FIELD OF THE INVENTION
- BACKGROUND OF THE INVENTION
The present invention relates to the coating of medical devices.
The positioning and deployment of medical devices within a target site of a patient is a common, often-repeated procedure of contemporary medicine. These devices or implants are used for innumerable medical purposes including the reinforcement of recently re-enlarged lumens, the replacement of ruptured vessels, and the treatment of disease such as vascular disease by local pharmacotherapy, i.e., delivering therapeutic drug doses to target tissues while minimizing systemic side effects. Such medical devices are implanted or otherwise utilized in body lumina and organs such as the coronary vasculature, esophagus, trachea, colon, biliary tract, urinary tract, prostate, brain, and the like.
Coatings are often applied to the surfaces of these medical devices to increase their effectiveness. These coatings may provide a number of benefits including reducing the trauma suffered during the insertion procedure, facilitating the acceptance of the medical device into the target site, and improving the post-procedure effectiveness of the device.
Coating medical devices also provides for the localized delivery of therapeutic agents to target locations within the body, such as to treat localized disease (e.g., heart disease) or occluded body lumens. Such localized drug delivery avoids the problems of systemic drug administration, such as producing unwanted effects on parts of the body which are not to be treated, or not being able to deliver a high enough concentration of therapeutic agent to the afflicted part of the body. Localized drug delivery is achieved, for example, by coating expandable stents, grafts, or balloon catheters, which directly contact the inner vessel wall, with the therapeutic agent to be locally delivered. Stents are often used to support tissue while healing takes place. Expandable stents are tube-like medical devices that often have a mesh-like patterned structure designed to support the inner walls of a lumen. These stents are typically positioned within a lumen and, then, expanded to provide internal support for it. For example, an intraluminal coronary stent may be used during a coronary bypass graft surgery, or other heart surgery, to keep the grafted vessel open to prevent the reclosure of the blood vessel. The coating on these medical devices may provide for controlled release, which includes long-term or sustained release, of a therapeutic agent.
Aside from facilitating localized drug delivery, medical devices are coated with materials to provide beneficial surface properties. For example, medical devices are often coated with radioopaque materials to allow for fluoroscopic visualization during placement in the body. It is also useful to coat certain devices to achieve enhanced biocompatibility and to improve surface properties such as lubriciousness.
Conventionally, coatings have been applied to medical devices by processes such as dipping and spraying. Dipping and spraying processes usually cannot apply multiple layers of different coatings without requiring appropriate drying time between coating steps, which can increase production time and costs. Further, dipping and spraying processes may result in uneven coating thickness.
- SUMMARY OF THE INVENTION
There is, therefore, a need for a cost-effective method for coating the surface of medical devices that results in even and uniform coatings and measured drug doses per unit device. The present invention provides methods and apparatus for coating medical devices by electroplating a plating material with a therapeutic agent onto the surface of medical devices. The methods of the present invention permit direct local delivery of therapeutic agents to targeted diseased locations, minimizing waste and loss of expensive therapeutic. The methods also allow the coatings to have uniform thicknesses and mechanical properties, and uniform drug dose.
The present invention regards a method and apparatus for coating at least a portion of a medical device (e.g., a stent). In accordance with one embodiment, a method for applying at least a portion of a coating material on a medical device having a surface is provided. This method includes forming a coating on a bio-compatible medical device by electroplating a mixture of a therapeutic agent, and a plating material onto the surface of the medical device. The electroplating may be performed at a relatively low temperature.
In another embodiment of the present invention, a method for applying at least a portion of a coating to a bio-compatible medical device is provided wherein the coating is electroplated onto the surface of the medical device and formed by varying the electroplating voltage to regulate the amount of the therapeutic agent and the amount of plating material that is coated.
In another embodiment of the present invention, a method for applying at least a portion of a coating to a bio-compatible medical device is provided wherein the surface of the medical device is treated, e.g. creating a porous surface layer, to increase the amount of the therapeutic agent that may be electroplated onto the medical device. The coating is formed by electroplating a therapeutic agent into and/or onto the porous surface layer.
