made by various techniques, including, but not limited to, melt spinning, electrospinning, or extrusion (i.e., for example, extruding from spinnerettes).

"Perivascular," "extravascular," "epivascular," and the like, as used herein, refer to application of a composition or therapeutic agent to an external (i.e., for example, non- luminal) surface of a blood vessel (i.e., for example, artery, vein, or capillary). Perivascular administration may be achieved, for example, by applying a composite material, as described herein, directly to an external (i.e., for example, adventitial) surface of blood vessel (i.e., for example., quadrantically or circumferentially) under direct vision (i.e., for example, at a time of surgery or via endoscopic procedures). A procedure may be performed intra-operatively under direct vision or with additional imaging guidance and/or may be performed in conjunction with an endovascular procedure, such as angioplasty, atherectomy or stenting or in association with an operative arterial procedure, such as endarterectomy, vessel or graft repair, and/or graft insertion. In one embodiment, perivascular delivery may involve wrapping, either completely or partially, the composite material loaded with a therapeutic agent around an injured blood vessel (i.e., for example, following a surgical procedure, such as a graft insertion).

"Peritubular," as used herein, refers to application of a composition or therapeutic agent to an external (i.e., for example, non-luminal) surface of a body passageway (i.e., for example, trachea) or cavity. Peritubular administration may be achieved, for example, by applying a composite material, as described herein, directly to an external surface of body passageway or cavity (i.e., for example, quadrantically or circumferentially) under direct vision (Le., for example, at the time of open surgery or via endoscopic procedures). The peritubular administration procedure may be performed in conjunction with a primary surgical procedure and may be performed under direct vision or with additional imaging guidance.

"Release of an agent" refers to a statistically significant presence of an agent, or a subcomponent thereof, which has disassociated from an implant/device and/or remains active on the surface of (or within) the device/implant. "Predictable" or "Predictably", when used in reference to therapeutic agent release rates and/or degradation rates of a composite drug delivery device, means that the construction of the device necessarily creates characteristics that provide reproducible release rates. Such characteristics are based primarily on surface area, but are also based upon characteristics including, but not limited to, denier, density, fiber elongation, and/or fiber tenacity. The construction of the device also creates characteristics that provide reproducible degradation rates. Degradation rates can be a function of characteristics of the device, such as denier, density, and fiber elongation and tenacity, as well as the chemical make-up of the device components. A combined interplay and/or interconnectivity between these characteristics result in a device that releases a therapeutic agent and degrades within stable parameters or boundaries.

"Biodegradable" refers to materials for which the degradation process is at least partially mediated by, and/or performed in, a biological system. "Degradation" refers to a chain scission process by which a polymer chain is cleaved into smaller oligomers and monomers. Chain scission may occur through various mechanisms, including, for example, by chemical reaction (i.e., for example, hydrolysis) or by a thermal or photolytic process. Polymer degradation may be characterized, for example, by using gel permeation chromatography (GPC), which monitors polymer molecular mass changes during erosion and drug release. Alternatively, degradation can be evaluated gravimetrically by measuring the percentage mass loss after contact of a sample with an aqueous environment (e.g., a buffer). Biodegradable also refers to materials that may be degraded by an erosion process mediated by, and/or performed in, a biological system.

"Erosion" refers to a process in which material is lost from the bulk. In the case of a polymeric system, a material may be a monomer, an oligomer, a part of a polymer backbone, or a part of the polymer bulk. Erosion includes, but is not limited to: (i) surface erosion, in which erosion affects only the surface and not the inner parts of a matrix; or (ii) bulk erosion, in which an entire system is rapidly hydrated and polymer chains are cleaved throughout the matrix. Depending on the type of polymer, erosion generally occurs by one of three basic mechanisms {see, i.e., for example, Heller, J., CRC Critical Review in Therapeutic Drug Carrier Systems (1984), 1(1), 39-90); Siepmann, J. et al., Adv. Drug Del. Rev. (2001), 48, 229-247): (1) water-soluble polymers that have been insolubilized by covalent cross-links and that solubilize as the cross-links or the backbone undergo a hydrolytic cleavage; (2) polymers that are initially water insoluble are solubilized by hydrolysis, ionization, or protonation of a pendant group; and (3) hydrophobic polymers are converted to small water-soluble molecules by backbone cleavage. Techniques for characterizing erosion include, but are not limited to, thermal analysis (i.e., for example, DSC), X-ray diffraction, scanning electron microscopy (SEM), electron paramagnetic resonance spectroscopy (EPR), NMR imaging, or recording mass loss during an erosion experiment. For microspheres, photon correlation spectroscopy (PCS) and some particles size measurement techniques may be applied to monitor the size evolution of erodible devices versus time.

Any concentration or numerical ranges recited herein are to be understood to include concentrations of any integer within a range and fractions thereof, such as one tenth and one hundredth of an integer, unless otherwise indicated. It should be understood that the terms "a" and "an" as used above and elsewhere herein refer to "one or more" of the enumerated components. As used herein, the term "about" means ± 15% of an indicated value. Detailed Description Of The Invention

The present invention relates generally to a composite drug delivery system and methods for improving and maintaining the integrity of body passageways or cavities following surgery or injury, and more specifically, to composite drug delivery systems that include therapeutic agents which may be delivered to body passageways or cavities for the purpose of preventing and/or reducing a proliferative biological response that may obstruct or hinder the optimal functioning of a passageway or cavity.

The present invention also relates generally to delivery systems and methods for improving the integrity of body passageways following surgery or injury comprising delivering to an external portion of a body passageway (i.e., a non-luminal surface) an absorbable and biodegradable composite, wherein the composite comprises at least one therapeutic agent. The integrity of a body passageway or cavity may be compromised due to a variety of factors resulting from, for example, an accidental injury, a congenital defect, or a surgical intervention. One example of a compromised body passageway is a blood vessel which has become occluded due to a formation of scar tissue at a site of a surgical intervention (i.e., for example, a bypass graft procedure).

Following implantation, a therapeutic agent may be released from a matrix as a polymer is degraded in a body. Composite materials contemplated by the present invention may be implanted in a peritubular or perivascular manner (i.e., for example, wrapped about an external surface of a body passageway or cavity, such as a blood vessel), thereby providing a predictable controlled, sustained release of a therapeutic agent in vivo. Delivery of a therapeutic agent to an external portion of a body passageway (i.e., for example, quadrantically or circumferentially) may avoid many of the disadvantages of traditional approaches. For example, by applying a composite drug delivery system to the exterior (i.e., for example, adventitial) surface of a blood vessel, the drug concentration may remain elevated for prolonged periods in regions where biological activity is most needed. Although it is not necessary to understand a mechanism of an invention, it is believed that local delivery of a therapeutic agent as described herein allows the administration of greater quantities of a therapeutic agent with less constraint upon a volume to be delivered. Further, drug delivery systems as described herein may deliver a therapeutically effective amount of a drug in a low total volume of material, thereby reducing the amount of polymer that is released into the body upon degradation.

I. Device Compositions A composite drug delivery system is provided by the present invention for the predictable and controlled release of a bioactive agent in vivo. A composite drug delivery system may be constructed from a polymer matrix which is reinforced by a fibrous construct. The fibrous reinforcement can serve to strengthen and support the polymer matrix (e.g., by providing structure or a scaffold to which the matrix can be affixed), such as to improve the handling and mechanical properties of the matrix.

A fibrous construct may include at least one type of fibrous material (i.e., for example, a material formed from one or more polymer fibers). The polymer matrix may be formed from an amphiphilic, amorphous polymer, such as a polyether-polyester copolymer. Drug delivery systems, as contemplated herein, may further include at least one bioactive agent. Such bioactive agents may reside in a polymer matrix and/or within one or more materials used to form a fibrous construct. A. Fibrous Construct

A fibrous construct may be composed of a plurality of fibers, wherein the fibers are arranged in such a manner (i.e., for example, interwoven, knotted, braided, overlapping, looped, knitted, interlaced, intertwined, webbed, felted, and the like) so as to form a porous structure. A fibrous construct may include, but is not limited to, fibers and/or filaments that are: i) randomly oriented relative to each some; or ii) arranged in an ordered array or pattern. In one embodiment, the fibrous construct comprises intertwined threads thereby forming a porous structure, which may be, for example, knitted, woven, or webbed. In one embodiment, a fibrous construct comprises a fabric, such as, for example, a knitted, braided, crocheted, woven, non- woven (i.e., for example, a melt-blown or wet-laid) or webbed fabric. A fabric may include, but not limited to, a natural or synthetic biodegradable polymer which has been formed into a mesh material, including, but not limited to, a knit mesh, a weave mesh, a sprayed mesh, a web mesh, a braided mesh, a looped mesh, and the like. A fibrous construct used in a drug delivery device as contemplated herein may be constructed to obtain desired mechanical and handling properties (i.e., for example, flexibility, tensile strength, thickness, and elasticity) that result in predictable device degradation properties, predictable therapeutic agent loading characteristics, and/or predictable therapeutic agent releasing characteristics. Although it is not necessary to understand the mechanism of an invention, it is believed that a fibrous construct should have mechanical properties such that the device will remain intact and sufficiently strong until the surrounding tissue has healed. For example, a fabric may serve to reinforce a polymer matrix until such time as the matrix has eroded. Alternatively, factors that affect the flexibility and mechanical strength of a fibrous construct may include, for example, porosity, fabric thickness, fiber diameter, polymer composition (i.e., type of monomers and initiators), process conditions, and additives used to prepare a construct.

In certain embodiments, it may be desired that a fabric has a particular strength profile, such that the fabric remains intact for a prolonged period of time after implantation in a patient. The strength of a fibrous construct (i.e., for example a fabric) may be evaluated by measuring the percentage of burst strength that is retained after contact with an aqueous medium (see, e.g., ASTM D 3787). For example, in certain embodiments, knitted fabrics are provided that have in vitro burst strength retentions of about 20-30 %. A fibrous construct's structure (i.e., for example, fiber density, surface area, and porosity) may impact the amount of therapeutic agent that may be loaded into a drug delivery device. Although it is not necessary to understand the mechanism of an invention, it is believed that a fabric having a loose weave characterized by a low fiber density and high porosity will have a lower thread count, resulting in a reduced total fiber volume and surface area. In one embodiment, the present invention contemplates a fibrous construct comprising an increased surface area, thereby allowing for a higher loading of a drug- carrying matrix, and resulting in a faster release of the drug.

Fibrous constructs can also be prepared having a range of surface areas. In some embodiments, the surface area characteristics depend upon various factors, such as, for example, fiber denier, number of threads per yarn, the overall dimensions of the construct, the stitch count, and the diameter of each thread. In one embodiment, a slight variation in denier, or number of filaments per fiber, contribute to significant fluctuations in the overall surface area. For example, for a knitted construct prepared using one 80 denier fiber made up of 20 filaments (each having a diameter of 0.02 mm), a 2.5 cm x 4 cm construct weighing 0.03 g may have a surface of about 4250 mm². In another example, a knitted construct using the identical fibers, but having a dimension of 3 cm x 6 cm, may have a surface area of about 8500 mm². It also may be possible to achieve a particular density by altering the denier, and/or number of filaments per fiber. Although it is not necessary to understand the mechanism of an invention, it is believed that by controlling the surface area, it may be possible to predict the amount of a matrix that can loaded onto the construct and the total drug loading of the device.

In one embodiment, a fibrous construct may be prepared for use as a perivascular wrap having a surface area ranging from about 3000 to about 10,000 mm², or about 3500 to about 5000 mm², or about 5000 to about 7000 mm², or about 7000 to about 9000 mm². In one embodiment, a wrap fibrous construct comprises a range of densities. Although it is not necessary to understand the mechanism of an invention, it is believed that the weight density (expressed in term of rag/cm²) of a construct can determine the amount of polymer matrix loaded onto the construct. In particular, the wrap density can be related to the amount of surface area available for contact with a polymer matrix. In one embodiment, a dense construct (i.e., for example, a construct having a high weight density) with a high surface area is loaded with a relatively larger amount of matrix as compared to a lower density material. The total amount of bioactive agent that can be affixed to the construct will depend, in turn, on the amount of agent loaded into the polymer matrix and the amount of polymer matrix that can be affixed to the construct. It is further believed that the amount of an agent that may be loaded into or onto a fabric having a low fiber density and high porosity will be lower than for a fabric having a high fiber density and lower porosity.

In one embodiment, a fibrous construct does not invoke biologically detrimental inflammatory and/or toxic response. In one embodiment, a fibrous construct is capable of being fully metabolized by the body, has an acceptable shelf life, and is easily sterilized and can withstand a sterilization procedure without undue damage to the material. Although it is not necessary to understand the mechanism of an invention, it is believed that for a viable therapeutic device it may be desirable to maximize the amount of matrix and loading of bioactive agent in the matrix (e.g., by tailoring the construct density appropriately), while minimizing the inflammatory or toxic response potentially associated with the agent or polymer matrix. In one embodiment, a fibrous construct comprises a pliable material having sufficient flexibility to conform to a particular anatomical structure at an implant site. For example, fibrous constructs and composite systems as contemplated herein typically possess physical characteristics which make them useful as peritubular or perivascular drug delivery platforms. In one embodiment, a fibrous construct comprises a relatively flat material (i.e., for example, a planar material such as a sheet of material). In one embodiment, the flat material remains substantially flat after implantation. In one embodiment, the flat material is re-configured to conform to the geometry of a tissue at a site of implantation. Alternatively, a flat material may take a variety of forms. In one embodiment, a flat material may be configured as a single layer of material having perpendicular edges (i.e., for example, a rectangle or square), wherein the material may be prepared by cutting a tube. In one embodiment, a flat material may be circular or triangular in shape. In other embodiments, the flat material may have an annular shape. In some embodiments, a flat material may be in a form of a tube (i.e., for example, a knitted tube) or some shape, which has been pressed flat. In one embodiment, the present invention contemplates a fibrous construct capable of: i) reinforcing a matrix; ii) supporting a matrix; and/or iii) releasing a predictable amount of a therapeutic agent. Examples of fibrous constructs include, but are not limited to, textiles, such as a knitted or woven fabric, mesh, sheet, and/or gauze. In certain embodiments, therapeutic compositions are provided in systems which include knitted fabrics (i.e., for example, meshes).

In one embodiment, the present invention contemplates a fibrous construct comprising fibers (i.e., for example, yarn). In one embodiment, the fiber comprises at least one filament (i.e., for example, a monofilament). In one embodiment, the fiber comprises a plurality of filaments (i.e., for example, strands). Although it is not necessary to understand the mechanism of an invention, it is believed that the number and type of filaments can be arranged such that a yarn comprises predictable physical properties. For example, a multifilament fiber results in a durable and strong fibrous construct. Typically, a fiber comprises greater than 5, or about 5-10, or about 10-15, or about 15 to 25, or about 25 to 50 filaments. In one embodiment, the fiber comprises about 20 filaments. In one embodiment, the present invention contemplates a fiber and/or filament comprising a diameter and length resulting in a predictable elasticity, porosity, surface area, flexibility, tenacity and/or tensile strength. In one embodiment, the diameter and/or length ranges in size depending on the form of a material (i.e., for example, knitted, woven, or non-woven). In one embodiment, the diameter of an individual filament typically ranges from about 1 μm to about 40 μm. In other embodiments, the filament diameter ranges from about 2 μm to about 25 μm. In certain, embodiments, each filament has an average diameter of greater than 15 microns and can range from about 15 to about 30 microns. In some embodiments, each filament can have an average diameter of about 10-20 microns; or 8-25 microns; or 10-30 microns; or 15-20 microns. The present invention contemplates methods of producing large diameter fibers (e.g., 10 to 25 μm) including, but not limited to, extrusion. The present invention contemplates methods of producing very fine diameter fibers (e.g., less than 10 μm) including, but not limited to, electrospinning.

In one embodiment, the present invention contemplates a method for preparing fibrous constructs (i.e., for example, knit fabrics) comprising fibers having dimensions appropriate for using standard melt-processing techniques, such as injection molding, compression molding, extrusion, electrospinning, melt spinning, solution spinning and gel state spinning. In some embodiments, the fibers (yarn) are prepared by spinning a plurality of extruded filaments, and the fiber is oriented and wound onto a spool, at which time the denier of a portion of the fiber is measured. The fiber is then re-oriented to bring it to the desired diameter and to obtain a consistent yarn density (denier).

Fibers contemplated by the present invention can be prepared to be of any length, ranging from short to long threads. For example, threads may be prepared that range in length from several microns to hundreds of meters in length.

In one embodiment, the present invention contemplates a fibrous construct comprising fibers that are of same dimension. In one embodiment, the fibers are of different dimensions. In one embodiment, the fibers comprise the same or different types of polymers (e.g., biodegradable). In certain embodiments, the fibers are made into woven materials comprising a regular or irregular array of warp and weft strands and may include, but not be limited to, one type of polymer in a weft direction and another type (i.e., for example, a second polymer having a same or a different degradation profile from a first polymer) in the warp direction. In other embodiments, the fibers are made into knit materials that may include one or more types (i.e., for example, monofilament, multifilament) and sizes of fibers and may include fibers made from a same or from different types of polymers (e.g., biodegradable). Althernative method embodiments comprise one or more polymeric fibers that are made into a form of a fibrous construct. Various methods can also be used to prepare a fibrous construct depending on whether the construct is in a knitted, woven, or non-woven form. One method for generating a fibrous construct involves weaving fibers into a textile (i.e., for example, a fabric). . In one embodiment, the present invention contemplates a method comprising fibers formed into a textile by knitting the fibers to form a fabric (i.e., for example, a fibrous mesh material). Although it is not necessary to understand the mechanism of an invention, it is believed that knitted materials differ from woven fabrics in that woven fabrics are relatively rigid, less compliant and stretchable and conformable as compared to knitted materials. Thus, it is believed that knitted materials are particularly well-suited for drug delivery applications in which a flexible, low density, highly compliant material is desired and can also be easily manipulated by a surgeon during a surgical procedure.

In one embodiment, the present invention contemplates a method of spinning a yarn using biodegradable polymers as contemplated herein, that may be subsequently knitted or woven into a fabric using a variety of techniques. For example, knitting of fibers to form a fibrous fabric material can be accomplished using any type of circular or flat knitting machine including, but not limited to, a Lawson-Hemphill FAK circular knitting machine and a Protti PT222 flat knitting machine.

In one embodiment, the present invention contemplates a fibrous construct comprising a random, non-woven network of fibers and/or filaments. In one embodiment, the non-woven network may be prepared, for example, by melt-blowing, wet-laying, or electrospinning a biodegradable polymer into a fabric. Numerous techniques for preparing biodegradable melt-blown fabrics may be used. Wadsworth et al., "Melt Processing of PLA Resin into Nonwovens", 3^rd Annual TANDEC Conference, Knoxville, 1993 and U.S. Patent No. 5,702,826 (herein incorporated by reference).

Although it is not necessary to understand the mechanism of an invention, it is believed that the density of the fibrous construct is a function of the thread count and yarn denier. It is further believed that polymer fibers having a range of deniers may be used in fibrous constructs contemplated by the present invention. In some embodiments, fibrous constructs may include, but are not limited to, polymer fibers with a yarn denier of about 80 to about 100, where a yam denier is defined as a mass (in grams) of 9000 meters of yarn. In some embodiments, the yarn denier may be about 70-90. Further, it is also believed that changes in denier may significantly impact the density of a fibrous construct. In one embodiment, the present invention contemplates a method to produce predictable fibrous construct densities by varying the stitch count, thereby compensating for fiber lot denier differences. It is further believed that polymer fibers also may have a range of yarn tenacities. In one embodiment, a fibrous construct may comprise polymer fibers having a yarn tenacity (also referred to as ultimate tensile strength) of about 1.5 g/denier to about 6 g/denier. In other embodiments, the construct comprises a yarn tenacity of about 3 g/denier to about 6 g/denier. In certain embodiments, polymer fibers with a yarn tenacity about 2 to about 4 g/denier have been shown to provide an optimal balance of breaking (or burst) strength retention and mass loss profiles. As used in yarn manufacture and textile engineering, tenacity, a strength of a yam or a filament of given size, may be measured by determining a breaking force in grams per denier unit of yarn or filament size (grams per denier, gpd), where a yarn is typically pulled at a rate of 12 inches per minute.

In one embodiment, a fibrous construct comprises polymer fibers with an elongation of about 20 to 50%. Although it is not necessary to understand the mechanism of an invention, it is believed that elongation is the increase in length of a specimen just before rupture occurs. Traditionally, a percentage elongation may be expressed as a ratio between a increase in distance between two gauge marks at rupture to an original distance between a marks; the quotient is multiplied by 100.

In one embodiment, the present invention contemplates one or more fiber filaments comprising a polymer or copolymer, wherein the polymer or copolymer has a degree of crystallinity. Although it is not necessary to understand a mechanism of an invention, it is believed that polymers having a degree of crystallinity typically exhibit a melting temperature or temperature range. The melting temperature can be readily determined using differential scanning calorimetry (DSC). In one embodiment, a composite material is provided wherein at least one polymer fiber has a melting temperature of about 205 ⁰C to about 225 ⁰C. In other embodiments, the melting temperature of the polymer fibers is about 200-225 ⁰C.

Another property that may be evaluated to identify the degree of crystallinity of a polymer fiber is the heat of fusion. The heat of fusion (expressed in terms of J/g) can also be determined using DSC. Although it is not necessary to understand the mechanism of an invention, it is believed that the degree of crystallinity may be correlated with a material's degradation profile. For example, polymers formed from the polymerization of glycolide may degrade rather slowly (e.g., about 120 days). In one embodiment, a copolymer comprising glycolide and L-lactide increases the crystallinity of the copolymer, thereby causing the construct to degrade more slowly when compared to a mixture of isomers (e.g., a racemic mixture). In one embodiment, a polymer degree of crystallinity may be controlled by altering the ratio of glycolide to lactide. In one embodiment, a copolymer comprising a 90:10 ratio of glycolide to L-lactide degrades more quickly (about 90 days or less) than a copolymer comprising a 95:5 ratio of glycolide to L-lactide (about 95-110 days). In one embodiment, the present invention contemplates a composition comprising a polymeric fiber having a copolymer of glycolide/L-lactide having about a 95:5 molar ratio. See, Examples 1-3. In one embodiment, the composition comprises a fabric comprising a 95:5 molar ratio of glycolide and lactide monomers. In one embodiment, the fabric comprises an initially slower breaking (or burst) retention strength profile and a faster mass loss profile as compared with a fiber made using higher ratio of glycolide to lactide (e.g., a 90/10 (mole) copolymer of glycolide/L-lactide, such as VICRYL). Although it is not necessary to understand the mechanism of an invention, it is believed that these properties may be attributed to the lower degree of order and crystallinity in the polyglycolide segment as compared to polymers having the larger ratio of glycolide to lactide. In one embodiment, an absorbable, biodegradable composite flat textile fabric comprises a multifilament yarn made from a copolymer having a molar weight ratio of about 95:5 glycolide/L-lactide. In one embodiment, the fabric comprises a single filament diameter of about 10 to about 20 microns. In one embodiment, the fabric comprises a yam denier of about 80 to about 100. In one embodiment, the fabric comprises a yam tenacity of about 3 to about 6 g/denier. In one embodiment, the fabric comprises an elongation of about 20% to about 50%. In one embodiment, the fabric comprises a melting temperature of about 205-220⁰C.

In one embodiment, the present invention contemplates a fibrous construct comprising a knitted fabric. In some embodiments, knitted fabrics comprise properties selected from the group comprising density, porosity, elongation, or tenacity. Although it is not necessary to understand a mechanism of an invention, it is believed that knitted fabrics are generally flexible and elastic enough to allow for easy manipulation during implantation. It is further believed that an elasticity of a knitted fabric also allows for a fibrous construct to alter its shape after implantation (post-surgery). Further, it is believed that the flexibility and elasticity of a knitted fabric allows a material to adapt to changes in the geometry of a body tissue that may result during the healing and/or arterialization process. In one embodiment, a composite drug delivery device made from a fibrous construct comprises a structure capable of stretching in multiple directions {i.e., for example, a knitted structure). In one embodiment, the knitted fibrous construct may be useful in bypass graft surgeries, where an artery is being connected to a vein via an ePTFE graft.

In one embodiment, the present invention contemplates a method comprising a graft procedure, wherein the blood may flow from an artery {i.e., for example, a high flow vessel), through a graft, and into a vein (i.e., for example, a low flow vessel). Although it is not necessary to understand the mechanism of an invention, it is believed that due to the significant discrepancy between blood flow rate and pressure between these two vessel types, an increased blood flow through the vein may cause the vein to expand in size to accommodate an increased blood volume. In one embodiment, the present invention contemplates a fibrous construct comprising a degree of elasticity capable of expanding in the days or weeks following implantation to accommodate an increase in vein size without constricting the vein.

In one embodiment, the present invention contemplates a porous fibrous construct comprising a plurality of pores, wherein fluid flows through the pores. In one embodiment, the pores facilitate tissue in-growth. In one embodiment, a fibrous construct comprises interstices sufficiently wide apart to allow light visible by eye, or fluids, to pass through the interstices. Although it is not necessary to understand a mechanism of an invention, it is believed that a flow of fluid through the interstices of a fabric depends on a variety of factors, including, for example, the stitch count or thread density.

