Directed and temporary release of drugs from medical devices

Abstract

The present disclosure relates to multi-layered polymeric systems for the directional and temporal release of drugs from medical devices. Incorporation of drugs into selected layers within the multi-layered polymeric system allows for the release of drugs in a desired direction over a desired time frame. When more than one drug is delivered, the direction, duration and release rate of each drug can be controlled independently of each other. These multi-layered polymeric systems can be used as is or can be installed into various peripheral stent systems such as drug-eluting coronary stent systems and carotid, hepatic, iliac, femoral, popliteal and renal artery stenting. Methods of manufacture are also described.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This disclosure claims priority from a provisional application entitled "Directional and temporal release of drugs from medical devices," filed on January 2, 2022, the entirety of which is incorporated herein by reference.

[0002] The present disclosure relates to the directed and temporal release of drugs from biomedical devices having multiple polymer layers. Specifically, the present invention relates to tailoring the release of drugs over a desired period of time to preferred regions near the stent. More specifically, the present invention relates to minimizing / preventing the release of drugs to regions near the stent whose presence is not required for optimal performance of the stent and / or may not be desirable for a certain period of time. [Background technology]

[0003] Balloon angioplasty, also called percutaneous transluminal coronary angioplasty (PTCA), was introduced in the early 1960s to replace as far as possible more invasive bypass surgery as a treatment for blocked arteries. However, patients undergoing the procedure often experienced reclosure of the vessel. The vessel closure can be short-term (acute reocclusion) and / or long-term (restenosis). Restenosis can be the result of a mechanical reflex, i.e., elastic recoil of the arterial wall, and / or injury to the vessel wall, and / or a natural healing response to the injury to the arterial wall caused by the angioplasty. The net result of the two processes is intimal hyperplasia, which can result in occlusion of the vessel. Restenosis can occur within 3-6 months due to either thrombosis or abnormal tissue growth. All restenosis after balloon angioplasty was one of the major problems that needed to be addressed.

[0004] Bare metal stents (BMS), introduced in the 1980s, partially addressed the problem of restenosis. BMS were intended to provide long-term support to dilated vessels to prevent them from restenosis over time. This often resulted in thrombus formation. Thrombi formed on the stent could detach from the stent and result in blockage elsewhere in the vasculature. To overcome this, patients were subjected to invasive antithrombotic and antiplatelet regimens including the administration of aspirin and clopidogrel for up to two months. However, antithrombotic regimens impair the patient's ability to heal the damage associated with the stent placement procedure or other concomitant procedures that may be required. This required a method to eliminate the invasive antithrombotic therapy that accompanies coronary stent placement.

[0005] Drug-eluting stents (DES) were introduced to alleviate the situation by controlling the proliferation of activated endothelial cells (ECs), accelerating their migration, and covering the stent surface. When ECs formed a continuous, dense membrane, they released nitrous oxide (NO), impeding the proliferation of SMCs. Another aim of drug-eluting stents was to inhibit the proliferation of smooth muscle cells (SMCs), which was achieved by the local release of antiproliferative agents such as paclitaxel or immunosuppressants such as sirolimus from the surface of the stent.

[0006] However, the use of drug-eluting stents often led to reclotting of the arteries due to thrombosis after discontinuation of dual antiplatelet therapy (DAPT), which required DAPT to be extended for 3 to 12 months or more. Patients treated with DAPT required continuous monitoring. This also created problems when DAPT had to be discontinued due to other medical conditions.

[0007] Among other reasons, delayed thrombosis may result from incomplete coating of the stent by ECs, which may leave the metal surface or polymer coating in contact with blood for an extended period of time, during which platelet adhesion may occur and the formation of thrombi may result. It may also result from incomplete release of the drug from the drug layer, which would inhibit the proliferation of ECs that migrate and attempt to cover the surface of the stent and coating layer. The thickness of the stent struts may also hinder the proliferation of ECs. The proliferation rate of ECs is negatively correlated with the height of the obstacles that ECs must overcome. By increasing the thickness of the coating layer, the thickness of the coated stent is increased overall, which may lead to problems with cracking, peeling, or detachment of the coating from the stent surface. An overview of previous efforts to address these issues is presented below.

[0008] US Pat. No. 5,873,313 describes the spray coating of medical devices with fine particles of heparin using a pressurized airbrush.

[0009] U.S. Patent No. 5,716,981 discloses a stent coated with a polymer carrier and paclitaxel. U.S. Patent Nos. 6,479,654, 6,475,779 and 6,363,938 describe the use of stents to deliver angiogenic agents. U.S. Patent Nos. 6,071,514 and 5,383,928 disclose the delivery of antithrombotic agents (antiplatelet agents). U.S. Patent No. 6,071,514 and 5,383,928. U.S. Patent No. 6,273,908 discloses the delivery of anticoagulant agents.

[0010] US Pat. No. 6,663,662 describes a multi-layer medical device coating incorporating a polymeric diffusion barrier layer for reducing the elution rate of a drug incorporated therein.

[0011] U.S. Patent Application Publication No. 2002 / 0082680 describes an expandable medical device having multiple drug-containing layers stacked within the openings of the struts, each layer containing different sized drug particles to tailor the release rate of the drug from the device.

[0012] US Pat. No. 6,770,729 discloses a medical device coating that includes a polymer and a bioactive material to enable its controlled release from the coating layer.

[0013] US Patent Application Publication No. 2005 / 0095267 describes an implantable medical device having a nanoparticle drug coating to improve drug solubility.

[0014] US Patent Publication No. 20050010170 describes applying a first homogeneous solution containing a drug and a polymer to an implantable medical device, followed by applying a second homogeneous solution containing a drug and a polymer thereon, the drug concentrations in the two polymer solutions being different.

[0015] US Patent Application Publication No. 2004 / 0073294 describes a system and method for loading drugs into the pores of a stent from a drug solution. The loaded stent is dried in an oven and then subsequent deposits are applied in a similar manner to achieve the desired drug release profile.

[0016] US 2006 / 0222755 discloses loading a drug into the holes of a stent, where the drug is in the form of a thin film that is loaded by punching. A multi-layer sheet of drug can be formed by incorporating layers of drug, drug / polymer, and polymer. A multi-layer sheet can be formed with layers of the same drug with different compositions or concentrations in the layers, or by incorporating different drugs in each layer to release different drugs at different times.

[0017] US Patent No. 7,169,179 discloses a stent having openings for directional delivery of multiple drugs to a blood vessel. The delivery of different drugs, such as anti-restenosis, anti-thrombotic, anti-platelet, anti-proliferative, anti-neoplastic, immunosuppressant, angiogenic, anti-inflammatory, or anti-angiogenic drugs, in different amounts, directions, and rates for delivering drugs and / or vasodilators to a blood vessel was disclosed.

[0018] U.S. Patent Application Publication No. 2011 / 0045055 discloses an implantable or insertable medical device that can delay the release of one or more drugs for a predetermined period of time after the device is implanted. This is accomplished by incorporating a temporary barrier layer that initially allows little or no release of the drug, and then releasing the drug according to a predetermined rate as a result of breakdown of the barrier layer.

[0019] US Patent No. 7,927,650 describes problems associated with the use of coatings for the delivery of drugs from stents. Surface coatings may offer little real control over drug release kinetics. The coatings are very thin, typically 5-8μ. The surface area of ​​the stent is very large in comparison, so the drug has a very short diffusion path for release to the surrounding tissue. Increasing the thickness of the coating may provide better control over the release kinetics, allowing for higher drug loading, but with the risk of cracking, delaminating and falling off of the coating from the stent surface. The patent disclosed loading the drug in powder form into the pores of the stent device, which is subsequently treated with a solvent to ensure adhesion of the drug within the pores.

[0020] U.S. Pat. No. 8,734,829 discloses a medical device that includes a substrate, a region on the substrate that contains a drug, a nanoporous polymeric layer disposed on the drug-containing region, and a microporous non-polymeric layer disposed on the nanoporous polymeric layer.

[0021] U.S. Patent Application Publication No. 2014 / 0288122 discloses a method of inhibiting platelet aggregation in a patient by administering to the patient a bolus injection of about 25 μg / kg of tirofiban, and administering to the patient an intravenous infusion of tirofiban at a rate of about 0.15 μg / kg / min for about 12 to about 72 hours after the bolus injection.