In another embodiment of the present invention, a method for applying at least a portion of a coating to a bio-compatible medical device is provided wherein the coating is formed by suspending a therapeutic agent in an electrolytic solution and electroplating a plating material onto the medical device wherein the plating material carries the suspended therapeutic agent such that the coating of plating material contains the suspended therapeutic agent.
In another embodiment of the present invention, an apparatus for applying a coating to a medical device having a surface is provided wherein the coating is formed by electroplating a mixture of a therapeutic agent and a plating material.
The present invention provides methods and apparatus for coating medical devices having a surface by electroplating a plating material with a therapeutic agent onto the surface of medical devices. The methods of the present invention permit coating the external surface of the medical devices, which, for example, directly contacts the diseased vessel wall, thereby permitting direct local delivery of therapeutic agents to targeted diseased locations. The methods also minimize wasted coating during the coating process, thereby minimizing the loss of expensive therapeutic. The methods also allow the coatings to have uniform thicknesses and mechanical properties, and uniform drug dose.
- BRIEF DESCRIPTION OF THE DRAWINGS
Alternate embodiments of the present invention also permit application of multiple layers of coating material by varying the electroplating voltage to regulate the amount of a first therapeutic agent, at least a second therapeutic agent, and a plating material. These methods of the present invention are time efficient and cost effective because they facilitate the uniform application of multiple layers of coating materials in a single coating process without requiring any intermediate drying step between the application of coating layers. This results in higher process efficiency.
FIG. 1 illustrates an electroplating apparatus for coating medical devices in accordance with a first embodiment of the present invention.
- DETAILED DESCRIPTION
FIG. 2 illustrates an electroplating apparatus for coating medical devices in accordance with an alternative embodiment of the present invention.
FIG. 1 illustrates an apparatus for coating a medical device having a surface in accordance with one embodiment of the present invention. The apparatus in this embodiment, as shown in FIG. 1 and generally designated as 10, provides for depositing a coating on a medical device 20 by electroplating a mixture of a therapeutic agent and a plating material. The coating material is electroplated onto an external surface 21 of medical device 20. The medical device 20 can be, for example, a stent having a patterned external surface as shown in FIG. 1.
As depicted in FIG. 1, the apparatus for coating a medical device by electroplating 10 includes an electroplating cell 30, cathode 40, anode 50, and voltage source 60. The electroplating cell 30 contains an electrolytic solution 31. The portion of the medical device 20 to be coated is positioned in the electrolytic solution 31 within electroplating cell 30 and electrically connected to voltage source 60 with a cathode wire 61. The medical device 20 serves as a cathode 40, or negatively charged electrode, of the electroplating cell 30, and is electrically connected to the negative pole of voltage source 60. Voltage source 60 may be a source that delivers constant or varying voltage. In FIG. 1, voltage source 60 is shown as a battery.
Referring again to FIG. 1, the plating material 51 is also placed in the electrolytic solution 31 and electrically connected to voltage source 60 with an anode wire 62. The plating material 51 serves as an anode 50, or positively charged electrode, of the electroplating cell 30, and is electrically connected to the positive pole of voltage source 60. A person of ordinary skill in the art will appreciate that a variety of electrical connection devices may be used as the cathode wire 61 or anode wire 62, to permit the flow of electrical charges between the voltage source 60 and cathode 40 or anode 50 respectively, such as copper wire or wire made from any other conductive material. The medical device 20 may be made from any bio-compatible metal or alloy. Typically, medical devices, e.g. stents, are made from stainless steel, tantalum, platinum, cobalt chrome alloys, elgiloy or nitinol alloys. The plating material 51 can be the same or different metal or alloy as that of the medical device to be coated. Examples of plating materials include, but are not limited to, gold, titanium, halfnium, zirconium, iridium, alumina, and niobium, as well as the oxides of some of those materials. The plating material may be a noble metal, such as platinum, for radioopacity characteristics.