Alternatively, materials having a more compact structure also may be used. In one embodiment, the present invention contemplates a method to produce a fabric having a porosity wherein the porosity may be interwoven with a second fabric that may be another material (i.e., for example, particles or polymer). In one embodiment, the method processes a fabric (i.e., for example, by heating) in order to reduce pore size and to create non-fibrous areas. Although it is not necessary to understand the mechanism of an invention, it is believed that fluid flow through a fibrous construct may also vary depending on the properties of a fluid, including, but not limited to, viscosity, hydrophilicity, hydrophobicity, ionic concentration, temperature, elasticity, pseudoplasticity, particulate content, and the like. It is believed that interstices do not prevent the release of impregnated or coated therapeutic agent(s) from a fabric, and interstices do not prevent exchange of tissue fluid at the application site.

In one embodiment, the present invention contemplates a fibrous construct loaded with an amount of therapeutic agent. In one embodiment, the amount of loaded therapeutic agent is predicted and/or controlled by a specific porosity of the construct. In one embodiment, the amount of loaded therapeutic agent is predicted and/or controlled by a specific fiber diameter. For example, less porous materials may have a lower number of threads per unit area, and, therefore, may have a lower loading. In one embodiment, a fibrous construct comprises a knitted fabric having sufficient porosity to allow for tissue ingrowth and fluid flow. The density or "openness" of a fibrous construct can be evaluated optically. One method for evaluating density optically involves capturing an image of the material using a digital photocamera interfaced with a computer. Digital images of a section of material can be magnified and manipulated via software to determine the mesh density. Once a digital image is recorded, the image can be thresholded such that the area accounting for the empty spaces in the mesh can be subtracted from the total area of the image. The mesh density can be calculated based on the percentage of the remaining digital image.

Alternatively, fabric density may be measured by weighing a sample of material having a defined surface area. According to this procedure, less porous fabrics will have densities that are greater than more porous materials. Fabrics can be prepared having a range of densities. In one embodiment, a fabric (i.e., for example, a knitted fabric) can be prepared to have a density of about 1.0 to about 10 mg/cm². In other embodiments, knitted fabrics can be prepared to have a density of about 1.5 to about 6 mg/cm². In yet other embodiments, knitted fabrics are provided having a density of about 2.5 mg/cm² to about 5.0 mg/cm². In yet other embodiments, knitted fabrics are provided having a density of about 3.0 to about 3.5 mg/cm².

In one embodiment, the present invention contemplates a porous fibrous construct, wherein the porosity is predicted and/or controlled by the stitch and/or yarn count (i.e., the number of stitches or loops per unit length). In one embodiment, a construct having a higher stitch count will be less porous than a material with a lower stitch count. In one embodiment, for two constructs having the same dimensions, a construct with a higher stitch count has a higher overall surface area than a construct with a lower stitch count.

In one embodiment, the present invention contemplates a porous fibrous construct, wherein the surface area of the construct predicts and/or controls the amount of matrix (and therapeutic agent) that is loaded onto the construct. Although it is not necessary to understand the mechanism of an invention, it is believed that two composite systems having the same dimensions (one using a higher stitch count construct and one using a lower stitch count construct) and carrying same total amount (weight) of drug-containing matrix, the material having the larger stitch count would typically have a thinner coating of matrix on the construct, which impacts the amount of drug that is released from the device. In one embodiment, the present invention contemplates biodegradable composite drug delivery systems loaded with predictable quantities of a bioactive agent at a therapeutically effective dosage. A composite drug delivery system may be prepared in accordance with the invention to have a unique combination of chemical and physical properties, depending, at least in part, on the choice of material and configuration of the fibers used to prepare the fibrous construct, the construction of the fibrous construct, the composition of the polymer matrix, and the bioactive agent. Further, depending on the choice of the polymer matrix, the bioactive agent may be contained in the device, and the amount and release profile of the drug can be tailored to meet the needs of the specific application. The drug delivery systems described herein are capable of releasing the bioactive agent to the treatment site in a controlled and sustained manner over an extended period of time after implantation into a patient, such that the agent can provide a therapeutic benefit.

The amount of drug and the ultimate release properties of the drug from a device involve a complex interplay of many physical and chemical variables. Depending on the system, the extent and rate of drug release may be correlated with the type and molecular weight of polymer matrix used to carry the drug and/or the total amount of drug that is loaded into the polymer matrix. For example, for a selected polymer matrix, the amount of drug may be altered by changing the amount and concentration of the drug in the polymer matrix and the amount of drug-carrying matrix that is affixed to the fibrous construct. Alternatively, or in addition, the amount of drug that can be loaded into the device may be altered by changing the overall surface area of the device. The total surface area, in turn, can be tailored by altering various properties of the fibers and the configuration of the underlying fibrous construct. For example, the amount of drug loading may be increased or decreased by manipulating such properties as the denier, density, and stitch count. Such changes can dramatically influence the ultimate drug loading and drug release profile. As noted above, the surface area of a fibrous construct, and, therefore, the amount of drug that can be affixed to the construct, can depend on the fabric density (expressed in terms of mg/cm²). Using a knitted fabric as an example of a fibrous construct, density is a function of at least two properties: 1) the fiber denier (that is, the denier of the fiber(s) used to form the knitted fabric) and 2) the stitch (yam) count (expressed in terms of # stitches or loops per unit length). Alterations in fiber denier and/or stitch count can impact the porosity of the knitted fabric, and, hence, the final surface area of device. Denier itself can be altered by adjusting, at least, the filament diameter and the number of filaments (thread) used to prepare the fiber (yam). For example, for two fabrics having equivalent overall dimensions and stitch counts, a fabric made with a lower denier fiber will generally yield a less dense fabric than a fabric made with a higher denier fiber. Similarly, a fabric with a lower stitch count (i.e., less stitches/cm) generally will produce a less dense fabric than one prepared using a higher stitch count, as long as the denier remains constant. It is assumed that when comparing two fabrics to evaluate the effect of changes in denier and stitch count, the following parameters are be held constant: 1) the coating solution has a fixed ratio of polymer to drug, 2) the coating solution has a fixed amount of solids (expressed in terms of weight of solids/volume of solution), and 3) the polymer used in the matrix has a fixed composition and fixed molecular weight. For some materials, denser fabrics may have a higher surface area and can, therefore, retain more drug-loaded polymer matrix than less dense fabrics. However, in some embodiments, a first material (A) may have a higher density than a second material (B), but material (A) may have a lower yarn count (hence a lower surface area) than material (B). Thus, the density can be higher for a lower yarn count material, because the denier of the threads used to make the yarn may be higher. The surface area can be affected by the fiber denier and the stitch count, as well.

For example, using the same assumptions as given above, two fabrics made from fibers with differing deniers may have the same overall dimensions and densities. The fabric made from the lower denier fiber may have a higher stitch count to obtain the same density, and, therefore, a higher surface area. In other cases, a fabric made with a lower denier fiber may yield a fabric with a lower surface area than one prepared using a higher denier fiber, given equivalent stitch counts. In other cases, two fabrics made from fibers with differing deniers may have the same overall dimensions and densities. The fabric made from the lower denier fiber will have a higher stitch count to obtain the same density, and, therefore, a higher surface area. As noted above, a fabric having a higher surface typically can carry more drug-loaded polymer matrix than a fabric of lower surface area. Thus, for certain types of materials, the overall drug loading (for a given coating weight) may be higher for a high surface area fabric than for a lower surface area material.

In one embodiment, the present invention contemplates a fibrous construct comprising a specific stitch (yarn) -count. In one embodiment, the stitch count may range from about 2-10 stitches per cm, or from about 10-20 stitches per cm, or from about 20-30 stitches per cm, or from about 30-100 stitches per cm, or from about 50-95 stitches per cm, or from about 25 to 70 stitches per cm, or from about 30-60 stitches per cm; or from about 35 to 55 stitches per cm. In some embodiments (e.g., perivascular drug delivery), the composite drug delivery device comprises a fibrous construct having about 35 to 50 stitches per cm. In one embodiment, a first fabric comprising a fibrous construct having about 40-45 stitches per cm loaded with a first weight of a bioactive agent (e.g., paclitaxel) releases about 35-45% of the bioactive agent over a 24 hour period. In one embodiment, a second fabric comprising a fibrous construct having about 50-55 stitches per cm loaded with a first weight of a bioactive agent (e.g., paclitaxel) releases about 45-55% of the bioactive agent over a 24 hour period. Although it is not necessary to understand the mechanism of an invention, it is believed that these data suggest that a higher stitch count fabric may result in a faster agent release than a lower stitch count fabric.

In one embodiment, the present invention contemplates a fibrous construct with sufficient flexibility such that the construct is capable of being wrapped around all or a portion of the external surface of a body passageway and/or cavity. For example, fibrous constructs may be used as a component of a composite system, which can be used as a perivascular wrap, which can be wrapped, either fully or partially, about a blood vessel. As such, fibrous constructs are typically in woven form or knitted sheets having a thickness ranging from about 25 microns to about 3000 microns; preferably from about 50 to about 1000 microns. Fibrous constructs suitable for wrapping around arteries and veins typically have thicknesses which range from about 100 to 600 microns or about 100-400 microns. In certain embodiments, a fibrous construct has a thickness of less than 500 microns; or less than 400 microns; or less than 300 microns; or less than 200 microns.

A composite material may also include multiple fibrous constructs in any combination or arrangement. In one embodiment, a portion of a device may be a knitted material and another portion may be a woven material. In another embodiment, a device may include more than one layer (i.e., for example, a layer of woven material fused to a layer of knitted material or to another layer of a same type or a different type of woven material). In one embodiment, a present invention contemplates a device comprising a multi-layer construction. In some embodiments, multi-layer constructions (i.e., for example, a device having two or more layers of material) may be used, for example, to enhance a performance properties of a device (i.e., for example, for enhancing a rigidity or for altering a porosity, elasticity, or tensile strength of a device) or for increasing a amount of drug loading. In one embodiment, a multi-layer device comprises more than one therapeutic agent

(i.e. for example, a first therapeutic agent and a second therapeutic agent). In one embodiment, a first layer of fibrous construct may be loaded with one type of agent and a second layer may be loaded with another type of agent. In some embodiments, the two layers may be unconnected or connected (i.e., for example, fused together, such as by heat welding or ultrasonic welding) and/or may be formed of a same type of fabric or from a different type of fabric having a different polymer composition and/or structure.

In one embodiment, the present invention contemplates a composite material comprising a portion of which is in a form selected from the group comprising a film, sheet, paste, gel, and the like, and combinations thereof. In one embodiment, the film portion is generally less than 5, 4, 3, 2, or 1, mm thick. In certain embodiments, the film is less than 0.75 mm thick, or less than 0.5 mm thick, 0.25 mm, or, 0.10 mm thick or less than 500 μm to 20 μm thick or 10 μm. In one embodiment, the film is flexible comprising an appropriate tensile strength (i.e., for example, greater than 50, preferably greater than 100, and more preferably greater than 150 or 200 N/cm²) and has controlled permeability. In one embodiment, a composite drug delivery device comprises a multi-layer construction having a film layer comprising a therapeutic agent and one or more layers of fibrous material (i.e., for example, a mesh). In one embodiment, a film layer is interposed between two layers of fabric. In one embodiment, a film layer is disposed on one side a fabric material. In one embodiment, a first film layer comprises a first therapeutic agent, wherein a first therapeutic agent is a same or different from a second, third, fourth etc. therapeutic agent in one or more of a some layers of fabric. In one embodiment, the device suitable for wrapping around a vein or artery includes a layer of fabric and a film layer loaded with a therapeutic agent. In one embodiment, the device may be wrapped around a body passageway or cavity, such that a film layer contacts an external surface of a passageway or cavity, thereby delivering an appropriate dosage of agent. The device also may provide sufficient mechanical strength to improve and maintain a structural integrity of a body passageway or cavity. In certain embodiments, the fabric may include a barrier layer that blocks the therapeutic agent from releasing from the fabric in a bidirectional manner (e.g., from both sides of a substantially flat piece of fabric). Fabrics having a barrier layer may be useful in situations benefiting from a unidirectional release of therapeutic agent from the device. For example, the presence of the barrier layer may keep the agent from releasing into parts of the body apart from the site of treatment.

In one embodiment, the present invention contemplates a fibrous construct fiber comprising a polymer, wherein the polymer may be biodegradable or non-biodegradable. In some embodiments, the polymer may be a bioresorbable polymer. In some embodiments, the polymer degrades via hydrolysis. The extent of degradation of the fibrous construct can be evaluated by measuring the mass loss after the construct has been exposed to a physiologically appropriate buffer (e.g., phosphate) at elevated temperature (e.g., about 50 ⁰C) over a period of several days.

Typically, for the procedures described herein, the polymer fibers used to form the construct absorb and/or lose their mechanical integrity in vivo within 120 days, a period long enough to provide for the in-growth of site-stabilizing tissue around the application site. Certain types of constructs absorb and/or lose their mechanical integrity in vivo within about 60-120 days, or within about 60-90 days, or within about 90 days. In certain embodiments, the polymer fibers absorb and/or lose their mechanical integrity within 50 days. In other embodiments, the biodegradable polymer is resorbed within about 20-25 days after implantation.

Biodegradable compositions that may be used to prepare fibers of the invention include naturally derived and synthetic biodegradable polymers. Examples of naturally derived polymers include, but are not limited to, albumin, collagen, hyaluronic acid and derivatives, sodium alginate and derivatives, chitosan and derivatives gelatin, starch, cellulose polymers (i.e., for example, methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, cellulose acetate phthalate, cellulose acetate succinate, hydroxypropylmethylcellulose phthalate), casein, dextran and derivatives, polysaccharides, and fibrinogen.

Synthetic biodegradable polymers and copolymers may be formed from one or more cyclic monomers (i.e., for example, D-lactide, L-lactide, D,L-lactide, meso-lactide, glycolide, ε-caprolactone, trimethylene carbonate (TMC), p-dioxanone (i.e., for example, l,4-dioxane-2-one or l,5-dioxepan-2-one, or a morpholinedione). Upon polymerization of the cyclic monomers, a polymer or copolymer formed may include, but are not limited to, residue units derived from polymerization of one or more D-lactide, L-lactide, D,L-lactide, glycolide, ε-caprolactone, trimethylene carbonate (TMC), p-dioxanone (i.e., for example, l,4-dioxane-2-one or l,5-dioxepan-2-one), or morpholinedione monomers. In certain embodiments, a polymer fiber comprises a plurality of glycolide and lactide (i.e., for example, L-lactide, D-lactide, or mixtures thereof, also referred to as D,L- lactide residues, or meso-lactide). In one embodiment, the polymer may comprise a plurality of glycolide and L-lactide residues. A ratio of glycolide to lactide residues in a copolymer may be varied depending on the desired properties of a fiber. For example, a polymer may have a molar ratio of glycolide to lactide (e.g., L-lactide) residues that is greater than about 80; or greater than about 85; or greater than about 90; or greater than about 95. A fiber may be formed from a polymer having about a 3:97 molar ratio of lactide (i.e., for example, D,L-lactide or L-lactide) to glycolide, or about a 5:95 molar ratio of lactide to glycolide, or about a 10:90 molar ratio of lactide to glycolide. In some embodiments, polymer fibers may comprise poly(lactide-co-glycolide) having a lactide:glycolide molar ratio between about 100:0 and about 2:98; preferably between about 15:85 and about 3:97; and most preferably between about 10:90 and about 3:97. In one embodiment, a polymer includes poly(lactide-co-glycolide) having a molar ratio of about 5:95 of D,L-lactide to glycolide residues. In one embodiment, a polymer includes poly(lactide-co-glycolide) having a molar ratio of about 5:95 of L-lactide to glycolide residues.

Certain compositions having molar ratios of glycolide to lactide of greater than 90:10 may be particularly well suited for the preparation of transient drug delivery devices, such as those used in tissue or wound repair. In one representative example (see Example 12), it was demonstrated that fabrics utilizing ratios of glycolide to lactide in excess of 90:10 (e.g., 95:5) retained their strength and maintained their mechanical integrity for a longer period of time (as compared to compositions prepared with lower ratios of glycolide to lactide) during the critical period of site healing, while permitting faster absorption and loss of mass following the healing period. This combination of properties may be particularly desirable for fabrics that are to be utilized in perivascular drug delivery applications. Polymer fibers may include, but are not limited to, polymers or copolymers formed from one or more hydroxyl acids (i.e., for example, lactic acid, glycolic acid, valeric acid, malic acid, or tartaric acid). Hydroxyl acid polymers include, for example, lactic acid or glycolic acid oligomers and polymers (i.e., for example, poly(D,L-lactic acid), poly(L-lactic acid) oligomers and polymers, poly(D-lactic acid) oligomers and polymers, poly(glycolic acid)), and copolymers of lactic acid and glycolic acid), poly(hydroxyvaleric acid), poly(malic acid), and poly(tartronic acid).

A fiber may comprise a biodegradable or bioerodible polyester, including, but not limited to, poly(L-lactide) poly(D,L lactide), copolymers of lactide and glycolide such as poly(D,L-lactide-co-glycolide) and poly(L-lactide-co-glycolide), poly(caprolactone), poly(glycolide), copolymers prepared from caprolactone and/or lactide and/or glycolide and/or polyethylene glycol (i.e., for example, copolymers of ε-caprolactone and lactide and copolymers of glycolide and ε-caprolactone), poly(valero lactone), polydioxanone, and copolymers of lactide and 1 ,4-dioxane-2-one. As noted above, a fibrous construct may be formed using polymer fibers with having a degree of crystallinity. Polymer fibers having a degree of crystallinity may be prepared, for example, from copolymers of glycolide and lactide {i.e., for example, L- lactide) having a large molar excess of glycolide. For example, fibers may be prepared from a copolymer having a molar ratio of glycolide: lactide of about 97:3 to about 85:15, or about 90:10, or about 95:5. In one embodiment, a fibrous construct comprises a multifilament fiber made of a copolymer of glycolide and L-lactide (about 95:5 molar ratio) and having a melting temperature of about 205-220 ⁰C.

Other examples of biodegradable materials include, but are not limited to, poly(hydroxybutyrate), poly(hydroxyvalerate), poly(hydroxybutyrate-co-hydroxyvalerate) copolymers, poly(alkylcarbonate), poly(orthoesters), tyrosine based polycarbonates and polyacrylates, poly(ethylene terephthalate), poly( anhydrides), poly(ester-amides), polyphosphazenes, or poly(amino acids).

Fabrics described herein may include, but are not limited to, fibers formed from one or more biodegradable polymers. However, in certain embodiments, a fiber may also include one or more non-biodegradable polymers and/or non-polymeric components.

In some embodiments, a fibrous construct of the present invention may comprise a combination of biodegradable and non-degradable polymers. Representative examples of non-biodegradable polymers include, but are not limited to, ethylene-co-vinyl acetate copolymers, acrylic-based and methacrylic-based polymers (i.e., for example, poly(acrylic acid), poly(methylacrylic acid), polymethylmethacrylate), poly(hydroxyethylmethacrylate), poly(alkylcynoacrylate), poly(alkyl acrylates), poly(alkyl methacrylates)), poly(ethylene), poly(propylene), polyamides (i.e., for example, nylon 6,6), poly(urethanes) (i.e., for example, poly(ester urethanes), poly(ether urethanes), polycarbonate urethanes), poly(ester-urea)), polyethers (i.e., for example, poly(ethylene oxide)), poly(propylene oxide), poly(ethylene oxide)-poly(propylene oxide) copolymers, diblock and triblock copolymers, poly(tetramethylene glycol)], silicone containing polymers and vinyl-based polymers (i.e., for example, polyvinylpyrrolidone, poly( vinyl alcohol), poly(vinyl acetate phthalate), and poly(styrene-co-isobutylene-co-styrene)). These compositions comprise copolymers as well as blends, crosslinked compositions and combinations of the above non-biodegradable polymers.

In one embodiment, a fibrous construct may further comprise additional components, including, but not limited to, some biological agents or non-biodegradable agents and/or polymers. Examples of additional components include antibiotic and antimicrobial agents, waxes, colorants, contrast agents, surfactants (i.e., for example, PLURONICs such as F-127, L- 122, L-92, L-81, and L-61 from BASF Corporation, Mount Olive, NJ), anti-oxidants (i.e., for example, hydroquinone, butylated hydroxyanisole, vitamin E), plasticizers (i.e., for example, triethyl citrate, poly(ethylene glycol)) and hydrating agents (i.e., for example maltose trehelose and poly(ethylene glycol)).

B. Matrix Compositions

The composite delivery system further comprises a matrix which is reinforced by a fibrous construct. A matrix may contact all or only a portion of a fibrous construct and may reside only at a surface of the construct or may be impregnated into a material forming a fiber.

In one embodiment, a matrix is in the form of a coating. Although it is not necessary to understand the mechanism of an invention, it is believed that a composition and amount of coating generally should yield a composite material having a porosity and density that is similar to that of the underlying fibrous substrate. It is further believed that the amount and type of coating that resides on or in a fiber not compromise the flexibility of the fibrous construct itself.

In one embodiment, a coating layer comprises a thickness of less than about 200 μm. In other embodiments, the coating may be less than 100 μm, or less than 50 μm, or less than 20 μm. In one embodiment, the present invention contemplates a coating that covers all or a portion of a fibrous construct. For example, in the case of a planar device (e.g., a sheet of material), the coating may be disposed on all or a portion of one side of the device or of both sides of the device. In one embodiment, the coating may, or may not, fill all or a portion of an interstitial space of the fibrous construct. In one embodiment, the coating fills less than 50% of a interstitial spaces of the fibrous construct, hi some embodiments, a coating fills less than about 40%, or less than about 30%, or less than about 20%, or less than about 10%, or less than about 5% of an interstitial space of the fibrous construct.

In some embodiments of the invention, a matrix completely fills an interstitial space of a fibrous construct. In one embodiment, a composite comprises a substantially non- porous fibrous construct at the time of implantation, wherein the construct becomes more porous as the matrix degrades over time. Although it is not necessary to understand the mechanism of an invention, it is believed that composite drug delivery devices having a greater percentage of matrix relative to fibrous construct allow for higher overall drug loadings. In certain embodiments of the invention, a matrix may comprise an amorphous composition or polymer (i.e., for example, an amphiphilic, amorphous polymer). Amorphous compositions are typically characterized by exhibiting a glass transition (T₆) temperature and no defined melting point. An amorphous matrix may exhibit a wide range of glass transition temperatures, depending on a composition and molecular weight of a polymer. In some embodiments, a matrix comprises a T_g of less than 150⁰C but may be less than 100°, or less than 50 ⁰C, or less than 30⁰C.

Although it is not necessary to understand the mechanism of an invention, it is believed that an amorphous matrix composition may degrade more quickly than a fibrous reinforcement. The rate at which a matrix degrades relative to a fibrous construct may be predicted to accommodate a particular application. For example, in certain embodiments, a composite material having differential degradability may be formed from a fibrous construct as described herein, which is coated with an amorphous, amphiphilic polymer matrix.

In one embodiment, the present invention contemplates a drug-carrying matrix that is capable of absorbtion and/or loss of mechanical integrity within about 50 days after implantation. In certain embodiments, the drug-carrying matrix is absorbed and/or loses its mechanical integrity by about 40 days after implantation. In certain embodiments, the drug-carrying matrix is absorbed and/or loses its mechanical integrity by about 21 days after implantation. In one embodiment, the present invention contemplates a matrix formulated from a variety of biodegradable and bioerodible polymers. A polymer matrix may include, but is not limited to, one or more biodegradable polymer(s), one or more non-degradable polymer(s) or a combination of one or more biodegradable polymer(s) and non-degradable polymer(s). Representative examples of biodegradable polymers include, but are not limited to, naturally derived and synthetic biodegradable polymers. Representative examples of naturally derived polymers include, but are not limited to, albumin, collagen, hyaluronic acid and derivatives, sodium alginate and derivatives, chitosan and derivatives gelatin, starch, cellulose polymers (for example methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, cellulose acetate phthalate, cellulose acetate succinate, hydroxypropylmethylcellulose phthalate), casein, dextran and derivatives, polysaccharides, and fibrinogen.

Representative examples of synthetic biodegradable polymers and copolymers include, but are not limited to, those formed from one or more cyclic monomers (i.e., for example, D-lactide, L-lactide, D,L-lactide, glycolide, ε-caprolactone, trimethylene carbonate (TMC), p-dioxanone (i.e., for example, 1 ,4-dioxane-2-one or 1 ,5-dioxepan-2- one), or a morpholinedione) and polymers and copolymers formed from one or more hydroxyl acids such as lactic acid or glycolic acid (i.e., for example, poly(D,L-lactic acid) oligomers and polymers, poly(L-lactic acid) oligomers and polymers, poly(D-lactic acid) oligomers and polymers, poly(glycolic acid), poly(hydroxyvaleric acid), poly(malic acid), poly(tartronic acid), copolymers of lactic acid and ε-caprolactone, and copolymers of lactic acid and glycolic acid).