[0022] US Patent No. 8,932,345 discloses a medical device coating that releases a drug at different rates from different regions of the medical device coating. Drug-containing particles of two or more different particle sizes are incorporated into a monolayer on the surface of the implantable device. The drug concentration is higher in a first region of the coating than in a second region of the coating. Such coatings are formed by a process in which the droplet size of the spray coating solution is altered during the coating process.

[0023] US Patent Publication No. 2021 / 0361449 describes a drug-eluting stent, methods of making, using, and altering the long-term stability of a drug-eluting stent, which may include a stent framework, a drug-containing layer, a drug embedded in the drug-containing layer, and a biocompatible base layer disposed on the stent framework and supporting the drug-containing layer. The thickness of the drug-containing layer may vary. The drug-containing layer may dissolve between 45 and 60 days after stent implantation.

[0024] From a clinical perspective, clot formation in the luminal region can result from acute stent thrombosis, which occurs within hours of stent implantation, and subacute and delayed stent thrombosis, which can occur up to 30 days or more after stent implantation. Dual antiplatelet therapy can be administered to overcome thrombosis, but is known to result in increased bleeding. DAPT has been reported to be less effective in addressing the problem in cases of intracranial biomedical devices. Some patient populations are resistant to DAPT.

[0025] Tirofiban is a platelet GP IIb / IIIa inhibitor and a potent antiplatelet aggregation agent. After systemic administration, it can inhibit platelet aggregation by up to 96%, which can reduce the incidence of major adverse cardiac events (MACE / MACCE), but increases the risk of bleeding. Intracoronary injection of tirofiban prevents platelet aggregation and microcirculatory dysfunction during stent placement in patients with acute myocardial intervention (AMI), as well as delayed percutaneous coronary intervention (PCI). Local sustained release of tirofiban HCl via a biomedical device in the luminal area will prevent acute, subacute and delayed thrombosis and bleeding risk.

[0026] Dysfunctional vascular endothelium leads to stent restenosis in the absence of antithrombotic and antiatherogenic properties (drugs). This endothelial dysfunction triggers vascular smooth muscle cell (VMSC) proliferation. As a result, VMSCs proliferate excessively, leading to occlusion of the vessel over time. Although drug-eluting stents reduce the rate of restenosis compared to bare metal stents, there is concern that DES may be associated with a higher risk of late and very late stent thrombosis, especially in the absence of DAPT or when DAPT is discontinued.

[0027] Sirolimus is an immunosuppressant that inhibits VMSC proliferation. Sustained release of sirolimus over an extended period of time in the abluminal region would help limit the overgrowth of VMSC into blood vessels. This can be achieved by limiting the loss of sirolimus into the luminal region. Thus, there is a need for directed and temporal release of both tirofiban and sirolimus from biomedical devices. Such a delivery system would find further application in other coated biomedical devices for the release of antithrombotic agents, vasodilators, vasorelaxants and antiproliferative agents in the luminal region, anti-inflammatory agents, steroids, vasodilators, vasorelaxants, lipid-lowering agents in the abluminal region. Summary of the Invention

[0028] It has now been surprisingly found that directional and temporal release of drugs can be achieved by a stent coated with multiple polymer layers. More specifically, it has been found that drug release can be minimized or inhibited in areas where its presence may not be needed or desired. This helps to extend the duration of drug release to areas where its presence is desired. Furthermore, the drug release kinetics from multiple polymer layers can be controlled.

[0029] Various embodiments of the present disclosure are described below, which are intended to illustrate the present disclosure and not to limit the scope of the disclosure.

[0030] 1. According to one embodiment of the present disclosure, a biomedical device coated with multiple polymer layers comprises at least one hydrophilic drug and one hydrophobic drug, wherein the hydrophobic drug is contained in at least one hydrophobic polymer layer.

[0031] 2. According to one embodiment of the present disclosure, the biomedical device coated with multiple polymer layers is selected from a stent, graft, balloon, catheter, filter or mesh-like structure, other similar intravascular device.

[0032] 3. According to one embodiment of the present disclosure, the multi-polymer layer coated stent of the present disclosure comprises a bilayer formed by sequentially coating two hydrophobic polymers, and the release of a water-soluble drug is controlled by the molecular weight at which the drug is incorporated (as reflected by the intrinsic viscosity of the polymer).

[0033] 4. According to one embodiment of the present disclosure, the multi-polymer layer coated stent of the present disclosure comprises a bilayer formed by coating a hydrophilic polymer containing a water-soluble drug and a hydrophobic polymer, where the release of the drug is controlled by molecular weight (as reflected by the K value of the hydrophilic polymer).

[0034] 5. According to one embodiment of the present disclosure, the multi-polymer layer coated stent of the present disclosure comprises a bilayer formed by coating two hydrophobic polymers, and the release of a water-soluble drug is modified by the hydrophobicity of the polymer in which the drug is incorporated.

[0035] 6. According to one embodiment of the present disclosure, the multi-polymer layer coated stent of the present disclosure comprises a bilayer formed by coating a hydrophobic polymer followed by coating a hydrophobic polymer containing a hydrophobic drug, where the hydrophobic drug is preferentially released in the abluminal region.

[0036] 7. According to one embodiment of the present disclosure, the multi-polymer layer coated stent of the present disclosure comprises a bilayer formed by coating a hydrophobic polymer followed by coating a hydrophobic polymer containing a hydrophobic drug, wherein the cumulative release of the hydrophobic drug in the luminal region is less than 5% over 6 hours.

[0037] 8. According to one embodiment of the present disclosure, the multi-polymer layer coated stent of the present disclosure comprises a bilayer formed by coating a hydrophobic polymer followed by coating a hydrophobic polymer containing a hydrophobic drug, wherein the cumulative release of the hydrophobic drug in the luminal region is less than 6% over 24 hours.

[0038] 9. According to one embodiment of the present disclosure, the multi-polymer layer coated stent of the present disclosure comprises a bilayer formed by coating a hydrophobic polymer followed by coating a hydrophobic polymer containing a hydrophobic drug, wherein the cumulative release of the hydrophobic drug in the luminal region is less than 20% in 14 days.

[0039] 10. According to one embodiment of the present disclosure, the multi-polymer layer coated stent of the present disclosure comprises a bilayer formed by coating a hydrophobic polymer followed by coating a hydrophobic polymer containing a hydrophobic drug, wherein the cumulative release of the hydrophobic drug over a 24 day period is about 50%.

[0040] 11. According to one embodiment of the present disclosure, the multi-polymer layer coated stent of the present disclosure comprises a bilayer formed by coating a hydrophobic polymer followed by coating a blend of two hydrophobic polymers containing a hydrophobic drug, and the cumulative release of the hydrophobic drug over a 24 day period is 75%.

[0041] 12. According to one embodiment of the present disclosure, the multi-polymer layer coated stent of the present disclosure comprises a bilayer formed by coating a hydrophobic polymer followed by coating a blend of a hydrophobic polymer and a hydrophilic polymer containing a hydrophobic drug, and the cumulative release of the hydrophobic drug over a 24 day period is 77%.

[0042] 13. According to one embodiment of the present disclosure, the multi-polymer layer coated stent of the present disclosure comprises a bilayer formed by coating a hydrophilic drug with a hydrophobic polymer layer followed by coating a hydrophobic polymer layer, wherein less than 10% of the hydrophilic drug is cumulatively released in the abluminal region in 24 hours.

[0043] 14. According to one embodiment of the present disclosure, the multi-polymer layer coated stent of the present disclosure comprises a triple layer formed by coating a composition comprising a hydrophilic drug and a hydrophilic polymer, followed by coating a hydrophobic polymer, followed by coating a hydrophobic polymer containing a hydrophobic drug, wherein less than 1% of the hydrophobic drug is cumulatively released in the luminal region for up to 24 hours.

[0044] 15. According to one embodiment of the present disclosure, the multi-polymer layer coated stent of the present disclosure comprises a triple layer formed by coating a composition comprising a hydrophilic drug and a hydrophilic polymer, followed by coating a hydrophobic polymer, followed by coating a hydrophobic polymer containing a hydrophobic drug, wherein the hydrophilic drug is preferentially released in the luminal region.

