Apparatus and Method for Delivery of Mitomycin Through an Eluting Biocompatible Implantable Medical Device
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.
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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 INVENTIONThe 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 INVENTIONCoronary 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 INVENTIONA 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.
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.
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 DESCRIPTIONAn apparatus for a biocompatible implantable medical device comprising a biocompatible drug release matrix is illustrated generally at 99 in
As shown in
The plurality of the circumferential rows of links 69 engage the plurality of circumferential bands 37. In a preferred embodiment of the present invention, each individual link from the plurality of circumferential rows of links 69 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 in
In a preferred embodiment of the present invention shown in
The effectiveness of the biocompatible implantable medical device 99 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 implantable medical device 99 and several methods for incorporating the drug within the biocompatible implantable medical device 99. Transport of the drug to the treatment area can occur by direct exposure, diffusion, molecular bond degradation or other methods known in the art.
In a preferred embodiment of the present invention, the primer layer 51 comprises a biocompatible polymer matrix 54 with or without a drug. In another embodiment of the present invention, the primer layer 51 comprises the biocompatible polymer matrix 54 and a drug (not shown) incorporated into the biocompatible polymer matrix 54. In a preferred embodiment of the present invention, the elution layer 52 comprises a biocompatible drug release matrix having the biocompatible polymer matrix 54 and the drug 55 incorporated into the biocompatible polymer matrix 54. In the embodiment of the present invention shown in
Various embodiments of the strand 75 of the biocompatible implantable medical device 99 are contemplated in the present invention. The number of coating layers and composition of each coating layer may vary.
In a preferred embodiment of the present invention, the strut 50 comprises a material allowing the biocompatible implantable medical device 99 to moved from an undeployed configuration (
In an embodiment of the present invention, the strut 50 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, the biocompatible polymer matrix 54 of the primer layer 51, the elution layer 52 and the burst control layer 53 have a similar composition. In another embodiment of the present invention, the biocompatible polymer matrix 54 of the primer layer 51, the elution layer 52 and the burst control layer 53 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, the drug 55 in the primer layer 51, the elution layer 52 and the burst control layer 53 have similar compositions. In another embodiment of the present invention, the drug 55 in the primer layer 51, the elution layer 52 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, the primer layer 51 comprises a biocompatible polymer matrix 54 that improves the adhesion of the elution layer 52 to the strut 50. In a preferred embodiment of the present invention, the elution layer 52 comprises a biocompatible drug release matrix having a biocompatible polymer matrix 54 and the drug 55 incorporated into the biocompatible polymer matrix 54. In the embodiment shown in
In a preferred embodiment of the present invention, the concentration of the drug 55 in the burst control layer 53 is lower than the concentration of the drug 55 in the elution layer 52. With the concentration of the drug 55 in the burst control layer 53 lower than the concentration of the drug 55 in the elution layer 52 and the materials comprising the biocompatible polymer matrices of the burst control layer 53 and the elution layer 52 the same, the burst dosage of the drug 55 eluted to the tissue is slowed, leaving a higher amount of the drug 55 to elude after the lower burst dosage of the drug 55. With the concentration of the drug 55 in the burst control layer 53 lower than the concentration of the drug 55 in the elution layer, a lower amount of the drug 55 is diffused at the outer edges of the biocompatible implantable medical device 99. In another embodiment of the present invention, the concentration of the drug 55 in the burst control layer 53 is higher than the concentration of the drug 55 in the elution layer 52. With the concentration of the drug 55 in the burst control layer 53 higher than the concentration of the drug 55 in the elution layer 52, a higher burst dosage of the drug 55 is eluted to the tissue, leaving a lesser amount of the drug 55 to elude after the higher burst dosage of the drug 55. 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, the primer layer 51, the elution layer 52 and the burst control layer 53 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, the primer layer 51, the elution layer 52 and the burst control layer 53 are a single layer. In an embodiment of the present invention, the chemical composition of the plurality of sub-layers of the biocompatible polymer matrix 54 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 the drug 55 incorporated into the biocompatible polymer matrix 54 varies from one sub-layer to the next sub-layer. In another embodiment of the present invention, the amount of drug incorporated into the biocompatible polymer matrix 54 is the same from one sub-layer to an adjacent sub-layer.