In one embodiment, a matrix may comprise a biodegradable or bioerodible polyester, such as a poly(lactide) (i.e., for example, poly(L-lactide), poly(D,L lactide)), copolymers of lactide and glycolide (i.e., for example, poly(D,L-lactide-co-glycolide) and poly(L-lactide-co-glycolide)), poly(caprolactone), poly(glycolide), poly(valerolactone), a copolymer of ε-caprolactone and lactide, a copolymer of glycolide and ε-caprolactone, a copolymer prepared from caprolactone and/or lactide and/or glycolide and/or polyethylene glycol, polydioxanone, and copolymers of lactide and 1 ,4-dioxane-2-one; A polymer may be, for example, a copolymer of lactic acid and glycolic acid, or a polymer or copolymer which includes one or more of a residue units of D-lactide, L- lactide, D,L-lactide, glycolide, ε-caprolactone, trimethylene carbonate, l,4-dioxane-2-one, l,5-dioxepan-2-one, or a trimethylene carbonate monomers, and combinations thereof. Some examples of biodegradable polymers for use in a matrix include, but are not limited to, poly(hydroxybutyrate), poly(hydroxyvalerate), poly(hydroxybutyrate-co- hydroxyvalerate) copolymers, poly(alkylcarbonate), poly(orthoesters), tyrosine based polycarbonates and polyacrylates, poly(ethylene terephthalate), poly(anhydrides), poly(ester-amides), polyphosphazenes, or poly(amino acids). A matrix may comprise an amphiphilic polymer. In one embodiment, an amphiphilic polymer is characterized by comprising a hydrophobic segment (i.e., for example, a block (A)) and a hydrophilic segment (i.e., for example, a block (B)). In one embodiment, an amphiphilic polymer may include, but is not limited to, two or more hydrophilic or hydrophobic blocks. For example, an amphiphilic polymer may be a diblock (A-B) copolymer or a triblock (A-B-A) or (B-A-B) copolymer. The amphiphilic polymer may be a block copolymer of a form (AB)_n-R or (BA)_n-R where R is a multifunctional compound. Multifunctional compounds may be prepared from the reaction of a multifunctional reagent (e.g., triethanolamine, trimethylolpropane, and pentaerythritol. In certain embodiments, amphiphilic polymers may be used to provide an amorphous polymeric matrix.

A hydrophobic block (A) may be prepared from hydroxyl acids and hydroxyl acid derivatives and may include, but is not limited to, one or more of a residue units of D- lactide, L-lactide, D,L-lactide, meso-lactide, glycolide, ε-caprolactone, trimethylene carbonate, l,4-dioxane-2-one or l,5-dioxepan-2-one, hydroxyvalerate, or hydroxybutyrate. For example, a hydrophobic block (A) may be prepared from one or more lactide, glycolide, ε-caprolactone, trimethylene carbonate, l,4-dioxan-2-one, 1 ,5-dioxepan-2-one, l,4-dioxepan-2-one, hydroxyvalerate, or hydroxybutyrate monomers. A hydrophobic block (A) may further comprise residues derived from D,L-lactide and glycolide. In certain embodiments, a polymer may have a lactide:glycolide molar ratio of about 85: 15 to about 15:85. Some exemplary polymers may have a lactide:glycolide molar ratio of about 85:15 to about 40:60.

A hydrophilic block (B) may be prepared from a hydrophilic monomer including, but not limited to, an alkylene oxide. Representative examples of poly(alkylene oxides) include, but are not limited to, poly(ethylene glycol), poly(ethylene oxide-co-propylene oxide), poly(propylene oxide-co- ethylene oxide-co- propylene oxide)and poly(ethylene oxide-co-propylene oxide-co-ethylene oxide).

In certain embodiments, an amphophilic matrix may include, but is not limited to, a polyether-ester copolymer (i.e., for example, a copolymer that comprises a polyether portion (i.e., for example, polyethylene glycol; PEG) and at least one ester linkage).

Polyether-polyester copolymers may be formed, for example, from a poly(alkylene oxide) block(s) to which has been grafted a cyclic monomer to form a diblock or triblock copolymer. An amphiphilic matrix may comprise a polyether-ester copolymer made from a poly(ethylene glycol) grafted with at least one cyclic monomer, such as glycolide, L- lactide, ε-caprolactone, trimethylene carbonate, p-dioxanone, or a morpholinedione.

Exemplary copolymers formed from grafting a cyclic monomer to a poly(alkylene oxide) include diblock copolymers (A-B) with block A comprising methoxypolyethylene glycol and block B comprising a polyester. In one embodiment, a diblock copolymer (A-B) comprises methoxypoly(ethylene glycol) - co — poly(D,L-lactide). In other embodiments, triblock copolymers (A-B-A) or (B-A-B) are provided with block A including polyoxyalkane and block B including a polyester. Exemplary methods for preparing poly(ester)-poly( ether) polymers are provided in U.S. Patent Nos. 5,612,052; 5,714,159; 6,413,539; and EP 0 737 703, EP 0 315 056 and EP 0 952 171 (all herein incorporated by reference). Diblock copolymers, such as polyether-ester diblock copolymers may include, but are not limited to, a poly(alkylene oxide) having a terminal alkyl moiety (i.e., for example, a methyl, ethyl, propyl, isopropyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, dodecyl, octadecyl). Polyether-ester copolymers may include, but are not limited to, a poly(ethylene glycol) monomethyl ether (MePEG) grafted with at least one cyclic monomer (i.e.. for example, glycolide, L-lactide, D-lactide, ε-capro lactone, trimethylene carbonate, p- dioxanone, or a morpholinedione).

A matrix may comprise an A-B diblock copolymer wherein an A block comprises methoxy poly(ethylene glycol) (MePEG), and a B block comprises a poly(lactide) (i.e., for example, PDLLA).

The methoxy poly(ethylene glycol) block and the poly(lactide) block may range in molecular weight. Generally, the MePEG block has a molecular weight in a range of about 200 g/mol to about 20,000 g/mol, or about 500 g/mol to about 2000 g/mol, or about 700 to about 800 g/mol, or about 740 g/mol to about 760 g/mol. The poly(lactide) block typically has a molecular weight in a range of about 200 g/mol to about 10,000 g/mol or about 500 g/mol to about 5000 g/mol.

In one embodiment, a block copolymer comprises a methoxypoly(ethylene glycol) : polyester ratio in a range of about 10:90 to about 30:70 (by weight). For example, a block copolymer may have a methoxypoly(ethylene glycol):polyester ratio of about 10:90 to 15:85, or about 15:85 to about 20:80, or about 18:72 to about 22:78, or about 20:80 to about 25:75, or about 25:75 to about 30:70. One example of an A-B diblock copolymer has a MePEG:lactide ratio (weight/weight) in a range of about 5:95 to about 40:60. Some examples of A-B diblock copolymers have a MePEG:lactide ratio (weight/weight) in a range of about 10:90 to about 30:70 or a MePEG:lactide ratio (weight/weight) of about 20:80. hi one embodiment, a matrix comprises a combination of biodegradable and non- degradable polymers. Representative examples of non-biodegradable polymers include, but are not limited to, ethylene-co-vinyl acetate copolymers, acrylic-based and methacrylic- based polymers (i.e., for example, poly(acrylic acid), poly(methylacrylic acid), poly(methylmethacrylate), poly(hydroxyethylmethacrylate), poly(alkylcynoacrylate), poly(alkyl acrylates), poly(alkyl methacrylates)), cellulose derivatives (i.e., for example, cellulose esters and nitrocellulose) polyolefins such as poly(ethylene) and poly(propylene), polyamides (i.e., for example, nylon 6,6), polyethers (i.e., for example, poly(ethylene oxide), poly(propylene oxide), poly(ethylene oxide)-poly(propylene oxide) copolymers, and poly(tetramethylene glycol)), silicone containing polymers and vinyl-based polymers (polyvinylpyrrolidone, poly(vinyl alcohol), poly( vinyl acetate phthalate)), and poly(styrene-co-isobutylene-co-styrene). Some exemplary non-biodegradable polymers include, but are not limited to, poly(hydroxyethylmethacrylates) and poly(urethanes) (i.e., for example, poly(ester urethanes), poly(ether urethanes), poly(carbonate urethanes), poly(ester-urea)). A variety of commercially available polyurethanes may be used, including, i.e., for example, polycarbonate urethanes, such as CHRONOFLEX AR or CHRONOFLEX AL (CardioTech International, Inc.), BIONATE (The Polymer Technology Group, Inc.), TECOFLEX (Lubrizol), and the like. These compositions include, but are not limited to, copolymers as well as blends, crosslinked compositions and combinations of the above non-biodegradable polymers.

In some embodiments, matrices may be prepared from polymers and copolymers having a range of molecular weights. Typically, a polymer has a molecular weight, such that a viscosity and solubility of a polymer allows for application (i.e., for example, coating) of a matrix to a fibrous construct and to provide appropriate release kinetics of a bioactive agent from polymer matrix; molecular weights generally exceed about 3 kDa and more typically range from about 4 kDa to about 15 kDa. In certain embodiments, a matrix comprises a polyether ester (e.g., MePEG-PDLLA) having a weight average molecular weight of about 3 kDa to about 9 kDa. In other embodiments, a matrix includes a polyether-polyester copolymer having a molecular weight of about 5-6 kDa, or about 6-7 kDa, or about 7-8 kDa, or about 8-9, or about 7-9 kDa, or about 8-12 kDa, or about 10-12 kDa, .

A particular embodiment of the polymer matrix include a MePEG750-PDLLA copolymer having a weight average molecular weight of about 5-6 kDa. Another embodiment includes a MePEG750-PDLLA copolymer having a weight average molecular weight of about 6-7 kDa. Yet another embodiment includes a MePEG750-PDLLA copolymer having a weight average molecular weight of about 7-8 kDa. Another embodiment includes a MePEG750-PDLLA copolymer having a weight average molecular weight of about 8-9 kDa.

In one embodiment, the present invention contemplates a method wherein a lower molecular weight drug-carrying matrix of a particular polymer composition releases a drug at a faster rate than a higher molecular weight version of the polymer composition. For example, when coated with a particular coating weight on a knitted fabric, a polyether- polyester copolymer weighing about 6000 Daltons may release about 50% of a drug (e.g., paclitaxel) over a 24 hour period, whereas the same copolymer, coated at the same coating weight, weighing about 8000 Daltons may release only about 25% of the drug over the same period of time.

In one embodiment, the present invention contemplates a matrix further comprising an additive, wherein the additive imparts particular properties to the matrix. In one embodiment, the additive is in a form selected from the group comprising a liquid, solid, semi-solid, or gel. For example, the additive may be a non-polymeric additive that is a viscous material (i.e., for example, having a viscosity in a range of between about 100 and about 3x 10⁶ centipoise) or may be solid (having a melting point greater than 10 ⁰C). Representative examples of non-polymeric additives that may be used in the matrix include sugar ester derivatives (i.e., for example, sucrose acetate isobutyrate, sucrose oleate, and a like), sugar amide derivatives, fatty acids, fatty acid salts (i.e., for example calcium stearate) lipids, waxes (i.e., for example, refined paraffin wax, microcrystalline wax). Other examples of additives include preservatives, antibacterial agents, and vitamins (i.e., for example, vitamin E).

II. Therapeutic Agents

A wide variety of bioactive agents may be utilized within a context of a present invention. Therapeutic drugs may include, but are not limited to, antiproliferative agents which inhibit some or all of a process involved in the development of intimal hyperplasia (i.e., for example, cell proliferation, cell migration or matrix deposition). Antiproliferative agents also include, but are not limited to, cell cycle inhibitors; anti-angiogenic agents, i.e., for example, anthracyclines, fucoidon, and taxanes; certain immunosuppressive compounds including, but not limited to, sirolimus and sirolimus analogues and derivatives; certain nonsteroidal anti-inflammatory agents including, but not limited to, dexamethasone and dexamethasone analogues and derivatives; certain antibiotic agents including, but not limited to, dactinomycin and dactinomycin analogues and derivatives; certain statins including, but not limited to, cervistatin and cervistatin analogues and derivatives; and certain estrogens including, but not limited to, 17-β-estradiol and 17-β-estradiol analogues and derivatives. Furthermore, antithrombotic agents and antiplatelet agents (i.e., for example, dipyridamole) may be used. Discussed in more detail below are (A) anthracyclines (i.e., for example, a doxorubicin and mitoxantrone), (B) taxanes (i.e., for example, paclitaxel and docetaxol), (C) sirolimus analogues. (D) antibiotic agents (i.e., for example, dactinomycin) , (E) statins (i.e., for example, cervistatin), and (F) estrogens (i.e., for example, 17-β-estradiol).

A. Anthracyclines Anthracyclines have a following general structure, where a R groups may be a variety of organic groups:

According to U.S. Patent 5,594,158 (herein incorporated by reference), suitable R groups are as follows: Ri is CH₃ or CH₂OH; R₂ is daunosamine or H; R₃ and R₄ are independently one of OH, NO₂, NH₂, F, Cl, Br, I, CN, H or groups derived from these; R₅ is hydrogen, hydroxy, or methoxy; and Re-₈ are all hydrogen. Alternatively, R₅ and R$ are hydrogen and R7 and Rg are alkyl or halogen, or vice versa.

According to U.S. Patent 5,843,903 (herein incorporated by reference), Rj may be a conjugated peptide. According to U.S. Patent 4,296,105 (herein incorporated by reference), R₅ may be an ether linked alkyl group. According to U.S. Patent 4,215,062 (herein incorporated by reference), R₅ may be OH or an ether linked alkyl group. Ri may also be linked to an anthracycline ring by a group other than C(O), such as an alkyl or branched alkyl group having a C(O) linking moiety at its end, such as -CH₂CH(CH₂- X)C(O)-Ri, wherein X is H or an alkyl group (see, i.e., for example, U.S. Patent 4,215,062, herein incorporated by reference). R₂ may alternately be a group linked by a functional group =N-NHC(O)-Y, where Y is a group such as a phenyl or substituted phenyl ring. Alternately, R₃ may have a following structure:

in which R₉ is OH either in or out of a plane of a ring, or is a second sugar moiety such as R₃. Rio may be H or form a secondary amine with a group such as an aromatic group, saturated or partially saturated 5 or 6 membered heterocyclic having at least one ring nitrogen (see U.S. Patent 5,843,903; herein incorporated by reference). Alternately, Rio may be derived from an amino acid, having a structure -C(O)CH(NHRn)(Ri 2), in which Rn is H, or forms a C₃.4 membered alkylene with Ri₂. R12 maybe H, alkyl, aminoalkyl, amino, hydroxy, mercapto, phenyl, benzyl or methylthio (see U.S. Patent 4,296,105) (herein incorporated by reference).

Exemplary anthracyclines are doxorubicin, daunorubicin, idarubicin, epirubicin, pirarubicin, zorubicin, and carubicin. Suitable compounds have a structures:

R₂ R₃ doxorubicin: OCH₃ C(O)CH₂OH OH out of ring plane epirubicin: OCH₃ C(O)CH₂OH OH in ring plane

(4' epimer of doxorubicin) daunorubicin: OCH₃ C(O)CH₃ OH out of ring plane idarubicin: H C(O)CH₃ OH out of ring plane

pirarubicin: OCH₃ C(O)CH₂OH

zorubicin: OCH₃ C(CH₃X=N)NHC(O)C₆H₅ OH carubicin: OH C(O)CH₃ OH out of ring plane

Some suitable anthracyclines are anthramycin, mitoxantrone, menogaril, nogalamycin, aclacinomycin A, olivomycin A, chromomycin A₃, and plicamycin having a structures:

R₁ R₁ R,

Mβnogaril H OCH, H

Nogalamydn O-sugar H COOCH, sugar

Some representative anthracyclines include, but are not limited to, FCE 23762 doxorubicin derivative (Quaglia et al, J. Liq. Chromatogr. /7(18):3911-3923, 1994), annamycin (Zou et al., J. Pharm. ScL 82(11):1151-1154, 1993), ruboxyl (Rapoport et al., J. Controlled Release 58(2): 153-162, 1999), anthracycline disaccharide doxorubicin analogue (Pratesi et al., Clin. Maycer Res. 4(l l):2833-2839, 1998), N-CtrifluoroacetyOdoxorubicin and 4'-0-acetyl-N-(trifluoroacetyl)doxorubicin (Berube & Lepage, Synth. Commun. 28(6): 1109-1116, 1998), 2-pyrrolinodoxorubicin (Nagy et al, Proc. Nat'l Acad. ScL U.S.A. 95(4): 1794- 1799, 1998), disaccharide doxorubicin analogues (Arcamone et al., J. Nat'l Maycer Inst. 89(\6): 1217-1223, 1997), 4-demethoxy-7-0-[2,6-dideoxy-4-0-(2,3,6- trideoxy-3-amino-α-L-lyxo-hexopyranosyl)-α-L-lyxo-hexopyranosyl] adriamicinone doxorubicin disaccharide analogue (Monteagudo et al, Carbohydr. Res. 300(1): 11-16, 1997), 2-pyirolinodoxorubicin (Nagy et al, Proc. Nat 'I Acad. Sd. U. S. A. 94(2):652-β56, 1997), morpholinyl doxorubicin analogues (Duran et al., Maycer Chemoar. Pharmacol. 3S(3):210-216, 1996), enaminomalonyl-β -alanine doxorubicin derivatives (Seitz et al., Tetrahedron Lett. 36(9):1413-16, 1995), cephalosporin doxorubicin derivatives (Vrudhula et al., J. Med. Chem. 3<S(8): 1380-5, 1995), hydroxyrubicin (Solary et al, Int. J. Maycer 5#(l):85-94, 1994), methoxymorpholino doxorubicin derivative (Kuhl et al., Maycer Chemoar. Pharmacol. 33(l)Λ0-l6, 1993), (6-maleimidocaproyl)hydrazone doxorubicin derivative (Willner et al., Bioconjugate Chem. 4(<S):52\-7, 1993), N-(5,5-diacetoxypent-l- yl) doxorubicin (Cherif & Farquhar, J. Med. Chem. 35(17):3208-14, 1992), FCE 23762 methoxymorpholinyl doxorubicin derivative (Ripamonti et al., Br. J. Maycer <J5(5):703-7, 1992), N-hydroxysuccinimide ester doxorubicin derivatives (Demant et al., Biochim. Biophys. Acta 777£(l):83-90, 1991), polydeoxynucleotide doxorubicin derivatives (Ruggiero et al., Biochim. Biophys. Acta 1 J 29(3):294-302, 1991), morpholinyl doxorubicin derivatives (EPA 434960), mitoxantrone doxorubicin analogue (Krapcho et al., J. Med. Chem. 54(8):2373-80. 1991), ADl 98 doxorubicin analogue (Traganos et al., Maycer Res. 5/(14):3682-9, 1991), 4-demethoxy-3'-N-trifluoroacetyldoxorubicin (Horton et al., Drug Des. Delivery 6(2): 123-9, 1990), 4'-epidoxorubicin (Drzewoski et al., Pol. J. Pharmacol. Pharm. 40(2): 159-65, 1988; Weenen et al, Eur. J. Maycer Clin. Oncol. 20(7):919-26, 1984), alkylating cyanomorpholino doxorubicin derivative (Scudder et al., J. Nat 'I Maycer Inst. 80(16): 1294-8, 1988), deoxydihydroiodooxorubicin (EPA 275966), adriblastin

(Kalishevskaya ef α/., Vestn. Mosk. Univ., 76(Biol. l):21-7, 1988), 4'-deoxydoxorubicin (Schoelzel et al., Leuk. Res. 70(12): 1455-9, 1986), 4-demethyoxy-4'-o-methyldoxorubicin (Giuliani et al., Proc. Int. Congr. Chemoar. 7(5:285-70-285-77, 1983), 3^f-deamino-3'- hydroxydoxorubicin (Horton et al., J. Antibiot. 57(8):853-8, 1984), 4-demethyoxy doxorubicin analogues (Barbieri et al, Drugs Exp. CHn. Res. 70(2):85-90, 1984), N-L- leucyl doxorubicin derivatives (Trouet et al, Anthracyclines (Proc. Int. Symp. Tumor Pharmacoar.), 179-81, 1983), 3'-deamino-3'-(4-methoxy-l-piperidinyl) doxorubicin derivatives (U.S. 4,314,054), 3'-deamino-3'-(4-mortholinyl) doxorubicin derivatives (U.S. 4,301,277), 4'-deoxydoxorubicin and 4'-o-methyldoxorubicin (Giuliani et al, Int. J. Maycer 27(1):5-13, 1981), aglycone doxorubicin derivatives (Chan & Watson, J. Pharm. Sd. tf7(12):1748-52, 1978), SM 5887 (Pharma Japan 1468:20, 1995), MX-2 (Pharma Japan 1420:19, 1994), 4'-deoxy-13(S)-dihydro-4'-iododoxorubicin (EP 275966), morpholinyl doxorubicin derivatives (EPA 434960), 3'-deamino-3^l-(4-methoxy-l- piperidinyl) doxorubicin derivatives (U.S. 4,314,054), doxorubicin- 14- valerate, morpholinodoxorubicin (U.S. 5,004,606), 3'-deamino-3'-(3"-cyano-4"-morpholinyl doxorubicin; 3'-deamino-3¹-(3"-cyano-4"-morpholinyl)-13-dihydoxorubicin; (3'-deamino- 3'-(3"-cyano-4"-moφholinyl) daunorubicin; 3'-deamino-3'-(3"-cyano-4"-morpholinyl)-3- dihydrodaunorubicin; and 3'-deamino-3'-(4"-inorpholinyl-5-iminodoxorubicin and derivatives (U.S. 4,585,859), 3'-deamino-3'-(4-methoxy-l-piperidinyl) doxorubicin derivatives (U.S. 4,314,054) and 3-deamino-3-(4-morpholinyl) doxorubicin derivatives (U.S. 4,301,277). B. Taxanes

In another embodiment, a therapeutic agent is a taxane, or a derivative or an analogue thereof. Briefly, taxanes such as, for example, paclitaxel, are compounds that disrupt mitosis (M-phase) by binding to tubulin to form abnormal mitotic spindles.

A taxane such as paclitaxel is a highly derivatized diterpenoid (Wani et al., J. Am. Chem. Soc. 93:2325, 1971) which has been obtained from a harvested and dried bark of Taxus brevifolia (Pacific Yew) and Taxomyces Andreanae and Endophytic Fungus of a Pacific Yew (Stierle et ai, Science 60:214-216, 1993). It has been formulated into commercial compositions, including a product TAXOL^® (Bristol Myers Squibb).

Analogues and derivatives of paclitaxel include, for example, commercial products such as TAXOTERE^® (Aventis), as well as compounds such as docetaxel, 10-desacetyl analogues of paclitaxel and 3'N-desbenzoyl-3'N-t-butoxy carbonyl analogues of paclitaxel) {see generally Schiff et ai, Nature 277:665-667, 1979; Long and Fairchild, Maycer Research 54:4355-4361, 1994; Ringel and Horwitz, J. Nat'l Maycer Inst. <S3(4):288-291, 1991;

Pazdur et al, Maycer Treat. Rev. 7P(4):351-386, 1993; WO 94/07882; WO 94/07881; WO 94/07880; WO 94/07876; WO 93/23555; WO 93/10076; WO94/00156; WO 93/24476; EP 590267; WO 94/20089; U.S. Patent Nos. 5,294,637; 5,283,253; 5,279,949; 5,274,137; 5,202,448; 5,200,534; 5,229,529; 5,254,580; 5,412,092; 5,395,850; 5,380,751; 5,350,866; 4,857,653; 5,272,171; 5,411,984; 5,248,796; 5,248,796; 5,422,364; 5,300,638; 5,294,637; 5,362,831; 5,440,056; 4,814,470; 5,278,324; 5,352,805; 5,411,984; 5,059,699; 4,942,184 (all herein incorporated by reference); Tetrahedron Letters 35(52):9709-9712, 1994; J. Med. Chem. 55:4230-4237, 1992; J. Med. Chem. 34:992-99%, 1991; J. Natural Prod. 57(10): 1404-1410, 1994; /. Natural Prod. 57(l l):1580-1583, 1994; J. Am. Chem. Soc. 7/0:6558-6560, 1988)(all herein incorporated by reference). Taxanes may be made by utilizing techniques cited within references provided herein, or, obtained from a variety of commercial sources, including for example, Sigma Chemical Co., St. Louis, Missouri (T7402 - from Taxus brevifolia).