[0045] 16. According to one embodiment of the present disclosure, a multi-polymer layer coated stent of the present disclosure comprises a triple layer formed by coating a composition comprising a hydrophilic drug and a hydrophilic polymer, followed by coating a hydrophobic polymer, followed by coating a hydrophobic polymer containing a hydrophobic drug, wherein 32-74% of the hydrophobic drug is cumulatively released in the abluminal region over 21 days.

[0046] 17. According to one embodiment of the present disclosure, the multi-polymer layer coated stent of the present disclosure comprises a triple layer formed by coating a composition comprising a hydrophilic drug and a hydrophilic polymer, followed by coating a hydrophobic polymer, followed by coating a hydrophobic polymer containing a hydrophobic drug, and 21-28% of the hydrophobic drug is cumulatively released in the luminal region over 21 days.

[0047] 18. According to one embodiment of the present disclosure, the multi-polymer layer coated stent of the present disclosure comprises a triple layer formed by coating a composition comprising a hydrophilic drug and a hydrophilic polymer, followed by coating a hydrophobic polymer, followed by coating a hydrophobic polymer containing a hydrophobic drug, and 68-98% of the hydrophilic drug is cumulatively released in the luminal region over a period of 9 days.

[0048] 19. According to one embodiment of the present disclosure, the multi-polymer layer coated stent of the present disclosure comprises a triple layer formed by coating a composition comprising a hydrophilic drug and a hydrophobic polymer, followed by coating a hydrophobic polymer, followed by coating a hydrophobic polymer containing a hydrophobic drug, and 40-46% of the hydrophilic drug is cumulatively released in the luminal region over 30 days.

[0049] 20. According to one embodiment of the present disclosure, the multi-polymer layer coated stent of the present disclosure comprises a triple layer formed by coating a composition comprising a hydrophilic drug and a hydrophobic polymer, followed by coating a hydrophobic polymer, followed by coating a hydrophobic polymer containing a hydrophobic drug, wherein 40-65% of the hydrophobic drug is cumulatively released in the abluminal region over 30 days.

[0050] 21. According to one embodiment of the present disclosure, the multi-polymer layer coated stent of the present disclosure comprises a triple layer formed by coating a composition comprising a hydrophilic drug and a hydrophilic polymer, followed by coating a composition comprising a hydrophilic drug and a hydrophobic polymer, followed by coating a hydrophobic polymer containing a hydrophobic drug, wherein the hydrophilic drug is not released in the abluminal region.

[0051] 22. According to one embodiment of the present disclosure, the multi-polymer layer coated stent of the present disclosure comprises four layers formed by coating a composition comprising a hydrophilic drug and a hydrophilic polymer, followed by coating a composition comprising a hydrophilic drug and a hydrophobic polymer, followed by coating a hydrophobic polymer layer, followed by coating a layer containing a hydrophobic drug and a hydrophobic polymer, wherein the hydrophobic drug is not released in the luminal region for up to at least 24 hours.

[0052] 23. According to one embodiment of the present disclosure, a multi-polymer layer coated stent of the present disclosure comprises four layers formed by coating a composition comprising a hydrophilic drug and a hydrophilic polymer, followed by coating a composition comprising a hydrophilic drug and a hydrophobic polymer, followed by coating a hydrophobic polymer layer, followed by coating a layer containing a hydrophobic drug and a hydrophobic polymer, wherein 75% of the hydrophobic drug is cumulatively released in the abluminal region over a period of 30 days.

[0053] 24. According to one embodiment of the present disclosure, a multi-polymer layer coated stent of the present disclosure comprises four layers formed by coating a composition comprising a hydrophilic drug and a hydrophilic polymer, followed by coating a composition comprising a hydrophilic drug and a hydrophobic polymer, followed by coating a hydrophobic polymer layer, followed by coating a layer containing a hydrophobic drug and a hydrophobic polymer, and 64% of the hydrophilic drug is cumulatively released in the luminal region in 30 days.

[0054] 25. According to one embodiment of the present disclosure, the multi-polymer layer coated stent of the present disclosure comprises four layers formed by coating a composition comprising a hydrophilic drug and a hydrophilic polymer, followed by coating a composition comprising a hydrophilic drug and a hydrophobic polymer, followed by coating a hydrophobic polymer layer, followed by coating a layer containing a hydrophobic drug and a hydrophobic polymer, wherein the hydrophilic drug in the hydrophilic polymer layer and the hydrophilic drug in the hydrophobic polymer layer are different.

[0055] 26. According to one embodiment of the present disclosure, a multi-polymer layer coated stent of the present disclosure comprises a bilayer formed by coating a hydrophobic polymer containing a water soluble drug, followed by a coating comprising a blend of a hydrophobic drug and a hydrophobic polymer, and the stent administered to a mammal inhibits thrombus formation for up to at least 10 days.

[0056] 27. According to one embodiment of the present disclosure, a multi-polymer layer coated stent of the present disclosure comprises a bilayer formed by coating a hydrophobic polymer containing a hydrophilic drug, followed by a coating comprising a blend of a hydrophobic drug and a hydrophobic polymer, and the stent administered to a mammal inhibits neointimal growth for up to at least 10 days.

[0057] 28. According to one embodiment of the present disclosure, the coated stent of the present disclosure comprises a bilayer formed by coating a hydrophobic polymer containing a water soluble drug, followed by another coating comprising a blend of a hydrophobic drug and a hydrophobic polymer, and the stent administered to a mammal shows endothelialization before 10 days and before 28 days.

[0058] 29. According to one embodiment of the present disclosure, the hydrophilic polymer is polyvinylpyrrolidone.

[0059] 30. According to one embodiment of the present disclosure, the hydrophilic drug is selected from the classes of antithrombotic agents, anticoagulants, antiplatelet agents, vasodilators, vasorelaxants, antihypertensive agents, cells, antibodies, peptides, elastin, and blood compatibility promoters.

[0060] 31. According to one embodiment of the present disclosure, an antithrombotic agent selected from argatroban, inogatran, melagatran and pharma- ceutically acceptable derivatives thereof.

[0061] 32. According to one embodiment of the present disclosure, an anticoagulant selected from warfarin / coumarin and derivatives thereof, vitamin K antagonists, heparin and derivatives thereof, low molecular weight heparin (LMWH) and derivatives thereof, such as bemiparin, nadroparin, reviparin, enoxaparin, parnaparin, certoparin, dalteparin, tinzaparin, synthetic pentasugar derivatives (Factor Xa inhibitors), such as fondaparinux, idraparinux, idrabiotaparinux.

[0062] 33. According to one embodiment of the present disclosure, an antiplatelet drug selected from the class of irreversible cyclooxygenase inhibitors, e.g., aspirin, triflunisal (Disglen); 34. According to one embodiment of the present disclosure, an antiplatelet drug selected from the class of adenosine diphosphate (ADP) receptor inhibitors, e.g., cangrelor, clopidogrel, prasugrel, ticagrelor, ticlopidine; 35. According to one embodiment of the present disclosure, an antiplatelet agent selected from the class of phosphodiesterase inhibitors, e.g., cilostazol.

[0063] 36. According to one embodiment of the present disclosure, an antiplatelet agent selected from the class of protease-activated receptor 1 (PAR-1) antagonists, such as vorapaxar.

[0064] 37. According to one embodiment of the present disclosure, an antiplatelet agent selected from the class of glycoprotein IIB / IIIA inhibitors, such as abciximab, eptifibatide, tirofiban, etc.

[0065] 38. According to one embodiment of the present disclosure, an antiplatelet agent selected from the class of adenosine reuptake inhibitors, such as dipyridamole.

[0066] 39. According to one embodiment of the present disclosure, an antiplatelet agent selected from the class of thromboxane inhibitors / thromboxane synthase inhibitors, e.g., terutroban.

[0067] 40. According to one embodiment of the present disclosure, the antihypertensive agent is selected from diuretics, beta blockers, ACE inhibitors, angiotensin II receptor blockers, calcium channel blockers, alpha blockers, alpha-2 receptor agonists.

[0068] 41. According to one embodiment of the present disclosure, a vasodilator selected from nitric oxide and its derivatives or precursors, prostaglandins, adenosine, minoxidil, etc.; 42. According to one embodiment of the present disclosure, a vasorelaxant selected from hydralazine, minoxidil.

