US20080161908A1 - Apparatus and Method for Delivery of Mitomycin Through an Eluting Biocompatible Implantable Medical Device - Google Patents

Abstract

The present invention is an apparatus and a method for delivery of mitomycin through an eluting biocompatible implantable medical device. A biocompatible drug release matrix comprises a biocompatible drug release matrix and a drug incorporated into the biocompatible drug release matrix. The drug has antibiotic and anti-proliferative properties and is an analogue related to the quinone-containing alkylating agents of a mitomycin family. The drug is initially released from the biocompatible drug release matrix at a faster rate followed by a release at a slower rate. The drug release rate maintains tissue level concentrations of the drug for at least two weeks after implantation of the medical device. The present invention provides a coating for a vascular prosthesis that elutes the drug at a controlled rate to inhibit proliferation of smooth muscle cells causing restenosis.

Description

RELATED APPLICATIONS
• This application is a divisional of U.S. Ser. No. 10/672,679, filed Sep. 26, 2003, which claims the benefit of U.S. Provisional Application Ser. No. 60/413,833, filed Sep. 26, 2002, the entirety of which are hereby incorporated herein by reference.
FIELD OF THE INVENTION
• The present invention relates to a medical device, and more particularly to an apparatus and a method for delivery of mitomycin through an eluting biocompatible implantable medical device.
BACKGROUND OF THE INVENTION
• Coronary artery disease (CAD) is the leading cause of death in the western world. In the United States, more than 13 million people are diagnosed with CAD every year. Since its introduction in the late 1970's, Percutaneous Transluminal Coronary Angioplasty (PTCA), also known as balloon angioplasty, emerged as the principal, less invasive alternative to Coronary Artery Bypass Grafting (CABG). A limitation of PTCA is a high rate of restenosis, a condition in which the vasculature renarrows within six months of a revascularization treatment to less than 50% of its original size. Restenosis is caused by the activation and growth of vascular smooth muscle cells that make the vessel more susceptible to complete blockage. Studies have shown restenosis affects between about 25% to about 45% of PTCA patients within six months after the procedure.
• Coronary stents lower restenosis rates by decreasing the vascular recoil after balloon angioplasty. A stent is a mesh-like tubular device resembling a spring that is capable of propping open a clogged artery when placed within the vessel using a specialized delivery device such as the balloon catheter used in angioplasty procedures. The stent serves as a permanent scaffolding for the newly widened vessel. Stents are percutaneous non-surgical treatments that lower the restenosis rate of PTCA by achieving a larger final luminal area. To date, stents have reduced the likelihood of acute closure after coronary revascularization procedures.
• Immediately after the implantation of a stent, the healing process within the vasculature causes an overgrowth of cells and substances within and around the stent, increasing the potential for a recurrence of the blockage. The healing process leads to neointima formation which is initiated by activation of vascular smooth muscle cells, followed by emigration and proliferation with subsequent elaboration of the abundant extracellular matrix by the smooth muscle cells. As the smooth muscle cells grow on and around the stent, the vasculature renarrows and restenosis continues. Inhibition of smooth muscle cell proliferation appears to prevent the development of subsequent blockages within the vasculature as the diameter of the passageway through the vasculature is reduced by the smooth muscle cell proliferation.
• Several therapeutic agents have been used in combination with stents to inhibit restenosis in the prior art. U.S. Pat. No. 6,569,195 to Yang et al. discloses a stent having a polymeric coating for controllably releasing an included active agent. The Yang et al. coating includes a blend of a first co-polymer having a first, high release rate and a second co-polymer having a second, lower release rate relative to the first release rate. U.S. Pat. No. 6,171,609 to Kunz discloses a therapeutic inhibitor of vascular smooth muscle cells. The Kunz device utilizes a cytoskeletal inhibitor and an amount of a cytostatic therapeutic agent to inhibit stenosis or reduce restenosis.
• U.S. Pat. No. 6,344,035 to Chudzik et al. discloses a coating composition for use with medical devices to improve the ability of the device to release a bioactive agent in vivo. The coating composition includes the bioactive agent with a mixture of a first polymer component such as poly(butyl methacrylate) and a second polymer component such as poly(ethylene-co-vinyl acetate). The Chudzik et al. device requires the mixture of a first polymer component such as poly(butyl methacrylate) and a second polymer component such as poly (ethylene-co-vinyl acetate). In addition, the Chudzik et al. device is limited by the ability of titrating the release rate of the bioactive agent.
• U.S. Pat. No. 5,788,979 to Alt et al. discloses a biodegradable coating with inhibitory properties for application to biocompatible materials. The Alt et al. device comprises a coating material comprising an anticoagulant drug wherein the coating material is adhesively applied to a surface of the biocompatible material in a substantially continuous overlying layer having a formulation, pattern and thickness selected according to a period of time in which the coating material exhibits the inhibitory action. The Alt et al. coating has shown a potential of triggering a severe vessel inflammation by activating cells after the polymer of the biodegradable coating is broken down in the vessel.
• The prior art is ineffective at inhibiting restenosis and subjects patients to undesirable health risks. The prior art is limited to mixtures of specific polymer components and does not provide adequate control of the drug elution to treat a lesion. In addition, the prior art has shown a potential of triggering a severe vessel inflammation by activating cells after the polymer is broken down in the vessel. Therefore, there remains a need in the art for a method of treating a localized area of a diseased vessel after delivery of a biocompatible implantable medical device that can control the elution of the drug and is does not harm the patient.
SUMMARY OF THE INVENTION
• A biocompatible drug release matrix for a medical device comprises a biocompatible polymer matrix and a drug incorporated into the biocompatible polymer matrix, wherein the biocompatible polymer matrix is co-solubilized with the drug in a solvent to form a solution and the solvent is evaporated from the solution.
• A biocompatible implantable medical device for delivering a drug to a treatment area in a vasculature of a body comprises: a tubular body having a proximal end, a distal end and a longitudinal axis therebetween; a proximal end band at the proximal end of the tubular body, a distal end band at the distal end of the tubular body and a plurality of intermediate bands between the proximal end band and the distal end band; a plurality of circumferential rows of links engaging the proximal end band, the plurality of intermediate bands and the distal end band to form the tubular body; and an elution layer comprising a biocompatible drug release matrix applied to the surface of the biocompatible implantable medical device having a biocompatible polymer matrix solubilized with the drug in a solvent to form a solution and the solvent is evaporated, wherein the drug is released from the biocompatible drug release matrix after implantation of the biocompatible implantable medical device to prevent restenosis.
• A method of inhibiting the growth of smooth muscle cells to inhibit restenosis comprising: providing a biocompatible implantable medical device; preparing a biocompatible polymer matrix; co-solubilizing the biocompatible polymer matrix with a drug in a solvent to form a biocompatible drug release matrix; applying the biocompatible drug release matrix to the biocompatible implantable medical device to form an elution layer of the biocompatible drug release matrix on the biocompatible implantable medical device; allowing the solvent to evaporate; and implanting the biocompatible implantable medical device into a vasculature of a body.
• A method of inhibiting the proliferation of smooth muscle cells after a stent implantation comprising: providing a stent; preparing a biocompatible polymer matrix; co-solubilizing the biocompatible polymer matrix with a drug in a solvent to form a solution; applying the solution onto the stent to form an elution layer of a biocompatible drug release matrix on the biocompatible implantable medical device; allowing the solvent to evaporate; engaging the stent onto a balloon of a balloon catheter; delivering the balloon catheter with the stent engaged onto the balloon of the balloon catheter into a vasculature of a body to a treatment site; and inflating the balloon of the balloon catheter to increase a diameter of the stent to implant the stent.
• A biocompatible drug release matrix for a medical device comprises a biocompatible drug eluting matrix and a drug incorporated into the biocompatible drug eluting matrix, wherein the drug is an analogue related to the quinone-containing alkylating agents of a mitomycin family.
• A method of inhibiting restenosis comprising: providing a medical device; applying a biocompatible drug eluting matrix comprising a biocompatible polymer matrix incorporating an analogue related to the quinone-containing alkylating agents of a mitomycin family to the medical device; and implanting the biocompatible implantable medical device into a vessel to elute the analogue related to the quinone-containing alkylating agents of a mitomycin family.
• The drug has antibiotic properties and anti-proliferative properties. The drug is an analogue related to the quinone-containing alkylating agents of a mitomycin family. The preferred drug is mitomycin C. The biocompatible drug release matrix releases the drug at a rate sufficient to maintain tissue level concentrations of the drug from about 0.01 micrograms per milliliter to about 25 micrograms per milliliter of the surrounding tissue for at least two weeks after implantation of the medical device. The biocompatible drug release matrix may be incorporated within a vascular prosthesis, be applied as a coating to a surface of the vascular prosthesis or comprise a film which covers the vascular prosthesis.
• The present invention is an apparatus and a method for delivery of mitomycin through an eluting biocompatible implantable medical device. Mitomycin C causes inhibition of smooth muscle cell proliferation in an anaerobic (low oxygen) environment. The present invention provides an effective method of treating a localized area of a diseased vasculature after delivery of a biocompatible implantable medical device that provides a coating that elutes mitomycin C at a controlled rate that inhibits the proliferation of smooth muscle cells causing restenosis, is reliable in consistently treating the localized area over a period of time and does not adversely affect healthy tissue proximal to an area of treatment.
BRIEF DESCRIPTION OF THE DRAWINGS
• The present invention will be further explained with reference to the attached drawings, wherein like structures are referred to by like numerals throughout the several views. The drawings shown are not necessarily to scale, with emphasis instead generally being placed upon illustrating the principles of the present invention.
• FIG. 1 is a perspective view of a biocompatible implantable medical device of the present invention capable of inhibiting restenosis.
• FIG. 2 is an enlarged fragmentary perspective view of a distal end of the biocompatible implantable medical device of the present invention.
• FIG. 3 is an enlarged view of a biocompatible implantable medical device of the present invention showing adjacent circumferential bands engaged by a plurality of links.
• FIG. 4 is a flattened view of a portion of a biocompatible implantable medical device of the present invention.
• FIG. 5 is a side plan view of a biocompatible implantable medical device of the present invention.
• FIG. 6 is an enlarged side view of a distal end of the biocompatible implantable medical device of the present invention with a plurality of circumferential bands and a plurality of circumferential links.