One of ordinary skill in the art will appreciate that a variety of acid or salt solutions may be used as the electrolytic solution 31 to ionize the therapeutic agent and carry ions of the plating material. The electrolytic solution 31 may be a solution of an acid or salt of the plating metal 51. For example, Pd salt, or Pd(NH3)2(NO2)2, in an ammoniacal bath medium may be used. Solutions containing 5-10 gms/liter of Pd, operated at 40-50 C, using fairly low current density of 0.5 amps/dm2 can produce coatings having 200-300 DPN and a thickness of up to 5 microns. Ammonium phosphate or sulfamate may also be used as conducting salts. In addition, the electrolytic solution may contain Pd chelates. This electrolytic solution may contain 5-10 gms/liter of Pd, buffered with monopotassium phosphate, and can produce very bright coatings over a wide range of operating solution conditions (e.g., pH of 4-12). In addition, an electrolyte containing Pd ammine salts (e.g., Pd(NH3)4×) in a solution of up to 30 gms/liter of Pd maintained at a pH of 9, a temperature of 50 C, and a current density of 4 amps/dm2 may be used to obtain high ductile coatings with low internal stresses at high deposition rates. The properties of the deposited coating may be varied from the previously expressed conditions by varying the electrolyte composition, agitation, temperature, pH, metal loading, current density, and voltage wave form. For example, if a high density coating deposition is desired, the metal ion concentration may be raised, the current densities may be lowered, and a mild to moderate agitation should be introduced. If a porous or less dense deposition is desired, then these same parameters may be changed in the opposite direction. However, a skilled artisan would appreciate that the acid or salt solution selected should not destroy the dissolved therapeutic agent.
Referring to FIG. 1, the portion of the medical device 20 to be coated is immersed in the electrolytic solution 31 in the electroplating cell 30. The medical device 20 may be freely immersed in electrolytic solution 31 or secured by a holder (not shown). The holder can be, for example, an inflatable balloon or a mandrel which secures the medical device by exerting a force upon the internal surface of the medical device, thereby permitting the external surface to be plated. It will be appreciated by one of ordinary skill in the art that a variety of holder devices can be designed to secure the medical device and permit access to portions of surface.
By holding the medical device 20 from its internal surface with a holder extending the length of the medical device, the holder may mask the internal surface, thereby preventing the coating material from adhering to the internal surface, if desired. Alternatively, if it is desired to coat the entire medical device 20, the holder may be omitted. Also, a person of ordinary skill in the art will appreciate that medical device 20 can be masked by a variety of masking methods known in the art to prevent coating certain portions of medical device 20. The holder, as one example, can be an inflatable balloon made with any material that is flexible and resilient. Latex, silicone, polyurethane, rubber (including styrene and isobutylene styrene), and nylon, are each examples of materials that may be used in manufacturing the inflatable balloon.
Forming a coating on medical device 20 by electroplating a mixture of a therapeutic agent and a plating material may be achieved by several methods. In one embodiment, the therapeutic agent is dissolved into the electrolytic solution 31 and dissociated, producing positively and negatively charged drug ions. As one example, the ionization of amiloride, a cationic drug has an excess of positively charged ionized groups that allows it to be attached to the cathode. The positively charged ions of the therapeutic agent are generally illustrated as 70 in FIG. 1 (labeled as “D” for drug, in this embodiment).
The electrolytic solution also ionizes into positively and negatively charged ions. As one example, the electrolytic solution may be Pd(NH3)(NO2)2, which contains positively charged metal ions, Pd++, as generally illustrated as 71 in FIG. 1 (labeled as “M” in this embodiment).
At the anode 50 of the electroplating cell 30, negatively charged electrons are removed from the plating material 51 and flow in the direction depicted by direction arrow A in FIG. 1 from the anode 50 to the cathode 40. The medical device 20, electrically connected to the negative pole of voltage source 60 and positioned as the cathode 40, receives the negatively charged electrons and thereby attracts the positively charged ions 70 and 71 in the electrolytic solution 31. Thus, at the negatively charged cathode 40 of the electroplating cell 30, a coating is formed onto the medical device 20 by electroplating a mixture of the therapeutic agent and plating material.