[0069] 43. According to one embodiment of the present disclosure, a blood compatibility enhancer selected from the group of compounds that act on the coagulation mechanism, the hemolysis mechanism, such as heparin surface coating, etc.

[0070] 44. According to one embodiment of the present disclosure, the hydrophobic polymer is selected from poly-ε-caprolactone (PCL), polylactide-co-ε-caprolactone (PLCL), polylactic acid (PLA), polylactide-co-glycolide (PLGA).

[0071] 45. According to one embodiment of the present disclosure, the hydrophobic drug is selected from the classes of antiproliferative agents, anti-inflammatory agents, antibiotics, bioactive molecules, vasodilators and vasorelaxants.

[0072] 46. ​​According to one embodiment of the present disclosure, an antiproliferative / cytostatic / cytostatic chemotherapeutic agent, for example an antiproliferative agent selected from rapamycin, everolimus, zotarolimus, paclitaxel, etc.; 47. According to one embodiment of the present disclosure, an anti-inflammatory drug selected from aspirin, naproxen, Cox2 inhibitors, such as celecoxib, rofecoxib, and steroids, such as dexamethasone; 48. According to one embodiment of the present disclosure, a vasodilator selected from nitric oxide and its derivatives or precursors, prostaglandins, adenosine, minoxidil, etc.; 49. According to one embodiment of the present disclosure, a vasorelaxant selected from hydralazine, minoxidil.

[0073] Objects and advantages of the present invention will become apparent from the following description read in conjunction with the accompanying drawings. [Brief description of the drawings]

[0074] [Figure 1] FIG. 1 shows the release of tirofiban HCl from dual layer coated stents 1a, 1b and 1c of Example 1 using a rolling bottle apparatus. [Diagram 2]FIG. 13 shows the release of aspirin, tirofiban hydrochloride and clopidogrel sulfate from rolling bottle and tube devices of dual layer coated stents 2a, 2b and 2c of Example 2. [Figure 3a] FIG. 13 shows the release of tirofiban HCl from the rolling bottle and tube apparatus of dual layer coated stents 3a and 3b of Example 3. [Figure 3b] FIG. 13 shows the release of tirofiban HCl from rotating bottle and tube devices of dual layer coated stents 3c and 3d of Example 3. [Figure 4] FIG. 1 shows the release of sirolimus, everolimus and dexamethasone acetate from rolling bottle and tube apparatus of dual layer coated stents 4a, 4b, 4c and 4d of Example 4. [Diagram 5] FIG. 1 shows the release of sirolimus, everolimus and dexamethasone acetate from rolling bottle and tube devices of dual layer coated stents 5a, 5b and 5c of Example 5. [Figure 6] FIG. 1 shows the release of everolimus and sirolimus from a rotating bottle apparatus for bilayer coated stents 6a, 6b and 6c of Example 6. [Figure 7] FIG. 13 shows the release of dexamethasone acetate from the rolling bottle and tube devices of dual layer coated stent 7 of Example 7. [Figure 8] FIG. 13 shows the release of clopidogrel sulfate, argatroban and tirofiban HCl from rotating bottle and tube devices of dual layer coated stents 8a, 8b and 8c of Example 8. [Figure 9] FIG. 13 shows the release of sirolimus from rolling bottle and tube devices of triple layer coated stents 9a, 9b, 9c and 9d of Example 9. [Figure 10] FIG. 13 shows the release of tirofiban HCl and aspirin from rolling bottle and tube devices of triple layer coated stents 9a, 9b, 9c and 9d of Example 9. [Figure 11]FIG. 13 shows the release of tirofiban HCl from rolling bottle and tube apparatus for triple layer coated stents 10a, 10b, 10c and 10d of Example 10. [Figure 12] FIG. 13 shows the release of sirolimus from rolling bottle and tube devices of triple layer coated stents 10a, 10b, 10c and 10d of Example 10. [Figure 13] FIG. 13 shows the release of tirofiban HCl and aspirin from rolling bottle and tube devices of triple layer coated stents 11a, 11b and 11c of Example 11. [Figure 14] FIG. 13 shows the release of tirofiban hydrochloride and sirolimus from the rolling bottle and tube apparatus of the four-layer coated stent 12 of Example 12. [Figure 15] FIG. 13 shows the release of tirofiban HCl, aspirin and sirolimus from the rolling bottle and tube devices of the four-layer coated stent 13 of Example 13. [Figure 16] FIG. 13 shows the release of sirolimus and tirofiban from the rotating bottle and tube devices of the single layer coated stent 14 of Example 14. [Figure 17] FIG. 1 shows the release of sirolimus and tirofiban HCl from the rolling bottle apparatus. [Figure 18] FIG. 1 shows histopathological evaluation of stents coated with multiple polymer layers containing sirolimus and tirofiban HCl administered in pigs. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0075] References herein to an "embodiment" or "one embodiment" mean that a particular feature, structure, characteristic, or function described in connection with the embodiment is included in at least one embodiment of the invention. The appearances of the phrase "in one embodiment" in various places in the specification do not necessarily all refer to the same embodiment.

[0076] References in this specification to a "preferred embodiment" mean that a particular feature, structure, characteristic, or function has been described in detail, thereby omitting known configurations and functions for the sake of a clear description of the present invention.

[0077] The foregoing descriptions of specific embodiments of the invention have been presented for purposes of illustration and description. They are not intended to be exhaustive or to limit the invention to the precise forms disclosed, and obviously many modifications and variations are possible in light of the above teaching.

[0078] Balloon angioplasty has emerged as a minimally invasive alternative to bypass surgery in many situations. The problems associated with balloon angioplasty have been alleviated by bare metal stents and subsequently by drug-eluting stents. However, drug-eluting stents still have limitations. Approaches to overcome these are summarized in the prior art. In this background, it has now surprisingly been found that drug release kinetics can be controlled from stents coated with multiple polymer layers. According to the present disclosure, the direction of release is controlled by the selection of the hydrophobic polymer layer and its location within the multiple layers. The duration of drug release is controlled by the selection of the polymer layer in which the drug is incorporated. A detailed description illustrating various aspects of the present disclosure, but without being limiting, is provided in the following paragraphs.

[0079] definition As used herein, "directional release" refers to the release of a drug from the surface of the medical device toward a desired direction or side of the artery, either in the luminal or abluminal region. In the case of multiple drugs, the direction of release may be different or the same.

[0080] As used herein, "temporary release" refers to the controlled release of a drug from the surface of a medical device over a desired time frame. When two or more drugs are used, the desired time frames are different from each other. The desired time frames may be different for the same drug in different situations.

[0081] As used herein, the phrase "preferentially released" means that the release of drug in a desired area is greater than the release in another area.

[0082] As used herein, "hydrophobic polymer" refers to a polymer that can be coated from a solvent that is not miscible with water.

[0083] For copolymers of lactic acid and glycolic acid that contain both hydrophobic and hydrophilic monomers, copolymers with a higher lactic acid content are considered to be more hydrophobic than copolymers with a lower lactic acid content.

[0084] As used herein, "hydrophilic polymer" refers to a polymer that can be coated from a solvent that is water-miscible.

[0085] Those skilled in the art know that the molecular weight of polymers is directly related to their intrinsic viscosity. In the case of polyvinylpyrrolidone, a higher K value indicates a higher molecular weight.

[0086] As used herein, the term hydrophobic drug refers to a drug that is soluble in a solvent that is immiscible with water.

[0087] Various embodiments of the present disclosure are described below, which are intended to illustrate the present disclosure and not to limit the scope of the disclosure.

[0088] According to one embodiment of the present disclosure, a multi-polymer layer coated biomedical device comprises at least one hydrophilic drug and one hydrophobic drug, the hydrophobic drug being contained in at least one hydrophobic polymer layer.

[0089] According to one embodiment of the present disclosure, the biomedical device coated with the multiple polymer layers is selected from a stent, graft, balloon, catheter, filter or mesh-like structure, other similar intravascular device.