• FIG. 7 is a side plan view of a biocompatible implantable medical device of the present invention in a flexed configuration.
• FIG. 8 is a front perspective view of a biocompatible implantable medical device of the present invention taken from a distal end of the biocompatible implantable medical device.
• FIG. 9 is a front view of a biocompatible implantable medical device of the present invention taken from a distal end of the biocompatible implantable medical device.
• FIG. 10 is a cross section view of a strand of a biocompatible implantable medical device of the present invention with a strut surrounded by a first coating layer, a second coating layer and a third coating layer.
• FIG. 11 is a cross section view of a strand of a biocompatible implantable medical device of the present invention with a strut surrounded by a first uniform coating layer and a second uniform coating layer.
• FIG. 12 is a cross section view of a strand of a biocompatible implantable medical device of the present invention with a strut surrounded by a single uniform coating layer.
• FIG. 13 is a cross section view of a strand of a biocompatible implantable medical device of the present invention with a strut surrounded by a single non-uniform coating layer.
• FIG. 14 is a chemical structure of mitomycin C.
• FIG. 15 is a perspective view of a biocompatible implantable medical device of the present invention with a film covering a portion of the biocompatible implantable medical device.
• FIG. 16 is a perspective view of a biocompatible implantable medical device of the present invention with a film covering a portion of the biocompatible implantable medical device and showing the covered portion of the biocompatible implantable medical device.
• FIG. 17 is a front view of a biocompatible implantable medical device of the present invention with a film covering the biocompatible implantable medical device.
• FIG. 18 is a side plan view of the present invention with a biocompatible implantable medical device engaged to a balloon of a balloon catheter.
• FIG. 19 is a fragmentary cross section perspective view of a biocompatible implantable medical device of the present invention and a balloon catheter.
• FIG. 20 is a cross section view of an inner wall of a vasculature in a body and a biocompatible implantable medical device of the present invention surrounding a balloon catheter with a balloon of the balloon catheter uninflated.
• FIG. 21 is a side plan view of a biocompatible implantable medical device of the present invention in an expanded configuration with a balloon of a balloon catheter inflated.
• FIG. 22 is a fragmentary cross section perspective view of a balloon catheter and a biocompatible implantable medical device of the present invention in an expanded configuration.
• FIG. 23 is a cross section view of a biocompatible implantable medical device of the present invention engaging an inner wall of a vasculature in a body.
• FIG. 24 is a side plan view of a biocompatible implantable medical device of the present invention in an expanded configuration and a balloon of a balloon catheter deflated.
• FIG. 25 is a cross section view of a strand of a biocompatible implantable medical device of the present invention engaging a wall of a vasculature, showing an effective treatment area of the wall of the vasculature.
• FIG. 26 is a cross section view of an effective treatment area of a wall of a vasculature in a body with a biocompatible implantable medical device of the present invention in an expanded configuration engaging the wall of the vasculature.
• FIG. 27 is an elution profile of mitomycin C showing the release of mitomycin C from a coating of a biocompatible implantable medical device of the present invention as a function of time.
• FIG. 28 is an elution profile of mitomycin C showing a high burst dosage (about 60%) of the drug followed by a slow release of the drug (about 8 weeks).
• FIG. 29 is an elution profile of mitomycin C showing a low burst dosage (about 20%)of the drug followed by a slow release of the drug (about 8 weeks).
• FIG. 30 is an elution profile of mitomycin C showing a high burst dosage (about 60%) of the drug followed by a fast release of the drug (about 3 weeks).
• FIG. 31 is an elution profile of mitomycin C showing a low burst dosage (about 20%)of the drug followed by a fast release of the drug (about 3 weeks).
• FIG. 32 is a table showing a total dose estimate of mitomycin C in a 13 mm stent for loss factors from 1% to 100%.
• FIG. 33 is a graph showing release of mitomycin C from a polymer stent coating stent delivered up to a forty day time period.
• While the above-identified drawings set forth preferred embodiments of the present invention, other embodiments of the present invention are also contemplated, as noted in the discussion. This disclosure presents illustrative embodiments of the present invention by way of representation and not limitation. Numerous other modifications and embodiments can be devised by those skilled in the art which fall within the scope and spirit of the principles of the present invention.
DETAILED DESCRIPTION
• An apparatus for a biocompatible implantable medical device comprising a biocompatible drug release matrix is illustrated generally at99 inFIG. 1. In a preferred embodiment of the present invention, the biocompatible implantablemedical device99 is a stent. The present invention can be used with stents known in the art including, but not limited to, the stents described in Assignee's co-pending patent applications Ser. No. 09/624,812 and Ser. No. 10/410,950, the entirety of these applications are hereby incorporated herein by reference. In another embodiment of the present invention, the biocompatible implantablemedical device99 is a catheter, a vascular prosthesis, an intravenous canule or a similar device. The biocompatible implantablemedical device99 has a tubular body comprising a plurality ofcircumferential bands37 and a plurality of circumferential row oflinks69 that engage the plurality ofcircumferential bands37. A circumferential row of links engages adjacent circumferential bands. The biocompatible implantablemedical device99 comprises aproximal end band98 located at aproximal end97, adistal end band96 located at adistal end95 and at least one intermediate band located betweenproximal end band98 anddistal end band96. In the embodiment of the present invention shown inFIG. 1, the biocompatible implantablemedical device99 comprises theproximal end band98, thedistal end band96 and intermediatecircumferential bands30,32,34,36,38,40,42,44 and46. The number of thecircumferential bands37, the number of the circumferential rows oflinks69, a length of the biocompatible implantablemedical device99 and a diameter of the biocompatible implantablemedical device99 vary depending upon the application of the biocompatible implantablemedical device99. The plurality ofcircumferential bands37 are arranged axially end to end, extending from theproximal end97 of the biocompatible implantablemedical device99 to thedistal end95 of the biocompatible implantablemedical device99. Each of the plurality of thecircumferential bands37 is comprised of acontinuous strand75 that is shaped in a zig-zag pattern shown inFIG. 1. The plurality of circumferential row oflinks69 engage adjacent circumferential bands. In the embodiment of the present invention shown inFIG. 1, circumferential rows oflinks60,62,64,66,68,70,72,74,76 and78 engage adjacent circumferential bands. For example, the circumferential row oflinks64 engages intermediatecircumferential bands32 and34.
• FIG. 2 shows an enlarged fragmentary view of thedistal end95 of the biocompatible implantablemedical device99 of the present invention.FIG. 2 illustrates the tubular shape of the biocompatible implantablemedical device99.FIG. 2 shows the circumferential row oflinks60 engaging thedistal end band96 and theintermediate band30. In addition, circumferential row oflink62 engages the adjacentintermediate bands30 and32.
• FIG. 3 shows a portion of adjacentcircumferential bands30,32 and alink35 from circumferential row oflink62 where thelink35 engages theintermediate band30 to theintermediate band32. A portion of thestrand75 for intermediatecircumferential band30 comprises aloop65 that further comprises twolegs71 and73. Thelegs71 and73 converge to form abend77 and agap79 opposing thebend77. In a continuing pattern, aloop105 is formed by theleg73 and aleg93 to form abend107 with agap109 opposing thebend107. In a similar manner, a portion of thestrand75 for adjacentcircumferential band36 comprises aloop85 that further comprises aleg81 and aleg83. Theleg81 and theleg83 converge to form abend87 with agap89 opposing thebend87. In a continuing pattern forcircumferential band32, aloop101 comprises theleg83 and theleg103, with theleg83 and theleg103 converging to form abend117 with agap111 opposing thebend117. Eachstrand75 for eachcircumferential band37 comprises a plurality of loops with each circumferentially adjacent loop sharing a common leg.
• As shown inFIG. 3, thecircumferential bands30 and32 are circumferentially formed of alternating bends and gaps. For example, anedge120 of thecircumferential band30, (shown as a broken line inFIG. 3) is formed partially of thebend77 and thegap109. Similarly, anedge122 of thecircumferential band32, (shown as a broken line inFIG. 3) is formed partially of thebend87 and thegap111. Within each of the plurality of thecircumferential bands37, a bend is longitudinally opposed by a gap. For example, with respect to thecircumferential band30, thebend77 longitudinally opposes thegap79 and thebend107 longitudinally opposes thegap109. Adjacent circumferential bands are longitudinally positioned so the bends forming the edge of one circumferential band are aligned with the bends forming the opposing edge of the adjacent circumferential band. For example, thebend77 of thecircumferential band30 is adjacent to thebend87 of thecircumferential band32.
• The plurality of the circumferential rows oflinks69 engage the plurality ofcircumferential bands37. In a preferred embodiment of the present invention, each individual link from the plurality of circumferential rows oflinks69 is formed by two oppositely oriented curves that are engaged to form a link. In a preferred embodiment of the present invention, the two oppositely oriented curves form a S link. In another embodiment of the present invention, the two oppositely oriented curves form a curved link. As shown inFIG. 3, thelink35 that engages thebend77 of thecircumferential band30 to thebend87 of thecircumferential band32 comprises alower curve124 and anupper curve125. When viewing thelink35 from thebend77, alower curve124 extends in a downward direction and anupper curve125 extends in an upward direction. Those skilled in the art will recognize that the two oppositely oriented curves can form a link of many shapes and be within the spirit and scope of the present invention.
• In a preferred embodiment of the present invention shown inFIG. 3, thebends77,87,107 and117 are all radiused to greater than approximately 180 degrees. In another embodiment of the present invention, thebends77,87,107 and117 are all radiused to less than approximately 180 degrees. Thebends77,87,107 and117 take the shape of a partial circle and engage the legs of the loops. For example, thebend77 engages theleg71 and theleg73 of theloop65. Narrowed portions are created between each of the bends and at the adjacent legs. For example, a narrowedportion84 is formed between thebend77 and theadjacent legs71 and73 respectively. Those skilled in the art will recognize that the bends can be radiused to any degree known in the art and be within the spirit and scope of the present invention.
• FIG. 4 shows a flattened view of the tubular body of the biocompatible implantablemedical device99 of the present invention. Thedistal end bend96 and the circumferentialintermediate bands30,32,34,36,38,40 and42 are constructed in a repeating pattern. The bends of each of thecircumferential bands96,30,32,34,36,38,40 and42 extend alternately toward thedistal end95 of the biocompatible implantablemedical device99 and then toward theproximal end97 of the biocompatible implantablemedical device99. In a preferred embodiment of the present invention, a link engages each pair of axially aligned opposing bends from the adjacent circumferential bands. More specifically, thebend77 in thecircumferential band30 extends toward theproximal end97 of the biocompatible implantablemedical device99 while theadjacent bend87 of thecircumferential band32 extends toward thedistal end95 of the biocompatible implantablemedical device99. The construction of the biocompatible implantablemedical device99 allows for a plurality ofclosed cells94. For each pair of axially aligned opposing bends, a link engages the axially aligned opposing bends, creating the closed cell configuration. Conversely, a configuration where each pair of axially aligned opposing bends does not comprise a link engaging the axially aligned opposing bends would create an open cell configuration.