The plating material 51, electrically connected to the positive pole of voltage source 60, as anode 50, becomes positively charged as electrons are removed. For example, if the plating material 51 were Iron metal, the Iron would oxidize into a positively charged state as electrons travel towards the cathode 40. The Iron metal anode, in its positively charged state, would then dissolve as Fe++ into the electrolytic solution 31, thereby replacing the Fe++ that is plated out of the electrolytic solution 31 (where the solution is FeSO4 which ionizes into Fe++ and SO4 −−) onto the medical device 20. The anode material can either be the metal to be deposited (as in the example above, where the electrode reaction is the electrodissolution of Fe that continuously supplies Fe ions), or the anode can be an inert material where the anodic reaction is oxygen evolution (in which the plating solution may eventually be depleted of metal ions). In some cases, the anode material may not be the same material as the plating material (e.g., Pd), in which case the electroplating reaction reduces metal ions from aqueous, organic, or fused salt electrolytes. This type of reaction at the cathode may generally be represented by the following equation:
M +n +ne − =>M
A corresponding reaction occurs at the anode.
Some examples, among others, of therapeutic agents that may be ionized are cationic drugs, such as amiloride, digoxin, morphine, procainamide, quinidine, quinine, ranitidine, triamterene, trimethoprim, and vancomycin. One of ordinary skill in the art will appreciate that a variety of other acid-stable drugs that may be dissociated in an electrolytic solution into ions may be used. Selection of the drug and plating formulation may be limited to a combination that does not result in the destruction of the drug during the electroplating process. Further, since electroplating, when compared to other processes such as sputtering, may be conducted at ambient or relatively low temperatures, less drug may be destroyed.
In another embodiment, the ratio of metal ions 71 and therapeutic agent ions 70 in the electrolytic solution 31 can be varied to control the amount and concentration of the therapeutic agent in the coating. A skilled artisan can appreciate that the ratio of metal to therapeutic agent ions can be controlled, for example, by initially dissolving a greater concentration of therapeutic agent into the electrolytic solution 31.
In another embodiment, the voltage can be varied to intermittently plate metal and therapeutic agent coating layers. One of ordinary skill in the art will appreciate that the plating material 51 and therapeutic agent may be selected such that they have disparate plating voltages. Thus, alternating coatings of metal and therapeutic agent layers can be achieved by first setting the voltage source 60 at the specific plating voltage for plating metal ions, and then subsequently changing the voltage of voltage source 60 to plate therapeutic agent ions.
In still another embodiment, two or more therapeutic agents with disparate plating voltages may be dissolved and ionized in the electrolytic solution 31. By varying the voltage of voltage source 60 alternately between the different plating voltages, multiple coatings of two or more therapeutic agents may be plated in a unitary coating process step without requiring an intermediate drying step between application of coating layers.
In yet another embodiment, the surface of the medical device is first treated to create a porous layer to increase the amount of the therapeutic agent that may be electroplated onto the medical device. Thereafter, the coating is formed by electroplating the therapeutic agent onto the treated surface and into the pores of the porous layer. Due to the large surface area of the porous structure, large amount of therapeutic agents can be drawn into the pores, and a larger concentration of therapeutic agent can be applied.
The porous layer can be created by several methods, including vapor deposition processes, CVD, PVD, plasma deposition, electroplating, sintering, sputtering or other methods known in the art. The deposited porous material may be the same as the substrate or the metal being electroplated. The amount of plated drug which can be loaded onto the porous layer is much greater than the amount of plated drug that can be loaded onto a flat surface. This is because the pores not only add more surface area upon which to load the plated drug, but also because the volume of the pores are filled with the plated drug. For example, the surface area of I gram of non-porous gold is about 8×10−5 m2/g, whereas the surface area of nanoporous gold made by a de-alloying process is about 2 m2/g. Although this embodiment described above involves a two-step process, by forming the porous layer first at relatively high temperatures, or annealing the substrate at relatively high temperatures to enhance the adhesion, the second step of therapeutic agent plating can be done at a lower temperature or room temperature. The shape of the pores in the porous surface may serve as a means to control the release rate of the therapeutic agent. For example, a pore with a narrow opening and a wide bottom may release drugs more slowly than a pore with a wide opening and a narrow bottom. Also, a pore with a jagged inner surface, or with varying narrow and wide radiuses throughout the depth of the pore, or a pore with an elongated tortuous passageway may also serve to meter the release rate of the drug.