Further representative examples of taxanes include, but are not limited to, 7-deoxy- docetaxol, 7,8-cyclopropataxanes, N-substituted 2-azetidones, 6,7-epoxy paclitaxels, 6,7- modifϊed paclitaxels, 10-desacetoxytaxol, 10-deacetyltaxol (from 10-deacetylbaccatin IH), phosphonooxy and carbonate derivatives of taxol, taxol 2',7-di(sodium 1,2- benzenedicarboxylate, 10-desacetoxy-l l,12-dihydrotaxol-10,12(18)-diene derivatives, 10- desacetoxytaxol, Protaxol (2'-and/or 7-O-ester derivatives ), (2'-and/or 7-O-carbonate derivatives), asymmetric synthesis of taxol side chain, fluoro taxols, 9-deoxotaxane, (13- acetyl-9-deoxobaccatine III, 9-deoxotaxol, 7-deoxy-9-deoxotaxol, 10-desacetoxy-7-deoxy- 9-deoxotaxol, derivatives containing hydrogen or acetyl group and a hydroxy and tert- butoxycarbonylamino, sulfonated 2'-acryloyltaxol and sulfonated 2'-O-acyl acid taxol derivatives, succinyltaxol, 2'-γ-aminobutyryltaxol formate, 2'-acetyl taxol, 7-acetyl taxol, 7- glycine carbamate taxol, 2'-OH-7-PEG(5000) carbamate taxol, 2'-benzoyl and 2',7- dibenzoyl taxol derivatives, some prodrugs (2'-acetyltaxol; 2',7-diacetyltaxol; 2'succinyltaxol; 2'-(beta-alanyl)-taxol); 2'-gamma-aminobutyryltaxol formate; ethylene glycol derivatives of 2'-succinyltaxol; 2'-glutaryltaxol; 2'-(N,N-dimethylglycyl) taxol; T- (2-(N,N-dimethylamino)propionyl)taxol; 2'-orthocarboxybenzoyl taxol; 2'-aliphatic carboxylic acid derivatives of taxol, prodrugs {2'-(N,N-diethylaminopropionyl)taxol, 2'- (N,N-dimethylglycyl)taxol, 7(N,N-dimethylglycyl)taxol, 2\7-di-(N,N- dimethylglycyl)taxol, 7-(N,N-diethylaminopropionyl)taxol, 2',7-di(N,N- diethylaminopropionyl)taxol, 2'-(L-glycyl)taxol, 7-(L-glycyl)taxol, 2',7-di(L-glycyl)taxol, 2'-(L-alanyl)taxol, 7-(L-alanyl)taxol, 2',7-di(L-alanyl)taxol, 2'-(L-leucyl)taxol, 7-(L- leucyl)taxol, 2',7-di(L-leucyl)taxol, 2'-(L-isoleucyl)taxol, 7-(L-isoleucyl)taxol, 2',7-di(L- isoleucyl)taxol, 2'-(L-valyl)taxol, 7-(L-valyl)taxol, 27-di(L-valyl)taxol, 2'-(L- phenylalanyl)taxol, 7-(L-phenylalanyl)taxol, 2',7-di(L-phenylalanyl)taxol, 2'-(L- prolyl)taxol, 7-(L-prolyl)taxol, 2',7-di(L-prolyl)taxol, 2'-(L-lysyl)taxol, 7-(L-lysyl)taxol, 2^?,7-di(L-lysyl)taxol, 2'-(L-glutamyl)taxol, 7-(L-glutamyl)taxol, 2',7-di(L-glutamyl)taxol, 2'-(L-arginyl)taxol, 7-(L-arginyl)taxol, 2',7-di(L-arginyl)taxol}, taxol analogues with modified phenylisoserine side chains, taxotere, (N-debenzoyl-N-tert-(butoxycaronyl)-lO- deacetyltaxol, and taxanes {i.e., for example, baccatin III, cephalomannine, 10- deacetylbaccatin III, brevifoliol, yunantaxusin and taxusin); and some taxane analogues and derivatives, including, but not limited to, 14-beta-hydroxy-10 deacetybaccatin TH, debenzoyl-2-acyl paclitaxel derivatives, benzoate paclitaxel derivatives, phosphonooxy and carbonate paclitaxel derivatives, sulfonated 2'-acryloyltaxol; sulfonated 2'-O-acyl acid paclitaxel derivatives, 18-site-substituted paclitaxel derivatives, chlorinated paclitaxel analogues, C4 methoxy ether paclitaxel derivatives, sulfenamide taxane derivatives, brominated paclitaxel analogues, girard taxane derivatives, nitrophenyl paclitaxel, 10- deacetylated substituted paclitaxel derivatives, 14-β -hydroxy- 10 deacetylbaccatin III taxane derivatives, C7 taxane derivatives, ClO taxane derivatives, 2-debenzoyl-2-acyl taxane derivatives, 2-debenzoyl and -2-acyl paclitaxel derivatives, taxane and baccatin III analogues bearing new C2 and C4 functional groups, n-acyl paclitaxel analogues, 10- deacetylbaccatin III and 7-protected-lO-deacetylbaccatin III derivatives from 10-deacetyl taxol A, 10-deacetyl taxol B, and 10-deacetyl taxol, benzoate derivatives of taxol, 2-aroyl- 4-acyl paclitaxel analogues, orthro-ester paclitaxel analogues, 2-aroyl-4-acyl paclitaxel analogues and 1-deoxy paclitaxel and 1-deoxy paclitaxel analogues. In one embodiment, a taxane comprises a formula (Cl):

wherein gray-highlighted portions may be substituted and non-highlighted portions comprise a taxane core. A side-chain (labeled "A" in a diagram) is desirably present in order for a compound to have good activity. Examples of compounds having this structure include, but are not limited to, paclitaxel (Merck Index entry 7117), docetaxel (taxotere, Merck Index entry 3458), and 3'-desphenyl-3'-(4-ntirophenyl)-N-debenzoyl-N-(t- butoxycarbonyl)- 10-deacetyltaxol .

In one embodiment, the present invention contemplates taxanes having a structure (C2) including, but not limited to, paclitaxel and paclitaxel analogues and derivatives. U.S. Patent No. 5,440,056 (herein incorporated by reference).

wherein X may be oxygen (paclitaxel), hydrogen (9-deoxy derivatives), thioacyl, or dihydroxyl precursors; Rj is selected from paclitaxel or taxotere side chains or alkanoyl of a formula (C3):

wherein R₇ is selected from hydrogen, alkyl, phenyl, alkoxy, amino, phenoxy (substituted or unsubstituted); Rg is selected from hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, phenyl (substituted or unsubstituted), alpha or beta-naphthyl; and R₉ is selected from hydrogen, alkanoyl, substituted alkanoyl, and aminoalkanoyl; where substitutions refer to hydroxyl, sulfhydryl, allalkoxyl, carboxyl, halogen, thioalkoxyl, N,N- dimethylamino, alkylamino, dialkylamino, nitro, and -OSO₃H, and/or may refer to groups containing such substitutions; R₂ is selected from substitutions including, but not limited to, hydrogen and/or oxygen-containing groups, including, but not limited to, hydrogen, hydroxyl, alkoyl, alkanoyloxy, aminoalkanoyloxy, and peptidyalkanoyloxy; R₃ is selected from hydrogen and/or oxygen-containing groups, including, but not limited to, hydrogen, hydroxyl, alkoyl, alkanoyloxy, aminoalkanoyloxy, and peptidyalkanoyloxy, and may further be a silyl containing group or a sulphur containing group; R₄ is selected from.acyl, alkyl, alkanoyl, aminoalkanoyl, peptidylalkanoyl and aroyl; R₅ is selected from acyl, alkyl, alkanoyl, aminoalkanoyl, peptidylalkanoyl and aroyl; Re is selected from hydrogen or oxygen-containing groups, , including, but not limited to, hydrogen, hydroxyl alkoyl, alkanoyloxy, aminoalkanoyloxy, and peptidyalkanoyloxy.

In one embodiment, paclitaxel analogues and derivatives useful in a present invention are disclosed in PCT International Patent Application No. WO 93/10076 (herein incorporated by reference). In one embodiment, an analogue or derivative has a side chain attached to a taxane nucleus at C₁₃, as shown in a structure below (formula C4), in order to confer antitumor activity to a taxane.

WO 93/10076 discloses that a taxane nucleus may be substituted at any position with a exception of a existing methyl groups. A substitutions may include, for example, hydrogen, alkanoyloxy, alkenoyloxy, aryloyloxy. In addition, oxo groups may be attached to carbons labeled 2, 4, 9, 10. As well, an oxetane ring may be attached at carbons 4 and 5. As well, an oxirane ring may be attached to a carbon labeled 4. In one embodiment, the present invention contemplates a 9-deoxo taxane. U.S. Patent 5,440,056 (herein incorporated by reference). 9-deoxo taxanes lack an oxo group at C₉ in formula C4 above. A taxane ring may be substituted at Ci, C7 and Cio (independently) with H, OH, O R, or O-CO-R where R is an alkyl or an aminoalkyl. As well, a taxane ring may be substituted at C₂ and C₄ (independently) with aroyl, alkanoyl, aminoalkanoyl or alkyl groups. A side chain of formula C3 may be substituted at R₇ and Rg (independently) with phenyl rings, substituted phenyl rings, linear alkanes/alkenes, and groups containing H, O or N. R₉ may be substituted with H, or a substituted or unsubstituted alkanoyl group. C. Sirolimus

In one embodiment, the present invention contemplates a therapeutic agent comprising sirolimus, or a derivative or an analogue thereof. Briefly, sirolimus (also referred to as "rapamycin") is a macrolide antibiotic. Therapeutically rapamycin is classified as an immunosuppressant. Although it is not necessary to understand the mechanism of an invention, it is believed that rapamycin acts as a cell cycle inhibitor and an mTOR (mammalian target of rapamycin) inhibitor. Exemplary structures of sirolimus, everolimus, and tacrolimus are provided below:

everolimus

tacrolimus

sirolimus

Sirolimus analogues and derivatives include, but are not limited to, tacrolimus and derivatives thereof (i.e., for example, EP0184162B1 and U.S. Patent No. 6,258,823; herein incorporated by reference) everolimus and derivatives thereof (i.e., for example, US Patent No. 5,665,772; herein incorporated by reference). Further representative examples of sirolimus analogues and derivatives include, but are not limited to, ABT-578 and others may be found in PCT Publication Nos. WO9710502, WO9641807, WO9635423, WO9603430, WO9600282, WO9516691, WO9515328, WO9507468, WO9504738, WO9504060, WO9425022, WO9421644, WO9418207, WO9410843, WO9409010, WO9404540, WO9402485, WO9402137, WO9402136, W09325533, WO9318043, WO9313663, WO9311130, WO9310122, WO9304680, WO9214737, and WO9205179. Representative U.S. patents include U.S. Patent Nos. 6,342,507, 5,985,890, 5,604,234, 5,597,715, 5,583,139, 5,563,172, 5,561,228, 5,561,137, 5,541,193, 5,541,189, 5,534,632, 5,527,907, 5,484,799, 5,457,194, 5,457,182, 5,362,735, 5,324,644, 5,318,895, 5,310,903, 5,310,901, 5,258,389, 5,252,732, 5,247,076, 5,225,403, 5,221,625, 5,210,030, 5,208,241, 5,200,411, 5,198,421, 5,147,877, 5,140,018, 5,116,756, 5,109,112, 5,093,338, and 5,091,389 (all of which are herein incorporated by reference)..

D. Anti-Inflammatory Agents

In one embodiment, the present invention contemplates a therapeutic agent comprising an anti-inflammatory agent. Anti-inflammatory agents include, but are not limited to, corticosteroids (i.e., for example, dexamethasone, hydrocortisone, triamcinolone), non-steroidal anti-inflammatory drugs (NSAIDs) (i.e., for example, nabumetone, indomethacin, naproxen, ibuprofen), anti-inflammatory cytokines (i.e., for example, IL-4, IL-10, IL- 13), cytokine antagonists (i.e., for example, IL-I receptor antagonist, TNF-α monoclonal antibody, soluble TNF receptor, platelet factor 4), and a like. Examples of anti-inflammatory agents also are described in, e.g., U.S. Patent No. 6,190,691; U.S. Patent No. 5,776,892; U.S. Patent No. 4,816,449; and U.S. Patent No. RE37,263 (all of which are herein incorporated by reference).

E. Actinomycin

In one embodiment, the present invention contemplates a therapeutic agent comprising actinomycin, or a derivative or an analogue thereof. Briefly, actinomycins are believed to be antibiotics isolated from a species oϊStreptomyces. Actinomycins are chromopeptides and most contain a chromophore, planar phenoxazone actinocin. Differences among actinomycins include, but are not limited to, peptide side chains which vary in a structure of a constituent amino acids. Therapeutically, actinomycin may act as an antibiotic neoplastic agent by possibly inhibiting the cell cycle.

F. Statins

In one embodiment, the present invention contemplates a therapeutic agent comprising a statin, or a derivative or an analogue thereof. Briefly, statins are believed to be competitive inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG- CoA) which catalyses an early rate limiting step in cholesterol biosynthesis.

Therapeutically, statins are effective for dyslipidemia by possibly inhibiting HMG-CoA reductase. Statins are also believed to have antiproliferative and antimigratory effects on cells. Representative statins include, but are not limited to, lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, and cervistatin. G. Estrogens

In one embodiment, the present invention contemplates a therapeutic agent comprising an estrogen. Estrogens include, but are not limited to, 17-/?-estradiol, or a derivative or an analogue thereof. Briefly, 17-/?-estradiol is a steroidal estrogen. Therapeutically, exogenous estrogen acts as an agonist of the naturally occurring estrogen pathway (i.e., for example, by interacting with the same receptor sites). Additional effects of estrogens include, but are not limited to, inhibition of cell migration and proliferation.

in. Formulations

Therapeutic devices of the present invention are fashioned in a manner appropriate to the intended use. In general, a composite drug delivery system of the invention may be formed by combining a fibrous construct with a matrix and at least one bioactive agent. A composite drug delivery system may provide predictable controlled, sustained release of a therapeutic agent. Following implantation, a therapeutic agent may be released from a matrix as a polymer is degraded in the body. The rate of degradation depends on a variety of factors, such as, for example, the chemical composition, crystallinity, construct porosity, construct thickness, construct density, and wettability of a polyiήer.

In one embodiment, the present invention contemplates a composite drug delivery device comprising a bioactive agent and a biodegradable polymer matrix reinforced with at least one fibrous construct. Although it is not necessary to understand the mechanism of an invention, it is believed that composite delivery system configurations may vary depending on the particular clinical application. For example, composite delivery device materials may include, but are not limited to, fabrics, sheets, gauzes, molds, meshes, tubes (i.e., for example, cylinders or toroids), sleeves, and the like. Further, a drug delivery system may comprise different sizes intended to cover all or only a portion of a tissue at a surgical site. For certain applications, a composite delivery device may comprise a substantially flat textile material {i.e., for example, a knitted fabric).

In general, a composite delivery device should be sufficiently flexible so as to be capable of being wrapped around all or a portion of the external surface of a body passageway or cavity. A composite delivery device should be flexible and resilient enough so as to conform, stretch, and adapt to a geometry of a surgical site. Flexible composite delivery devices typically have a thickness ranging from about 25 microns to about 3000 microns; preferably from about 50 to about 1000 microns. Composite delivery devices suitable for wrapping around arteries and veins typically have thicknesses which range from about 100 to 600 microns. In certain embodiments, a composite delivery device has a thickness of less than 500 microns; or less than 400 microns; or less than 300 microns; or less than 200 microns. In certain embodiments, composite delivery devices may have a thickness of about 100 to about 400 microns.

In some embodiments, a composite delivery device may be porous or non-porous, depending on a type of selected fibrous construct and/or matrix. For coated fibrous constructs, the porosity of a system also may be altered depending on a thickness of a matrix coating. For certain applications (i.e., for example, perivascular drug delivery), a composite delivery device comprises sufficient porosity to allow for tissue in-growth and a passage of fluid through a device. A porosity of a fabric may be measured by weighing a sample of material having a defined surface area. Less porous fabrics typically have densities that are greater than more porous materials. Composite materials typically have a density range of about 1 rag/cm² to about 50 mg/cm². A density range may be about 1 mg/cm² to about 25 mg/cm², or about 1 mg/cm² to about 10 mg/cm², or about 1 mg/cm² to about 7 mg/cm², or about 2 mg/cm² to about 5 mg/cm². The relative amount of matrix-to-fibrous construct in a composite delivery device may vary widely depending on: i) the composition of the fibrous construct and the polymer matrix; the characteristics of a therapeutic agent to be delivered from a composite delivery device; and iii) the desired physical properties of a composite delivery device. Further, the amount of matrix may be chosen so as to minimize any unwanted inflammatory or toxic responses triggered by the presence of the implant. In some cases, it may be desired to minimize the amount of matrix so as to reduce an inflammatory response. In one embodiment, a composite material has a weight ratio of a matrix-to-reinforcing fibrous construct of between about 90/10 and about 10/90; or between about 90/10 and about 70/30; or between about 70/30 and about 50/50; or between about 50/50 and about 30/70; or between about 30/70 and about 10/90.

In one embodiment, a composite drug delivery device comprises a knitted fabric comprising about 20-25% (by weight) of polymer matrix.

A therapeutic composite drug delivery device and compositions therein should be biocompatible and should be stable for several months and capable of being sterilized (i.e.. for example, by gamma irradiation or ethylene oxide (EtO)) and maintained under sterile conditions.

Although it is not necessary to understand the mechanism of an invention, it is believed that composite drug delivery devices and associated compositions described herein may degrade by a variety of mechanisms and over different periods of time depending on a specific composition of a fibrous construct and matrix materials. Further, the degradation properties of the polymer matrix and the underlying fibrous reinforcement often will be different. For some types of composite systems, the fibrous construct can degrade or erode more quickly than the polymer matrix. However, for other types of systems, the polymer matrix may be more quickly degraded or eroded than the fibrous construct. It is further believed that some composite drug delivery systems degrade via hydrolysis and are capable of being fully degraded in vivo over a period of about 1 and about 200 days. In some cases, the composite drug delivery systems may be fully degraded within about 120 days. Certain hydrolysable systems may be fully degraded in vivo between about 60 to about 90 days. In certain embodiments, the system may be fully degraded in vivo within 40 days after implantation into a patient. Other types of hydrolysable systems may be fully degraded in vivo between about 15 to about 25 days. Polymer and carrier compositions of a present invention may be formulated in a variety of forms to produce a composite drug delivery device suitable for application to a outside surface of a body passageway or cavity. A material may be placed into contact with an external surface of a body passageway, organ, or cavity, or a portion thereof by wrapping a fabric around a tubular anatomical structure (i.e., for example, a blood vessel). Typically, a material is placed in direct contact with a tissue surface (i.e., a material touches a surface of a tissue). However, a material may indirectly contact a surface of a tissue, for example, by treating a tissue surface with a solution, gel, or some type of material prior to application of a material to a surface.

In one embodiment, a therapeutic agent and biodegradable polymer may be formed into a matrix and combined with a fibrous construct (i.e., for example, a knitted fabric) for application to a venous or arterial anastomosis. In one embodiment, the application comprises an external portion of an anastomosis. A composite drug delivery device may used as an anastomosis implant which may initially be in the form of a substantially flat fabric or sheet, which is sized and wrapped fully, or partially, about an external surface of at least one blood vessel at an anastomotic site. For example, the anastomotic site may be a distal or a proximal anastomosis site. Generally, distal anastomosis sites are known to be particularly prone to the development of intimal hyperplasia. Treatment of a distal anastomosis site can minimize this response and subsequent stenosis of the body passageway at the site of graft insertion.

In one embodiment, a composite drug delivery device comprises an epivascular (i.e., for example, perivascular) wrap capable of preventing vascular stenosis. Composite drug delivery devices used for perivascular delivery of a bioactive agent to a body passageway (i.e., for example, a blood vessel) may include various materials and may take a variety of forms, including, but not limited to, fabrics, films, sheets, gauzes, molds, meshes, tubes, sleeves, and the like. A composite drug delivery device may be sized to cover all or only a portion of a tissue at a surgical site. In one embodiment, a composite drug delivery device may be secured and/or affixed to itself or to a structure (i.e., for example, a bodily tissue and/or organ) using, for example, sutures, staples, or another type of fixation devices. In one embodiment, the composite drug delivery device is wrapped about a treatment site (e.g., graft anastomotic site) and secured in place by one or more sutures the connect abutting pieces of the device.

In one embodiment, the present invention contemplates compositions and devices of a present invention formulated to comprise: i) one or more therapeutic agent(s) (i.e., for example, anti-scarring agents); ii) a variety of additional compounds; or iii) certain physical properties (i.e., for example, elasticity, a particular melting point or a specified release rate). In some embodiments, compositions are contemplated in order to achieve a desired effect (i.e., for example, several preparations of microspheres may be combined in order to achieve both a quick and a slow or prolonged release of one or more factors).

In some embodiments, a composite material may further comprise additional ingredients including, but not limited to, radioopaque or echogenic materials and magnetic resonance imaging (MRI) responsive materials (i.e., MRI contrast agents) to enable visualization of a device including, but not limited to, ultrasound, fluoroscopy, and/or MRI. A composite material may also comprise a colorant (i.e., for example, dye) to facilitate visualization during or after implantation. For example, a drug delivery device may be made with or coated with a composition which is echogenic or radiopaque (i.e., for example, made with echogenic or radiopaque with materials including, but not limited to, powdered tantalum, tungsten, barium carbonate, bismuth oxide, barium sulfate, or, by a addition of microspheres or bubbles which present an acoustic interface). For MRI visualization contrast agents including, but not limited to, gadolinium (III) chelates or iron oxide compounds may be incorporated into a device, such as, for example, as a component in a coating or within a void volume (i.e., for example, interstitial space) of a device. In one embodiment, a composite drug delivery device may include, or be administered in combination with, at least one therapeutic agent and, optionally, a pharmaceutically or physiologically acceptable carrier, excipients or diluents. For example, a composite drug delivery device may comprise a combination of therapeutic agents, including, but not limited to, a combination of a fibrosis-inhibiting agent and an anti-thrombotic agent and/or antiplatelet agent and/or a thrombolytic agent, which reduces a likelihood of thrombotic events upon implantation of a medical implant. Alternatively, a fibrous construct may include one type of therapeutic agent (i.e., for example, an anti- scarring agent, such as paclitaxel) and may be applied to a treatment site in conjunction with a second type of therapeutic agent, such as dipyridamole (i.e., for example, in a form of a gel). For example, a fibrous construct may include, but not limited to, a combination of a fibrosis-inhibiting therapeutic agent, such as paclitaxel or rapamycin, and an antithrombotic or anti-platelet agent, such as dipyridamole. Some representative examples of anti-thrombotic, antiplatelet, and thrombolytic agents include, but are not limited to, heparin, heparin fragments, organic salts of heparin, heparin complexes (i.e., for example, benzalkonium heparinate, tridodecylammonium heparinate), dextran, sulfonated carbohydrates such as dextran sulphate, Coumadin, coumarin, heparinoid, danaparoid, argatroban chitosan sulfate, chondroitin sulfate, danaparoid, lepirudin, hirudin, AMP, adenosine, 2-chloroadenosine, acetylsalicylic acid, phenylbutazone, indomethacin, meclofenamate, hydrochloroquine, iloprost, streptokinase, factor Xa inhibitors, such as DX9065a, magnesium, and tissue plasminogen activator. Further examples include, but are not limited to, plasminogen, lys-plasminogen, alpha-2-antiplasmin, urokinase, aminocaproic acid, ticlopidine, clopidogrel, trapidil (triazolopyrimidine), naftidrofuryl, auriritricarboxylic acid and glycoprotein Ilb/IIIa inhibitors such as abcixamab, eptifibatide, and tirogiban. Some agents capable of affecting a rate of clotting include, but are not limited to, glycosaminoglycans, danaparoid, 4-hydroxycourmarin, warfarin sodium, dicumarol, phenprocoumon, indan-l,3-dione, acenocoumarol, anisindione, and rodenticides including, but not limited to, bromadiolone, brodifacoum, diphenadione, chlorophacinone, and pidnone.

In one embodiment, the present invention contemplates a composite material comprising an amount (i.e., dose) of a desired therapeutic agent(s), total dosage delivered, wherein drug dosage is a function of device surface area and the duration of drug delivery. In one embodiment, the drug dosage is dependent, at least in part, on the solubility of a . compound and the location at which a drug is administered.

In one embodiment, devices of the present invention comprise a bioactive agent that may inhibit fibrosis. Agents that inhibit fibrosis may be used to minimize fibrosis (e.g., scarring) associated with or incurred as a result of a surgical intervention.

Regardless of the method of incorporation of a fϊbrosis-inhibiting agent into a device, the total amount of agent may be in an amount ranging from about 0.01 μg (micrograms) to about 2500 mg (milligrams). Generally, an anti-scarring agent may be in an amount ranging from 0.01 μg to about 10 μg; or from 10 μg to about 1 mg; or from 1 mg to about 10 mg; or from 10 mg to about 100 mg; or from 100 mg to about 500 mg; or from 500 mg to about 2500 mg.

A total surface amount of anti-scarring agent on, in or near a device may be in an amount ranging from less than 0.01 μg to about 2500 μg per mm² of device surface area. Generally, an anti -scarring agent may be in a amount ranging from less than 0.01 μg; or from 0.01 μg to about 10 μg; or from 10 μg to about 250 μg; or from 250 μg to about 1000 μg, or from 1000 μg to about 2500 μg per mm² of device surface area. Utilizing a taxane such as paclitaxel as an example, whether contained within, or applied to, a matrix or fibrous construct, a total amount of paclitaxel applied to or incorporated into a device would not be expected to exceed 25 mg (range of about 0.1 μg to about 25 mg). In one embodiment, a total amount of a drug applied to a device should be in a range of about 1 μg to about 10 mg. In certain embodiments (e.g., a composite system for use in A-V hemodialysis access or A-A peripheral bypass grafting procedures), devices may include about 0.3 mg to about 2.5 mg of paclitaxel. In certain embodiments, composite drug delivery devices are provided that include, but are not limited to, about 0.6 mg; or 0.8 mg; or about 1.3 mg; or about 1.6 mg; of about 2.2 mg of paclitaxel.

A dose per unit area of a device (i.e., an amount of drug as a function of a surface area of a portion of a device to which drug is applied and/or incorporated) should fall within a range of about 0.1 μg to about 10 μg per mm² of surface area. In certain embodiments, paclitaxel is present at some device surfaces at a dose density of about 0.25 μg/mm² to about 5 μg/mm². For other composite drug delivery devices, paclitaxel is present at the device surface at a dose density of about 0.05 to about 1 mg/cm². Alternatively, other composite drug delivery devices comprise paclitaxel at dose densities of about 0.05 to 0.5 mg/cm², or about 0.06 to 0.2 mg/cm², or about 0.03 to 0.3 mg/cm², or about 0.1 to 0.5 mg/cm²; or about 0.1 to 0.2 mg/cm². In certain embodiments (e.g., a composite system for use in A-V hemodialysis access or A-A peripheral bypass grafting procedures), composite drug delivery devices are provided that include, but are not limited to, about 0.13 to about 0.18 mg/cm², or about 0.10 to about 0.20 mg/cm², or 0.06 to about 0.1 mg/cm² of paclitaxel. In certain embodiments, the total paclitaxel dose loading is about 0.9 micrograms/mm². Another exemplary device is an absorbable, biodegradable composite flat textile fabric with paclitaxel present in an amphiphilic matrix at a concentration equivalent to more than 0.005 mg/cm² of a fabric.