• FIG. 5 shows a side plan view of the biocompatible implantablemedical device99 of the present invention.FIG. 6 shows an enlarged side view of thedistal end95 of the biocompatible implantablemedical device99 of the present invention.FIG. 6 illustrates the tubular shape of the biocompatible implantablemedical device99 of the present invention. Theloop65 of intermediatecircumferential band30 is engaged to the adjacent loop ofcircumferential band32 by thelink35. Thelink39 is located behind thelink35, located approximately 180 degrees from thelink35.
• FIG. 7 shows a side plan view of the biocompatible implantablemedical device99 of the present invention in a flexed configuration. In preferred embodiment of the present invention, the plurality ofcircumferential bands37 and the plurality of circumferential row oflinks69 are comprised of a pliable, shape sustaining material that allows the biocompatible implantablemedical device99 to be bent, deflected or flexed. The biocompatible implantablemedical device99 comprises a perforated tubular material in a design that optimizes the radial strength and the ability of the biocompatible implantablemedical device99 to be flexed, bent and deflected. The flexibility of the biocompatible implantablemedical device99 provides conformability in a vasculature of a body while still providing a relatively rigiddistal end95 andproximal end97. The flexibility of the biocompatible implantablemedical device99 allows the biocompatible implantablemedical device99 to be inserted through the tortuous paths of the vasculature. The combination of bends radiused greater than approximately 180 degrees, multiple jointed loops of the plurality ofcircumferential bands37 and the plurality of the circumferential row of links provides a range of expandability for the biocompatible implantablemedical device99. In addition, the jointed pattern of the biocompatible implantablemedical device99 provides conformability so that when the biocompatible implantablemedical device99 is deployed, the biocompatible implantablemedical device99 will conform to irregular contours of the walls of the vasculature.
• FIG. 8 shows a front perspective view of the biocompatible implantablemedical device99 of the present invention taken from thedistal end95 of the biocompatible implantablemedical device99.FIG. 9 shows a front view of the biocompatible implantablemedical device99 of the present invention from thedistal end95 of the biocompatible implantablemedical device99. In the embodiment of the present invention shown inFIG. 8 andFIG. 9, thedistal end band96 comprises twelve loops and twelve bends with a total of sixbends127 located at thedistal end95 of thedistal end band96 and a total of sixbends129 located proximal to the six bends at thedistal end95 ofdistal end band96. Those skilled in the art will recognize the circumferential bands can comprise any number of loops and bends and be within the spirit and scope of the present invention.
• The effectiveness of the biocompatible implantablemedical device99 to inhibit the growth of smooth muscle cells is governed by providing an effective concentration of a drug throughout a treatment area over a necessary period of time to inhibit restenosis. The present invention includes several designs for the biocompatible implantablemedical device99 and several methods for incorporating the drug within the biocompatible implantablemedical device99. Transport of the drug to the treatment area can occur by direct exposure, diffusion, molecular bond degradation or other methods known in the art.
• FIG. 10 shows a cross section view of an embodiment of astrand75 of the biocompatible implantablemedical device99 of the present invention comprising astrut50 surrounded by aprimer layer51, anelution layer52 and aburst control layer53. Theprimer layer51 comprises abiocompatible polymer matrix54 that improves the adhesion of theelution layer52 to thestrut50. Theelution layer52 comprises abiocompatible polymer matrix54 and adrug55 that elutes to treat a tissue. Theburst control layer53 controls and limits the kinetics of the burst dose of thedrug55 from theelution layer52.
• In a preferred embodiment of the present invention, theprimer layer51 comprises abiocompatible polymer matrix54 with or without a drug. In another embodiment of the present invention, theprimer layer51 comprises thebiocompatible polymer matrix54 and a drug (not shown) incorporated into thebiocompatible polymer matrix54. In a preferred embodiment of the present invention, theelution layer52 comprises a biocompatible drug release matrix having thebiocompatible polymer matrix54 and thedrug55 incorporated into thebiocompatible polymer matrix54. In the embodiment of the present invention shown inFIG. 10, the incorporation of thedrug55 into thebiocompatible polymer matrix54 is shown as a plurality of small particles in theelution layer52. In an embodiment of the present invention, theburst control layer53 comprises thebiocompatible polymer matrix54 and thedrug55 incorporated into thebiocompatible polymer matrix54. In another embodiment of the present invention, theburst control layer53 comprises thebiocompatible polymer matrix54 without thedrug55. Those skilled in the art will recognize theprimer layer51, theelution layer52 and theburst control layer53 can be comprised of combinations of the biocompatible polymer matrix and the drug and be within the spirit and scope of the present invention.
• Various embodiments of thestrand75 of the biocompatible implantablemedical device99 are contemplated in the present invention. The number of coating layers and composition of each coating layer may vary.FIG. 11 shows an alternative embodiment of thestrand75 of the biocompatible implantablemedical device99 of the present invention having thestrut50 surrounded by theprimer layer51 and theelution layer52. The biocompatible drug release matrix of theelution layer52 comprises thedrug55 embedded into thebiocompatible polymer matrix54. In one embodiment of the present invention, theprimer layer51 and theelution layer52 are symmetric around thestrut50 and theprimer layer51 and theelution layer52 have an equal and uniform thickness. In another embodiment of the present invention, theprimer layer51 and theelution layer52 are asymmetric around thestrut50 and theprimer layer51 and theelution layer52 vary in thickness. Those skilled in the art will recognize the layers surrounding the strand can be placed at various positions around the strut and be of varying thickness and be within the spirit and scope of the present invention.
• FIG. 12 shows an alternative embodiment of thestrand75 of the biocompatible implantablemedical device99 of the present invention having thestrut50 surrounded by theelution layer52. As shown inFIG. 12, thestrut50 is surrounded by a uniformthickness elution layer52 positioned symmetrically around thestrut50.FIG. 13 shows an alternative embodiment of thestrand75 of the present invention with thestrut50 surrounded by a varyingthickness elution layer52 positioned asymmetrically around thestrut50.
• In a preferred embodiment of the present invention, thestrut50 comprises a material allowing the biocompatible implantablemedical device99 to moved from an undeployed configuration (FIG. 1) to an expanded configuration (FIG. 21) without compromising the properties of thestrut50 or the adhesion between theprimer layer51, theelution layer52 or theburst control layer53. Thestrut50 is comprised of a high strength material that maintains its material properties when the biocompatible implantablemedical device99 is moved from the undeployed configuration to the expanded configuration. Preferably, thestrut50 comprises a strong, flexible and biocompatible material. In a preferred embodiment of the present invention, thestrut50 comprises stainless steel or a stainless steel alloy. In an embodiment of the present invention, thestrut50 comprises stainless steel alloy 316L. In another embodiment of the present invention, thestrut50 comprises nitinol. Nitinol, also known as nickel titanium, is a shape memory alloy that exhibits superelasticity and high damping capability. Nitinol is a flexible, biocompatible material that allows the biocompatible implantablemedical device99 to be articulated through the tortuous paths of the vasculature, while providing high strength. The properties of nitinol can be modified by changes in alloy composition, mechanical working and heat treatment. In another embodiment of the present invention, thestrut50 comprises a material including, but not limited to gold, silver, copper, zirconium, platinum, titanium, niobium, niobium alloys, cobalt-chromium alloys or combinations of the above. Those skilled in the art will recognize the strut can comprise many other biocompatible materials known in the art and be within the spirit and scope of the present invention.
• In an embodiment of the present invention, thestrut50 comprises a layer of tantalum or other radiopaque materials. Tantalum is a grayish silver, heavy metal that is biocompatible and has a history of uses in prosthetic devices. Tantalum is corrosion resistant, is immune to attack by body fluids and is radiopaque. The use of tantalum or other radiopaque materials provides enhanced radiographic imaging of the biocompatible medical device during implantation and subsequent fluoroscopic visualization.
• In an embodiment of the present invention, thebiocompatible polymer matrix54 of theprimer layer51, theelution layer52 and theburst control layer53 have a similar composition. In another embodiment of the present invention, thebiocompatible polymer matrix54 of theprimer layer51, theelution layer52 and theburst control layer53 have a different composition. Those skilled in the art will recognize the biocompatible polymer matrix of the primer layer, the elution layer and the burst control layer can vary from one layer to the next and be within the spirit and scope of the present invention.
• In an embodiment of the present invention, thedrug55 in theprimer layer51, theelution layer52 and theburst control layer53 have similar compositions. In another embodiment of the present invention, thedrug55 in theprimer layer51, theelution layer52 and the burst control layer vary in composition. Those skilled in the art will recognize the drug in the primer layer, the elution layer and the burst control layers can vary from one layer to the next and be within the spirit and scope of the present invention.
• In a preferred embodiment of the present invention, theprimer layer51 comprises abiocompatible polymer matrix54 that improves the adhesion of theelution layer52 to thestrut50. In a preferred embodiment of the present invention, theelution layer52 comprises a biocompatible drug release matrix having abiocompatible polymer matrix54 and thedrug55 incorporated into thebiocompatible polymer matrix54. In the embodiment shown inFIG. 10, the incorporation of thedrug55 into thebiocompatible polymer matrix54 is shown as a plurality of small particles in theelution layer52. Theburst control layer53 controls and limits the kinetics of the burst dose of thedrug55 from theelution layer52. In a preferred embodiment of the present invention, theelution layer52 is symmetric around thestrand75 and has a uniform thickness. In another embodiment of the present invention, theelution layer52 is asymmetric around thestrand75 and has a varying thickness. Those skilled in the art will recognize the layers surrounding the strut can be placed at various positions around the strut and be of varying thickness and be within the spirit and scope of the present invention.