Alternatively, the process of forming the porous layer and plating the therapeutic agent may be conducted in one step. Since the porous layer can be created by electroplating, a mixture of the therapeutic agent and porous plating material may be electroplated in one step similar to the electroplating process described herein.
Also, the coating density may vary depending on the concentration of the therapeutic agent in the coating layer. If the concentration is relatively high, the coating can be denser. Further, the concentration of the therapeutic agent may be higher at the outer surface of the treated layer than the interior porous layers. Thus, more therapeutic agents may be released first from the outer surface once the device is deployed in a patient, which may be preferred. Thereafter, the release can be slower as the therapeutic agent is released from the interior porous layers. One of ordinary skill in the art will appreciate that the concentration of the therapeutic agent in the coating layer can be varied by increasing or decreasing the porosity of the porous layer, which permits more or less of the therapeutic agent to be plated, upon treating the surface of the medical device.
By first treating the surface of the medical device to create an interconnected porous network layer of coating, therapeutic agents may be released in a slow and controlled manner. The therapeutic agent is released through the path in the metal matrix. Further, by creating a nano-porous layer, the therapeutic agent may be applied without a polymer binder. The treatment process of creating a porous layer is further described in the following pending patent applications: “Functional Coatings and Designs for Medical Implants,” by Weber, Holman, Eidenschink and Chen, application Ser. No. 10/759,605; and “Medical Devices Having Nanostructured Regions for Controlled Tissue Biocompatibility and Drug Delivery,” by Helmus, Xu and Ranada, filed on even date with the instant application. These applications are incorporated herein.
In FIG. 2, an apparatus for coating a medical device in accordance with another embodiment of the present invention is illustrated. In this embodiment, generally designated as 20, an electroplating cell 30 is shown which contains an electrolytic solution 31 having metal ions 71 and drug particles, generally illustrated as 72 in FIG. 2, suspended within the electrolytic solution 31. Where the desired therapeutic agent or drug coating cannot be dissolved in the electrolytic solution 31 and become ionized, the therapeutic agent or drug may be produced in fine particles, e.g. nano-meter sized particles, and suspended. During the plating process, these particles will become trapped by the metal ions 71, and will plate to the medical device 20—similar to the way that contamination elements are trapped by plating material ions and become plated to a substrate in conventional electroplating processes. The amount of the therapeutic agent or drug particles 72 that are deposited onto the surface of medical device 20 varies with the concentration of the therapeutic agent or drug suspended in the electrolytic plating solution 31. One of ordinary skill in the art will appreciate that particles of two or more therapeutic agents or drugs may be suspended in the electrolytic solution to allow multiple coatings.
The medical devices used in conjunction with the present invention include any device amenable to the coating processes described herein. The medical device, or portion of the medical device, to be coated or surface modified may be made of metal, polymers, ceramics, composites or combinations thereof. Whereas the present invention is described herein with specific reference to a vascular stent, other medical devices within the scope of the present invention include any devices which are used, at least in part, to penetrate the body of a patient. Non-limiting examples of medical devices according to the present invention include catheters, guide wires, balloons, filters (e.g., vena cava filters), stents, stent grafts, vascular grafts, intraluminal paving systems, soft tissue and hard tissue implants, such as orthopedic reair plates and rods, joint implants, tooth and jaw implants, metallic alloy ligatures, vascular access ports, artificial heart housings, heart valve struts and stents (used in support of biologic heart valves), aneurysm filling coils and other coiled coil devices, trans myocardial revascularization (“TMR”) devices, percutaneous myocardial revascularization (“PMR”) devices, hypodermic needles, soft tissue clips, holding devices, and other types of medically useful needles and closures, and other devices used in connection with drug-loaded polymer coatings. Such medical devices may be implanted or otherwise utilized in body lumina and organs such as the coronary vasculature, esophagus, trachea, colon, biliary tract, urinary tract, prostate, brain, lung, liver, heart, skeletal muscle, kidney, bladder, intestines, stomach, pancreas, ovary, cartilage, eye, bone, and the like. Any exposed surface of these medical devices may be coated with the methods and apparatuses of the present invention.