Although it is not necessary to understand the mechanism of an invention, it is believed that analogues and derivatives of paclitaxel (such as docetaxel and other described previously) or some fibrosis-inhibiting compounds with similar functional activity can be utilized wherein the above dosing parameters are adjusted to a relative potency for the analogue or derivative as compared to a parent compound (i.e., for example, a compound twice as potent as paclitaxel is administered at half the above parameters, a compound half as potent as paclitaxel is administered at twice the above parameters, etc.). A composite drug delivery device typically releases one or more therapeutic agents over a period of several hours, days, or months with a specific release profile being appropriate for a specific indication being treated. A composite drug delivery device of the i present invention may release a therapeutic agent at one or more phases, the one or more phases having similar or different performance (i.e., for example, release) profiles. A therapeutic agent may be made available to a tissue at amounts which may be sustainable, intermittent, or continuous (i.e., for example, constant); in one or more phases; and/or rates of delivery. A rate may decrease and/or increase over time, and it may optionally include a substantial non-release period. A release rate may comprise a plurality of rates, which may be, for example, substantially constant, decreasing, increasing, or substantially non- releasing. In one embodiment, an anti-scarring agent is made available to a susceptible tissue site in a programmed, sustained, and/or controlled manner which results in increased efficiency and/or efficacy.

In one embodiment, a composite drug delivery device of the invention releases one or more therapeutic agents effective to reduce or inhibit any one or more components of fibrosis (or scarring), including, but not limited to: i) formation of new blood vessels

(angiogenesis); ii) migration and proliferation of connective tissue cells (such as fibroblasts or smooth muscle cells); iii) deposition of extracellular matrix (ECM); and iv) remodeling (maturation and organization of a fibrous tissue). Drug release rates may be programmed to impact fibrosis or scarring by releasing an anti-scarring agent at a time such that at least one of the components of fibrosis is inhibited or reduced. Moreover, a predetermined release rate may reduce agent loading and/or concentration as well as potentially providing minimal drug washout and thus, increasing the efficiency of drug effect.

An amount of bioactive agent released from a composition as a function of time may be determined based on in vitro release characteristics of an agent from a composition. An in vitro release rate may be determined by placing a bioactive agent within a composition or device in an appropriate buffer such as 0. IM phosphate buffer (pH 7.4)) at 37°C. Samples of a buffer solution are periodically removed for analysis by HPLC, and a buffer is replaced to avoid any saturation effects.

The in vitro release of an anti-scarring agent per day may range from an amount ranging from about 0.01 μg (micrograms) to about 2500 mg (milligrams). Generally, an anti-scarring agent that may be released in a day may be in a amount ranging from 0.01 μg to about 10 μg; or from 10 μg to about 1 mg; or from 1 mg to about 10 mg; or from 10 mg to about 100 mg; or from 100 mg to about 500 mg; or from 500 mg to about 2500 mg. A bioactive agent that is on, in, or near, a device may be released from a composition in a time period that may be measured from a time of implantation, which ranges from about less than 1 day to about 180 days. Generally, a release time may also be from about less than 1 day to about 7 days; from 7 days to about 14 days; from 14 days to about 28 days; from 28 days to about 56 days; from 56 days to about 90 days; from 90 days to about 180 days. Based on in vitro analysis, a percentage of therapeutic agent that is released over time may be in a range of about 0% to about 85% over a period of 0-10 days, depending on the amount and type of agent that is present in a device. In some embodiments, the percentage released ranges from about 0% to about 70% over a period of 0-10 days. In certain embodiments, composite drug delivery devices are provided that release about 50% of a drug (i.e., for example, paclitaxel) by about 9 days; about 40% after about 4 days; about 30% after about 2 days; or about 20% after about 1 day. In other embodiments, composite drug delivery devices are provided that release about 40% to about 60%, or about 50% to about 80% of the therapeutic agent by about 7 days. For certain applications {e.g., perivascular delivery), a composite system may be used that releases about 25-55% of the drug (e.g., paclitaxel) after about 24 hours.

Although it is not necessary to understand the mechanism of an invention, it is believed that the amount of drug released over a given period of time may be altered by changing the composition or properties of the polymer matrix. In particular, the release properties of the matrix may be affected by altering the molecular weight of a polymer used to prepare the matrix, such that for a given polymer composition, it may be possible to alter (decrease or increase) the amount of drug that is released from the device. For example, for a given polymer composition (e.g., a polyether-polyester copolymer), an increase in the molecular weight can lead to a decrease in the release rate. Further, the release rate from a lower molecular weight polymeric matrix will likely be higher than from a higher molecular weight matrix. For example, in one embodiment, a matrix that includes a polyether-polyester copolymer having a molecular weight of about 5000 to 7000 Daltons may release about 30-60% of the drug after 24 hours. A matrix prepared from a similar copolymer, but having a molecular weight of about 7000 to 8000 Daltons may release about 10-25% of the drug after 24 hours. hi certain embodiments, composite systems are provided that release about 40-45% of a drug (e.g., paclitaxel) over a period of 24 hours. In other embodiments, composite systems are provided that release about 30-35% of a drug (e.g., paclitaxel) over a period of 24 hours. In yet other embodiments, composite systems are provided that release about 50- 55% of a drug (e.g., paclitaxel) over a period of 24 hours. In one embodiment, a device is provided that includes a knitted fabric having a density of about 2.5 nag/cm² to about 5.0 mg/cm², wherein the fabric comprises a fiber made of a polymer having a molar ratio of glycolide:L-lactide of about 97:3 to about 85:15; and a matrix comprising a polyether-polyester copolymer and a therapeutic agent, wherein the device in vitro releases about 0% to about 85% of the therapeutic agent over a period of 0 to about 7 days after.

As different polymer and non-polymer materials will release a bioactive agent (i.e., for example paclitaxel) at differing rates, the above dosing parameters should be utilized in combination with a release rate of a drug from a device surface such that a minimum concentration of about 10^"8 to about 10^"4 M of agent is maintained on a device surface. In one embodiment, paclitaxel is released from a surface of a device such that inhibitory activity is maintained for a period ranging from several hours to several months. In a further embodiment, paclitaxel is released in effective concentrations for a period ranging from about 1 to about 90 days. A composite drug delivery device may release therapeutic agents in a unidirectional manner (i.e., for example, in a direction facing a adventitial tissue of a blood vessel) or in multiple directions (i.e., for example, multidirectional and/or omnidirectional).

FV. Methods of Making a Composite Drug Delivery System In one embodiment, the present invention contemplates methods of making composite drug delivery devices and/or systems. In one embodiment, a method comprises combining a fibrous construct with a matrix and at least one bioactive agent. In one embodiment, a method comprises combining a biodegradable polymer matrix with a fibrous construct (i.e., for example, a knitted fabric) and a biodegradable polymer. In one embodiment, the method further comprises incorporating a bioactive agent into a fibrous construct, and/or a matrix of a composite drug delivery system. In one embodiment, the bioactive agent(s) may be incorporated into a device by, for example, occlusion in a polymer used to make a matrix or in a void volume of a fibrous construct, or dissolution in a polymer matrix. In one embodiment, the method comprises incorporating a bioactive agent into a polymer matrix using methods including, but not limited to, addition of a solvent with subsequent removal of a solvent or dissolution of a therapeutic agent directly into a polymer and blending a therapeutic agent with a polymer. In one embodiment, the method comprises controlling the release of a bioactive agent from a polymer matrix.

Methods used for incorporating a therapeutic agent into a non-polymeric material are similar to those used for incorporating a therapeutic agent into a polymer, as described above.

In one embodiment, the method comprises incorporating a therapeutic agent into a carrier {i.e., for example, microparticles, microspheres, nanospheres, micelles, liposomes, or emulsions). In one embodiment, the method further comprises attaching a carrier onto, or into, a polymer matrix. Carriers may be used, for example, to further modulate the release kinetics of a bioactive agent from a delivery system.

In one embodiment, the method comprises attaching a therapeutic agent directly to a fiber (i.e., for. example, by physisorption, chemisorption, ligand/receptor interaction, covalent bonds, hydrogen bonds, ionic bonds, and the like). In one embodiment, a therapeutic agent may be attached to a fibrous construct by binding the agent to fibers via covalent or non-covalent linkages. Certain manufacturing techniques {i.e., for example, electrospinning) may be used, such as to produce fibers which attach an agent onto a structure of a fiber itself.

In one embodiment, the method comprises pretreating individual fibers {i.e., for example, before fabric assembly) or fabrics before incorporating a therapeutic agent. Although it is not necessary to understand the mechanism of an invention, it is believed that the pretreatments enhance adhesion and/or to introduce reactive sites for attaching a drug or an intermediate {i.e., for example, a linker) to a material. Surface treatment techniques include, but are not limited to, applying a priming solution, plasma treatment, corona treatment, radiation treatment and surface hydrolysis, oxidation or reduction. In one embodiment, a therapeutic agent may be incorporated directly onto a material {i.e., for example, a fiber) that is used to produce a fibrous construct. For example, a therapeutic agent may be admixed into a melt-processable composition that includes a biodegradable polymer. Drug-loaded fibers prepared in this manner may be used to produce a fibrous construct, as described herein.

The present invention contemplates numerous methods that may be used to combine the various components of a composite material. In one embodiment, the method comprises coating a fiber or a fibrous construct with a drug-loaded matrix. In one embodiment, the method comprises incorporating a bioactive agent into a polymeric composition, and then coating the composition onto filaments or fibers. In one embodiment, the method further comprises integrating the coated filaments or fibers with a polymer matrix to produce a fibrous construct (i.e., for example, by knitting). Alternatively, or in addition, the method comprises incorporating a therapeutic agent into a polymeric composition and coating the composition onto a formed fibrous construct (i.e., for example, a knitted fabric). For example, a therapeutic agent may be incorporated into a polymer composition that is coated or absorbed directly into, or onto, a knitted or woven fabric. A therapeutic agent or a therapeutic agent/carrier composition may be applied to a fibrous construct using various coating methods including, but not limited to, painting, dip coating, spray coating, solvent casting, extrusion, roll coating, or spin coating, to produce a coating. For certain combinations of materials, spin coating may be used to efficiently deposit a thin, uniform coating of matrix on a fibrous substrate.

Application of a matrix to fibers, filaments, and fibrous constructs may produce a coating which adheres to a surface of a fiber or filament (i.e., for example, surface adherent coating). A coating typically remains on the fibers or fibrous construct until implantation of the device. Upon implantation, a coating may bioerode and/or biodegrade in vivo, depending on the characteristics of a composition.

In one embodiment, the present invention contemplates sterile composite drug delivery devices and/or compositions. In one embodiment, the method comprises sterilizing drug delivery devices and/or compositions (i.e., for example, by gamma radiation, electron beam, cobalt-60 or ethylene oxide). In one embodiment, the method comprises preparing drug delivery devices and/or compositions under an aseptic environment. Alternatively, a combination of aseptic manufacture and sterilization may also be used to prepare sterile devices and/or compositions. Many pharmaceuticals are manufactured to be sterile and this criterion is defined by a USP XXII. The term "USP" refers to U.S. Pharmacopeia (see www.usp.org, Rockville, MD). Sterilization methods include, but are not limited to, gas sterilization (i.e., for example, ethylene oxide), ionizing radiation (i.e., for example, approximately 2,500 rads), thermal treatments or filtration. When appropriate, filtration may be accomplished using a filter with suitable pore size, for example 0.22 μm and of a suitable material, inert material such as TEFLON.

Pharmaceutical devices or compositions provided herein may be placed within one or more containers {i.e., for example, a kit), along with packaging material that provide instructions. Generally, such instructions include a tangible expression describing a reagent concentration, as well as within certain embodiments, relative amounts of excipient ingredients or diluents {i.e., for example, water, saline or PBS) that may be necessary to reconstitute a pharmaceutical composition. Kit containers and contents may also be sterile.

A kit container may comprise a polymer or a metal foil or a paper product or a combination of these. In one embodiment, a kit comprises polymer composition that degrades via hydrolysis, wherein the composition may be packaged in a container that reduces the amount of water absorption by the composition as compared to a composition that is not packaged in such a container. These kit containers may or may not contain a desiccant. hi another embodiment, a kit container comprising a composition may be packaged in a secondary container that is more resistant to moisture permeation than a first or primary container of a composition. In another embodiment, a desiccant may be placed between a primary kit container and a secondary kit container. Although it is not necessary to understand the mechanism of an invention, it is believed that properties of a kit container should include, but are not limited to: i) acceptable light transmission characteristics in order to prevent light energy from damaging a composition in a container; ii) an acceptable limit of extractables within a container material; and iii) an acceptable barrier capacity for moisture and/or oxygen. Although it is not necessary to understand the mechanism of an invention, it is believed that oxygen penetration may be controlled by including in a kit container, a positive pressure of an inert gas, such as high purity nitrogen, or a noble gas, such as argon. In one embodiment, the present invention contemplates a kit comprising pharmaceutical devices, products, or compositions including (a) a composite drug delivery system according to the invention, and (b) a notice associated with a container in form prescribed by a governmental agency regulating a manufacture, use, or sale of devices or pharmaceuticals, which notice is reflective of approval by a agency of a device or compound that, for example, disrupts microtubule function or is anti-angiogenic or is antiproliferative or is immunosuppressive and a like, for human or veterinary administration to treat non-tumorigenic angiogenesis-dependent diseases such as, for example, restenosis or stenosis. In another embodiment, the present invention contemplates a kit comprising pharmaceutical devices, products, or compositions including (a) a composite drug delivery system according to the invention, (b) a vascular graft; and (c) a notice associated with a container in form prescribed by a governmental agency regulating a manufacture, use, or sale of devices or pharmaceuticals, which notice is reflective of approval by the agency of the device or compound that, for example, disrupts microtubule function or is anti- angiogenic or is anti-proliferative or is immunosuppressive and a like, for human or veterinary administration to treat the site of a bypass graft insertion or hemodialysis access procedure.

Exemplary vascular grafts for use in a kit as described herein include straight, tapered, step, regular walled, thin walled, reinforced, and externally or internally supported {e.g., externally spiral or ring supported) vascular graft styles. Representative examples of vascular grafts that may be included in a kit include ePTFE non-supported or reinforced (externally supported) vascular grafts, such as the LIFESPAN vascular grafts available from Edwards Lifesciences Corporation (Irvine, CA). Other examples of commercially available ePTFE grafts that can be included in a kit include those from W.L. Gore, Impra, Boston Scientific Corporation, and Baxter Healthcare.

Exemplary vascular grafts that can be used in combination with the composite systems described herein include externally supported, tape-reinforced, prosthetic graft such as are described in, e.g., EP 0 830 110 Bl. The described grafts include a tubular base graft formed of expanded, sintered fluoropolymer {e.g., ePTFE) and a strip of reinforcement tape helically wrapped around the outer surface of the tubular base graft in a first helical pitch. The strip of reinforcement tape has an inner surface which is in abutment with the outer surface of the tubular base graft, and an outer surface. The vascular graft further includes an external support member that is helically wrapped around the outer surface of the reinforcement tape in a second helical pitch which is different from the first helical pitch of said reinforcement tape.

In one embodiment, the present invention contemplates a kit comprising: a) a composite drug delivery system and b) a vascular graft, wherein the graft is for use in an A- A peripheral bypass grafting procedure. Representative examples of grafts for use in this indication include vascular grafts with inner diameters ranging from 4 to 8 mm, have lengths ranging from about 10-80 cm (which the surgeon can cut to length during a surgical procedure) and may be reinforced and/or include an external support on all or a portion of the graft, which can aid in improving crush resistance. In some embodiments, the kit may be packaged with a tapered graft. For example, the tapered graft may have an internal diameter that tapers from 7 mm inner diameter to 4 mm inner diameter.

In another embodiment, the present invention contemplates a kit comprising: a) a composite drug delivery system and b) a vascular graft, wherein the graft is for use in an A- V hemodialysis access procedure. Representative examples of grafts for use in this indication include vascular grafts with inner diameters ranging from 4 to 8 mm, have lengths ranging from about 10-80 cm and may be reinforced and/or include an external support. In some embodiments, the kit may be packaged with a tapered graft having an inner diameter that tapers from 7 mm to 4 mm. In other embodiments, the vascular graft may have an inner diameter of 6 mm or 7 mm

V. Clinical Applications A composite drug delivery device contemplated by the present invention may be utilized to treat and/or prevent a wide variety of conditions, including, without limitation: (a) prevention of surgical adhesions between tissues following surgery (i.e., for example, gynecologic surgery, vasostomy, hernia repair, nerve root decompression surgery and laminectomy); (b) prevention of hypertrophic scars or keloids (i.e., for example, resulting from tissue bums or some wounds); (c) in affiliation with devices and implants that lead to scarring as described herein (i.e., for example, as a sleeve or fabric around a breast implant to reduce or inhibit scarring); and (d) prevention of intimal hyperplasia and/or restenosis (i.e., for example, resulting from insertion of vascular grafts or hemodialysis access devices).

In one embodiment, the present invention provides materials and methods for improving the integrity of body passageways and/or cavities following surgery and/or injury, and more specifically, to devices and compositions comprising therapeutic agents which may be delivered to external walls of body passageways or body cavities for preventing and/or reducing a proliferative biological response that may obstruct (either fully or partially) or hinder an optimal functioning of a passageway or cavity, including, but not limited to, iatrogenic complications of arterial and venous catherization, complications of vascular dissection, complications of gastrointestinal passageway rupture and dissection, complications associated with vascular surgery, aortic dissection, cardiac rupture, aneurysm, cardiac valve dehiscence, fistula formation, passageway rupture, and/or surgical wound repair.

A composite drug delivery device may be used in conjunction with graft placement (i.e., for example arterio- venous (A-V) bypass, peripheral bypass, coronary artery bypass graft (CABG)), and A-V hemodialysis access. The device is intended to enhance the long- term patency of the vascular graft by reducing or preventing the onset of initimal hyperplasia at the treatment site.

The composite drug delivery device may be used with any type of graft material, including, for example, synthetic grafts made from ePTFE or polyester grafts. Representative examples of commercially available ePTFE grafts, (i.e., for example, W.L. Gore, Impra, Boston Scientific Corporation, Baxter). Vascular grafts that may be used include those available from Angiotech Pharmaceuticals, Inc. (Canada) under a tradename LIFESPAN (see, Figure 2).

In order to further the understanding of such conditions, representative complications leading to a compromised (e.g..occluded) body passageway or cavity integrity are discussed in more detail below. A. Cardiac Bypass Surgery

Coronary artery bypass graft ("CABG") surgery was introduced in the 1950's, and still remains a highly invasive, open surgical procedure, although less invasive surgical techniques are being developed. CABG surgery is a surgical procedure that is performed to overcome many types of coronary artery blockages (see, Figure 1). The purpose of bypass surgery is to increase the circulation and nourishment to the heart muscle that has been reduced due to arterial blockage. This procedure involves a surgeon accessing the heart and diseased arteries, usually through an incision in the middle of a chest. Often, healthy arteries or veins are "harvested" from a patient to create "bypass grafts" that channel the needed blood flow around blocked portions of a coronary arteries. Arteries or veins are connected from the aorta to the surface of the heart beyond a blockages thereby forming an autologous graft. This allows blood to flow through these grafts and "bypass" a narrowed or closed vessel. A use of synthetic graft materials to create a "bypass" has been limited due to a lack of appropriate biocompatibility of these synthetic grafts. CABG has significant short term limitations, including medical complications, such as stroke, multiple organ dysfunction, inflammatory response, respiratory failure and post-operative bleeding, each of which may result in death. Another problem associated with CABG is restenosis. Restenosis is typically defined as a renarrowing of an arterial blood vessel within six months of a CABG procedure. It typically occurs in approximately 25% to 45% of patients, and is a result of an excessive healing response to arterial injury after a revascularization procedure. Restenosis may occur within a short period following a procedure or may develop over a course of months or years. Longer term or " late" restenosis may result from excessive proliferation of scar tissue at a treatment site, the causes of which are not well understood. Thus, any product that may reduce the incidence or magnitude of a restenotic process following CABG surgery would greatly enhance the well-being of a patient.

In order to prevent restenotic complications associated with CABG surgery, such as those discussed above, a wide variety of therapeutic agents may be delivered to an external portion of a blood vessel. Exemplary therapeutic agents, either alone or in combination, include microtubule stabilizing agents and some cell cycle inhibitors, anti-angiogenic agents, anti-inflammatory agents, immunosuppressive agents, antithrombotic agents, antiplatelet agents and some factors involved in the prevention or reduction of a restenotic process. In one embodiment, the present invention contemplates a method comprising providing a composite drug delivery device, and applying the device to an external portion of a vessel following an interventional and/or surgical procedure in order to prevent a restenotic complication.

B. Peripheral Bypass Surgery

Peripheral arterial disease (PAD) refers to diseases of any of the blood vessels outside of the heart. PAD is a range of disorders that may affect blood vessels in the hands, arms, legs, or feet. The most common form of PAD is atherosclerosis. Atherosclerosis is a gradual process in which cholesterol and scar tissue build up in the arteries to form a substance called plaque. This build-up causes a gradual narrowing of an artery, which leads to a decrease in the amount of blood flow through that artery. When the flow of blood decreases, it results in a decrease of oxygen and nutrient supply to a body's tissues, which in turn may result in pain sensation. When arteries to the legs are affected, the most common symptom is pain in a calf when walking. This is known as intermittent claudication. Peripheral bypass surgery is a procedure to bypass an area of stenosed (narrowed) or blocked artery that is a result of atherosclerosis. In this surgical procedure, a synthetic graft (artificial blood vessels) or an autologous graft, vein, is implanted to provide blood flow around a diseased area. First, a surgeon makes an incision in the leg, thigh, calf or ankle skin. A location of an incision may vary based on which vessels need to be bypassed and where there is healthy artery to connect to maintain a blood flow. A bypass graft is sewn into an artery above a stenosis or blockage, and below a stenosis or blockage. This bypass provides a means whereby blood will reach a tissue that has not been receiving enough blood and oxygen. Synthetic bypass grafts used in the legs are usually made of ePTFE.

Restenosis and occlusion of bypass grafts are recurring problem in peripheral bypass surgery. Restenosis is believed to be caused by neointimal growth (hyperplasia) and is especially pronounced within artificial graft material. Consequently, restenosis is usually present at an anastomotic site where a graft and artery are connected via a surgical procedure. An intimal tissue typically grows from a native vessel into a graft. In order to prevent a restenotic complications associated with peripheral bypass surgery, such as those discussed above, a wide variety of therapeutic agents may be delivered to a external portion of a blood vessel. Exemplary therapeutic agents, either alone or in combination, include microtubule stabilizing agents and some cell cycle inhibitors, anti-angiogenic agents, antiinflammatory agents, immunosuppressive agents, antithrombotic agents, antiplatelet agents and some factors involved in the prevention or reduction of a restenotic process. In one embodiment, the present invention contemplates a method comprising providing a composite drug delivery device and applying the device to an external portion of a vessel or anastomotic site following an interventional or surgical procedure in order to prevent a restenotic complications. In one embodiment, the device may be applied to a distal anastomosis, proximal anastomosis or to both a proximal and distal anastomosis. Where a vein graft is used, a composite may also be applied around a vein at various locations along a vein {i.e., for example, where there are valves).

Revascularization is usually considered the gold standard intervention for patients with peripheral arterial disease (PAD) of the lower extremities who suffer from severely occluded arteries resulting in incapacitating claudication or limb-threatening ischemia. Typically, a femoropopliteal bypass is performed by implanting a graft from the femoral artery in the groin to just distal to the obstruction in the popliteal artery. In cases where no suitable veins are available with which to construct a native graft, one can implant a prosthetic graft — commonly made from polytetrafluoroethylene (PTFE). Hirsch et al., "ACC/AHA 2005 Guidelines for the Management of Patients with Peripheral Arterial Disease (Lower Extremity, Renal, Mesenteric, and Abdominal Aortic)" J Am Coll Cardiol 47:1-192 (2006). Unfortunately, failure of PTFE grafts is a common occurrence, resulting from stenosis caused by neointimal hyperplasia at the distal anastomosis. Lemson et al., "Intimal hyperplasia in vascular grafts" Eur J Endovasc Surg 19:336-350 (2000).

In order to prevent a restenotic complications associated with a bypass grafting procedure, a wide variety of therapeutic agents may be delivered to the external portion of a blood vessel. Exemplary therapeutic agents, either alone or in combination, include microtubule stabilizing agents and some cell cycle inhibitors, anti-angiogenic agents, antiinflammatory agents, immunosuppressive agents, antithrombotic agents, antiplatelet agents and some factors involved in a prevention or reduction of a restenotic process. In one embodiment, the present invention contemplates a method comprising providing a composite drug delivery device and applying the device to an external portion of a vessel/anastomotic site following an interventional and/or surgical procedure in order to prevent complication associated with the formation of intimal hyperplasia (e.g., stenosis or restenosis).

An exemplary therapeutic agent for use in a composite drug delivery system in this indication is paclitaxel. Paclitaxel is a broad spectrum chemotherapeutic agent known to inhibit the development of neointimal hyperplasia and preceding cellular and biochemical events. Masaki et al., "Inhibition of neointimal hyperplasia in vascular grafts by sustained perivascular delivery of paclitaxel" Kidney Int 66:2061-2069 (2004); and Kelly et al., "Perivascular paclitaxel wraps block arteriovenous graft stenosis in a pig model" Nephrol Dial Transplant 21 :2425-2431 (2006).