• In a preferred embodiment of the present invention, the concentration of thedrug55 in theburst control layer53 is lower than the concentration of thedrug55 in theelution layer52. With the concentration of thedrug55 in theburst control layer53 lower than the concentration of thedrug55 in theelution layer52 and the materials comprising the biocompatible polymer matrices of theburst control layer53 and theelution layer52 the same, the burst dosage of thedrug55 eluted to the tissue is slowed, leaving a higher amount of thedrug55 to elude after the lower burst dosage of thedrug55. With the concentration of thedrug55 in theburst control layer53 lower than the concentration of thedrug55 in the elution layer, a lower amount of thedrug55 is diffused at the outer edges of the biocompatible implantablemedical device99. In another embodiment of the present invention, the concentration of thedrug55 in theburst control layer53 is higher than the concentration of thedrug55 in theelution layer52. With the concentration of thedrug55 in theburst control layer53 higher than the concentration of thedrug55 in theelution layer52, a higher burst dosage of thedrug55 is eluted to the tissue, leaving a lesser amount of thedrug55 to elude after the higher burst dosage of thedrug55. Those skilled in the art will recognize the concentration of the drug in the burst control layer can vary relative to the concentration of the drug in the elution layer and be within the spirit and scope of the present invention.
• In an embodiment of the present invention, theprimer layer51, theelution layer52 and theburst control layer53 are comprised of a plurality of sub-layers applied sub-layer by sub-layer to produce the respective layer. In another embodiment of the present invention, theprimer layer51, theelution layer52 and theburst control layer53 are a single layer. In an embodiment of the present invention, the chemical composition of the plurality of sub-layers of thebiocompatible polymer matrix54 varies. In another embodiment of the present invention, the chemical composition of the plurality of sub-layers of the biocompatible polymer matrix is the same. In an embodiment of the present invention, the amount of thedrug55 incorporated into thebiocompatible polymer matrix54 varies from one sub-layer to the next sub-layer. In another embodiment of the present invention, the amount of drug incorporated into thebiocompatible polymer matrix54 is the same from one sub-layer to an adjacent sub-layer.
• In an embodiment of the present invention, thebiocompatible polymer matrix54 comprises a single polymer. In another embodiment of the present invention, thebiocompatible polymer matrix54 comprises a plurality of polymers. Those skilled in the art will recognize the biocompatible polymer matrix can comprise one or several polymers and be within the spirit and scope of the present invention.
• In an embodiment of the present invention, thebiocompatible polymer matrix54 comprises polyvinyl pyrrolidone (PVP) with at least one isocyanate. In another embodiment of the present invention, thebiocompatible polymer matrix54 comprises a polymer mixture of hydrophilic and hydrophobic polymers including, but not limited to, polyurethanes, polyvinyl pyrrolidone, poly methyl methacrylate (PMMA), hydroxyetyl methacrylate (HEMA) and cellulose esters. Bioactive agents are entrapped into the hydrophilic and hydrophobic polymer with the hydrophilic and hydrophobic polymers controlling the elution of the bioactive agent. In another embodiment of the present invention, the biocompatible polymer matrix comprises parylene and derivatives of parylene. Parylene and derivatives of parylene are appropriate for theburst control layer53 because of parylene's biocompatibility, flexibility and ability coat complex geometry and small features evenly. Examples of polymers used in the biocompatible polymer matrix are found in U.S. Pat. No. 4,642,267; U.S. Pat. No. 5,069,899; U.S. Pat. No. 5,355,832; U.S. Pat. No. 5,447,799; U.S. Pat. No. 5,525,348; U.S. Pat. No. 5,997,517; U.S. Pat. No. 6,110,483; U.S. Pat. No. 6,306,176; U.S. Pat. No. 6,368,611; and U.S. Pat. No. 6,358,557, the entirety of these patents are hereby incorporated herein by reference.
• In an embodiment of the present invention, thebiocompatible polymer matrix54 comprises polybutylmethacrylate and polyethylvinylacetate. In one embodiment of the present invention, the concentrations of polybutylmethacrylate and polyethylvinylacetate are approximately equal. In another embodiment of the present invention, the concentrations of polybutylmethacrylate and polyethylvinylacetate are not equal. In an embodiment of the present invention, thebiocompatible polymer matrix54 comprises a polyurethane-polycarbonate co-polymer. In an embodiment of the present invention, thebiocompatible polymer matrix54 comprises a thermoplastic polyurethane elastomer that exhibits characteristics including, but not limited to, low coefficient of friction, low extractables, dimensional stability, gamma sterilizable, chemical inertness, and biodurability. Such thermoplastic polyurethane elastomers are ChronoThane™ and ChronoFlex C™ (commercially available from CardioTech International, Inc., Woburn, Mass. (www.cardiotech-inc.com)). In the embodiment of the present invention where thebiocompatible polymer matrix54 is the thermoplastic polyurethane elastomer, a ratio of the weight of the biocompatible polymer matrix and the drug is about 4 to about 1. Other ratios of the weight of thebiocompatible polymer matrix54 and the drug are possible and would be limited by the desired dosage of thedrug55 across the biocompatible implantablemedical device99, the resulting elution kinetics of thedrug55 and the amount of thebiocompatible polymer matrix54 required to yield the mechanical requirements for the particular layer to survive intact during the manufacture, implantation and long-term stability of the biocompatible implantablemedial device99.
• In an embodiment of the present invention, thebiocompatible polymer matrix54 comprises an erodible polymer. Erodible polymers are non-permanent polymers that erode away over time while providing long-term biocompatibility. Erodible polymers reduce the risk of long-term breakdown of thebiocompatible polymer matrix54. The erodible polymer may be bioabsorbable polymers and resorbable polymers. Examples of erodible polymers include, but are not limited to, polyactide, polyactide with glycolide, polyester-amides, polyurethanes, poly(ethylene-urethane), poly(ester-urethane) and poly(ether-polyester-urethane), amino-acid based polyurethanes, polycaprolactone based polyurethanes, polyurethanes synthesized from poly(butylene succinate) polyol, poly(ethylene glycol), and 4,4′-methylenebis(cyclohexyl isocyanate), fat, carbohydrates, protein compounds and other natural biological substances. Those skilled in the art will recognize there are other erodible polymers known in the art that are within the spirit and scope of the present invention.
• In another embodiment of the present invention, thebiocompatible polymer matrix54 includes, but is not limited to hybrid polymers, composites and polymer blends, hydrogels, acrylate terpolymers, tri-block polymers, polyethylene vinyl-acetate methacrylic tri-block terpolymer, ethyl-vinyl acetate, polyethyl vinyl-acetate, polybutyl methacrylic acid and polyethyl vinyl-acetate blends, polyurethanes and polyurethane-polycarbonate blends, silicone-urethane copolymers, polyvinyl pyrrolidone, polyester resins, parylene, lipids, sugars, gelatin, albumin and other biological materials. Those skilled in the art will recognize the biocompatible polymer matrix can be comprised of many materials known in the art and be within the spirit and scope of the present invention.
• In an embodiment of the present invention, thedrug55 is stored within a plurality of perforations or reservoirs in thestrut50 of the biocompatible implantablemedical device99. The perforations or reservoirs allow for increased drug loading capability while focusing the release of thedrug55 toward the target cells. In addition, the perforations or reservoirs minimize the amount of thedrug55 lost in the blood stream. The perforations or reservoirs are placed in thestrut50 of the biocompatible implantablemedical device99 by laser drilling, casting, molding, machining or other methods known in the art.
• In an embodiment of the present invention, thedrug55 is dissolved in a solvent and applied to thestrut50 of the biocompatible implantablemedical device99. After the solvent evaporates, thedrug55 will recrystallize on the surface of thestrut50. After recrystallization of thedrug55 on the surface of thestrut50, theburst control layer53 may be applied to the surface of thestrut50. Theburst control layer53 can comprise the materials of thebiocompatible polymer matrix54 discussed herein.
• The biocompatible drug release matrix is comprised of thebiocompatible polymer matrix54 and thedrug55. In one embodiment of the present invention, thedrug55 is added to thebiocompatible polymer matrix54 and mixed. In another embodiment of the present invention, thedrug55 is soaked into thebiocompatible polymer matrix54. Those skilled in the art will recognize thedrug55 can be incorporated into the biocompatible polymer matrix in many other ways known in the art and be within the spirit and scope of the present invention.
• In a preferred embodiment of the present invention, a mixture of thebiocompatible polymer matrix54 and thedrug55 are mixed with a solvent. The choice of solvent affects the biocompatible drug release matrix, and more particularly, the interaction between thedrug55 and thebiocompatible polymer matrix54. In a preferred embodiment of the present invention, the solvent has low toxicity. The solvent is used to create a wet mixture of thebiocompatible polymer matrix54 and thedrug55 that can be deposited or applied to the surface of the biocompatible implantablemedical device99. The solvent allows for the mixing and a uniform distribution of thedrug55 in thebiocompatible polymer matrix54. The solvent evaporates, leaving thebiocompatible polymer matrix54 and thedrug55 on thestrut50 of the biocompatible implantablemedical device99. Thedrug55 remains suspended within thebiocompatible polymer matrix54 on the surface of thestrut50. In a preferred embodiment of the present invention, the solvent used to mix with thebiocompatible polymer matrix54 and thedrug55 is water or saline. In another embodiment of the present invention, the solvents used to mix with thebiocompatible polymer matrix54 and thedrug55 include, but are not limited to, methanol, acetone, chloroform, tetrahydrofuran, ethanol, toluene, dimethyl sulfoxide, petroleum ethers, other hydrocarbons, butyl acetate, cyclohexanone, carbon tetrachloride, ether, benzene, organic solvents and other combinations of the above. Those skilled in the art will recognize other solvents known in the art can be used in the present invention that are within the spirit and scope of the present invention.
• As described above, the biocompatible polymer matrix54 (with or without the drug55) for theprimer layer51, theelution layer52 and theburst control layer53 can comprise a plurality of sub-layers or a single layer. Many processes exist for applying the drug and thebiocompatible polymer matrix54 on thestrut50. Most processes for applying thebiocompatible polymer matrix54 involve direct application of thebiocompatible polymer matrix54. In addition, a secondary cycle may be required to fix the respective coating layer by evaporation of the solvent or an applied energy to bond, cure, polymerize or otherwise stabilize the respective coating layer. Processes used to apply thebiocompatible polymer matrix54 include, but are not limited to, brush coating, dip coating, spray coating, electrostatic deposition, ion sputtering, vapor deposition, chemical vapor deposition, pulsed chemical vapor deposition, controlled vacuum ultrasonic nanodrop spray deposition, flash evaporation and surface polymerization, polymer multi-layer deposition and combinations of the above. Those skilled in the art will recognize other methods of applying a biocompatible polymer matrix are known in the art and within the spirit and scope of the present invention.
• In an embodiment of the present invention, the biocompatible drug release matrix coated on the surface of the biocompatible implantablemedical device99 is between about 5 microns to about 120 microns thick. Those skilled in the art will recognize the thickness of the biocompatible drug release matrix can vary and be within the spirit and scope of the present invention.
• In a preferred embodiment of the present invention, thedrug55 is mitomycin C. The chemical formula of mitomycin C is C₁₅H₁₈N₄O₅and the chemical structure of mitomycin C is shown inFIG. 14. In another embodiment of the present invention, thedrug55 is an analogue related to the quinone-containing alkylating agents of the mitomycin family having anti-proliferative and antibiotic properties. In the present invention, thedrug55 may include, but is not limited to, mitomycin A, mitomycin A analogue 7-(2-hydroxyethoxy) mitosane (BMY 2551), mitomycin B, mitomycin C, KW-2149, BMS-191174, BMY 25282, BMY 25067, MC-77, MC-62, porfiromycin, acetylmitomycin C, FR-900482, FR-66979, FK-973, and combinations of the above. Those skilled in the art will recognize there are other derivatives, substitutes or analogues related to the mitomycin family known in the art are within the spirit and scope of the present invention.