In an embodiment of the present invention, the biocompatible polymer matrix 54 comprises a single polymer. In another embodiment of the present invention, the biocompatible polymer matrix 54 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, the biocompatible polymer matrix 54 comprises polyvinyl pyrrolidone (PVP) with at least one isocyanate. In another embodiment of the present invention, the biocompatible polymer matrix 54 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 the burst control layer 53 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, the biocompatible polymer matrix 54 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, the biocompatible polymer matrix 54 comprises a polyurethane-polycarbonate co-polymer. In an embodiment of the present invention, the biocompatible polymer matrix 54 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 the biocompatible polymer matrix 54 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 the biocompatible polymer matrix 54 and the drug are possible and would be limited by the desired dosage of the drug 55 across the biocompatible implantable medical device 99, the resulting elution kinetics of the drug 55 and the amount of the biocompatible polymer matrix 54 required to yield the mechanical requirements for the particular layer to survive intact during the manufacture, implantation and long-term stability of the biocompatible implantable medial device 99.
In an embodiment of the present invention, the biocompatible polymer matrix 54 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 the biocompatible polymer matrix 54. 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, the biocompatible polymer matrix 54 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, the drug 55 is stored within a plurality of perforations or reservoirs in the strut 50 of the biocompatible implantable medical device 99. The perforations or reservoirs allow for increased drug loading capability while focusing the release of the drug 55 toward the target cells. In addition, the perforations or reservoirs minimize the amount of the drug 55 lost in the blood stream. The perforations or reservoirs are placed in the strut 50 of the biocompatible implantable medical device 99 by laser drilling, casting, molding, machining or other methods known in the art.
In an embodiment of the present invention, the drug 55 is dissolved in a solvent and applied to the strut 50 of the biocompatible implantable medical device 99. After the solvent evaporates, the drug 55 will recrystallize on the surface of the strut 50. After recrystallization of the drug 55 on the surface of the strut 50, the burst control layer 53 may be applied to the surface of the strut 50. The burst control layer 53 can comprise the materials of the biocompatible polymer matrix 54 discussed herein.
The biocompatible drug release matrix is comprised of the biocompatible polymer matrix 54 and the drug 55. In one embodiment of the present invention, the drug 55 is added to the biocompatible polymer matrix 54 and mixed. In another embodiment of the present invention, the drug 55 is soaked into the biocompatible polymer matrix 54. Those skilled in the art will recognize the drug 55 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 the biocompatible polymer matrix 54 and the drug 55 are mixed with a solvent. The choice of solvent affects the biocompatible drug release matrix, and more particularly, the interaction between the drug 55 and the biocompatible polymer matrix 54. In a preferred embodiment of the present invention, the solvent has low toxicity. The solvent is used to create a wet mixture of the biocompatible polymer matrix 54 and the drug 55 that can be deposited or applied to the surface of the biocompatible implantable medical device 99. The solvent allows for the mixing and a uniform distribution of the drug 55 in the biocompatible polymer matrix 54. The solvent evaporates, leaving the biocompatible polymer matrix 54 and the drug 55 on the strut 50 of the biocompatible implantable medical device 99. The drug 55 remains suspended within the biocompatible polymer matrix 54 on the surface of the strut 50. In a preferred embodiment of the present invention, the solvent used to mix with the biocompatible polymer matrix 54 and the drug 55 is water or saline. In another embodiment of the present invention, the solvents used to mix with the biocompatible polymer matrix 54 and the drug 55 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 matrix 54 (with or without the drug 55) for the primer layer 51, the elution layer 52 and the burst control layer 53 can comprise a plurality of sub-layers or a single layer. Many processes exist for applying the drug and the biocompatible polymer matrix 54 on the strut 50. Most processes for applying the biocompatible polymer matrix 54 involve direct application of the biocompatible polymer matrix 54. 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 the biocompatible polymer matrix 54 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 implantable medical device 99 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, the drug 55 is mitomycin C. The chemical formula of mitomycin C is C15H18N4O5 and the chemical structure of mitomycin C is shown in
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, the drug 55 is linked to a compound to alter the release kinetics, decrease the toxicity or enhance the potency of the drug 55. 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 the drug 55 can be altered by molecular bond degradation, a breakdown of the link of the drug 55 and the compound. The drug 55 may be covalently bonded to a the compound that acts as a carrier molecule. Typically, the drug 55 will not be active until the bond between the drug 44 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 the drug 55 and the compound. Once the bond is broken down, the drug 55 is available to treat the surrounding tissue. The carrier molecule is selected to enhance or modify the diffusion properties of the drug 55, to alter the potency of the drug 55 and to provide extremely long elution rates of the drug 55. Linking the drug 55 to the compound might also decrease the toxicity of the drug 55, thereby altering the dosage of the drug 55.