A composite system prepared in accordance with the invention may be used in the treatment of PAD. hi one embodiment, a sheet of knitted PLGA mesh material is coated (i.e., for example, via a dip coating or spin coating process) with a paclitaxel loaded polymeric (i.e., for example, a MePEG750/PDLLA (20:80) copolymer) carrier. In one embodiment, the knitted mesh comprises poly (L-lactide-co-glycolide) with a 5:95 molar ratio of lactide:glycolide. The lactide:glycolide polymer may be synthesized, extruded into fibers, knitted into a fabric, and annealed. The mesh (i.e., for example, a knitted fabric having a size of 4.0 cm x 2.5 cm is washed in IPA prior to coating.

In one embodiment, a fibrous construct may be coated with a coating solution that contains by weight 3.62% paclitaxel, 25.38% MePEG-PDLLA polymer (e.g., MW about 6000-7000), and 71.0% acetone. In some embodiments, the coating solution is spin coated onto the mesh material (yielding a device comprising about 1.6 mg of paclitaxel or 0.16 mg/cm²), packaged, and sterilized by gamma radiation.

A bioresorbable Vascular Wrap™ paclitaxel-eluting mesh (Angiotech, Inc., Vancouver, Canada) is provided as a practical means of delivering a therapeutic dose to the distal anastomotic site of a PTFE graft and vessel. For example, in a bypass procedure involving placement of a vascular graft between the femoral and popliteal arteries, the device may be applied at the distal anastomosis where the ePTFE graft is attached to the popliteal artery. In sheep models, this technology has proven to be well-tolerated and effective in inhibiting neointimal hyperplasia at the distal anastomosis of both artery-to- artery and artery-to-vein ePTFE bypass grafts. Further, this technology has proven to be well-tolerated and effective in inhibiting neointimal hyperplasia at the distal anastomosis of both artery-to-artery ePTFE bypass grafts in humans. C. Arterio- Venous (AV) Fistula The arterio-venous (AV) fistula is a surgically created vascular connection which allows a flow of blood from an artery directly to a vein. An AV fistula was first created by researchers for kidney failure patients who undergo kidney dialysis.

Hemodialysis requires a viable artery and vein to draw blood from and return it to a body. A repeated puncturing often either causes a vein or artery to fail or causes some other complications for a patient. An AV fistula increases the amount of possible puncture sites for hemodialysis and minimizes damage to a patient's natural blood vessels. The connection that is created between a vein and artery forms a large blood vessel that continuously supplies an increased blood flow for performing hemodialysis. Restenosis and eventual occlusion are one of the most important problems in a long term patency of an AV fistula. In order to prevent a restenotic complications associated with a surgical formation of an AV fistula, a wide variety of therapeutic agents may be delivered to the external portion of a blood vessel. Exemplary therapeutic agents, either alone or in combination, include microtubule stabilizing agents and some cell cycle inhibitors, anti- angiogenic agents, anti-inflammatory agents, immunosuppressive agents, antithrombotic agents, antiplatelet agents and some factors involved in a prevention or reduction of a restenotic process. In one embodiment, the present invention contemplates a method comprising providing a composite drug delivery device and applying the device to an external portion of a vessel/anastomotic site following an interventional and/or surgical procedure in order to prevent complication associated with the formation of intimal hyperplasia (e.g., stenosis or restenosis). In another embodiment, a composite drug delivery device may be used in conjunction with graft placement for arterio-venous access. Fox example, the device may be used in an elbow AV hemodialysis access procedure. In one embodiment, the present invention contemplates a method comprising a hemodialysis access procedure involving placement of a vascular graft to connect an artery (e.g., brachial artery) and a vein (e.g., cephalic or basilica vein). The composite drug delivery device may be applied to the distal anastomosis at the junction of the graft and vein. In one embodiment, the device enhances the long-term patency of the vascular graft by reducing or preventing the onset of intimal hyperplasia at the venous anastomosis.

The composite drug delivery device may be used in this indication with any type of graft material, including, for example, synthetic grafts made from ePTFE or polyester grafts.

In order to prevent a restenotic complications associated with an A-V hemodialysis access procedure, a wide variety of therapeutic agents may be delivered to the external portion of a blood vessel. Exemplary therapeutic agents, either alone or in combination, include microtubule stabilizing agents and some cell cycle inhibitors, anti-angiogenic agents, anti-inflammatory agents, immunosuppressive agents, antithrombotic agents, antiplatelet agents and some factors involved in a prevention or reduction of a restenotic process. In one embodiment, the present invention contemplates a method comprising providing a composite drug delivery device and applying the device to an external portion of a vessel/anastomotic site following an interventional and/or surgical procedure in order to prevent complication associated with the formation of intimal hyperplasia (e.g., stenosis or restenosis). An exemplary therapeutic agent for use in a composite drug delivery system in this indication is paclitaxel.

In one embodiment, a sheet of knitted PLGA mesh material is coated (i.e., for example, via a dip coating or spin coating process) with a paclitaxel loaded polymeric (i.e., for example, a MePEG750/PDLLA copolymer) carrier. In one embodiment, the knitted mesh comprises poly (L-lactide-co-glycolide) with a 5:95 molar ratio of lactide:glycolide. The lactide:glycolide polymer may be synthesized, extruded into fibers, knitted into a fabric, and annealed. The mesh (i.e., for example, a knitted fabric having a size of 3.0 cm x 6.0 cm is washed in IPA prior to coating.

In one embodiment, a fibrous construct may be coated with a coating solution that contains by weight 2.19% paclitaxel, 24.16% MePEG-PDLLA polymer (MW about 7000- 9000), and 73.65% acetone. In some embodiments, the coating solution is spin coated onto the mesh material (yielding a device comprising about 1.6 mg of paclitaxel or 0.089 mg/cm²), packaged, and sterilized by gamma radiation.

A bioresorbable Vascular Wrap™ paclitaxel-eluting mesh (Angiotech, Inc., Vancouver, Canada) is provided as a practical means of delivering a therapeutic dose to the distal anastomotic site of a PTFE graft and vessel in an A-V hemodialysis access procedure. This technology appears to be well-tolerated and effective in inhibiting neointimal hyperplasia at the distal anastomosis of an artery-to-vein ePTFE grafts in humans.

D. Arterio- Venous (AV) Graft Surgery An AV graft surgical procedure is used for similar applications as those for an AV fistula (Le., for example, hemodialysis patients). For an AV graft surgery, a synthetic graft material is used to connect an artery to a vein rather than a direct connection of an artery to a vein as is the case for a AV fistula. An incidence of intimal hyperplasia, which leads to occlusion of a graft, is one of the main factors that affect long term patency of these grafts. This intimal hyperplasia may occur at a venous anastomosis and at the floor of a vein. A product that may reduce and/or prevent this occurrence of intimal hyperplasia will increase the duration of patency of these grafts. In order to reduce the occurrence of intimal hyperplasia at a venous anastomosis of an AV graft, a wide variety of therapeutic agents may be delivered to an external portion of a blood vessel. Exemplary therapeutic agents, either alone or in combination, include microtubule stabilizing agents and some cell cycle inhibitors, anti-angiogenic agents, anti-inflammatory agents, immunosuppressive agents, antithrombotic agents, antiplatelet agents and some factors involved in the prevention or reduction of a restenotic process. In one embodiment, the present invention contemplates a method comprising providing a composite drug delivery device and applying the device to an external portion of a vessel/anastomotic site following an interventional and/or surgical procedure in order to prevent a restenotic complications. A composite may be applied to a distal anastomosis, proximal anastomosis or to both a proximal and distal anastomosis.

E. Anastomotic Closure Devices

Anastomotic closure devices provide a means for rapidly repairing an anastomosis. The use of some of these devices requires an invasive surgical procedure. In one embodiment of this invention, following use of an anastomotic closure device, a composite drug delivery device containing a therapeutic agent may be wrapped around an anastomosis and/or an anastomotic closure device, if it is left at a surgical site.

In one embodiment, the invention provides a method for treating or preventing intimal hyperplasia comprising delivering to an anastomotic site a composite drug delivery device. Exemplary anastomotic sites include, but are not limited to, venous anastomosis, arterial anastomosis, arteriovenous fistula, arterial bypass, and arteriovenous graft, hi one embodiment, a composite drug delivery device includes, but is not limited to, a knitted polymer fabric formed from a biodegradable polymer and a therapeutic agent, thereby delivering the therapeutic agent to an external portion of an anastomotic site.

F. Transplant Applications

There are many applications in which various organs in a human body fail to function in a manner to sustain a well being of a patient. When an appropriate donor organ is available, an impaired organ may be replaced by a donor organ (i.e., for example, lung, heart, kidney etc). One of the potential complications following these transplant surgeries comprises stenosis of a blood vessel at or near a anastomotic site between a donor and recipient vessels. For example, transplant renal artery stenosis is a complication that may occur following a kidney transplant. Transplant renal artery stenosis is when the artery from an abdominal aorta to a kidney narrows, limiting blood flow to a kidney. This may also make it difficult to keep blood pressure under control. Treatment typically involves expanding a narrowed segment using a small balloon.

In one embodiment, the present invention contemplates a method for treating stenosis comprising applying a composite drug delivery device around an anastomotic site (junction of a donor and recipient vessels) in a perivascular manner, hi a similar manner, the drug delivery device may be applied in a peritubular manner to a exterior surfaces of a trachea and or bronchi following a lung transplant procedure. Exemplary therapeutic agents include, but are not limited to, microtubule stabilizing agents and some cell cycle inhibitors, anti-angiogenic agents, anti-inflammatory agents, immunosuppressive agents, anti-thrombotic agents, anti-platelet agents ether alone or in combination. In addition, other proteins and hormones are also contemplated that are involved in a prevention or reduction of a stenotic process.

VI. Administration

In one embodiment, a composite drug delivery device (i.e., for example, a composite material) may be applied to any bodily conduit or any tissue. Any therapeutic agent may be delivered to an external portion of a body passageway or cavity, such as around an injured blood vessel (i.e., for example, following a surgical procedure, such as a graft insertion). For example, a therapeutic agent may be applied to an adventitial surface of a body passageway or cavity, which would allow drug concentrations to remain elevated for prolonged periods in regions where biological activity is most needed. In one embodiment, a composite material (with a therapeutic agent such as paclitaxel) may be wrapped, either completely or partially, around an injured blood vessel (i.e., for example, following a surgical procedure, such as a graft insertion). Prior to implantation, a composite material may be trimmed or cut from a sheet of bulk material to match the configuration of a widened foramen, canal, or dissection region, or at a minimum, to overlay a exposed tissue area. In one embodiment, the composite may be bent or shaped to match a particular configuration of a placement region. In one embodiment, the composite material may also be rolled in a cuff shape or cylindrical shape and placed around a exterior periphery of a desired tissue. In one embodiment, the composite material may be provided in a relatively large bulk sheet and cut into shapes to mold a particular structure and surface topography of a tissue or device to be wrapped. Alternatively, a composite material may be pre-shaped into one or more patterns for subsequent use. A composite material may be typically rectangular in shape and be placed at a desired location within a surgical site by direct surgical placement or by endoscopic techniques. A composite material may be secured into place by wrapping it onto itself (i.e., self-adhesive), or by securing it with sutures, staples, sealant, and a like. In some situations, it may be desirable to first fasten a sutures to a composite material prior to use. Alternatively, a composite material may adhere readily to tissue, therefore additional securing mechanisms may not be required.

A procedure may be performed intra-operatively under direct vision or with additional imaging guidance. For example, therapeutic devices may be directed via ultrasound, CT, fluoroscopic, MRI or endoscopic guidance to a disease site. Such a procedure may also be performed in conjunction with endovascular procedures, including, but not limited to, angioplasty, atherectomy or stenting or in association with an operative arterial procedure, such as endarterectomy, vessel or graft repair or graft insertion. In certain embodiments, a composite material may be adapted to contain and/or release an agent that inhibits one or more general components of a process of fibrosis (i.e., for example, scarring), including, but not limited to: i) formation of new blood vessels (i.e., for example, angiogenesis); ii) migration and proliferation of connective tissue cells (i.e., for example, fibroblasts or smooth muscle cells); iii) deposition of extracellular matrix (ECM); and iv) remodeling (i.e., for example, maturation and organization of a fibrous tissue).

As composite materials (i.e., for example, a drug delivery device) may be made in a variety of configurations and sizes, the exact dose administered will vary with device size, surface area and design. However, certain principles can be applied in an application of this art. Drug dose can be calculated as a function of dose per unit area (i.e., for example, a portion of a device being coated), total dose administered, and appropriate surface concentrations of active drug can be determined. Drugs are to be used at concentrations that range from several times more than to 10%, 5%, or even less than 1% of a concentration typically used in a single chemotherapeutic systemic dose application. In certain embodiments, a drug is released in effective concentrations for a period ranging from 1 day to six months. In one embodiment, a drug is released in effective concentrations for a period ranging from 1 week to 3 months and more preferably for a period ranging from 3 weeks to 3 months. Exemplary dosage ranges for various bioactive agents that can be used in conjunction with composite materials in accordance with the invention include but are not limited to, fibrosis-inhibiting agents:

A) Cell cycle inhibitors including, but not limited to, doxorubicin and mitoxantrone, and/or doxorubicin analogues and derivatives thereof: total dose not to exceed 25 mg

(range of 0.1 μg to 25 mg); preferred 1 μg to 5 mg. A dose per unit area of 0.01 μg - 100 μg per mm²; preferred dose of 0.1 μg/mm² — 10 μg/mm². Minimum concentration of 10^"8 - 10^"4 M of doxorubicin is to be maintained on a device surface. Mitoxantrone and analogues and derivatives thereof: total dose not to exceed 5 mg (range of 0.01 μg to 5 mg); preferred 0.1 μg to 1 mg. A dose per unit area of a device of 0.01 μg - 20 μg per mm²; preferred dose of 0.05 μg/mm² - 3 μg/mm². Minimum concentration of 10^"8 - 10⁴ M of mitoxantrone is to be maintained on a device surface.

B) Cell cycle inhibitors including, but not limited to, paclitaxel and/or analogues and derivatives (i.e., for example, docetaxel) thereof: total dose not to exceed 10 mg (range of 0.1 μg to 10 mg); preferred 1 μg to 3 mg. In some embodiments, the total dose is about 1.0 to about 2.0 mg, or about 1.2 to about 1.8 mg, or about 1.6 mg. In one embodiment, the device is a knitted fabric having a size of 3.0 cm x 6.0 cm that comprises about 1.2 mg to about 2.0 mg of paclitaxel, preferably about 1.4 mg to about 1.8 mg of paclitaxel or about 1.6 mg of paclitaxel. In another embodiment, the device is a knitted fabric having a size of 4.0 cm x 2.5 cm that comprises about 1.2 mg to about 2.0 mg of paclitaxel, preferably about 1.4 mg to about 1.8 mg of paclitaxel or about 1.6 mg of paclitaxel. A dose per unit area of a device of 0.1 μg - 10 μg per mm ; preferred dose of 0.25 μg/mm² - 5 μg/mm². In some embodiments, the dose per unit area of device is about 0.05 mg/cm² to about 0.10 mg/cm², or about 0.10 mg/cm². In other embodiments, the dose per unit area of device is about 0.10 mg/cm² to about 0.20 mg/cm². Minimum concentration of 10^"8 - 10^"4 M of paclitaxel is to be maintained on a device surface.

C) Cell cycle inhibitors including, but not limited to, podophyllotoxins (i.e., for example, etoposide): total dose not to exceed 10 mg (range of 0.1 μg to 10 mg); preferred 1 μg to 3 mg. A dose per unit area of a device of 0.1 μg - 10 μg per mm²; preferred dose of 0.25 μg/mm² — 5 μg/mm². Minimum concentration of 10^"8 - 10^"4 M of etoposide is to be maintained on a device surface.

D) Immunomodulators including, but not limited to, sirolimus and everolimus. Sirolimus (i.e., rapamycin, RAPAMUNE): Total dose not to exceed 10 mg (range of 0.1 μg to 10 mg); preferred 10 μg to 1 mg. A dose per unit area of 0.1 μg - 100 μg per mm²; preferred dose of 0.5 μg/mm² — 10 μg/mm². Minimum concentration of 10^*8 - 10^"4 M is to be maintained on a device surface. Everolimus and derivatives and analogues thereof: Total dose should not exceed 10 mg (range of 0.1 μg to 10 mg); preferred 10 μg to 1 mg. A dose per unit area of 0.1 μg - 100 μg per mm² of surface area; preferred dose of 0.3 μg/mm² — 10 μg/mm². Minimum concentration of 10^"8 - 10^"4 M of everolimus is to be maintained on a device surface.

E) Heat shock protein 90 antagonists (i.e., for example, geldanamycin) and/or analogues and derivatives thereof: total dose not to exceed 20 mg (range of 0.1 μg to 20 mg); preferred 1 μg to 5 mg. A dose per unit area of a device of 0.1 μg - 10 μg per mm²; preferred dose of 0.25 μg/mm — 5 μg/mm . Minimum concentration of 10^" - 10 M of geldanamycin is to be maintained on a device surface.

F) HMG-CoA reductase inhibitors (i.e., for example, simvastatin) and/or analogues and derivatives thereof: total dose not to exceed 2000 mg (range of 10.0 μg to 2000 mg); preferred 10 μg to 300 mg. A dose per unit area of a device of 1.0 μg - 1000 μg per mm²; preferred dose of 2.5 μg/mm² — 500 μg/mm². Minimum concentration of 10^"8 - 10^"3 M of simvastatin is to be maintained on a device surface.

G) Inosine monophosphate dehydrogenase inhibitors (i.e., for example, mycophenolic acid, l-alpha-25 dihydroxy vitamin D₃) and analogues and derivatives thereof: total dose not to exceed 2000 mg (range of 10.0 μg to 2000 mg); preferred 10 μg to 300 mg. A dose per unit area of a device of 1.0 μg - 1000 μg per mm²; preferred dose of 2.5 μg/mm² — 500 μg/mm². Minimum concentration of 10^" - 10^" M of mycophenolic acid is to be maintained on a device surface.

H) NF kappa B inhibitors (i.e., for example, Bay 11-7082) and/or analogues and derivatives thereof: total dose not to exceed 200 mg (range of 1.0 μg to 200 mg); preferred 1 μg to 50 mg. A dose per unit area of a device of 1.0 μg - 100 μg per mm²; preferred dose of 2.5 μg/mm² - 50 μg/mm². Minimum concentration of 10^"8 - 10^"4 M of Bay 11-7082 is to be maintained on a device surface.

I) Antimycotic agents (i.e., for example, sulconizole) and/or analogues and derivatives thereof: total dose not to exceed 2000 mg (range of 10.0 μg to 2000 mg); preferred 10 μg to 300 mg. A dose per unit area of a device of 1.0 μg - 1000 μg per mm²; preferred dose of 2.5 μg/mm² - 500 μg/mm². Minimum concentration of 10^~8 - 10^'3 M of sulconizole is to be maintained on a device surface.

J) p38 MAP kinase inhibitors (i.e., for example, SB202190) and/or analogues and derivatives thereof: total dose not to exceed 2000 mg (range of 10.0 μg to 2000 mg); preferred 10 μg to 300 mg. A dose per unit area of a device of 1.0 μg - 1000 μg per mm²; preferred dose of 2.5 μg/mm² — 500 μg/mm². Minimum concentration of 10^"8 - 10^"3 M of SB202190 is to be maintained on a device surface.

K) Anti-angiogenic agents (i.e., for example, halofuginone bromide) and/or analogues and derivatives thereof: total dose not to exceed 10 mg (range of 0.1 μg to 10 mg); preferred 1 μg to 3 mg. A dose per unit area of a device of 0.1 μg - 10 μg per mm²; preferred dose of 0.25 μg/mm² - 5 μg/mm². Minimum concentration of 10^~8- 10^ M of halofuginone bromide is to be maintained on a device surface.

In certain embodiments, paclitaxel may be delivered from a device that contains from 0.001 mg/cm² to 5 mg/cm² (preferably 0.01 to 1.0 mg/cm²) over a selected period of time (i.e., for example., 1 to 120 days). .

Experimental

The following examples are offered by way of illustration, and not by way of limitation.

EXAMPLE l SYNTHESIS OF 5/95 PLG

A reactor, 8 CV HELICONE mixer, cleaned according to a standard cleaning protocol and dried, is charged with L-lactide (245.3 g, 1.7 moles, 55 eq.), glycolide (3754.7 g, 32.4 moles, 1043 eq.) and heated to 70⁰C for 1 hour. Decyl alcohol (4.90 g, 0.031 moles, 1 eq) is added to a reactor at a molar ratio of monomer to initiator of 1100/1. A temperature is increased to 110 ⁰C to allow the monomers to melt. Once melted, the temperature is decreased to 100 ⁰C. After the internal reactor temperature reaches 100 ⁰C, 0.05 M Tin (II) 2-ethylhexanoate solution in toluene (8.518 mL, 4.3 x 10-4 moles, 0.01 eq) is added at a molar ratio of monomeπcatalyst of 80,000/1. The temperature is increased to 220⁰C and maintained for 2.33 h. Polymer is removed, cut into small rods, allowed to cool, and ground using a Wiley Mill grinder. The ground polymer is sieved to remove fine particles and dried under reduced pressure (> 28 in. Hg) at 70 °C for 12 - 20 h. The polymer is further dried using a rotary evaporator at 80 °C for 2 h and 100 ⁰C for 4.25 h to remove trace monomer and solvent.

EXAMPLE 2

EXTRUSION OF A POLYMER 5/95 PLG INTO A MULTIFILAMENT YARN A 5/95 polymer prepared as in Example 1 is converted into a 20 filament yam by a melt spinning process in which the polymer is melted in sequentially heated zones of an extruder with a ³A" diameter barrel and fed through a 20 hole spinneret by a heated Zenith melt pump. The molten polymer streams are collected around a non-heated roller and fed into a two-stage orientation unit to impart strength and desired yarn denier. The oriented yarn is collected on spools by a Leesona winder after which wound yarn is transferred to storage at room temperature under reduced pressure. EXAMPLE 3

KNITTING AND ANNEALING OF A FABRIC

A fabric is constructed from oriented multifilament yarn using a circular knitting machine (Lawson-Hemphill FAK) and subsequently annealed in two dimensions at constant strain using a stainless steel tube. The knitting process uses circular knitting machine that produces a 3.25 inch diameter knitted tube. The knitted tube is made using yarn of a set denier and produced to yield a structure with a specified weight per unit area. Knitted tubes are placed over a 3.50 inch stainless steel tube, stretched to a set length and an annealed at 95° C for 30-60 minutes. The tubes are slit and cut to length.

EXAMPLE 4

SYNTHESIS OF POLYMER MEPEG750-PDLLA-2080 POLYMER

To synthesize a MePEG750-PDLLA polymer having a 20:80 ratio of MePEGrPDLLA (by weight), 40 g of MePEG (molecular weight = 750; Sigma- Aldrich, St. Louis, MO) was weighed in a 500 RB flask and 160 g of D,L-lactide (PURASORB^®, PURAC, Lincolnshire, IL) was weighed in a weigh boat. Both reagents were dried under a vacuum overnight at room temperature. A stannous 2-ethyl-hexanoate catalyst (600 mg: Sigma) was added into the RB flask containing the MePEG and a magnetic stir bar. The flask was purged with N₂ (oxygen free) for 5 minutes, capped with a glass stopper, placed into an oil-bath (maintained at 135°C), and a Coming Model p620 magnetic stirrer was gradually turned up to setting #6. After 30 minutes, the flask was removed from the oil-bath and was cooled to room temperature in a water bath. The D,L-lactide was added into the flask, which was then purged with oxygen-free N₂ for 15 minutes, the flask was capped and again placed in the oil-bath (135 ⁰C). A magnetic stirrer was turned on to setting #3 and a polymerization reaction was allowed to continue for at least five (5) hours. The flask was removed from the oil bath and the molten polymer poured into a glass container and allowed to cool to room temperature. EXAMPLE 5 PURIFICATION OF MEPEG750-PDLLA-2080

A MePEG750-PDLLA-2080 polymer was prepared as outlined in Example 4. 75 g MePEG750-PDLLA-208O was dissolved in 100 ml of ethyl acetate (Fisher, HPLC grade) in a 250 ml conical flask. The polymer was precipitated by slowly adding the solution into 900 ml isopropanol (Caledon, HPLC grade) in a 2 L conical flask while stirring. The solution was stirred for 30 minutes and the suspension cooled to 5°C using a cooling system. The supernatant was separated and the precipitant transferred to a 400 ml beaker. The polymer was pre-dried in a forced-air oven at 50⁰C for 24 hours to remove a bulk of a solvent. The pre-dried polymer was transferred to a vacuum oven (50⁰C) and further dried for 24 hours to remove residual solvent. The purified polymer was stored at 2-8°C.