• Mitomycin is a quinone-containing alkylating agent with anti-proliferative and antibiotic properties. In addition, mitomycin is an alkylating agent that inhibits the DNA synthesis. Mitomycin is a chemotherapeutic antibiotic used for some types of cancer. Mitomycin effectively inhibits in-vitro proliferation of smooth muscle cells at various concentrations without adverse effects to a patient. Mitomycin is cytostatic at certain dosages and cytotoxic at different dosages.
• In an embodiment of the present invention, thedrug55 is linked to a compound to alter the release kinetics, decrease the toxicity or enhance the potency of thedrug55. The compound to alter the release kinetics of the drug includes, but is not limited to, albumin, sodium chloride, chitosan, mannitol, heparin, steroids, glucose, glycoproteins, lipoproteins, estradiol, fibrin, antimitotics, and combinations of the above. Those skilled in the art will recognize the drug can be linked to other compounds known in the art to alter the release kinetics of the drug and be within the spirit and scope of the present invention.
• The release kinetics and transport of thedrug55 can be altered by molecular bond degradation, a breakdown of the link of thedrug55 and the compound. Thedrug55 may be covalently bonded to a the compound that acts as a carrier molecule. Typically, thedrug55 will not be active until the bond between thedrug44 and the carrier molecule breaks down through exposure to moisture (i.e., bodily fluids), exposure to heat or another applied energy source, or chemical triggers. For example, a systemic pharmaceutical trigger such as swallowing a pill, locally delivered pharmaceuticals via infusion catheter or locally delivering heat energy in the form of heat or light can affect the breakdown of the link of thedrug55 and the compound. Once the bond is broken down, thedrug55 is available to treat the surrounding tissue. The carrier molecule is selected to enhance or modify the diffusion properties of thedrug55, to alter the potency of thedrug55 and to provide extremely long elution rates of thedrug55. Linking thedrug55 to the compound might also decrease the toxicity of thedrug55, thereby altering the dosage of thedrug55.
• FIG. 15 shows the biocompatible implantablemedical device99 of the present invention having afilm31 of thebiocompatible polymer matrix54 and thedrug55 covering a portion of the biocompatible implantablemedical device99.FIG. 16 shows the biocompatible implantablemedical device99 of the present invention having thefilm31 covering a portion of the biocompatible implantablemedical device99 with biocompatible implantablemedical device99 visible through thefilm31.FIG. 17 shows a front view of the biocompatible implantablemedical device99 having thefilm31 covering the biocompatible implantablemedical device99. In the embodiment of the present invention shown inFIG. 15, thefilm31 comprising thebiocompatible polymer matrix54 and thedrug55 is applied to theprimer layer51. In another embodiment of the present invention, thefilm31 comprising thebiocompatible polymer matrix54 and thedrug55 is applied to thestrut50. In the embodiment of the present invention shown inFIG. 15, thefilm31 covers anouter surface33 of theprimer layer51 between theproximal end97 and thedistal end95 of the biocompatible implantablemedical device99. In another embodiment of the present invention, thefilm31 covers aninner surface63 of the primer layer between theproximal end97 and thedistal end95 of the biocompatible implantablemedical device99. In another embodiment of the present invention, thefilm31 covers theouter surface33 of theprimer layer51 and theinner surface63 of the primer layer between theproximal end97 and thedistal end95 of the biocompatible implantablemedical device99.
• Thefilm31 of the biocompatible implantablemedical device99 can be deposited or stretched over thestrut50 or theprimer layer51 of the biocompatible implantablemedical device99. In one embodiment of the present invention, thefilm31 is deposited or stretched on thestrut50 or theprimer layer51 so thefilm31 plastically deforms on an expansion of the biocompatible implantablemedical device99. A plastic deformation of thefilm31 is a permanent deformation of thefilm31 that prevents radial compressive forces from thefilm31 transferring to theprimer layer51 and/or thestrut50 after expansion of the biocompatible implantablemedical device99. In another embodiment of the present invention, thefilm31 expands elastically with the biocompatible implantablemedical device99. In one embodiment of the present invention, thefilm31 comprises the same materials of thebiocompatible polymer matrix54 as discussed above. In an embodiment of the present invention, thefilm31 is a porous structure comprised of the same materials as thebiocompatible polymer matrix54. In another embodiment of the present invention, thefilm31 comprises thebiocompatible polymer matrix54 and thedrug55 to provide a more even distribution of thedrug55 over theouter surface106 and inner surface of the biocompatible implantablemedical device99. In another embodiment, the covering consists of a plurality of films spaced along the length of the biocompatible implantablemedical device99 allowing for greater flexibility than asingle film31 alone.
• FIG. 18 shows a side plan view of the biocompatible implantablemedical device99 of the present invention engaged on anoutside surface57 of aballoon41 of aballoon catheter48. In a preferred embodiment of the present invention, the biocompatible implantablemedical device99 is crimped onto theoutside surface57 of theballoon41 of theballoon catheter48. Crimping is performed to engage the biocompatible implantablemedical device99 onto theoutside surface57 of theballoon41 through an interference fit. In one embodiment of the present invention, the biocompatible implantablemedical device99 is heated so the material comprising theballoon41 softens around the biocompatible implantablemedical device99 to increase the retention forces between theballoon41 and the biocompatible implantablemedical device99. High retention forces between theballoon41 and the biocompatible implantablemedical device99 are desirable so the biocompatible implantablemedical device99 does disengage theballoon catheter48 prior to the full expansion of theballoon41. An inside surface of the biocompatible implantablemedical device99 engages theoutside surface57 of theballoon41 of theballoon catheter48. Theballoon41 of theballoon catheter48 is supported by theballoon catheter48 between aproximal end58 of theballoon catheter48 and adistal end56 of theballoon catheter48. Theballoon41 engages theballoon catheter48 at an at least one engagement position along a longitudinal axis of theballoon catheter48. In a preferred embodiment of the present invention, theballoon41 engages theballoon catheter48 at adistal engagement position47 and aproximal engagement position49 in a manner known in the art. In the embodiment of the present invention shown inFIG. 18, theballoon41 is a tri-fold balloon.
• The biocompatible implantablemedical device99 slides along the outer surface of theballoon catheter48 and positioned over theballoon41 of theballoon catheter48. In a preferred embodiment of the present invention, the biocompatible implantablemedical device99 is centered with respect to the length span of theballoon41. Once the biocompatible implantablemedical device99 is positioned with respect to the balloon, the biocompatible implantablemedical device99 is engaged onto theballoon41 of theballoon catheter48, causing an inner surface of the biocompatible implantablemedical device99 to engage to theouter surface57 of theballoon41 of theballoon catheter48. The biocompatible implantablemedical device99 is engaged onto theballoon41 of the balloon catheter in a manner known in the art. The diameter of the biocompatible implantablemedical device99 decreases after engaging the biocompatible implantablemedical device99 onto theouter surface57 of theballoon41 of theballoon catheter48. The pliable, shape sustaining material that comprises thestrut50 of the biocompatible implantablemedical device99 provides flexibility for the biocompatible implantablemedical device99 to be moved from a larger diameter in an unengaged state to a smaller diameter in an engaged state.
• Theballoon catheter48 is a small diameter hollow tube that is threaded through a vein or an artery of the vasculature. Theballoon catheter48 is a thin, flexible device that is used to deliver various medical devices to a treatment site in the vasculature. Various medical devices can be delivered through an inside of theballoon catheter48 or along an outside surface of theballoon catheter48. Theballoon catheter48 can be used to deliver fluids into the body or withdraw fluids from the body.
• In a preferred embodiment of the present invention, theballoon catheter48 comprises a strong, flexible and biocompatible material. In one embodiment of the present invention, theballoon catheter48 comprises polytetrafluoroethylene (PTFE). In another embodiment of the present invention, theballoon catheter48 comprises a material including, but not limited to, rubber, latex, silicone, PTFE, nylon, polyamide, polyethylene, polyurethanes, polyimide, stainless steel alloys, nickel-titanium alloy and similar materials. Those skilled in the art will recognize the balloon catheter may comprise many other materials known in the art and be within the spirit and scope of the present invention.
• FIG. 19 shows a fragmentary cross section perspective view of the biocompatible implantablemedical device99, theballoon41 and theballoon catheter48. In the embodiment of the present invention shown inFIG. 19, a cross section of the biocompatible implantablemedical device99 is simplified to illustrate the coating as a single layer as opposed to theindividual primer layer51,elution layer52 and burstcontrol layer53. The biocompatible implantablemedical device99 comprises anouter surface106 and aninner surface104 engaged to theouter surface57 of theballoon41 of theballoon catheter48. As discussed above, the biocompatible implantablemedical device99 comprises an at least one layer surrounding thestrut50. In a preferred embodiment of the present invention shown inFIG. 19, aninflation lumen90 is located inside of theballoon catheter48. In another embodiment of the present invention, theinflation lumen90 is located outside of theballoon catheter48. Theballoon41 of theballoon catheter48 comprises theouter surface57 and aninner surface59. Theballoon catheter48 comprises a lumen extending along the longitudinal axis of theballoon catheter48.
• Theinflation lumen90 is used to deliver a medium from an inflation mechanism to inflate theballoon41. Theinner surface59 of theballoon41 is in communication with theinflation lumen90. The medium is delivered from the inflation mechanism and moves along theinflation lumen90 and out of an at least oneinflation opening45. As the medium is delivered, the medium engages theinner surface59 of theballoon41 and theballoon41 expands.
• In a preferred embodiment of the present invention, the medium is a liquid medium. In another embodiment of the present invention, the medium is water with a radiopaque contrast agent. In another embodiment of the present invention, the medium is saline. In another embodiment of the present invention, the medium is a gas. Those skilled in the art will recognize there are many media used to inflate a balloon known in the art that can be used and be within the spirit and scope of the present invention.
• Theballoon catheter48 with the biocompatible implantablemedical device99 engaged onto theballoon41 of theballoon catheter48 is inserted into thevasculature43. Theballoon catheter48 is moved within the vasculature to a treatment area comprising a lesion in thevasculature43. In an embodiment of the present invention, theballoon catheter48 is pushed to move the biocompatible implantablemedical device99 to the lesion. In another embodiment of the present invention, theballoon catheter48 is twisted to move the biocompatible implantablemedical device99 to the lesion. In another embodiment of the present invention, theballoon catheter48 is rotated within the vasculature to move the biocompatible implantablemedical device99 to the lesion. Those skilled in the art will recognize the balloon catheter can be moved within the vasculature in many ways known in the art and be within the spirit and scope of the present invention.