The coating materials used in conjunction with the present invention are any desired, suitable substances. In some embodiments, the coating materials comprise therapeutic agents, applied to the medical devices alone or in combination with solvents in which the therapeutic agents are at least partially soluble or dispersible or emulsified, and/or in combination with polymeric materials as solutions, dispersions, suspensions, latices, etc. The solvents may be aqueous or non-aqueous. Coating materials with solvents may be dried or cured, with or without added external heat, after being deposited on the medical device to remove the solvent. The therapeutic agent may be any pharmaceutically acceptable agent such as a non-genetic therapeutic agent, a biomolecule, a small molecule, or cells. The coating on the medical devices may provide for controlled release, which includes long-term or sustained release, of a therapeutic agent.
Exemplary non-genetic therapeutic agents include anti-thrombogenic agents such as heparin, heparin derivatives, prostaglandin (including micellar prostaglandin E1), urokinase, and PPack (dextrophenylalanine proline arginine chloromethylketone); anti-proliferative agents such as enoxaprin, angiopeptin, sirolimus (rapamycin), tacrolimus, everolimus, monoclonal antibodies capable of blocking smooth muscle cell proliferation, hirudin, and acetylsalicylic acid; anti-inflammatory agents such as dexamethasone, rosiglitazone, prednisolone, corticosterone, budesonide, estrogen, estrodiol, sulfasalazine, acetylsalicylic acid, mycophenolic acid, and mesalamine; anti-neoplastic/anti-proliferative/anti-mitotic agents such as paclitaxel, epothilone, cladribine, 5-fluorouracil, methotrexate, doxorubicin, daunorubicin, cyclosporine, cisplatin, vinblastine, vincristine, epothilones, endostatin, trapidil, halofuginone, and angiostatin; anti-cancer agents such as antisense inhibitors of c-myc oncogene; anti-microbial agents such as triclosan, cephalosporins, aminoglycosides, nitrofurantoin, silver ions, compounds, or salts; biofilm synthesis inhibitors such as non-steroidal anti-inflammatory agents and chelating agents such as ethylenediaminetetraacetic acid, O,O′-bis(2-aminoethyl)ethyleneglycol-N,N,N′,N′-tetraacetic acid and mixtures thereof, antibiotics such as gentamycin, rifampin, minocyclin, and ciprofolxacin; antibodies including chimeric antibodies and antibody fragments; anesthetic agents such as lidocaine, bupivacaine, and ropivacaine; nitric oxide; nitric oxide (NO) donors such as lisidomine, molsidomine, L-arginine, NO-carbohydrate adducts, polymeric or oligomeric NO adducts; anti-coagulants such as D-Phe-Pro-Arg chloromethyl ketone, an RGD peptide-containing compound, heparin, antithrombin compounds, platelet receptor antagonists, anti-thrombin antibodies, anti-platelet receptor antibodies, enoxaparin, hirudin, warfarin sodium, Dicumarol, aspirin, prostaglandin inhibitors, platelet aggregation inhibitors such as cilostazol and tick antiplatelet factors; vascular cell growth promotors such as growth factors, transcriptional activators, and translational promotors; vascular cell growth inhibitors such as growth factor inhibitors, growth factor receptor antagonists, transcriptional repressors, translational repressors, replication inhibitors, inhibitory antibodies, antibodies directed against growth factors, bifunctional molecules consisting of a growth factor and a cytotoxin, bifunctional molecules consisting of an antibody and a cytotoxin; cholesterol-lowering agents; vasodilating agents; agents which interfere with endogeneus vascoactive mechanisms; inhibitors of heat shock proteins such as geldanamycin; and any combinations and prodrugs of the above.