EXAMPLE 6 COATING OF MEPEG75 Q-PDLL A-2080 ON A PLGA (5:95) FABRIC A knitted PLGA (5/95) fabric is prepared in accordance with Example 2 having a dimension of 3 x 6 cm² was washed with isopropanol (Caledon, HPLC) and dried in a forced-air oven at 50⁰C. 3 g MePEG750-PDLLA-2080 was dissolved in 15 ml ethyl acetate (20% solution; Fisher HPLC grade) in a 20 mL glass scintillation vial. Paclitaxel (10.13 mg) (Hauser, Boulder, CO) was added to the polymer solution, and the paclitaxel was completely dissolved by using a vortex mixer. The fabric was coated with the polymer/paclitaxel solution by dipping into such a solution. The excess solution was then removed and the coated fabric was dried using an electric fan for 2-3 minutes. The coated fabric was placed in a PTFE petri-dish and was further dried for 60 minutes using an electric fan in a fume-hood. The coated fabric was then transferred into a vacuum oven and dried under vacuum overnight at room temperature. The dried coated fabric was packed between two pieces of release-liners (Rexam PET 10, Rexam, Oakbrook , IL 10024) and sealed in a TYVEK pouch bag. EXAMPLE 7

IN VITRO RELEASE PROFILE OF PACLITAXEL FROM A FABRIC

An in vitro method is described for measuring a release profile of paclitaxel from fabric samples coated with MePEG750-PDLLA (20:80). A portion of a fabric was sampled by cutting a sample piece, weighing the sample

(approx. 5-7 mg), and placing in a screw top culture tube (16xl25mm, Kimax). A phosphate/albumin buffer (15 mL) was added to a culture tube. The samples were placed on a rotating disk (30 rpm, 20° incline) (Glas-col, Terre Haute, IN) in an incubator (VWR, Model 1380 Forced Air Oven) that was set at 37°C. After a specific incubation period, the culture tubes were removed from the incubation oven, the buffer was transferred to a second culture tube using a pipette, 15 mL of a phosphate/albumin buffer was added to the original fabric sample tube and the culture tubes were returned to the rotating disk in the incubation oven. The buffer was exchanged 3 times during the initial 24 hours, exchanged daily for the next 4 days and then exchanged on three times per week (i.e., for example, Monday, Wednesday, and Friday) until the release study was completed.

Extraction of paclitaxel from a Release Buffer

Dichloromethane (1 mL) was added to 14 ml of paclitaxel-containing buffer. The tubes were vigorously shaken by hand for 10 seconds and placed on a tube rotator (Armolyne Labquake Shaker) for 15 minutes. The samples were centrifuged at 1500 rpm for 10 min. The supernatant buffer was withdrawn from a culture tube and the samples were then placed in a heating block (Pierce, ReactiArm/ReactiVap ) at 45°C. The samples were dried using a stream of nitrogen. The culture tubes that contained dried samples were capped and placed in a -20⁰C freezer until HPLC analysis of the samples could be performed.

Determination of paclitaxel content by HPLC An acetonitrile/water solution (50:50) was added (1 mL) to a culture tube containing a dried extract. The samples were vortex ed for 60 seconds. The samples were centrifuged for 15 min at 1500 rpm. Approximately 500 μL of a supernatant was transferred to an HPLC autosampler vial (Agilent). The HPLC chromatographic conditions used for a determination of the paclitaxel content were: solvent:water/ACN 47:53, Column: Hypersil ODS 125 x 4 mm, 5 μm (Agilent), flow: lmL/min, UV detection @ 232 nm, Gradient: isocratic, runtime: 5 min, injection volume: 10 μL. An external calibration curve using paclitaxel and 7-epipaclitaxel was used to quantify the paclitaxel in the extracts. The release profile of paclitaxel from the samples with three different loadings of paclitaxel (0.6 mg, 1.3 mg, and 2.2 mg) was plotted as percent paclitaxel release against time (Figure 13 & Table 1).

Table 1: Amount of paclitaxel release (%) over time (days)

EXAMPLE 8

EVALUATION OF PACLITAXEL CONTAINING FABRIC ON INTIMAL HYPERPLASIA DEVELOPMENT IN A RAT BALLOON INJURY CAROTID ARTERY MODEL

A rat balloon injury carotid artery model was used to demonstrate the efficacy of a paclitaxel loaded knitted system on a development of intimal hyperplasia fourteen days following placement.

Control Group

Wistar rats weighing 400 - 500 g were anesthetized with 1.5% halothane in oxygen and the left external carotid artery was exposed. An A2 French Fogarty balloon embolectomy catheter (Baxter, Irvine, CA) was advanced through an arteriotomy in an external carotid artery down a left common carotid artery to an aorta. The balloon was inflated with enough saline to generate slight resistance (approximately 0.02 ml) and it was withdrawn with a twisting motion to the carotid bifurcation. The balloon was then deflated and the procedure repeated twice more. This technique produced distension of the arterial wall and denudation of the endothelium. The external carotid artery was ligated after removal of the catheter. The right common carotid artery was not injured and was used as a control.

Local Perivascular Paclitaxel Treatment

Immediately after injury of the left common carotid artery, a 1 cm long distal segment of the artery was exposed and treated with a 1x1 cm paclitaxel-containing system. The wound was then closed and the animals were kept for 14 days.

Histology and immunohistochemistrv _

At a time of sacrifice, the animals were euthanized with carbon dioxide and pressure perfused at 100 mmHg with 10% phosphate buffered formaldehyde for 15 minutes. Both carotid arteries were harvested and left overnight in fixative. The fixed arteries were processed and embedded in paraffin wax. Serial cross-sections were cut at 3 μm thickness every 2 mm within and outside the implant region of the injured left carotid artery and at corresponding levels in the control right carotid artery. Cross-sections were stained with Mayer's hematoxylin-and-eosin for cell count and with Movat's pentachrome stains for morphometry analysis and for extracellular matrix composition assessment.

Results

From Figures 3-5, it is evident that perivascular delivery of paclitaxel using a paclitaxel- loaded delivery device resulted is a dramatic reduction in intimal hyperplasia.

EXAMPLE 9

EVALUATION OF PACLITAXEL CONTAINING FABRIC ON INTIMAL HYPERPLASIA DEVELOPMENT IN A SHEEP CAROTID ARTERY BYPASS GRAFT MODEL

Expanded polytetrafluoroethylene (ePTFE) is the most common material used for prosthetic vascular grafts, but the majority of these grafts fail over time, usually because of stenosis at a distal anastomosis site due to development of intimal hyperplasia.

One objective of this study was evaluation of the extent of intimal hyperplasia formation following use of a biodegradable, bioresorbable fabric containing paclitaxel and placed at an ePTFE distal anastomosis site. Paclitaxel is a drug that inhibits processes important in intimal hyperplasia development, including without limitation, inhibition of smooth muscle cell proliferation, cell migration, and matrix deposition.

The left and right carotid arteries of anesthetized sheep were exposed by sharp dissection. A tunnel was formed from one carotid artery to the other to accommodate the ePTFE graft. For the study, an ePTFE graft from Impra (Tucson, AZ) was used. The ePTFE graft was tunneled and trimmed for appropriate length and configuration. Using standard vascular technique, the ePTFE graft was anastomosed end-to-side with running 6-0 polypropylene suture. The angle of the junction between graft and native vessel was approximately 45°. The length of an implanted graft ranged from 9.5 - 15 cm (average 11 cm). The graft implant configuration is illustrated in Figure 6. Paclitaxel was incorporated into a 2 cm x 5 cm section of knitted fabric (PLG) in the following doses and animal test groups: Group 1, 0 mg; Group 2, 0.6 mg; Group 3, 1.8 mg; and Group 4, 3.0 mg. The fabric was placed at a distal end of a graft at an anastomosis site. To place the fabric, a long side was pulled under the artery and up around either side of the distal end of a graft. One edge was positioned as close to the heel of an anastomosis as possible. The top edges of the fabric were sewn together with one suture on either side of a graft so that no gaps were left in the circumferential direction. One suture was placed at the proximal end and the other at the distal end of a fabric, and sewn to nearby connective tissue to prevent slippage of a fabric away from the anastomosis (see Figure 6). The surgical sites were closed in layers with running absorbable sutures. Standard antibiotics and analgesics were administered after surgery for several days as required. At approximately 56 days post-graft implant, animals were anesthetized. Contrast media was injected and angiograms performed of the distal graft and artery at the distal anastomosis. Immediately prior to euthanasia, the animals received heparin (150 U/kg, IV) and immediately after euthanasia, the ePTFE graft was rinsed in situ with lactated Ringers solution and perfusion- fixed in situ with 10% neutral buffered formalin (NBF). The specimens were excised en bloc and allowed to immersion fix in 10% NBF at least 24 hours prior to histological processing. The fixed specimens were trimmed and mapped accurately for corresponding cross sectional location in reference to the ePTFE graft configuration. The scheme for sectioning is illustrated in Figure 7. A total of nine sections were cut at the distal end of the graft: two cut perpendicular to an artery on either side of the anastomosis (Al and A5), one perpendicular to an artery through the "toe" of the anastomosis (A2), one or two cut through the floor of an anastomosis adjacent to the "toe" (A3 and A4), three cuts perpendicular to the graft at its distal end, and one through the center of the graft. Adjacent sections were cut at approximately 3 mm intervals. The specimens were paraffin-embedded, cross-sectioned, and four sets of slides made, two stained with hematoxylin and eosin (H&E), and one each stained with Masson's trichrome and Verhoeff Van Gieson (VVG). These stains were selected for air ability to show tissue cellularity (H&E), collagen, smooth muscle and fibrin (Masson's Trichrome), and elastin (VVG).

Morphometric Analysis: A morphometric analysis system may comprise, for example, an Olympus BX40 microscope, Optronics Image Sensor DEI-750, Sony HR Trinitron monitor, and PC computer equipped with Media Cybernetics Image-Pro Plus software v. 3.0 for Windows. Digital images are created, labeled, and stored according to applicable BioDevelopment Associates SOPs. With regard to the results, the following definitions apply: Proximal- toward the heart; Distal- away from the heart; Anastomosis- surgical connection of graft to native vessel; "Toe" of

Anastomosis- where graft and vessel meet at an obtuse angle; "Heel" of Anastomosis- where graft and vessel meet at an acute angle; "Floor" of Anastomosis- region between toe and heal; Stenosis- narrowing of graft or vessel lumen; Neointima- hyperplastic lesion on luminal surface characterized by proliferating smooth muscle cells (SMC); Pseudointima- lesion on luminal surface composed of aged thrombus, which is not undergoing typical reorganization by SMC proliferation.

Morphometric measurements of histological cross sections included neointimal area (IA), maximal neointimal thickness (MIT), luminal area (LA), and area inside a graft (GA). GA = IA + LA. Area inside the graft was a reference measurement from which stenosis was determined (percent stenosis 100*IA/GA). In asymmetrical sections through the floor of an anastomosis, where graft sections were not complete, only MIT was measured.

Morphometric analysis was performed on sections A2 ("toe" section cut perpendicular to a native vessel), and on sections A6, A7 and A8 (a first three complete graft sections cut perpendicular to the graft at it's distal end) {see Figure 7). Group results were compared using a one-tailed t-test. Each of the paclitaxel fabric groups was compared to the zero-dose fabric group. A summary presentation of group morphometric data is shown in Tables 3-5. Group averages for all parameters in all sections in all paclitaxel groups were less than corresponding data from a zero-dose controls. Intraluminal lesions that represented permanent or semi-permanent luminal obstructions, and thus contributed functionally to reduction in blood flow, were included in a morphometric analysis. Both neointimal (hyperplastic lesion characterized by proliferating SMC) and pseudointimal (aged adherent thrombus not undergoing typical reorganization by SMC migration and proliferation) were included in the analysis, whereas fresh thrombus was not. In reporting morphometric data, no distinction was made between neointima and pseudointima since both represented stenotic lesions.

The MIT in Section 2 ("toe" section) for Group 1 (controls) was 0.82 ± 0.29 mm (group average ± SD). Low, mid, and high dose paclitaxel groups had values of 0.78 ± 0.30 mm, 0.59 ± 0.14, mm and 0.54 ± 0.23 mm, respectively (5%, 28%, and 34% less than controls), but these differences were not statistically significant at the 95% confidence interval (p > 0.05). MIT in section 6 (first full cross section of graft adjacent to a distal anastomosis) in the controls was 1.31 ± 0.82 mm. Low, medium, and high dose paclitaxel groups had MIT in section 6 of 0.38 ± 0.12 mm, 0.31 ± 0.29 mm, and 0.34 ± 0.20 mm, respectively. The reductions in MIT in Groups 1, 2 and 3 were statistically significant (p < 0.05). In sections 7 and 8 (approximately 3 mm and 6 mm past section 6), MIT in a controls was 0.95 ± 0.67 mm and 0.89 ± 0.64 mm, respectively. Although MIT in sections 7 and 8 in all the paclitaxel groups was approximately 70% less than controls, only two values, section 7 Group 3 and section 8 Group 4, were statistically significant (p < 0.05).

The IA of the control group was 7.41 ± 5.12 mm, 6.28 ± 4.31 mm, and 5.57 ± 4.62 mm in sections 6, 7, and 8, respectively. In the paclitaxel groups, IA was reduced approximately 70- 80%. Reductions in IA for section 6 in Groups 3 and 4 and for section 7 in Group 2, 3 and 4 were statistically significant (p < 0.05).

The percent stenosis due to neointima in the control group in section 6 was 28.4 ± 19.5 mm². As was the case for the other parameters, stenosis did not decrease markedly at sites 3 and 6 mm into the graft from an anastomosis. Likewise, the effect of paclitaxel on reducing stenosis was similar to the effect on IA, with approximately 70-80% reduction in stenosis, and 7 of 9 values were significantly lower than controls (p < 0.05).

There did not appear to be a marked dose effect of paclitaxel on luminal lesions (neointima and/or pseudointima) that contributed to stenosis. Figures 8-10 clearly illustrate this point. There is an indication that stenosis was reduced slightly more at the mid paclitaxel dose than the low dose, but clearly are is no further gain in efficacy at the high dose.

The attrition rate in this study due to early graft occlusion was larger than expected at the outset. The attrition rate appeared to have a dose dependence, which is supported by the histopathology analysis. At the lowest paclitaxel dose, 0.6 mg, there was the marked and significant reduction in lesions causing luminal narrowing at the distal end of a graft. This effect did not increase markedly with increased dose, suggesting that the low dose achieved near maximal response in terms of efficacy to inhibit stenosis. An inhibitory effect of paclitaxel did not affect the mechanical integrity of an anastomosis (no evidence of leakage) in the dose range tested. Intraluminal endothelialization is not affected by paclitaxel. Finally, paclitaxel in the doses tested is not toxic to the native artery wall. Thus, the results of this study suggest that low and mid doses represent a useful clinical range of efficacy and safety. EXAMPLE 10

EVALUATION OF PACLITAXEL-ELUTING BIOABSORBABLE FABRIC ON NEOINΉMAL HYPERPLASIA DEVELOPMENT IN A SHEEP MODEL OF DIALYSIS ACCESS FAILURE

Commercially available, 6-mm internal diameter ePTFE grafts (IMPRA FLEX ePTFE

Vascular Grafts, 6 mm ID, Bard Peripheral Vascular, Inc., Tempe, AZ) were placed between the left common carotid artery and right external jugular vein in 40 castrated male sheep using standard vascular technique. Animals were randomized (8 per group) to one of five treatment groups: no fabric; or, fabric with 0.0, 0.3, 1.7 or 1.2 μg/mm² of paclitaxel (for a total dose of 0.0, 0.6, 1.3 or 2.2 mg, respectively). For those animals in the fabric groups, the sterilized 3 cm by 6 cm paclitaxel-eluting, bioabsorbable fabric (prepared as described in Examples 1-6) was placed around the distal end of a graft-vein anastomosis by pulling the long side (6 cm) of the fabric under an artery and up around either side of the distal end of the graft. One edge of the fabric was positioned as close to the heel of an anastomosis as possible. Sutures were placed at the proximal and distal ends of a fabric and sewn to nearby connective tissue to prevent slippage. The surgical site was then closed. Standard antibiotics and analgesics were administered after surgery for several days as required. Surgeons were blinded to treatment group for the 32 animals that received the fabric.

Immediately after implantation and at weekly intervals thereafter, graft patency was assessed by palpation and/or auscultation with a stethoscope for evidence of blood flow through the graft. Animals with graft failure occurring prior to the scheduled sacrifice were euthanized following confirmation of occlusion using Doppler ultrasonography, the remaining animals were euthanized between 56 and 58 days after graft implantation. Animals were sedated, and the grafted and attached vessels were surgically exposed. Animals received intravenous heparin (150 U/kg) and were euthanized with an overdose of intravenous sodium pentobarbital. Contrast medium was injected and angiograms were taken of the graft and vein at the distal anastomosis to confirm patency. The artery was immediately cannulated proximal to an arterial anastomosis, and the ePTFE graft was rinsed in situ with Ringer's lactate solution, followed by 10% neutral buffered formalin. The specimens were excised and allowed to immersion-fix in formalin for a minimum of 24 hours prior to histological processing. Six sections were an cut at the venous end of the graft and vessel (Figure 11). Adjacent sections were cut at 2.5 to 4.5 mm intervals. Specimens were paraffin-embedded, and cut as thin sections for histology. Slides were stained with hematoxylin and eosin. The study pathologist performed all qualitative and quantitative analyses of these sections in a blinded fashion. Assessment of the blinded histopathology observations relative to treatment group assignation was performed retrospectively.

Histopatho logical assessment included characterization of cellular composition of vascular and perivascular tissue and graft in the vicinity of the venous anastomosis. Efficacy was measured by morphometric analyses of the cross-sectional samples. Quantitative analyses were made with computer-aided morphometry using Image-Pro Plus software version 4.5.1.22 for Windows XP (Media Cybernetics, Silver Spring, MD). Morphometric measurements included maximal neointimal thickness, combined area of neointima and mural thrombus, and area inside the graft (Figure 12); the pathologist then calculated values for neointimal area and luminal area using these measured parameters. Percent stenosis was calculated as a ratio of the luminal area to the area inside the graft. For these morphometric outcomes, Section 5, cut from the graft at its distal (venous) end, was determined to be a cross-section of primary interest. Because paclitaxel is known to inhibit angiogenesis as well as cellular proliferation, capillary density was measured to determine if reduction in neointimal hyperplasia was associated with reduction in neovascularization. Therefore, capillary density was measured in the neointima within the PTFE graft at the toe of the graft (Section 4 or 3, whichever had the best arc of ePTFE with adjacent vein). For this calculation, capillaries were identified and counted under light microscopy using up to 40Ox magnification as needed; the density was calculated as the number of capillaries per mm² of neointima.

Animals whose grafts occluded prior to the scheduled sacrifice were excluded from the analysis. Results from the morphometric analyses were tabulated, and group means and standard deviations were calculated. Nonparametric tests were used to compare groups: P values were generated using a Wilcoxon Rank Sum test; they were significant at the .05 level. For each cross- section of interest, the zero-dose fabric group was compared to the no fabric group; all active fabric groups were an compared to the zero-dose fabric group. Linear regression analyses of the neointimal area and capillary density were also performed. In this study, the following definitions were used: Distal — away from the heart; Anastomosis — surgical connection of graft to native vessel; "Toe" of Anastomosis — where graft and vessel meet at an obtuse angle; "Stenosis — narrowing of graft or vessel lumen; Neointima — hyperplastic lesion on luminal surface characterized by proliferating smooth muscle cells.

Results: Grafts occluded early in 5 animals. Three of the 5 treatment groups were represented among the early occlusions: 1 graft in the zero-dose fabric group occluded after week 6; 2 grafts in the 0.3 μg/mm² paclitaxel fabric group occluded after week 3 or 4; and, 2 grafts in the 1.2 μg/mm² paclitaxel fabric group occluded after week 3. For the 35 animals that completed the study, histological analysis revealed that, compared with the no-fabric control group, the addition of fabric alone resulted in an increase in the thickness of the fibrous tissue encapsulating the graft (from 0.8 mm to 1.5 mm) and an increase in peri graft macrophages from minimal to mild. Macrophages were concentrated around disintegrating fabric debris. Among groups that received paclitaxel, there was more fabric debris at higher paclitaxel doses and fewer macrophages. In the no fabric and fabric alone control groups, the nodes of the graft wall were completely filled with spindle-shaped cells (presumably myofibroblasts). In contrast, in the highest paclitaxel dose group, there were almost no spindle-shaped cells in the nodes of the graft wall; only degenerating blood and fibrin debris were present. There was no apparent dose effect of paclitaxel on either perigraft inflammation or on the process of endothelialization (cells with the histologic appearance of endothelium covered the neointima in all groups). There was some enlargement of the vein at the anastomosis in most cases and some thickening of the vein; this was evident across all treatment groups. There was no evidence of loss of integrity of the vein wall at any dose. Sections through the vein revealed no apparent atrophy or decrease in vein wall thickness, no surface thrombus, and an apparent intact endothelial lining (although immunohistochemistry was not performed for definitive cell typing).

At the first cross section through the graft above the graft-vein anastomosis (Section 5), intimal hyperplasia was extensive in both the no fabric and zero-dose fabric groups (Table 2). Neointimal area was significantly lower in all paclitaxel fabric groups compared with the zero- dose fabric group (P < .008). Similar trends were observed for the outcomes of mural thrombus area and percent stenosis in both sections. Capillary density in the neointima at the graft-vein anastomosis (Section 4 or 3) also decreased with paclitaxel; it was significantly lower in both the 0.3 μg/mm² and 1.2 μg/mm² paclitaxel fabric groups compared with the zero-dose fabric group (P = .022 and P = .001, respectively). Linear regression analyses indicated that are was an inverse relationship between neointimal area inside the graft and drug dose (coefficient of determination, r² = +0.85), and between capillary density in the neointima and drug dose (r² = +0.77). The relationship between capillary density and intimal area was both direct (r² = +0.99) and significant at the 99% confidence interval (P < .01).

The results (see, Tables 3-5) demonstrate that application of the paclitaxel-eluting fabric to the venous anastomosis inhibited neointimal growth without apparent toxicity to the adjacent vein.

Table 2. Morpbometric Data at the Graft-Vein Anastomosis

Group Statistic Neointimal Mural Luminal Capillary

Area Thrombus Stenosis Density

(mm²) Area (%) (capillaries/mm²)

(mm²)

No Fabric (n=8) mean ± SD 10.5 ± 6.8 2.6 ± 1.9 49.4 ± 22.4 11.9 ± 5.8

Fabric, 0.0 mg mean ± SD 6.4 ± 3.2 3.8 ± 2.9 40.9 ± 14.1 8.9 ± 5.6

(n=7) P vs. No Fabric .28 .40 .87 .28

Fabric, 0.6 mg mean ± SD 0.9 ± 1.4 0.2 ± 0.3 3.6 ± 4.3 3.6 ± 2.9

(n=6) P vs. Fabric, .008 .002 .001 .02

O mg

Fabric, 1.3 mg mean ± SD 1.3 ± 1.5 1.5 ± 2.3 9.9 ± 10.0 4.6 ± 6.0

(n=8) P vs. Fabric, .004 .071 .001 .07

O mg

Fabric, 2.2 mg mean ± SD 1.2 ± 1.4 0.6 ± 1.2 6.8 ± 5.6 1.1 ± 1.7

(n=6) P vs. Fabric, .008 .008 .001 .001

O mg

Neointimal area, mural thrombus area and luminal stenosis were measured in Section 5, the cross-section taken perpendicular to the graft at its most distal end; capillary density was measured in the neointima at the toe of the graft (Sections 4 or 3, whichever had the best arc with the adjacent vein). All P values are based on pairwise comparisons made using the Wilcoxon Rank-Sum test.

Effect of Paclitaxel on Intimal Hyperplasia, Summary of Results Table 3. Percent Change in Maximal Intimal Thickness

Table 4. Percent Change in Intimal Area

Table 5. Percent Change in % Stenosis

EXAMPLE 11 PREVENTING STENOSIS OF PERIPHERAL BYPASS GRAFTS

This example describes a 2-year, prospective, single-blind, randomized, active- controlled, two-arm, multicenter, clinical study conducted in adults (>18 years) with peripheral artery disease (PAD) and symptoms of chronic limb ischemia, who were selected by the surgeon and scheduled to undergo femoropopliteal peripheral bypass surgery with a 6 mm expanded PTFE graft.

Subjects were randomized 2:1 to the Treatment and Control groups, respectively. Preoperatively, subjects were excluded if they were pregnant, had recent clinically significant cardiac disease history, had an immune compromised condition, or had a life expectancy of less than one year. Intraoperatively, subjects were excluded if they had excessive bleeding at an anastomotic site. Graft placement was performed according to the investigators' standard medical practice. For subjects randomized to the Treatment group, a 2.5 cm x 4 cm biodegradable paclitaxel-eluting mesh (dose density of 1.6 μg/mm², total dose of 1.6 mg) was placed around the distal graft anastomosis (and sutured to itself above and below the anastomosis to avoid slippage) immediately following graft placement and prior to wound closure. The ePTFE graft was combined with a bioresorbable paclitaxel-eluting mesh made of a poly DL- lactide-co-glycolide (PLGA) polymer, coated with a poly ethylene glycol-b-DL-lactide (PEG) polyester (Vascular Wrap™)

Subjects were evaluated preoperatively, intraoperatively, at hospital discharge, and at 6 weeks and 3, 6, 12 and 24 months postoperatively. Safety outcomes that were monitored throughout the study included the frequency, severity and relatedness to treatment of adverse events (AEs) and of serious adverse events (SAEs). The primary efficacy outcome was the internal diameter of the distal graft anastomoses at 2 years, as measured by ultrasound; an unpaired one-tailed t-test was used to compare groups at the 5% significance level.