• FIG. 20 shows a cross section view of thevasculature43 of the body, alesion80 along an inner surface of thevasculature43, the biocompatible implantablemedical device99 and theballoon catheter48 after the biocompatible implantablemedical device99 is moved within alumen82 of thelesion80 and positioned proximal to thelesion80.FIG. 20 shows a vasculature after an angioplasty procedure is performed. The angioplasty procedure compresses thelesion80 into the inside wall of thevasculature43. In the embodiment of the present invention shown inFIG. 20, theballoon41 is uninflated and the outer surface of the biocompatible implantablemedical device99 does not engage an inner surface of thelesion80. In the embodiment of the present invention shown inFIG. 20, a cross section of the biocompatible implantablemedical device99 comprises thestrut50 surrounded by amatrix layer92. In one embodiment of the present invention, the matrix layer comprises theprimer layer51, theelution layer52 and theburst control layer53. In another embodiment of the present invention, the matrix layer comprises theprimer layer51 and theelution layer52. In another embodiment of the present invention, the matrix layer comprises theelution layer52. Those skilled in the art will recognize the matrix layer can be comprised of various layers having various compositions and be within the spirit and scope of the present invention.
• FIG. 21 shows a side plan view of the biocompatible implantablemedical device99 in an expanded configuration after inflation of theballoon41 of theballoon catheter48. The construction of the biocompatible implantablemedical device99 of the present invention with the plurality of circumferential row oflinks69 and the plurality ofcircumferential bands37 allows the biocompatible implantablemedical device99 to be expanded from an undeployed configuration (FIG. 1) to the expanded configuration (FIG. 21). As the medium engages theinner surface59 of theballoon41, theballoon41 inflates to a larger diameter causing the biocompatible implantablemedical device99 to expand in diameter with theinflated balloon41. The biocompatible implantablemedical device99 increases from the smallest diameter corresponding to the biocompatible implantablemedical device99 engaged onto theuninflated balloon41, to the diameter of the biocompatible implantablemedical device99 before the biocompatible implantablemedical device99 is engaged onto theballoon41 of theballoon catheter48, and finally to a largest diameter where theballoon41 is inflated and theouter surface106 of the biocompatible implantablemedical device99 engages thelesion80.
• In the embodiment of the present invention shown inFIG. 21, the plurality ofcircumferential bands37 are expanded. The design of the biocompatible implantablemedical device99 with the plurality offlexible links69 and the pliable, shape forming material comprising both thestruts50 and the plurality oflinks69 allows the biocompatible implantablemedical device99 to expand to the configuration shown inFIG. 21. For the biocompatible implantablemedical device99 in the expanded configuration shown inFIG. 21, alternating bends within a circumferential band are spaced farther apart when compared to the configuration where the biocompatible implantablemedical device99 is engaged onto theballoon41 of theballoon catheter48 or the configuration of the biocompatible implantablemedical device99 before the biocompatible implantablemedical device99 is engaged onto theballoon41 of theballoon catheter48. For example, alternatingbends77 and107 incircumferential band30 are spaced further apart circumferentially than in the undeployed configuration shown inFIG. 4. Thegaps79 and109 are spaced further apart circumferentially in the expanded configuration ofFIG. 21. In addition, the plurality ofcircumferential links69 allow for the biocompatible implantablemedical device99 to expand in a longitudinal direction.
• FIG. 22 shows a fragmentary cross section perspective view of the biocompatible implantablemedical device99 in the expanded configuration, theinflated balloon41 and theballoon catheter48. In the embodiment of the present invention shown inFIG. 22, the tri-folds of theballoon41 are expanded such that there is no overlap of the material comprising theballoon41.
• FIG. 23 shows a cross section view of thevasculature43 and thelesion80 with the biocompatible implantablemedical device99 in the expanded configuration, theinflated balloon41 and theballoon catheter48. The inflation of theballoon41 expands the biocompatible implantablemedical device99 into the expanded configuration and pushes the biocompatible implantablemedical device99 adjacent to the compressed lesion and into the wall of thevasculature43. Theouter surface106 of the biocompatible implantablemedical device99 engages thelesion80 and compresses into the wall of thevasculature43. InFIG. 23, the biocompatible implantablemedical device99 is implanted adjacent to the wall of thevasculature43.
• FIG. 24 shows a side plan view of the biocompatible implantablemedical device99 in the expanded configuration and theballoon41 of theballoon catheter48 deflated. Theballoon41 of theballoon catheter48 is deflated by removing the medium from within the balloon in a manner known in the art. Once the biocompatible implantablemedical device99 is implanted into the wall of thevasculature43, theballoon41 is deflated and theballoon catheter48 with theballoon41 is removed from the vasculature, leaving the biocompatible implantablemedical device99 implanted into the wall of thevasculature43.
• FIG. 25 shows a cross section view of thestrand75 of the biocompatible implantablemedical device99 of the present invention engaging a wall of the vasculature and a profile of the drug elution across the thickness of the wall.FIG. 26 shows a cross section of the vasculature with the implanted biocompatible implantablemedical device99 of the present invention engaging the inner wall of the vasculature. Thetreatment area147 illustrates an effective treatment area of thedrug55. The concentration of thedrug55 is greater near the surface of the biocompatible implantablemedical device99 and decreases farther away from the surface of the biocompatible implantablemedical device99.
• With the biocompatible implantablemedical device99 implanted into the wall of thevasculature43, fluids engaging the biocompatible drug release matrix are transported into thebiocompatible polymer matrix54 and dissolve thedrug55 out of thebiocompatible polymer matrix54 to inhibit the proliferation of smooth muscle cells from thelesion80. The fluid diffuses within thebiocompatible polymer matrix54 and dissolves thedrug55, therefore elution occurs and thedrug55 treats the smooth muscle cells from thelesion80. The fluid transports out of thebiocompatible polymer matrix54 along with thedrug55 by virtue of a concentration gradient. Thebiocompatible polymer matrix54 adds resistance to the transport of the fluid and slows the release of thedrug55. As thedrug55 moves out of thebiocompatible polymer matrix54 and is transferred to the vessel wall, thebiocompatible polymer matrix54 for the specific coating layer is left porous. The drug engages the smooth muscle cells of thelesion80 along the vessel wall and inhibits the growth of the smooth muscle cells to keep the vasculature open.
• The effectiveness of the inhibition of smooth muscle cell growth is a function of the total dose provided by the biocompatible implantablemedical device99 and the drug elution kinetics. The possibilities of loading an optimal therapeutic dose are limited by the total amount of drug that can be incorporated into thebiocompatible polymer matrix54. An inadequate amount of thedrug55 will not produce the desired effects of inhibiting restenosis, while an overabundance of thedrug55 can be toxic.
• The total dose (D_t) can be described per the biocompatible implantablemedical device99, in micrograms per millimeter (μg/mm) of length of the biocompatible implantablemedical device99 or in micrograms per millimeter squared (μg/mm²) of surface area of the biocompatible implantablemedical device99. After implantation of the biocompatible implantablemedical device99, thedrug55 is released based upon the properties of the biocompatible polymer matrix and the specific kinetics of thedrug55. Thedrug55 moves through the surrounding tissues in the treatment area and results in a concentration within the tissue (measured in μg/mm³tissue, μg/ml of tissue or μg/mg tissue). The concentration of the drug within the tissue varies depending upon the distance from thestrut50 and the resistance from the various transport paths within the surrounding tissue.
• Thebiocompatible polymer matrix54 provides control over the rate of elution of thedrug55. For thedrugs55 entrapped in thebiocompatible polymer matrix54, the dissolution of thedrug55 is controlled by numerous factors including, but not limited to, the biocompatible polymer matrix/drug ratio (which can be adjusted), the total dose incorporated into the polymer matrix, characteristics of the polymer matrix, drug linking, the coating layers. The dissolution of thedrug55 may also be controlled by the ratio of hydrophilic to hydrophobic polymers within the biocompatible implantablemedical device99 with a higher amount of the hydrophobic polymer reducing the rate of diffusion of fluids within thebiocompatible polymer matrix54. Thedrug55 at the outer coating surface dissolves away fairly easily, while thedrug55 deeper within the coating layer elutes more slowly. As discussed above, slower removal of thedrug55 results because the body fluid must first diffuse into thebiocompatible polymer matrix54, then thedrug55 must be dissolved and diffuse back out. The drug/biocompatible polymer matrix loading allows more of thedrug55 to be available sooner for release, and upon release leaves more voids in the biocompatible drug release matrix for faster diffusion and penetration of fluids into deeper structures of thebiocompatible polymer matrix54. Theburst control layer53 acts as a restriction to further reduce the rate of diffusion in and out of theelution layer52.
• The drug elution kinetics are dependent upon various factors including, but not limited to, the type and amount of thedrug55 used, the type and amount ofbiocompatible polymer matrix54, the type and amount of solvent used and the use of theburst control layer53. For example, the drug elution kinetics profile is dependent upon the thickness of the coating layer, the ratio of thedrug55 to thebiocompatible polymer matrix54, the ration of hydrophilic to hydrophobic polymers, the compatibility of thedrug55 and thebiocompatible polymer matrix54 and the solubility of thedrug55. Due to losses of thedrug55 from the treatment area through diffusion of thedrug55 into the blood and surrounding tissues, or inactivation of thedrug55 from exposure to proteins, it is difficult to predict the exact dosage of thedrug55 and the drug elution kinetics for the biocompatible implantablemedical device99. However, tissue deposition studies are used to adjust the drug elution kinetics and dosage of thedrug55 to provide the desired biological effect of inhibition of the proliferation of smooth muscle cells. In general, the drug elution kinetics is affected by the amount of thedrug55 in thebiocompatible polymer matrix54. The higher the amount of thedrug55 relative to thebiocompatible polymer matrix54, the higher the amount of drug elution since there is more of thedrug55 to dissolve and more vacancies in thebiocompatible polymer matrix54 for the diffusion to occur.
• One example of a study was conducted to investigate the vascular smooth muscle cell proliferation (VSMC) from varying concentrations of the mitomycin C. The results of the study, demonstrated about 66% of the VSMC are inhibited with a dose of about 0.334 micrograms per milliliter, while about 98% of the VSMC are inhibited under a dose of about 25.1 micrograms per milliliter. An extrapolation from a logarithmic curve defined by points of the VSMC at various dosages of mitomycin C suggests that about 50% VSMC inhibition occurs at approximately 0.067 micrograms/milliliter of mitomycin C. A lower dosage of mitomycin C would still permit the advance of VSMC and contribute to increased restenosis and may be sufficient. Depending upon the observed biological effects from potentially cytotoxic local tissue levels, a higher concentration of mitomycin C may also still be sufficient.