[0090] According to one embodiment of the present disclosure, the multi-polymer layer coated stent of the present disclosure comprises a bilayer formed by sequentially coating two hydrophobic polymers, and the release of a water-soluble drug is controlled by the molecular weight at which the drug is incorporated (as reflected by the intrinsic viscosity of the polymer).

[0091] According to one embodiment of the present disclosure, the multi-polymer layer coated stent of the present disclosure comprises a bilayer formed by coating a hydrophilic polymer containing a water-soluble drug and a hydrophobic polymer, where the release of the drug is controlled by molecular weight (as reflected by the K value of the hydrophilic polymer).

[0092] According to one embodiment of the present disclosure, the multi-polymer layer coated stent of the present disclosure comprises a bilayer formed by coating two hydrophobic polymers, and the release of a water-soluble drug is modified by the hydrophobicity of the polymer in which the drug is incorporated.

[0093] According to one embodiment of the present disclosure, the multi-polymer layer coated stent of the present disclosure comprises a bilayer formed by coating a hydrophobic polymer followed by coating a hydrophobic polymer containing a hydrophobic drug, where the hydrophobic drug is preferentially released in the abluminal region.

[0094] According to one embodiment of the present disclosure, the multi-polymer layer coated stent of the present disclosure comprises a bilayer formed by coating a hydrophobic polymer followed by coating a hydrophobic polymer containing a hydrophobic drug, wherein the cumulative release of the hydrophobic drug in the luminal region is less than 5% over 6 hours.

[0095] According to one embodiment of the present disclosure, the multi-polymer layer coated stent of the present disclosure comprises a bilayer formed by coating a hydrophobic polymer followed by coating a hydrophobic polymer containing a hydrophobic drug, wherein the cumulative release of the hydrophobic drug in the luminal region is less than 6% over 24 hours.

[0096] According to one embodiment of the present disclosure, the multi-polymer layer coated stent of the present disclosure comprises a bilayer formed by coating a hydrophobic polymer followed by coating a hydrophobic polymer containing a hydrophobic drug, wherein the cumulative release of the hydrophobic drug in the luminal region is less than 20% in 14 days.

[0097] According to one embodiment of the present disclosure, the multi-polymer layer coated stent of the present disclosure comprises a bilayer formed by coating a hydrophobic polymer followed by coating a hydrophobic polymer containing a hydrophobic drug, and the cumulative release of the hydrophobic drug over a 24 day period is about 50%.

[0098] According to one embodiment of the present disclosure, the multi-polymer layer coated stent of the present disclosure comprises a bilayer formed by coating a hydrophobic polymer followed by coating a blend of two hydrophobic polymers containing a hydrophobic drug, with a cumulative release of the hydrophobic drug of 75% over a 24 day period.

[0099] According to one embodiment of the present disclosure, a multi-polymer layer coated stent of the present disclosure comprises a bilayer formed by coating a hydrophobic polymer followed by coating a blend of a hydrophobic polymer and a hydrophilic polymer containing a hydrophobic drug, and the cumulative release of the hydrophobic drug over a 24 day period is 77%.

[0100] According to one embodiment of the present disclosure, the multi-polymer layer coated stent of the present disclosure comprises a bilayer formed by coating a hydrophilic drug with a hydrophobic polymer layer followed by coating a hydrophobic polymer layer, wherein less than 10% of the hydrophilic drug is cumulatively released in the abluminal region in 24 hours.

[0101] According to one embodiment of the present disclosure, the multi-polymer layer coated stent of the present disclosure comprises a triple layer formed by coating a composition comprising a hydrophilic drug and a hydrophilic polymer, followed by coating a hydrophobic polymer, followed by coating a hydrophobic polymer containing a hydrophobic drug, wherein less than 1% of the hydrophobic drug is cumulatively released in the luminal region for up to 24 hours.

[0102] According to one embodiment of the present disclosure, the multi-polymer layer coated stent of the present disclosure comprises a triple layer formed by coating a composition comprising a hydrophilic drug and a hydrophilic polymer, followed by coating a hydrophobic polymer, followed by coating a hydrophobic polymer containing a hydrophobic drug, where the hydrophilic drug is preferentially released in the luminal region.

[0103] According to one embodiment of the present disclosure, a multi-polymer layer coated stent of the present disclosure comprises a triple layer formed by coating a composition comprising a hydrophilic drug and a hydrophilic polymer, followed by coating a hydrophobic polymer, followed by coating a hydrophobic polymer containing a hydrophobic drug, wherein 32-74% of the hydrophobic drug is cumulatively released in the abluminal region over 21 days.

[0104] According to one embodiment of the present disclosure, the multi-polymer layer coated stent of the present disclosure comprises a triple layer formed by coating a composition comprising a hydrophilic drug and a hydrophilic polymer, followed by coating a hydrophobic polymer, followed by coating a hydrophobic polymer containing a hydrophobic drug, and 21-28% of the hydrophobic drug is cumulatively released in the luminal region over 21 days.

[0105] According to one embodiment of the present disclosure, the multi-polymer layer coated stent of the present disclosure comprises a triple layer formed by coating a composition comprising a hydrophilic drug and a hydrophilic polymer, followed by coating a hydrophobic polymer, followed by coating a hydrophobic polymer containing a hydrophobic drug, and 68-98% of the hydrophilic drug is cumulatively released in the luminal region over a period of 9 days.

[0106] According to one embodiment of the present disclosure, the multi-polymer layer coated stent of the present disclosure comprises a triple layer formed by coating a composition comprising a hydrophilic drug and a hydrophobic polymer, followed by coating a hydrophobic polymer, followed by coating a hydrophobic polymer containing a hydrophobic drug, and 40-46% of the hydrophilic drug is cumulatively released in the luminal region over a 30 day period.

[0107] According to one embodiment of the present disclosure, the multi-polymer layer coated stent of the present disclosure comprises a triple layer formed by coating a composition comprising a hydrophilic drug and a hydrophobic polymer, followed by coating a hydrophobic polymer, followed by coating a hydrophobic polymer containing a hydrophobic drug, wherein 40-65% of the hydrophobic drug is cumulatively released in the abluminal region over a 30 day period.

[0108] According to one embodiment of the present disclosure, the multi-polymer layer coated stent of the present disclosure comprises a triple layer formed by coating a composition comprising a hydrophilic drug and a hydrophilic polymer, followed by coating a composition comprising a hydrophilic drug and a hydrophobic polymer, followed by coating a hydrophobic polymer containing a hydrophobic drug, wherein the hydrophilic drug is not released in the abluminal region.

[0109] According to one embodiment of the present disclosure, the multi-polymer layer coated stent of the present disclosure comprises four layers formed by coating a composition comprising a hydrophilic drug and a hydrophilic polymer, followed by coating a composition comprising a hydrophilic drug and a hydrophobic polymer, followed by coating a hydrophobic polymer layer, followed by coating a layer containing a hydrophobic drug and a hydrophobic polymer, wherein the hydrophobic drug is not released in the luminal region for up to at least 24 hours.

[0110] According to one embodiment of the present disclosure, a multi-polymer layer coated stent of the present disclosure comprises four layers formed by coating a composition comprising a hydrophilic drug and a hydrophilic polymer, followed by coating a composition comprising a hydrophilic drug and a hydrophobic polymer, followed by coating a hydrophobic polymer layer, followed by coating a layer containing a hydrophobic drug and a hydrophobic polymer, wherein 75% of the hydrophobic drug is cumulatively released in the abluminal region over a period of 30 days.

[0111] According to one embodiment of the present disclosure, the multi-polymer layer coated stent of the present disclosure comprises four layers formed by coating a composition comprising a hydrophilic drug and a hydrophilic polymer, followed by coating a composition comprising a hydrophilic drug and a hydrophobic polymer, followed by coating a hydrophobic polymer layer, followed by coating a layer containing a hydrophobic drug and a hydrophobic polymer, and 64% of the hydrophilic drug is cumulatively released in the luminal region over 30 days.

[0112] According to one embodiment of the present disclosure, the multi-polymer layer coated stent of the present disclosure comprises four layers formed by coating a composition comprising a hydrophilic drug and a hydrophilic polymer, followed by coating a composition comprising a hydrophilic drug and a hydrophobic polymer, followed by coating a hydrophobic polymer layer, followed by coating a layer containing a hydrophobic drug and a hydrophobic polymer, wherein the hydrophilic drug in the hydrophilic polymer layer and the hydrophilic drug in the hydrophobic polymer layer are different.