Exemplary biomolecules include peptides, polypeptides and proteins; oligonucleotides; nucleic acids such as double or single stranded DNA (including naked and cDNA), RNA, antisense nucleic acids such as antisense DNA and RNA, small interfering RNA (siRNA), and ribozymes; genes; carbohydrates; angiogenic factors including growth factors; cell cycle inhibitors; and anti-restenosis agents. Nucleic acids may be incorporated into delivery systems such as, for example, vectors (including viral vectors), plasmids or liposomes.
Non-limiting examples of proteins include monocyte chemoattractant proteins (“MCP-1) and bone morphogenic proteins (“BMP's”), such as, for example, BMP-2, BMP-3, BMP-4, BMP-5, BMP-6 (Vgr-1), BMP-7 (OP-1), BMP-8, BMP-9, BMP-10, BMP-11, BMP-12, BMP-13, BMP-14, BMP-15. Preferred BMPS are any of BMP-2, BMP-3, BMP-4, BMP-5, BMP-6, and BMP-7. These BMPs can be provided as homdimers, heterodimers, or combinations thereof, alone or together with other molecules. Alternatively, or in addition, molecules capable of inducing an upstream or downstream effect of a BMP can be provided. Such molecules include any of the “hedghog” proteins, or the DNA's encoding them. Non-limiting examples of genes include survival genes that protect against cell death, such as anti-apoptotic Bc1-2 family factors and Akt kinase and combinations thereof. Non-limiting examples of angiogenic factors include acidic and basic fibroblast growth factors, vascular endothelial growth factor, epidermal growth factor, transforming growth factor α and β, platelet-derived endothelial growth factor, platelet-derived growth factor, tumor necrosis factor α, hepatocyte growth factor, and insulin like growth factor. A non-limiting example of a cell cycle inhibitor is a cathespin D (CD) inhibitor. Non-limiting examples of anti-restenosis agents include p15, p16, p18, p19, p21, p27, p53, p57, Rb, nFkB and E2F decoys, thymidine kinase (“TK”) and combinations thereof and other agents useful for interfering with cell proliferation.
Exemplary small molecules include hormones, nucleotides, amino acids, sugars, and lipids and compounds have a molecular weight of less than 100 kD.
Exemplary cells include stem cells, progenitor cells, endothelial cells, adult cardiomyocytes, and smooth muscle cells. Cells can be of human origin (autologous or allogenic) or from an animal source (xenogenic), or genetically engineered.
Any of the therapeutic agents may be combined to the extent such combination is biologically compatible.
Any of the above mentioned therapeutic agents may be incorporated into a polymeric coating on the medical device or applied onto a polymeric coating on a medical device. The polymers of the polymeric coatings may be biodegradable or non-biodegradable. Non-limiting examples of suitable non-biodegradable polymers include polyisobutylene copolymers and styrene-isobutylene-styrene block copolymers such as styrene-isobutylene-styrene tert-block copolymers (SIBS); polyvinylpyrrolidone including cross-linked polyvinylpyrrolidone; polyvinyl alcohols, copolymers of vinyl monomers such as EVA; polyvinyl ethers; polyvinyl aromatics; polyethylene oxides; polyesters including polyethylene terephthalate; polyamides; polyacrylamides; polyethers including polyether sulfone; polyalkylenes including polypropylene, polyethylene and high molecular weight polyethylene; polyurethanes; polycarbonates, silicones; siloxane polymers; cellulosic polymers such as cellulose acetate; polymer dispersions such as polyurethane dispersions (BAYHDROL®); squalene emulsions; and mixtures and copolymers of any of the foregoing.
Non-limiting examples of suitable biodegradable polymers include polycarboxylic acid, polyanhydrides including maleic anhydride polymers; polyorthoesters; poly-amino acids; polyethylene oxide; polyphosphazenes; polylactic acid, polyglycolic acid and copolymers and mixtures thereof such as poly(L-lactic acid) (PLLA), poly(D,L,-lactide), poly(lactic acid-co-glycolic acid), 50/50 (DL-lactide-co-glycolide); polydioxanone; polypropylene fumarate; polydepsipeptides; polycaprolactone and co-polymers and mixtures thereof such as poly(D,L-lactide-co-caprolactone) and polycaprolactone co-butylacrylate; polyhydroxybutyrate valerate and blends; polycarbonates such as tyrosine-derived polycarbonates and arylates, polyiminocarbonates, and polydimethyltrimethylcarbonates; cyanoacrylate; calcium phosphates; polyglycosaminoglycans; macromolecules such as polysaccharides (including hyaluronic acid; cellulose, and hydroxypropylmethyl cellulose; gelatin; starches; dextrans; alginates and derivatives thereof), proteins and polypeptides; and mixtures and copolymers of any of the foregoing. The biodegradable polymer may also be a surface erodable polymer such as polyhydroxybutyrate and its copolymers, polycaprolactone, polyanhydrides (both crystalline and amorphous), maleic anhydride copolymers, and zinc-calcium phosphate.