• The drug elution kinetics should yield tissue concentration levels in the desired range during the healing cycle where smooth muscle cell activation and growth occurs. The proliferative phase of smooth muscle cell growth decreases after about fourteen days after the initial treatment (i.e. angioplasty procedure). In one embodiment, it may be desirable to yield a quicker burst dose of thedrug55 in the first few days (i.e., twenty-four to seventy-two hours) and then sustain a slow and steady level release of thedrug55 beyond the proliferative cycle, in a time as much as forty-five to sixty days from implant, to further protect against restenosis.
• The use of theburst control layer53 also affects the drug elution kinetics. Theburst control layer53 acts as a restriction to limit the diffusion of thedrug55 out of theelution layer52 and burstcontrol layer53. In many cases, a large amount of thedrug55 is diffused from thebiocompatible polymer matrix54, thereby inhibiting the proliferation of smooth muscle cells with a large dosage of thedrug55 immediately. Over time as the smooth muscle cells proliferate, there is less of thedrug55 available to effectively inhibit the proliferation of smooth muscle cells, increasing the possibility for restenosis to occur. In particular, theburst control layer53 with thebiocompatible polymer matrix54 absent of thedrug55 is used to reduce the initial dump of thedrug55 from thebiocompatible polymer matrix54. In addition, theburst control layer53 comprising thebiocompatible polymer matrix54 and an amount of thedrug55 can also affect the drug elution kinetics.
• In a preferred embodiment of the present invention, the biocompatible implantable medical device is designed so between about 10% and about 60% of thedrug55 is delivered to thelesion80 in the first few days after implantation of the biocompatible implantablemedical device99. By allowing between about 10 percent and about 60 percent of thedrug55 to be delivered to thelesion80 in the first few days after implantation, the remainder of thedrug55 is allowed to slowly diffuse out over time to effectively inhibit restenosis.
• FIG. 27 shows an elution profile of mitomycin C showing the release of mitomycin C from a coating of a biocompatible implantablemedical device99 of the present invention as a function of time. The vertical axis represents the percent of thedrug55 eluted to the tissue while the horizontal axis represents the time from implantation of the biocompatible implantablemedical device99. Treatment using the present invention can be viewed as four stages of drug elution that may require a variable amount of thedrug55 to achieve the desired effect. Upon implantation (t₀)of the biocompatible implantablemedical device99, there is an initial burst of the drug, D_B, (Stage I) or a rapid release within about the first one to three days of exposure, t_B, followed by a period of sustained release of thedrug55. The smooth muscle cell proliferation cycle during healing typically peaks at about two weeks and inhibition of the smooth muscle cells during this time period (Stage II) is essential. Late term elution (Stage III) occurs after the two weeks and is characterized by residual elution of thedrug55. Over the period of sustained release (t_m), an addition amount of thedrug55 is eluted from the biocompatible implantablemedical device99, shown as D_MinFIG. 27. Late term elution of thedrug55 beyond the first two weeks after implantation my beneficially inhibit smooth muscle cell proliferation. Stage IV begins when there is nodrug55 on or eluting from the biocompatible implantablemedical device99. As discussed previously, the amount of thedrug55 eluted from theFIG. 27, is typically less than the amount of thedrug55 in the biocompatible implantable medical device, shown as D_TinFIG. 27.
• As discussed above, the drug release kinetics can be tailored to alter the burst dosage and the sustained release of thedrug55.FIG. 28 shows an elution profile of mitomycin C illustrating a high burst dosage (about 60% total dose elution) followed by a slow release of thedrug55 over about eight weeks.FIG. 29 shows an elution profile of mitomycin C illustrating a low burst dosage (about 20% total dose elution) followed by a slow release of thedrug55 over about eight weeks.FIG. 30 shows an elution profile of mitomycin C illustrating a high burst dosage (about 60% total dose elution) followed by a fast release of thedrug55 over about three weeks.FIG. 31 shows an elution profile of mitomycin C illustrating a low burst dosage (about 20% total dose elution) followed by a fast release of thedrug55 over about three weeks.
• In an embodiment of the present invention, a total dosage of about 10 micrograms of the drug per millimeter of a length of the biocompatible implantablemedical device99 is coated on the biocompatible implantablemedical device99. In another embodiment of the present invention, a total dosage of between about 0.5 and about 50 micrograms of the drug per millimeter of length of the biocompatible implantablemedical device99 is coated on the biocompatible implantablemedical device99. Those skilled in the art will recognize that the dosage of the drug per millimeter of a length of the biocompatible implantable medical device can vary and be within the spirit and scope of the present invention. An example calculation of the total dosage of the drug is shown below for several loss factors.
• An analytical method of calculating the dosage of thedrug55 on the biocompatible implantablemedical device99 is given byEquation 1 as follows:
• $\begin{array}{cc}\begin{array}{c}{D}_T=\frac{1}{X}·C·T·V\\ =\frac{1}{X}·C·T·L_v·\frac{\mathrm{<figure-callout\; label="\pi "\; filenames="US20080161908A1-20080703-D00025.png,US20080161908A1-20080703-D00026.png"\; state="\{\{state\}\}">\pi </figure-callout>}}{4}\left({\left(D+2t\right)}^2-D^2\right)\\ =\frac{1}{X}·C·T·L_v·\pi ·t·\left(D+t\right)\end{array}& \left(1\right)\end{array}$
• Equation 1 is a first order approximation of the total dose of thedrug55 assuming a daily consumption rate of thedrug55. InEquation 1, L_vis the treated length of the biocompatible implantablemedical device99, t is an effective treatment penetration depth, T is a constant elution time, C is a desired inhibitory concentration, V is a treated tissue volume, and X is the loss factor. For an L (Length)=13 mm long stent expanded to D (Diameter)=4.0 mm, an effective treatment penetration depth of t=1.5 mm, a constant (steady) elution for T=45 days maintaining a desired inhibitory concentration of C=0.667 μg/ml per day, the following relationship between total dosage an loss factor can be estimated as:
• $D_T=\frac{1}{X}·0.667\frac{\mathrm{\mu g}}{\mathrm{ml}·\mathrm{day}}·45\mathrm{days}·17\mathrm{mm}·\pi ·1.5\mathrm{mm}·\left(4.0\mathrm{mm}+1.5\mathrm{mm}\right)·\frac{1\mathrm{ml}}{1000{\mathrm{<figure-callout\; label="mm"\; filenames="US20080161908A1-20080703-D00025.png,US20080161908A1-20080703-D00026.png"\; state="\{\{state\}\}">mm</figure-callout>}}^3}=\frac{13.2\mathrm{\mu g}}{X}$
• The loss factor, X, is a sum of the losses from direct diffusion of thedrug55 into the bloodstream, both during insertion and immediately after implantation, as well as losses resulting from thedrug55 trapped in thebiocompatible polymer matrix54 permanently (typically less than 10% of the total dosage loss). It is also possible to incorporate non-linearity of the elution rate within the loss factor. Using the above equation with loss factors ranging from 1% to 100%, the total dose of the drug is calculated with the results listed inFIG. 32.
• FIG. 33 shows a graph showing release of mitomycin C from a polymer stent coating stent delivered up to a forty day time period. The clinical data that formsFIG. 33 comes from a study of biocompatible implantable medical devices (stents) of the present invention implanted into porcine coronary arteries to analyze neointimal formation. The stent included a biocompatible polymer having polybutylmethacrylate (PBMA) and polyethylenevinylacetate (PEVA) in equivalent concentrations (1:1) co-solubilized with mitomycin C in a suitable solvent. The solution was then deposited via nebulizer onto a stent, where a homogeneous drug delivery matrix was formed by solvent evaporation. The dose of mitomycin was about 200 mcg per stent corresponding to about 20% loading rate. Thus, the total mass of the coating including drug was between about 1800 mcg and about 2000 mcg.
• The drug release profile kinetics of mitomycin C release from the polymer used for stent coating was determined, in vitro, using the drug assay. Drug/polymer coated stents were placed in physiologic buffer solution at 37° C. in a rotating incubator bath. Buffer samples were drawn at periodic intervals and assayed using a UV-VIS spectrophotomer. Rate curves were prepared to demonstrate the amount of drug released per day, given varying percent-loadings of drug. The 30-day release profile was determined in for mitomycin-loaded stents. After a burst dose between about 25 mcg and about 60 mcg the first day, the mitomycin eluting stent delivered up to 30 days in a smooth-shaped kinetic release curves shown inFIG. 33.
• As shown inFIG. 33, the various burst dosages resulted in varying kinetic release curves. Coronary angiogram and intravascular ultrasound (IVUS) imaging assessment of the treated arterial segments was performed following the same procedure as at the baseline and post-implantation. Coronary artery blood flow was assessed and a TIMI (thrombolysis in myocardial infarction) score assigned. By angiography, there was no evidence of in-stent restenosis in the stents implanted in the suitable vessel segments in each coronary artery. The restenosis rate was 0% and then flow was TIMI III. There was evidence of mild to moderate restenosis (<50%) at both ends in both stents (“edge effect”) visible at angiography. By IVUS, there was total abolition of neointimal formation in the entire stent length in the stents. The edge effect was evident in the stents also by IVUS.
• The present invention is a method of inhibiting the growth of smooth muscle cells to inhibit restenosis comprising: providing a biocompatible implantable medical device; preparing a biocompatible polymer matrix; co-solubilizing the biocompatible polymer matrix with a drug in a solvent to form a biocompatible drug release matrix; applying the biocompatible drug release matrix to the biocompatible implantable medical device to form an elution layer of the biocompatible drug release matrix on the biocompatible implantable medical device; allowing the solvent to evaporate; and implanting the biocompatible implantable medical device into a vasculature of a body.
• The present invention is a method of inhibiting the proliferation of smooth muscle cells after a stent implantation comprising: providing a stent; preparing a biocompatible polymer matrix; co-solubilizing the biocompatible polymer matrix with a drug in a solvent to form a solution; applying the solution onto the stent to form an elution layer of a biocompatible drug release matrix on the biocompatible implantable medical device; allowing the solvent to evaporate; engaging the stent onto a balloon of a balloon catheter; delivering the balloon catheter with the stent engaged onto the balloon of the balloon catheter into a vasculature of a body to a treatment site; and inflating the balloon of the balloon catheter to increase a diameter of the stent to implant the stent.
• The present invention is a method of inhibiting restenosis comprising: providing a medical device; applying a biocompatible drug eluting matrix comprising a biocompatible polymer matrix incorporating an analogue related to the quinone-containing alkylating agents of a mitomycin family to the medical device; and implanting the biocompatible implantable medical device into a vessel to elute the analogue related to the quinone-containing alkylating agents of a mitomycin family.
• The present invention is an apparatus and a method for delivery of mitomycin through an eluting biocompatible implantable medical device. Mitomycin C causes inhibition of smooth muscle cell proliferation in an anaerobic (low oxygen) environment. The present invention provides an effective method of treating a localized area of a diseased vasculature after delivery of a biocompatible implantable medical device that provides a coating that elutes mitomycin C at a controlled rate that inhibits the proliferation of smooth muscle cells causing restenosis, is reliable in consistently treating the localized area over a period of time and does not adversely affect healthy tissue proximal to an area of treatment.
• All patents, patent applications, and published references cited herein are hereby incorporated herein by reference in their entirety. While this invention has been particularly shown and described with references to preferred embodiments thereof, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the scope of the invention encompassed by the appended claims.