[0113] According to one embodiment of the present disclosure, a multi-polymer layer coated stent of the present disclosure comprises a bilayer formed by coating a hydrophobic polymer containing a water soluble drug, followed by a coating comprising a blend of a hydrophobic drug and a hydrophobic polymer, and the stent administered to a mammal inhibits thrombus formation for up to at least 10 days.

[0114] According to one embodiment of the present disclosure, a multi-polymer layer coated stent of the present disclosure comprises a bilayer formed by coating a hydrophobic polymer containing a hydrophilic drug, followed by a coating comprising a blend of a hydrophobic drug and a hydrophobic polymer, and the stent administered to a mammal inhibits neointimal growth for up to at least 10 days.

[0115] According to one embodiment of the present disclosure, the coated stent of the present disclosure comprises a bilayer formed by coating a hydrophobic polymer containing a water soluble drug, followed by another coating comprising a blend of a hydrophobic drug and a hydrophobic polymer, and the stent administered to a mammal shows endothelialization before 10 days and before 28 days.

[0116] According to one embodiment of the present disclosure, the hydrophilic polymer is polyvinylpyrrolidone.

[0117] According to one embodiment of the present disclosure, the hydrophilic drug is selected from the classes of antithrombotic agents, anticoagulants, antiplatelet agents, vasodilators, vasorelaxants, antihypertensive agents, cells, antibodies, peptides, elastin, and hemocompatibility promoters.

[0118] According to one embodiment of the present disclosure, the antithrombotic agent is selected from argatroban, inogatran, melagatran and pharma- ceutically acceptable derivatives thereof.

[0119] According to one embodiment of the present disclosure, the anticoagulant is selected from warfarin / coumarin and its derivatives, vitamin K antagonists, heparin and its derivatives, low molecular weight heparin (LMWH) and its derivatives such as bemiparin, nadroparin, reviparin, enoxaparin, parnaparin, certoparin, dalteparin, tinzaparin, synthetic pentasugar derivatives (Factor Xa inhibitors) such as fondaparinux, idraparinux, idrabiotaparinux.

[0120] According to one embodiment of the present disclosure, an antiplatelet agent selected from the class of irreversible cyclooxygenase inhibitors, e.g., aspirin, triflunisal (Disgres); According to one embodiment of the present disclosure, an antiplatelet drug selected from the class of adenosine diphosphate (ADP) receptor inhibitors, e.g., cangrelor, clopidogrel, prasugrel, ticagrelor, ticlopidine; According to one embodiment of the present disclosure, an antiplatelet agent selected from the class of phosphodiesterase inhibitors, such as cilostazol.

[0121] According to one embodiment of the present disclosure, an antiplatelet agent selected from the class of protease-activated receptor 1 (PAR-1) antagonists, such as vorapaxar.

[0122] According to one embodiment of the present disclosure, an antiplatelet agent selected from the class of glycoprotein IIB / IIIA inhibitors, such as abciximab, eptifibatide, tirofiban, and the like.

[0123] According to one embodiment of the present disclosure, an antiplatelet agent selected from the class of adenosine reuptake inhibitors, such as dipyridamole.

[0124] According to one embodiment of the present disclosure, an antiplatelet agent selected from the thromboxane inhibitor / thromboxane synthase inhibitor class, such as terutroban.

[0125] According to one embodiment of the present disclosure, the antihypertensive agent is selected from diuretics, beta blockers, ACE inhibitors, angiotensin II receptor blockers, calcium channel blockers, alpha blockers, alpha-2 receptor agonists.

[0126] According to one embodiment of the present disclosure, a vasodilator selected from nitric oxide and its derivatives or precursors, prostaglandins, adenosine, minoxidil, etc.; According to one embodiment of the present disclosure, the vasorelaxant is selected from hydralazine, minoxidil.

[0127] According to one embodiment of the present disclosure, the hemocompatibility enhancer is selected from the group of compounds that act on the coagulation mechanism, the hemolysis mechanism, such as heparin surface coatings.

[0128] According to one embodiment of the present disclosure, the hydrophobic polymer is selected from poly-ε-caprolactone (PCL), polylactide-co-ε-caprolactone (PLCL), polylactic acid (PLA), polylactide-co-glycolide (PLGA).

[0129] According to one embodiment of the present disclosure, the hydrophobic drug is selected from the classes of antiproliferative agents, anti-inflammatory agents, antibiotics, bioactive molecules, vasodilators and vasorelaxants.

[0130] According to one embodiment of the present disclosure, an antiproliferative / cytostatic / cytostatic chemotherapeutic agent, such as an antiproliferative agent selected from rapamycin, everolimus, zotarolimus, paclitaxel, and the like.

[0131] According to one embodiment of the present disclosure, the anti-inflammatory drug is selected from aspirin, naproxen, Cox2 inhibitors such as celecoxib, rofecoxib and steroids such as dexamethasone.

[0132] According to one embodiment of the present disclosure, a vasodilator selected from nitric oxide and its derivatives or precursors, prostaglandins, adenosine, minoxidil, and the like.

[0133] According to one embodiment of the present disclosure, the vasorelaxant is selected from hydralazine, minoxidil.

[0134] Drug Coating Procedure 1. Clean L605 electro polished stents of size 2.75×12 mm (OD×L) were removed from the vial using a hypodermic needle and their initial weight was recorded before being loaded into the two collates of the coating machine.

[0135] 2. The solution was poured into the spray gun cup, the coater was started and the flow of coating solution was monitored.

[0136] 3. After complete coating, the stent was carefully removed from the collet. The coated stent should be handled in such a way that the coating is not damaged. The coated stent was placed on a weighing pan and its weight was measured.

[0137] 4. The stents were then placed in their respective vials and kept in a vacuum oven at -27±2Hg and room temperature for a minimum of 12 hours for drying purposes. The vial caps were pierced so that a vacuum could be created inside the vials.

[0138] 5. After the drying process, the stents were removed from the vacuum oven and weighed.

[0139] 6. For the abluminus layer coating, the stent was mounted on a mandrel and steps 2, 3, 4 and 5 were repeated.

[0140] Procedure for drug release in tubes The coated stent crimped onto a balloon was inserted into a silicone tube. It was expanded by applying pressure using an inflation device. The tube was immersed in a glass tube containing 4 ml of phosphate buffered saline at pH 7.4, used as the release medium. The glass tube was loaded into a dissolution apparatus. The apparatus was set at 10 RPM and 250°C. 1 ml samples were removed from the release medium at 0.25 hours, 0.5 hours, 1 hour, 3 hours, 6 hours, 24 hours, 48 ​​hours and multiple equidistant time points thereafter until no further release was observed. Immediately after each sampling, 1 ml of buffer medium was replaced. The amount of drug in 4 ml was calculated from HPLC analysis of the aliquots using a UV detector. The cumulative amount of drug release and the % of drug release at each time point were then calculated.

[0141] Drug release was monitored by recording absorbance at 226 nm for tirofiban HCl, 240 nm for aspirin, 276 nm for sirolimus, 277 nm for everolimus, 240 nm for clopidogrel sulfate, 254 nm for dexamethasone acetate, and 254 nm for argatroban.

[0142] Drug release procedure in the rolling bottle apparatus The coated crimped stent was inserted into a glass tube containing 4 ml of release medium (phosphate buffered saline, pH 7.4) and the stent was expanded by applying pressure using an inflation device. The glass tube was loaded into a rotating bottle apparatus. The apparatus was set at 10 RPM and 250°C. 1 ml samples were removed from the release medium at 0.25 hours, 0.5 hours, 1 hour, 3 hours, 6 hours, 24 hours, 48 ​​hours and every 24 hours thereafter until no further release was observed. Immediately after each sampling, 1 ml of buffer medium was replaced. The amount of drug in 4 ml was calculated from HPLC analysis of the aliquots using a UV detector. The cumulative amount of drug release and % drug release at each time point were then calculated.

[0143] The drug released under this experimental condition (rolling bottle apparatus) represents the amount of drug released in both the luminal and abluminal regions under in vivo conditions. The amount of drug that would be released in the abluminal region is calculated by subtracting the drug released during the tube experiment from the drug simultaneously released during the rolling bottle experiment.