The film 31 of the biocompatible implantable medical device 99 can be deposited or stretched over the strut 50 or the primer layer 51 of the biocompatible implantable medical device 99. In one embodiment of the present invention, the film 31 is deposited or stretched on the strut 50 or the primer layer 51 so the film 31 plastically deforms on an expansion of the biocompatible implantable medical device 99. A plastic deformation of the film 31 is a permanent deformation of the film 31 that prevents radial compressive forces from the film 31 transferring to the primer layer 51 and/or the strut 50 after expansion of the biocompatible implantable medical device 99. In another embodiment of the present invention, the film 31 expands elastically with the biocompatible implantable medical device 99. In one embodiment of the present invention, the film 31 comprises the same materials of the biocompatible polymer matrix 54 as discussed above. In an embodiment of the present invention, the film 31 is a porous structure comprised of the same materials as the biocompatible polymer matrix 54. In another embodiment of the present invention, the film 31 comprises the biocompatible polymer matrix 54 and the drug 55 to provide a more even distribution of the drug 55 over the outer surface 106 and inner surface of the biocompatible implantable medical device 99. In another embodiment, the covering consists of a plurality of films spaced along the length of the biocompatible implantable medical device 99 allowing for greater flexibility than a single film 31 alone.
The biocompatible implantable medical device 99 slides along the outer surface of the balloon catheter 48 and positioned over the balloon 41 of the balloon catheter 48. In a preferred embodiment of the present invention, the biocompatible implantable medical device 99 is centered with respect to the length span of the balloon 41. Once the biocompatible implantable medical device 99 is positioned with respect to the balloon, the biocompatible implantable medical device 99 is engaged onto the balloon 41 of the balloon catheter 48, causing an inner surface of the biocompatible implantable medical device 99 to engage to the outer surface 57 of the balloon 41 of the balloon catheter 48. The biocompatible implantable medical device 99 is engaged onto the balloon 41 of the balloon catheter in a manner known in the art. The diameter of the biocompatible implantable medical device 99 decreases after engaging the biocompatible implantable medical device 99 onto the outer surface 57 of the balloon 41 of the balloon catheter 48. The pliable, shape sustaining material that comprises the strut 50 of the biocompatible implantable medical device 99 provides flexibility for the biocompatible implantable medical device 99 to be moved from a larger diameter in an unengaged state to a smaller diameter in an engaged state.
The balloon catheter 48 is a small diameter hollow tube that is threaded through a vein or an artery of the vasculature. The balloon catheter 48 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 the balloon catheter 48 or along an outside surface of the balloon catheter 48. The balloon catheter 48 can be used to deliver fluids into the body or withdraw fluids from the body.
In a preferred embodiment of the present invention, the balloon catheter 48 comprises a strong, flexible and biocompatible material. In one embodiment of the present invention, the balloon catheter 48 comprises polytetrafluoroethylene (PTFE). In another embodiment of the present invention, the balloon catheter 48 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.