Subjects: 109 subjects were enrolled and underwent surgery to implant a PTFE graft. Of these, 71 were randomized to the Treatment group and 38 to the Control group; 34 and 23 subjects from each group, respectively, completed the study. Most subjects (-80%) were male; the median age was 63 years. Subjects in both the Treatment and Control groups had multiple risk factors for PAD: smoking (79% and 87%, respectively); diabetes (41% and 45%); hypertension (80% and 74%); and hypercholesterolemia (47% and 26%). Safety: At 12 months, approximately 80% of subjects in both groups had experienced

AEs. No AEs or SAEs were considered by the investigator to be related to the use of the paclitaxel mesh. AEs leading to death occurred in a lower percentage of Treatment than Control subjects (11% vs 18%). Treatment subjects also had a lower incidence of amputations than Control subjects (15.5% vs 18.4%) and the mean interval of limb retention was twice as long (153 days vs 76 days). The difference between groups was particularly noteworthy among diabetics; in this population, 14% of Treatment subjects and 24% of Control subjects underwent amputation.

Efficacy: At 24 months, the difference in the mean internal diameter of the distal anastomosis between the Treatment and Control groups was statistically significant (p=.033). This trial provides the first clinical evidence for the safety and efficacy of the paclitaxel- eluting mesh implanted with a PTFE vascular graft, for use in arterial bypass surgery necessitated by peripheral vascular disease. The incidences of AEs and SAEs were comparable in the Treatment and Control groups, and no AEs were considered related to the paclitaxel mesh, hi addition, the paclitaxel mesh was associated with a reduction in the overall incidence of amputation and prolonged limb retention, and was of particular benefit to diabetic subjects for whom the incidence of amputations was 42% lower. The paclitaxel mesh maintained the mean internal diameter of the distal anastomosis throughout the 24 months of study, compared with a gradual decrease in mean diameter among Control subjects suggesting the development of . neointimal hyperplasia in the latter group; by 24 months, the difference in mean diameters was significant.

EXAMPLE 12 COMPARISON OF KNITED MATRIALS

Due to the unavailability of a VICRYL mesh of comparable construction to that of the mesh prepared in Examples 1-3 (denoted as MX-2 mesh), a 90/10 glycolide/L-lactide copolymer was prepared and converted to a knitted mesh (denoted as MX-I mesh) under processing conditions similar to those used in preparing the MX-2 meshes. The physicochemical properties and simulated biological properties of the two meshes were investigated and key results are summarized in Table 6. The corresponding data in the table show that (1) both MX-I (VICRYL- type) and MX-2 meshes are constructed of fibers having comparable diameter; (2) the constituent polymers of MX-I and MX-2 meshes have practically the same molecular weight (measured in terms of inherent viscosity); and (3) both meshes are constructed to exhibit comparable area density. The physicochemical and simulated biological properties of each material were analyzed (where n indicates the number of specimens tested) to demonstrate the clinically relevant differences between the two mesh materials.

The thermal properties data in indicate that (1) compared with MX-2, MX-I melts at a lower temperature and exhibits a lower heat of fusion and, hence, lower degree of crystallinity (which, in turn, may be related to the more ordered crystallizable polyglycolide segments in fibers of MX-2); and (2) at the early Table 6 stages of degradation under accelerated in vitro conditions (to simulate their comparative performance in the biological environment), the MX-2 mesh retains a higher fraction of its original strength than MX-I and conversely loses a larger fraction of its mass. These properties can be linked to achieving functional performance for a perivascular drug delivery device for use at a graft anastomosis, where a prolonged strength profile associated with a brief mass retention is desired. Such behavior results in a maximum retention of mechanical integrity during the initial critical period of tissue healing, while encouraging early replacement of the absorbable mass with natural tissue and hence, early transfer of load and mechanical stabilization of the treated vascular graft.

Table 6. Comparative Properties of MX-I Mesh (VICRYL-type) and a MX-2 Mesh

EXAMPLE 13 SYNTHESIS OF POLYMER MEPEG750-PDLLA (Mw = 8000 - 9000)

A 1000 mL round bottom flask equipped with a magnetic stir bar, cleaned and dried according to a standard protocol, is charged with MePEG (60 g, 0.08 moles, 1 eq) and tin (H) 2- ethylhexanoate catalyst (0.9 g, 2.2 x 10^"3 moles, 0.028 eq). A connecting tube and stopcock are added to the flask and the flask is heated at 70 ⁰C under vacuum for 30 min. The flask is removed from the oil bath and placed under a positive N₂ pressure. Once the flask has cooled to room temperature, the flask is charged with D,L-lactide (240 g, 1.67 moles, 21 eq) and a N₂ atmosphere is maintained. The D,L-lactide is previously dried at 40 ⁰C for at least 1 h. The flask is heated to 135 ⁰C for 6 h and magnetic stirring is begun as soon as possible and maintained throughout the reaction step. EXAMPLE 14 SYNTHESIS OF POLYMER MEPEG7S Q-PDLLA fMw = 6000 - 700(tt

A 1000 mL round bottom flask, cleaned and dried according to a standard protocol, is charged with MePEG (75.8 g, 0.10 moles, 1 eq) and tin (ET) 2-ethylhexanoate catalyst (0.9 g, 2.2 x 10^'3 moles, 0.022 eq). A connecting tube and stopcock are added to the flask and the flask is heated at 70 ⁰C under vacuum for 30 min. The flask is removed from the oil bath and placed under a positive N₂ pressure. Once the flask has cooled to room temperature, the flask is charged with D,L-lactide (240 g, 1.67 moles, 16.5 eq) and a N₂ atmosphere is maintained. The D,L- lactide is previously dried at 40 ⁰C for at least 1 h. The flask is heated to 135 ⁰C for 6 h and stirring is begun as soon as possible and maintained throughout the reaction step.

EXAMPLE 15

PURIFICATION OF MEPEG750-PDLLA (M_Ψ = 6000 - 7000 AND 8000 - 9000)

The MePEG750-PDLLA polymer is prepared as outlined in example 4. Once cooled to ambient conditions the flask is transferred to a rotary evaporator and heated at 110 ⁰C. The flask is rotated very slowly and evacuated for 2 h. Once D,L-lactide content is verified to be less than 10 % of height of polymer peak by GPC, no further devolatilization is necessary. While the polymer is still molten it is transferred in approximately equal portions to two separate 2000 mL beakers. To one beaker add 10 mL/gram polymer of isopropyl alcohol (IPA) and cover the opening. To the beaker is added a UP400S Ultrasonic Processor probe and sonication is performed for 1.5 - 2 h on cycle "1 " at 40 % amplitude. The probe is removed and the beaker is covered and is refrigerated (2 — 4 ⁰C) for at least 16 h. The process is repeated for the second beaker.

The first beaker is removed from the refrigerator and the IPA is decanted. The polymer is transferred to four 50 mL conical centrifuge tubes. The tubes are centrifuged in pairs at 7200 rpm for 20 min. Immediately after centrifugation the supernatant (~ 5 mL) is decanted. The process is repeated for the second beaker. The polymer is transferred to a 1000 mL pear shaped flask. The flask is placed on a rotary evaporator and heated at 80 ⁰C. The flask is rotated slowly, evacuated, and once IPA distillation is controlled (5 — 10 min) the setpoint of the oil bath is lowered to 55 ⁰C. The process is repeated for the second set of centrifuge tubes. After 24 h the polymer is equilibrated with dry N₂, transferred to a storage container, and stored at 2 — 8 ⁰C.

EXAMPLE 16

COATING OF MEPEG750-PDLLA ON A PLGA FABRIC (3 CM X 6 CM)

The fabric is cut from larger sheets (~ 25cm x ~ 30cm) into smaller sections (3 cm x 6 cm) using an Accu-Cut cutter and cutting die. Each 3 cm x 6 cm section is weighed prior to coating using a calibrated 5-place balance. The MePEG750-PDLLA (24.2 g) is added to paclitaxel (2.2 g) and both are dissolved with acetone (73.6 g) to afford the coating solution. The fabric sections are placed on a spin chuck that is attached to a CEE-100 spin coating machine. Coating solution (—400 μL) is dispensed onto the fabric section so that the fabric is immersed in solution. The spin coater begins with a short dwell (5 s) and then the machine goes into a controlled spin cycle for 10 s at 650 rpm before stopping. The fabric is dried for ~ 5 min on a drying bed (ambient conditions). The coated fabric is placed into a vacuum chamber at ambient temperature for >12 h. After vacuum drying, the coated fabric is weighed to determine post-coating weight in order to gravimetrically calculate total paclitaxel content on each individual part. Coated fabric is secured in a release liner sleeve and placed in a labeled PoIy- Tyvek^® heat sealed pouch. The sealed Poly-Tyvek^® pouch and a desiccant are placed into a labeled outer foil-foil pouch and heat-sealed. The sealed, coated fabric is gamma sterilized at 25 to 35 kGy.

EXAMPLE 17 COATING OF MEPEG750-PDLLA ON A PLGA FABRIC (2.5 CM X 4 CM) The fabric is cut from larger sheets (~ 25 cm x ~ 30 cm) into smaller sections (2.5 cm x

4 cm) using an Accu-Cut cutter and cutting die. Each 2.5 cm x 4 cm section is weighed prior to coating using a calibrated 5-place balance. The MePEG750-PDLLA (25.4 g) is added to paclitaxel (3.6 g) and both are dissolved with acetone (71 g) to afford the coating solution.

The fabric sections are placed on a spin chuck that is attached to a CEE-100 spin coating machine. Coating solution (~275 μL) is dispensed onto the fabric section so that the fabric is immersed in solution. The spin coater begins with a short dwell (5 s) and then the machine goes into a controlled spin cycle for 10 s at 650 rpm before stopping. The fabric is dried for ~ 5 min on a drying bed (ambient conditions). The coated fabric is placed into a vacuum chamber at ambient temperature for >12 h. After vacuum drying, the coated fabric is weighed to determine post-coating weight in order to gravimetrically calculate total paclitaxel content on each individual part. Coated fabric is secured in a release liner sleeve and placed in a labeled PoIy- Tyvek^® heat sealed pouch. The sealed Poly-Tyvek^® pouch and a desiccant are placed into a labeled outer foil-foil pouch and heat-sealed. The sealed, coated fabric is gamma sterilized at 25 to 35 kGy.

EXAMPLE 18

IN VITRO RELEASE PROFILE OF PACLITAXEL FROM A COATED FABRIC

An in vitro method is described for measuring a release profile of paclitaxel from fabric samples coated with MePEG750-PDLLA (20:80) and paclitaxel.

A portion of a fabric was sampled by cutting a sample piece, weighing a sample (approx. 5-7 mg), and placing in a TEFLON lined screw top culture tube (16xl25mm, Kimax). A phosphate/albumin buffer (15 mL) was added to a culture tube. The samples were placed on a rotating disk (30 rpm, 10° incline) (Glas-col, Terre Haute, IN) in an incubator (VWR, Model 1380 Forced Air Oven) that was set at 37°C. After a specific incubation period, the culture tubes were removed from the incubation oven, the buffer was transferred to a second culture tube using a pipette, 15 mL of a phosphate/albumin buffer was added to a original fabric sample tube and a culture tubes were returned to a rotating disk in a incubation oven. The buffer was exchanged 3 times during a initial 24 hours, exchanged daily for a next 4 days and then exchanged on three times per week (i.e., for example, Monday, Wednesday, and Friday) until the release study was completed.

Dichlorome thane (1 mL) was added to 14 ml of paclitaxel-containing buffer. The tubes were vigorously shaken by hand for 10 seconds and an placed on a tube rotator (Armolyne Labquake Shaker) for 5 minutes. The samples were centrifuged at 1500 rpm for 5 min. The supernatant buffer was withdrawn from a culture tube and a samples were an placed in^'a heating block (TurboVap) at 35°C. The samples were dried using a stream of nitrogen. The culture tubes that contained dried samples were capped and placed in a -20⁰C freezer until HPLC analysis of the samples could be performed. An acetonitrile/water solution (85:15) was added (1 mL) to a culture tube containing a dried extract. The samples were vortexed for 60 seconds. The samples were centrifuged for 15 min at 1500 rpm. Approximately 500 μL of a supernatant was transferred to an HPLC autosampler vial (Agilent). The HPLC chromatographic conditions used for a determination of paclitaxel content were: solvent: water/ ACN 40:60, Column: Luna Cl 8 150 x 4.6 mm, 3 μm (Phenomenex), flow: lmL/min, UV detection @ 227 nm, Gradient: isocratic, runtime: 10 min, injection volume: 10 μL. An external calibration curve using paclitaxel and 7-epipaclitaxel was used to quantify paclitaxel in the extracts.

EXAMPLE 19

EFFECT OF POLYMER MOLECULAR WEIGHT ON IN VITRO RELEASE (IVR) OF PACLITAXEL FROM A COATED FABRIC

The in vitro method described in Example 18 was used to measure the release profile of paclitaxel from fabric samples coated with MePEG750-PDLLA (20:80) of three different molecular weights (5673, 6575, and 6792 Daltons) and 1.6 mg of paclitaxel. The coating contained 87.6% polymer (by weight) and 12.4% paclitaxel. Knitted PLGA meshes were dip coated using coating procedures similar to that described in Example 6. The IVR profile (shown in Table 7 and Figure 14) shows that variations in polymer molecular weight have a significant effect on the amount of paclitaxel released over the time period tested, hi particular, the data in Table 7 shows that polymers of lower molecular weight release a greater amount of paclitaxel after as compared to polymers of higher molecular weight.

Table 7: Cumulative % Release of Paclitaxel from MePEG750-PDLLA Coatings

MePEG75O-PDLLA (Daltons) Day O Day 1 Day 2 Day 3 Day 4 Day 7

5673 0 51. 6 63.5 71. 9 77.9 82.6

6575 0 41. 4 51.3 58. 5 64 70.2

6792 0 31. 4 40.2 46. 8 51.7 56.5 EXAMPLE 20

EFFECT OF POLYMER MOLECULAR WEIGHT ON IN VITRO RELEASE (IVR) OF PACLITAXEL FROM A COATED FABRIC Knitted PLGA meshes were coated using coating procedures similar to those used in

Examples 16 and 17 with a MePEG750-PDLLA polymer having various molecular weights ranging from 5383 to 11,927 Daltons. The coatings contained 1600 micrograms of paclitaxel, and the weight ratio of polymer to paclitaxel in the coating was held constant (7.01:1). The IVR of each sample was tested 6 times (n=6) according to the protocol described in Example 18. The data (see, Figure 15) shows that variations in polymer molecular weight have a significant effect on the amount of paclitaxel released over the time period tested. In particular, the data shows that polymers of lower molecular weight release a greater amount of paclitaxel after 24 hours as compared to polymers of higher molecular weight.

All of the above U.S. patents, U.S. patent application publications, U.S. patent applications, foreign patents, foreign patent applications and non-patent publications referred to in this specification and/or listed in the Application Data Sheet are incorporated herein by reference, in air entirety.

From the foregoing it will be appreciated that, although specific embodiments of the invention have been described herein for purposes of illustration, various modifications may be made without deviating from the spirit and scope of the invention. Accordingly, the invention is not limited except as by the appended claims.

Claims

ClaimsWe claim:

1. A device, comprising: a) a fabric having a density of about 2.5 mg/cm² to about 5.0 mg/cm²; b) a matrix coating said fabric, wherein said coating comprises a polyether-polyester copolymer; and c) a therapeutic agent within said matrix, wherein said matrix is capable of releasing in vitro up to about 85% of said therapeutic agent in about 7 days.

2. The device of Claim 1, wherein said fabric comprises a polymer fiber with a molar ratio of glycolide:L-lactide of about 97:3 to about 85:15.

3. The device of Claim 1, wherein said device releases about 40% to about 60% of said therapeutic agent in about 7 days.

4. The device of Claim 1, wherein said device releases about 50% to about 80% of said therapeutic agent in about 7 days.

5. The device of Claim 1, wherein said device releases about 25% to about 55% of said therapeutic agent within 24 hours.

6. The device of Claim 1, wherein said fabric comprises a density of about 3.0-3.5 mg/cm²

7. The device of Claim 1, wherein said fiber comprises a denier of about 80 to 100 grams.

8. The device of Claim 7, wherein said fiber has a denier of about 70 to 90 grams.

9. The device of Claim 1, wherein said fiber comprises a plurality of filaments, wherein said filaments have diameters of about 10-30 microns.

10. The device of Claim 9, wherein said filaments have diameters of about 15-25 microns.

11. The device of Claim 1, wherein said fabric comprises a stitch count of about 5 to about 25 stitches/cm.

12. The device of Claim 1, wherein said fabric comprises a stitch count of about 30 to about 100 stitches/cm.

13. The device of Claim 1, wherein said matrix is about 10 mg to about 25 mg.

14. The device of Claim 13, wherein said matrix is about 10 mg about 15 mg.

15. The device of Claim 14, wherein said matrix is about 15 to about 25 mg.

16. The device of Claim 1, wherein said therapeutic agent is about 0.3 mg to about 2.2 mg.

17. The device of Claim 16, wherein said therapeutic agent is about 1.25 mg to about 2.0 mg.

18. The device of Claim 17, wherein said therapeutic agent is about 0.13 mg/cm² to about 0.20 mg/cm².

19. The device of Claim 18, wherein said therapeutic agent is about 0.06 mg/cm² to about 0.1 mg/cm².

20. The device of Claim 1, wherein said fiber comprises a tenacity of about 3 g/denier to 6 g/denier.

21. The device of Claim 1, wherein said fiber comprises an elongation of about 10% to about 50%.

22. The device of Claim 1, wherein said fiber comprises a melting temperature of about 200- 225 ⁰C.

23. The device of Claim I, wherein said fiber comprises at least one filament having a diameter of about 8 to 25 microns.

24. The device of Claim 2, wherein said polyether-polyester copolymer comprises a weight average molecular weight of at least 3 kDa.

25. The device of Claim 24, wherein said polyether-polyester copolymer comprises a molecular weight of about 6000 to about 9000 Da.

26. The device of Claim 24, wherein said polyether-polyester copolymer comprises a molecular weight of about 6000 to about 7000 Da.

27. The device of Claim 21, wherein said polyether-polyester copolymer comprises a molecular weight of about 7000 to about 9000 Da.

28. The device of Claim 1, wherein said matrix and said fabric comprise a weight ratio of about 90/10 to about 70/30.

29. The device of Claim 28, wherein said weight ratio comprises about 70/30 to about 50/50.

30. The device of Claim 28, wherein said weight ratio comprises about 50/50 to about 30/70.

31. The device of Claim 28, wherein said weight ratio comprises about 30/70 to about 10/90.

32. The device of Claim 1, wherein said polyether copolymer is a polyether glycol.

33. The device of Claim 32, wherein said polyether glycol is a polyethylene glycol.

34. The device of Claim 33, wherein said polyethylene glycol is polyethylene glycol monomethyl ether.

35. The device of Claim 32, wherein said polyether glycol is selected from the group consisting of a polypropylene glycol, a copolymer of ethylene and propylene oxide, a copolymer of polyethylene glycol, and a polypropylene glycol..

36. The device of Claim 1, wherein said polyester copolymer comprises at least one monomer selected from the group consisting of glycolide, L-lactide, D,L-lactide, ε- caprolactone, trimethylene carbonate, p-dioxanone, and morpholinedione.

37. The device of Claim 1, wherein said polyether-polyester copolymer comprises at least one monomer residue selected from the group consisting of glycolide, L-lactide, D, L- lactide, and meso-lactide.

38. The device of Claim 1, wherein said matrix further comprises a graft copolymer selected from the group consisting of a polyethylene glycol monomethyl ether, glycolide monomers, and lactide monomers.

39. The device of any one of claims 1-38, wherein said therapeutic agent comprises paclitaxel or an analogue or derivative thereof.

40. The device of Claim 39, wherein said therapeutic agent is paclitaxel.

41. The device of any one of Claims 1-38, wherein said therapeutic agent is selected from the group consisting of sirolimus, everolimus, tacrolimus, an analogue and a derivative thereof.

42. The device of Claim 1, wherein said device is less than 500 microns thick.

43. The device of Claim 42, wherein said device is about 100 microns to about 400 microns thick.

44. The device of Claim 1 , wherein said device degrades over a period of about 60 days to about 120 days in vivo.

45. The device of claim 44, whersin the device degrades over a period of about 60 days to about 90 days in vivo.

46. The device of Claim 1 , where in said fabric is knitted.

47. The device of Claim 29, wherein said knitted fabric has a surface area ranging from about 3000 to about 10,000 mm².

48. The device of Claim 47, wherein said surface area ranges from about 3500 to about 5000 mm².

49. The device of Claim 48, wheiein said surface area ranges from about 7000 to about 9000 mm².

50. The device of Claim 1, wherein said matrix comprises about 80% to about 95% by weight of said polyether-polysster copolymer and about 5% to about 20% of said therapeutic agent.

51. The device of Claim 1 , wher.in said matrix comprises about 80% to about 90% by weight of said polyether-polyester copolymer and about 10% to about 20% of said therapeutic agent.

52. The device of Claim I, wherein said matrix comprises about 85% to about 90% by weight of said polyetber-pol] 'ester copolymer and about 10% to about 15% of said therapeutic agent.

53. The device of Claim 1, when an said matrix comprises about 85% to about 95% by weight of said polyether-poJyester copolymer and about 5-15% of said therapeutic agent.

54. The device of Claim 1, wherein said matrix comprises about 90% to about 95% by weight of said polyether-polyester copolymer and about 5% to about 10% of said therapeutic agent.

55. A method for making a comp osite drug delivery device, comprising: a) providing; i) a biodegradϊble fibrous construct; ii) a biodegrac able, amphihilic, amorphous polymer composition comprising at least one bioactive agent; b) contacting said fibious construct with polymer composition.

56. The method of Claim 55₃ whorein said polymer composition reinforces said fibrous construct.

57. The method of Claim 56, whurein said composition predictably controls the release of said at least one bioactive agent.

58. The method of Claim 55, whorein said fibrous construct is foπned by weaving.

59. The method of Claim 55, wherein said fibrous construct is formed by knitting.

60. The method of Claim 55, wh<;rei said fibrous construct comprises a flat textile fabric.

61. The method of Claim 55, whurcin said composition is viscous.

62. The method of Claim 55, whurein said composition is a liquid.

63. The method of Claim 55, whiarein said contacting is selected from the group consisting of coating, painting, dipping, spin-casting, and spraying.

64. The method of Claim 55, whf jrein said device is formed into a wrap.

65. The method of Claim 64, wherein said wrap is a perivascular wrap.

66. The method of Claim 55, whwein said composition is a solid.

67. The method of Claim 55, wherein said therapeutic agent is selected from the group consisting of paclitaxel or an analogue or derivative thereof, rapamycin. actiπomycin, 17- β-estradiol, lovastatin, simvaϋtatin, pravastatin, fluvastatin, atorvastatin, cervistatin, doxorubicin, daunorubicm, icarubicin, epirubicin, pirarubicin, zorubicin, carubicin, and an analogue or derivative thereof.

68. A method, comprising: a) providing; i) a subject comprising a body tissue in need of a therapeutic agent; ϋ) a composite diug delivery device layered with a polymer composition, wherein said composition comprises a therapeutic agent; and b) contacting said device with said body tissue under conditions such that said drug is delivered.

69. The method of Claim 68, wh srein said therapeutic agent improves a body passageway lumen or cavity integrity.

70. The method of Claim 68, wherein said body tissue comprises an external portion of a body passageway or cavity.

71. The method of Claim 68, wherein said device comprises an absorbable, biodegradable, flat textile fabric.

72. The method of Claim 68, wherein said therapeutic agent treats or prevents intimal hyperplasia.

73. The method of Claim 68, whiϊrein said body tissue comprises an anastomotic site.

74. The method of Claim 73, whurein said anastomotic site is selected from a group consisting of a venous anastomosis, an arterial anastomosis, an arteriovenous fistula, and an arteriovenous graft.

75. The method of Claim 73, whisrein said contacting comprise an external portion of said anastomotic site.

76. A kit comprising a composite drug delivery device and a therapeutic agent.

77. The kit of Claim 76, wherein said device is placed in a first container.

78. The kit of Claim 77, wherein said therapeutic agent is placed in a second container.

79. The kit of Claim 76, wherein said device is layered with said therapeutic agent and is placed in the same container. _:

80. The kit of Claim 76, wherein said kit further comprises instructions.

81. The kit of Claim 80, wherein said instructions provide information comprising the relative amounts of excipient ingredients or diluents.

82. The kit of Claim 76, wherein said kit is sterile.

83. The kit of Claim 76, wherein said kit further comprises at least one water resistant container.

84. The kit of Claim 83, wherein said container further comprises a dessicant.

85. The kit of Claim 76, wherein said kit further comprises at least one opaque container.

86. The kit of Claim 76, wherein said kit further comprises at least one container filled with an inert gas.

87. The kit of Claim 76, wherein said kit further comprises a vascular graft.

88. The kit of Claim 83, wherein said vascular graft comprises ePTFE.

89. The kit of Claim 76, wherein said therapeutic agent comprises an anti-proliferative drug.

90. The kit of Claim 76, wherein said therapeutic agent comprises an immunosupressive drug.

91. The kit of Claim 80, wherein said instructions provide a method for using said kit for an

A-A peripheral bypass grafting procedure.

92. The kit of Claim 87, wherein said vascular graft comprises an A-A peripheral bypass graft.

93. The kit of Claim 87, wherein said instructions provide a method for using said kit for an A-V hemodialysis access procedure.

94. The kit of Claim 87, wherein said vascular graft comprises an A-V hemodialysis access graft.

95. The kit of Claim 90, wherein said vascular graft comprises an A-A peripheral bypass graft.

96. The kit of Claim 90, wherein said instructions provide a method for using said kit for an A-V hemodialysis access procedure.

97. The kit of Claim 90, wherein said vascular graft comprises an A-V hemodialysis access graft.