[0144] These and other embodiments will be apparent to those skilled in the art and others upon consideration of the following detailed description of several embodiments, however, it should be understood that this summary and detailed description are merely illustrative of some examples of various embodiments and are not intended to limit the invention as claimed. EXAMPLES

[0145] Only some examples and implementations are disclosed. Variations, modifications, and enhancements to the described examples and implementations, as well as other implementations, can be made based on what is disclosed.

[0146] Examples are set forth herein below and are illustrative of different amounts and types of reactants and reaction conditions that may be utilized in carrying out the present disclosure. However, it will be apparent that the present disclosure can be carried out with amounts and types of reactants and reaction conditions other than those used in the examples, and the resulting devices will have various properties and applications according to the disclosure above and as pointed out below.

[0147] Example 1 Three stents 1a, 1b, 1c were spray coated with three solutions containing the drug tirofiban HCl, and poly-ε-caprolactone polymer with intrinsic viscosities (IV) of 1.07, 1.3, and 1.9, respectively. The solutions were made in dichloromethane:methanol (90:10 vol / vol). The polymer-drug ratio was 3:1. The polymer content of the solutions was (0.09 wt / vol%). The tirofiban HCl loading on the stents was 75-100 μg. The stents were dried and further spray coated with poly-ε-caprolactone polymer (IV 1.07) (0.09 wt / vol%) dissolved in dichloromethane. The weight of the coated polymer was 250-300 μg. The stents were dried and drug release experiments were performed using a rotating bottle apparatus (RBA) and monitored by HPLC. The cumulative drug release versus time is shown in Figure 1.

[0148] Example 2 Three stents 2a, 2b, 2c were spray coated with polyvinylpyrrolidone (K90) solutions in methanol (0.09 wt / vol% polymer) containing a) aspirin b) tirofiban HCl and c) clopidogrel sulfate, respectively. The polymer:drug ratio was 3:1. Drug loadings ranged from 75 to 100 μg. The stents were allowed to dry completely. Stents 2a and 2b were then spray coated with poly-ε-caprolactone (PCL, IV 1.9) and stent 2c was spray coated with poly-ε-caprolactone (IV 1.3) solution in dichloromethane (0.09 wt / vol% polymer). Poly-ε-caprolactone loadings on the stents ranged from 250 to 300 μg. The stents were dried and the release of the drug was performed using a rotating bottle apparatus (RBA) and a tube apparatus. Drug release was monitored by HPLC. The cumulative drug release as a function of time is shown in Figure 2.

[0149] Example 3 Four stents 3a, 3b, 3c, 3d were loaded with tirofiban HCl from a polymer solution with a polymer / tirofiban HCl ratio of 3:1. The solution used to coat stent 3a contained polyvinylpyrrolidone (K30) (0.09 wt / vol%) in methanol, stent 3b contained polyvinylpyrrolidone (K12) (0.09 wt / vol%) in methanol, stent 3c contained 0.09 wt / vol% poly(D,L-lactide-co-glycolide) (50:50:) in dichloromethane-methanol (90:10 v / v) (HFIP, IV-0.65 in hexafluoroisopropanol), and stent 3d contained 0.09 wt / vol% poly(L-lactide-co-ε-caprolactone copolymer (80:20) (IV-1.12 in chloroform) in dichloromethane-methanol (90:10 v / v). The tirofiban HCl loading on the stents was 75-1 The doses ranged from 0.00 to 100 μg. The stents were allowed to dry. Stents 3a and 3c were then coated using a solution of poly-ε-caprolactone (IV 1.9 in chloroform) containing (0.09 wt / vol%) polymer. Stent 3b was coated with poly(D,L lactide-co-glycolide) 75:25 (MW-75000) (0.09 wt / vol% polymer) dissolved in dichloromethane, and stent 3d was coated with 0.09 wt / vol% poly-ε-caprolactone (IV-1.07) dissolved in dichloromethane. The stents were allowed to dry. Tirofiban HCl release experiments were performed using a rolling bottle apparatus (RBA) and a tube apparatus, and the release was monitored by HPLC. The cumulative release versus time is shown in Figure 3a and Figure 3b.

[0150] Example 4 Four stents 4a, 4b, 4c and 4d were spray coated. Stents 4a, 4b were spray coated with 0.09% wt / vol poly-ε-caprolactone (IV 1.9) dissolved in dichloromethane. 4c was spray coated with 0.09% wt / vol poly(D,L lactide-co-glycolide) copolymer 75:25 (MW-75000) dissolved in dichloromethane, and 4d was coated with 0.09% wt / vol poly-ε-caprolactone (IV 1.07) dissolved in dichloromethane. Polymer loading ranged from 250 to 300 μg. The stents were allowed to dry. Stent 4a was spray coated with a solution (0.09% wt / vol polymer) containing poly-ε-caprolactone (IV 1.07) and everolimus (polymer-drug ratio 3:1) dissolved in dichloromethane. Stents 4b and 4c were spray coated with a solution containing poly-ε-caprolactone (IV 1.07) and sirolimus (polymer-drug ratio 3:1) dissolved in dichloromethane (0.09% wt / vol polymer). Stent 4d was spray coated with a 0.09% wt / vol solution containing poly(D,L-lactide-co-glycolide) copolymer 75:25 (MW-75000) and dexamethasone acetate (polymer-drug ratio 3:1 wt / wt) dissolved in dichloromethane-methanol (90:10 v / v). The stents were dried and drug release experiments were performed using a rolling bottle apparatus (RBA) and a tube apparatus. Drug release was monitored by HPLC. The cumulative release versus time results are shown in Figure 4.

[0151] Example 5 Three stents, 5a, 5b and 5c, were spray coated. Stent 5a was coated with a drug-polymer solution containing 0.09 wt / vol% poly-ε-caprolactone (IV 1.07) and everolimus (polymer-drug ratio 3:1) dissolved in dichloromethane. Stent 5b was spray coated with a drug-polymer solution having 0.09 wt / vol% of the polymer poly-ε-caprolactone (IV 1.07) and dexamethasone acetate (polymer-drug ratio 3:1) dissolved in dichloromethane-methanol (90:10 vol / vol), and stent 5c was spray coated with a drug-polymer solution containing 0.09 wt / vol% PLGA 75:25 (MW-75000) and sirolimus (polymer-drug ratio 3:1) dissolved in dichloromethane. Drug loading on the stents ranged from 75 to 100 μg. The stents were allowed to dry. All three stents were further spray coated with 0.09% w / v poly-ε-caprolactone (IV1.9) dissolved in dichloromethane. The stents were dried and drug release experiments were performed using a rolling bottle apparatus (RBA) as well as a tube apparatus. The release was monitored by HPLC. The cumulative drug release as a function of time is shown in Figure 5.

[0152] Example 6 Three stents 6a, 6b and 6c were spray coated. Stents 6a and 6b were spray coated with 0.09% w / v poly-ε-caprolactone (IV 1.9) dissolved in dichloromethane, and stent 6c) was spray coated with 0.09% w / v PLGA 75:25 (MW-75000) dissolved in dichloromethane. The samples were dried and further spray coated. Stent 6a was spray coated with a drug-polymer solution containing a 1:1 weight ratio of poly-ε-caprolactone (IV 1.07) and poly(D,L-lactide-co-glycolide) (IV 0.65), and everolimus (polymer-drug ratio 3:1) using 0.09% w / v polymer dissolved in dichloromethane. Stent 6b was spray coated with a drug-polymer solution using 0.09 wt / vol polymer dissolved in dichloromethane-methanol 90:10 vol / vol, containing poly-ε-caprolactone PCL (IV 1.07) and polyvinylpyrrolidone (K30) in a weight ratio of 1:1, and everolimus (polymer-drug ratio 3:1). Stent 6c was coated with 0.09 wt / vol% poly-ε-caprolactone (IV 1.07) dissolved in dichloromethane and sirolimus (polymer-drug ratio 3:1). Drug loading on the stent ranged from 75 to 100 μg. The stent was allowed to dry. Drug release experiments were performed using a rolling bottle apparatus (RBA) and the release was monitored by HPLC. The cumulative drug release as a function of time is shown in Figure 6.