The inflation lumen 90 is used to deliver a medium from an inflation mechanism to inflate the balloon 41. The inner surface 59 of the balloon 41 is in communication with the inflation lumen 90. The medium is delivered from the inflation mechanism and moves along the inflation lumen 90 and out of an at least one inflation opening 45. As the medium is delivered, the medium engages the inner surface 59 of the balloon 41 and the balloon 41 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.
The balloon catheter 48 with the biocompatible implantable medical device 99 engaged onto the balloon 41 of the balloon catheter 48 is inserted into the vasculature 43. The balloon catheter 48 is moved within the vasculature to a treatment area comprising a lesion in the vasculature 43. In an embodiment of the present invention, the balloon catheter 48 is pushed to move the biocompatible implantable medical device 99 to the lesion. In another embodiment of the present invention, the balloon catheter 48 is twisted to move the biocompatible implantable medical device 99 to the lesion. In another embodiment of the present invention, the balloon catheter 48 is rotated within the vasculature to move the biocompatible implantable medical device 99 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.
In the embodiment of the present invention shown in
With the biocompatible implantable medical device 99 implanted into the wall of the vasculature 43, fluids engaging the biocompatible drug release matrix are transported into the biocompatible polymer matrix 54 and dissolve the drug 55 out of the biocompatible polymer matrix 54 to inhibit the proliferation of smooth muscle cells from the lesion 80. The fluid diffuses within the biocompatible polymer matrix 54 and dissolves the drug 55, therefore elution occurs and the drug 55 treats the smooth muscle cells from the lesion 80. The fluid transports out of the biocompatible polymer matrix 54 along with the drug 55 by virtue of a concentration gradient. The biocompatible polymer matrix 54 adds resistance to the transport of the fluid and slows the release of the drug 55. As the drug 55 moves out of the biocompatible polymer matrix 54 and is transferred to the vessel wall, the biocompatible polymer matrix 54 for the specific coating layer is left porous. The drug engages the smooth muscle cells of the lesion 80 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 implantable medical device 99 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 the biocompatible polymer matrix 54. An inadequate amount of the drug 55 will not produce the desired effects of inhibiting restenosis, while an overabundance of the drug 55 can be toxic.
The total dose (Dt) can be described per the biocompatible implantable medical device 99, in micrograms per millimeter (μg/mm) of length of the biocompatible implantable medical device 99 or in micrograms per millimeter squared (μg/mm2) of surface area of the biocompatible implantable medical device 99. After implantation of the biocompatible implantable medical device 99, the drug 55 is released based upon the properties of the biocompatible polymer matrix and the specific kinetics of the drug 55. The drug 55 moves through the surrounding tissues in the treatment area and results in a concentration within the tissue (measured in μg/mm3 tissue, μg/ml of tissue or μg/mg tissue). The concentration of the drug within the tissue varies depending upon the distance from the strut 50 and the resistance from the various transport paths within the surrounding tissue.
The biocompatible polymer matrix 54 provides control over the rate of elution of the drug 55. For the drugs 55 entrapped in the biocompatible polymer matrix 54, the dissolution of the drug 55 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 the drug 55 may also be controlled by the ratio of hydrophilic to hydrophobic polymers within the biocompatible implantable medical device 99 with a higher amount of the hydrophobic polymer reducing the rate of diffusion of fluids within the biocompatible polymer matrix 54. The drug 55 at the outer coating surface dissolves away fairly easily, while the drug 55 deeper within the coating layer elutes more slowly. As discussed above, slower removal of the drug 55 results because the body fluid must first diffuse into the biocompatible polymer matrix 54, then the drug 55 must be dissolved and diffuse back out. The drug/biocompatible polymer matrix loading allows more of the drug 55 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 the biocompatible polymer matrix 54. The burst control layer 53 acts as a restriction to further reduce the rate of diffusion in and out of the elution layer 52.