Claims (21)

1. A biocompatible medical device for delivering a drug to a treatment area in a vasculature of a body comprising:

a tubular body having a proximal end, a distal end and a longitudinal axis therebetween;

a proximal end band at the proximal end of the tubular body, a distal end band at the distal end of the tubular body and a plurality of intermediate bands between the proximal end band and the distal end band;

a plurality of circumferential rows of links engaging the proximal end band, the plurality of intermediate bands and the distal end band to form the tubular body; and

an elution layer comprising a biocompatible drug release matrix applied to the surface of the biocompatible medical device, the biocompatible drug release matrix having a biocompatible polymer matrix co-solubilized with the drug in a solvent to form a solution and the solvent is evaporated from the solution,

wherein the drug is released from the biocompatible drug release matrix after implantation of the biocompatible medical device to prevent restenosis.

2. The biocompatible medical device ofclaim 1 further comprising a primer layer surrounding a strut of the biocompatible medical device.

3. The biocompatible medical device ofclaim 1 further comprising a burst control layer surrounding the elution layer.

4. The biocompatible medical device ofclaim 1 wherein the proximal end band, the distal end band and the plurality of intermediate bands are arranged axially end to end, extending from the proximal end to the distal end of the biocompatible medical device.

5. The biocompatible medical device ofclaim 1 wherein the biocompatible polymer matrix comprises a mixture of hydrophilic and hydrophobic polymers selected from the group consisting of polyurethanes, polyvinyl pyrrolidone, poly methyl methracrylate (PMMA), hydroxyetyl methacrylate and cellulose esters.

6. The biocompatible medical device ofclaim 1 wherein the solvent is selected from the group consisting of water, saline, tetrahydrofuran, methanol, acetone, butyl acetate, cyclohexane, carbon tetrachloride, ether, chloroform, benzene, ethanol, toluene, dimethyl sulfoxide, petroleum ethers, other hydrocarbons and other organic solvents.

7. The biocompatible medical device ofclaim 1 wherein the elution layer releases the drug at a rate sufficient to produce surrounding tissue level concentrations of the drug from about 0.01 micrograms per milliliter to about 25 micrograms per milliliter after implantation of the biocompatible medical device.

8. The biocompatible medical device ofclaim 1 wherein the drug has antibiotic properties and anti-proliferative properties.

9. The biocompatible medical device ofclaim 1 wherein the drug is an analogue related to the quinone-containing alkylating agents of a mitomycin family.

10. The biocompatible medical device ofclaim 1 wherein the drug is mitomycin C.

11. The biocompatible medical device ofclaim 1 wherein a total dosage of about 0.5 micrograms to about 50 micrograms of the drug per millimeter of a length of the biocompatible medical device is coated on the biocompatible medical device.

12. The biocompatible medical device ofclaim 1 wherein the biocompatible drug release matrix coated on the surface of the biocompatible medical device is between about 5 microns to about 120 microns thick.

13. The biocompatible medical device ofclaim 1 wherein an initial dose of between about 10 percent and about 60 percent of the drug is delivered to the vasculature in the first few days after implantation of the biocompatible medical device.

14. The biocompatible medical device ofclaim 1 wherein initially the drug is released from the biocompatible polymer matrix at a faster rate followed by a release of the drug at a slower rate.

15. A biocompatible implantable stent comprising:

a tubular body having a proximal end, a distal end and a longitudinal axis therebetween;

a plurality of circumferential bands arranged axially end to end, extending from the proximal end to the distal end of the tubular body;

a plurality of circumferential rows of links engaging adjacent circumferential bands to form the tubular body; and

an elution layer applied to the surface of the biocompatible implantable stent, the elution layer comprising a biocompatible erodible polymer matrix co-solubilized with a mitomycin family drug in a solvent to form a solution and the solvent is evaporated from the solution,

wherein the mitomycin family drug is released from the biocompatible erodible polymer matrix after implantation of the biocompatible implantable stent to prevent restenosis.

16. The biocompatible implantable stent ofclaim 15 further comprising a burst control layer surrounding the elution layer.

17. The biocompatible implantable stent ofclaim 15 wherein the erodible polymer matrix is selected from the group consisting of polyactide, polyactide with glycolide, polyester-amides, polyurethanes, poly(ethylene-urethane), poly(ester-urethane) and poly(ether-polyester-urethane), amino-acid based polyurethanes, polycaprolactone based polyurethanes, polyurethanes synthesized from poly(butylene succinate) polyol, poly(ethylene glycol), and 4,4′-methylenebis(cyclohexyl isocyanate), fat, carbohydrates and protein compounds.

18. A biocompatible delivery device comprising:

a biocompatible polymer matrix co-solubilized with a mitomycin family drug in a solvent to form a biocompatible drug release matrix applied to the delivery device to form an elution layer on the delivery device.

19. The biocompatible delivery device ofclaim 18 wherein the mitomycin family drug is released from the biocompatible polymer matrix to prevent restenosis.

20. A method of inhibiting the growth of smooth muscle cells to inhibit restenosis comprising:

providing a biocompatible medical device;

preparing a biocompatible polymer matrix;

co-solubilizing the biocompatible polymer matrix with a mitomycin family drug in a solvent to form a biocompatible drug release matrix;

applying the biocompatible drug release matrix to the biocompatible implantable medical device to form an elution layer of the biocompatible drug release matrix on the biocompatible implantable medical device; and

implanting the biocompatible implantable medical device into a vasculature of a body.

21. A method of inhibiting restenosis comprising:

preparing a biocompatible polymer matrix;

co-solubilizing the biocompatible polymer matrix with a mitomycin family drug in a solvent to form a biocompatible drug release matrix; and

applying the biocompatible drug release matrix to a delivery device to form an elution layer of the biocompatible drug release matrix on the delivery device.

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