In a preferred embodiment, the polymer is polyacrylic acid available as HYDROPLUS® (Boston Scientific Corporation, Natick, Mass.), and described in U.S. Pat. No. 5,091,205, the disclosure of which is incorporated by reference herein. In a more preferred embodiment, the polymer is a co-polymer of polylactic acid and polycaprolactone.
Such coatings used with the present invention may be formed by any method known to one in the art. For example, an initial polymer/solvent mixture can be formed and then the therapeutic agent added to the polymer/solvent mixture. Alternatively, the polymer, solvent, and therapeutic agent can be added simultaneously to form the mixture. The polymer/solvent mixture may be a dispersion, suspension or a solution. The therapeutic agent may also be mixed with the polymer in the absence of a solvent. The therapeutic agent may be dissolved in the polymer/solvent mixture or in the polymer to be in a true solution with the mixture or polymer, dispersed into fine or micronized particles in the mixture or polymer, suspended in the mixture or polymer based on its solubility profile, or combined with micelle-forming compounds such as surfactants or adsorbed onto small carrier particles to create a suspension in the mixture or polymer. The coating may comprise multiple polymers and/or multiple therapeutic agents.
The release rate of drugs from drug matrix layers is largely controlled, for example, by variations in the polymer structure and formulation, the diffusion coefficient of the matrix, the solvent composition, the ratio of drug to polymer, potential chemical reactions and interactions between drug and polymer, the thickness of the drug adhesion layers and any barrier layers, and the process parameters, e.g., drying, etc. The coating(s) applied by the methods and apparatuses of the present invention may allow for a controlled release rate of a coating substance with the controlled release rate including both long-term and/or sustained release.
The coatings of the present invention are applied such that they result in a suitable thickness, depending on the coating material and the purpose for which the coating(s) is applied. It is also within the scope of the present invention to apply multiple layers of polymer coatings onto the medical device. Such multiple layers may contain the same or different therapeutic agents and/or the same or different polymers, which may perform identical or different functions. Methods of choosing the type, thickness and other properties of the polymer and/or therapeutic agent to create different release kinetics are well known to one in the art.
The medical device may also contain a radio-opacifying agent within its structure to facilitate viewing the medical device during insertion and at any point while the device is implanted. Non-limiting examples of radio-opacifying agents are bismuth subcarbonate, bismuth oxychtoride, bismuth trioxide, barium sulfate, tungsten, and mixtures thereof.
In addition to the previously described coating layers and their purposes, in the present invention the coating layer or layers may be applied for any of the following additional purposes or combination of the following purposes: to alter surface properties such as lubricity, contact angle, hardness, or barrier properties; to improve corrosion, humidity and/or moisture resistance; to improve fatigue, mechanical shock, vibration, and thermal cycling; to change/control composition at surface and/or produce compositionally graded coatings; to apply controlled crystalline coatings; to apply conformal pinhole free coatings; to minimize contamination; to change radiopacity; to impact bio-interactions such as tissue/blood/fluid/cell compatibility, anti-organism interactions (fungus, microbial, parasitic microorganisms), immune response (masking); to control release of incorporated therapeutic agents (agents in the base material, subsequent layers or agents applied using the above techniques or combinations thereof); or any combinations of the above using single or multiple layers.
One of skill in the art will realize that the examples described and illustrated herein are merely illustrative, as numerous other embodiments may be implemented without departing from the spirit and scope of the present invention.