The drug elution kinetics are dependent upon various factors including, but not limited to, the type and amount of the drug 55 used, the type and amount of biocompatible polymer matrix 54, the type and amount of solvent used and the use of the burst control layer 53. For example, the drug elution kinetics profile is dependent upon the thickness of the coating layer, the ratio of the drug 55 to the biocompatible polymer matrix 54, the ration of hydrophilic to hydrophobic polymers, the compatibility of the drug 55 and the biocompatible polymer matrix 54 and the solubility of the drug 55. Due to losses of the drug 55 from the treatment area through diffusion of the drug 55 into the blood and surrounding tissues, or inactivation of the drug 55 from exposure to proteins, it is difficult to predict the exact dosage of the drug 55 and the drug elution kinetics for the biocompatible implantable medical device 99. However, tissue deposition studies are used to adjust the drug elution kinetics and dosage of the drug 55 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 the drug 55 in the biocompatible polymer matrix 54. The higher the amount of the drug 55 relative to the biocompatible polymer matrix 54, the higher the amount of drug elution since there is more of the drug 55 to dissolve and more vacancies in the biocompatible polymer matrix 54 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 the drug 55 in the first few days (i.e., twenty-four to seventy-two hours) and then sustain a slow and steady level release of the drug 55 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 the burst control layer 53 also affects the drug elution kinetics. The burst control layer 53 acts as a restriction to limit the diffusion of the drug 55 out of the elution layer 52 and burst control layer 53. In many cases, a large amount of the drug 55 is diffused from the biocompatible polymer matrix 54, thereby inhibiting the proliferation of smooth muscle cells with a large dosage of the drug 55 immediately. Over time as the smooth muscle cells proliferate, there is less of the drug 55 available to effectively inhibit the proliferation of smooth muscle cells, increasing the possibility for restenosis to occur. In particular, the burst control layer 53 with the biocompatible polymer matrix 54 absent of the drug 55 is used to reduce the initial dump of the drug 55 from the biocompatible polymer matrix 54. In addition, the burst control layer 53 comprising the biocompatible polymer matrix 54 and an amount of the drug 55 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 the drug 55 is delivered to the lesion 80 in the first few days after implantation of the biocompatible implantable medical device 99. By allowing between about 10 percent and about 60 percent of the drug 55 to be delivered to the lesion 80 in the first few days after implantation, the remainder of the drug 55 is allowed to slowly diffuse out over time to effectively inhibit restenosis.
As discussed above, the drug release kinetics can be tailored to alter the burst dosage and the sustained release of the drug 55.
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 implantable medical device 99 is coated on the biocompatible implantable medical device 99. 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 implantable medical device 99 is coated on the biocompatible implantable medical device 99. 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 the drug 55 on the biocompatible implantable medical device 99 is given by Equation 1 as follows:
Equation 1 is a first order approximation of the total dose of the drug 55 assuming a daily consumption rate of the drug 55. In Equation 1, Lv is the treated length of the biocompatible implantable medical device 99, 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:
The loss factor, X, is a sum of the losses from direct diffusion of the drug 55 into the bloodstream, both during insertion and immediately after implantation, as well as losses resulting from the drug 55 trapped in the biocompatible polymer matrix 54 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 in
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 in
As shown in
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
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 of claim 1 further comprising a primer layer surrounding a strut of the biocompatible medical device.
3. The biocompatible medical device of claim 1 further comprising a burst control layer surrounding the elution layer.
4. The biocompatible medical device of claim 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 of claim 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 of claim 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 of claim 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 of claim 1 wherein the drug has antibiotic properties and anti-proliferative properties.
9. The biocompatible medical device of claim 1 wherein the drug is an analogue related to the quinone-containing alkylating agents of a mitomycin family.
10. The biocompatible medical device of claim 1 wherein the drug is mitomycin C.
11. The biocompatible medical device of claim 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 of claim 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 of claim 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 of claim 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 of claim 15 further comprising a burst control layer surrounding the elution layer.
17. The biocompatible implantable stent of claim 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 of claim 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.
Type: Application
Filed: Mar 17, 2008
Publication Date: Jul 3, 2008
Applicant:
Inventors: Juan F. Granada (Pearland, TX), Simon M. Furnish (New York, NY)
Application Number: 12/049,918