[0153] Example 7 Stents 7 were spray coated with a drug-polymer solution (0.09 wt / vol % polymer) containing poly(D,L-lactide-co-glycolide) 75:25 (MW-75000) and dexamethasone acetate (polymer-drug ratio 3:1) dissolved in dichloromethane. The drug loading was 86 μg. The stents were dried and further spray coated with 0.09 wt / vol % poly-ε-caprolactone (IV1.9) dissolved in dichloromethane. The stents were dried and dexamethasone acetate release experiments were performed using a rolling bottle apparatus (RBA) and a tube apparatus. The release was monitored by HPLC. The cumulative release as a function of time is shown in Figure 7.

[0154] Example 8 Three stents, 8a, 8b and 8c, were spray coated. Stent 8a was spray coated with 0.09% w / v poly-ε-caprolactone (IV 1.07) in dichloromethane-methanol (90:10 v / v) and clopidogrel (polymer-drug ratio 3:1). Stent 8b was spray coated with 0.09% w / v poly-ε-caprolactone (IV 1.07) solution in dichloromethane-methanol (90:10 v / v) and argatroban (polymer-drug ratio 3:1). Stents (8c) were spray coated with 0.09 wt / vol% poly(D,L-lactide-co-glycolide) (75:25) (MW-75000) in dichloromethane-methanol 90:10 vol / vol and tirofiban HCl (polymer-drug ratio 3:1). Drug loading ranged from 75 to 100 µg. The stents were dried and further spray coated with 0.09 wt / vol% poly-ε-caprolactone (IV1.9) solution in dichloromethane. After the stents were dried, drug release experiments were performed using a rotating bottle apparatus (RBA) and a tube apparatus, and drug release was monitored by HPLC. The results of cumulative drug release versus time are shown in Figure 8.

[0155] Example 9 Four stents 9a, 9b, 9c and 9d were spray coated. Stent 9a was spray coated with a 0.09% wt / vol solution of polyvinylpyrrolidone (K90) in methanol and aspirin (polymer-drug ratio 3:1). Stent 9b was spray coated with a 0.09% wt / vol solution of polyvinylpyrrolidone (K90) in methanol and tirofiban HCl (polymer-drug ratio 3:1). Stent 9c was spray coated with a 0.09% wt / vol solution of polyvinylpyrrolidone (K30) in methanol and tirofiban HCl (polymer-drug ratio 3:1). Stent 9d was spray coated with a 0.09% wt / vol solution of polyvinylpyrrolidone (K12) in methanol and tirofiban HCl (polymer-drug ratio 3:1). The drug loading in the stents ranged from (75 μg to 100 μg). The stents were dried and all stents were spray coated with a 0.09 wt / vol% solution of poly-ε-caprolactone (IV1.9) in dichloromethane. The weight of the coated polymer ranged from 250 to 300 μg. Three stents except 9b were dried and further spray coated with 0.09 wt / vol% solution of poly-ε-caprolactone (IV1.07) in dichloromethane and sirolimus (polymer-drug ratio 3:1). Stent 9b was spray coated with a 0.09 wt / vol% solution of poly-ε-caprolactone (IV1.3) in dichloromethane and sirolimus (polymer-drug ratio 3:1). The stents were dried and the release of the drug was monitored using HPLC. The release experiments were performed using both rolling bottle and tube experiments. The cumulative release versus time results are shown in Figure 9 and Figure 10.

[0156] Example 10 Four stents 10a, 10b, 10c and 10d were coated as follows: Stent 10a was spray coated with a 0.09% w / v solution of poly(D,L-lactide-co-glycolide) (75:25, MW 75000) in dichloromethane-methanol (90:10 vol / vol) and tirofiban hydrochloride (polymer-drug ratio, 3:1). The drug loading was 82 μg. The stent was allowed to dry. It was then spray coated with a 0.09% w / v solution of poly-ε-caprolactone (IV 1.9) in dichloromethane. The deposited polymer was 262 μg. The stent was allowed to dry. It was then spray coated with a 0.09% w / v solution of poly-ε-caprolactone (IV 1.3) in dichloromethane and sirolimus (polymer-drug ratio, 3:1). The sirolimus loading was 86 μg.

[0157] Stent 10b was spray coated with a 0.09% w / v solution of poly(D,L-lactide-co-glycolide) (50:50, IV 0.65) in dichloromethane-methanol (90:10 vol / vol) and tirofiban HCl (polymer-drug ratio 3:1). The stent was allowed to dry. The tirofiban HCl loading was 91 μg. It was then spray coated with a 0.09% w / v solution of poly-ε-caprolactone (IV 1.9) in dichloromethane. The polymer deposited was 285 μg. The stent was allowed to dry again. It was spray coated with a 0.09% w / v solution of poly-ε-caprolactone (IV 1.9) in dichloromethane and sirolimus (polymer-drug ratio 3:1). The sirolimus deposited was 79 μg.

[0158] Stents 10c were spray coated with a 0.09% w / v solution of poly(D,L-lactide-co-glycolide) (50:50, IV 0.65) in dichloromethane-methanol (90:10 v / v) and tirofiban HCl (polymer-drug ratio, 3:1 w / w). The drug loading was 96 μg. The stents were allowed to dry. It was then spray coated with a 0.09 wt / vol polymer solution in dichloromethane containing a 1:1 weight ratio of ester-terminated poly(D,L-lactide) (IV -0.65 dl / g in chloroform) and poly-ε-caprolactone (IV 1.07). The polymer loading was 250-300 μg. The stent was allowed to dry. It was then spray coated with a solution of 0.09 wt / vol% poly-ε-caprolactone (IV 1.9) in dichloromethane and sirolimus (polymer-drug ratio 3:1 wt / wt). The drug loading was 83 μg.

[0159] Stents 10d were spray coated with a 0.09% w / v solution of poly(D,L-lactide-co-glycolide) (50:50, IV 0.65) in dichloromethane-methanol (90:10 v / v) and tirofiban HCl (polymer-drug ratio, 3:1 w / w). The drug loading was 87 μg. The stents were allowed to dry. This was then spray coated with 0.09 wt / vol% poly(L-lactide-co-ε-caprolactone) copolymer (80:20) (IV-1.12) in dichloromethane. The polymer loading was 250-300 μg. The stent was allowed to dry. This was further spray coated with a 0.09 wt / vol% solution of poly-ε-caprolactone (IV1.9) in dichloromethane and sirolimus (polymer-drug ratio 3:1). The sirolimus loading was 93 μg. The stent was allowed to dry.

[0160] The release of tirofiban HCl and sirolimus from all stents was monitored by HPLC. Release experiments were performed using a rolling bottle apparatus and tube experiments. The results of cumulative drug release versus time are shown in Figures 11 and 12.

[0161] Example 11 Three stents, 11a, 11b and 11c, were coated.

[0162] Stent 11a was spray coated with a solution of polyvinylpyrrolidone (K90) and tirofiban HCl (polymer-drug ratio 3:1) dissolved in methanol (0.09% w / v polymer). The tirofiban HCl content was 42 μg. The stent was dried. It was then spray coated with a 0.09% w / v poly-ε-caprolactone (IV1.07) and aspirin (polymer-drug ratio 3:1) solution in dichloromethane-methanol (90:10 v / v). The aspirin loading was 46 μg. The stent was dried. The stent was then spray coated with a 0.09% w / v polymer solution of poly-ε-caprolactone (IV1.9) in dichloromethane. The polymer loading was 289 μg. The stent was dried. Drug release experiments were performed using a rolling bottle apparatus (RBA) as well as a tube apparatus, and the release was monitored by HPLC.

[0163] Stent 11b was spray coated with a 0.09% w / v polyvinylpyrrolidone (K90) solution in methanol and tirofiban HCl (polymer-drug ratio 3:1). The tirofiban HCl content was 45 μg. The stent was dried. It was then spray coated with poly-ε-caprolactone (IV1.07)n (0.09% w / v) in dichloromethane-methanol (90:10 v / v) and tirofiban HCl (polymer-drug ratio 3:1 w / w). The tirofiban HCl loading was 40 μg. The stent was dried. The stent was then spray coated with a 0.09% w / v poly-ε-caprolactone (IV1.9) solution in dichloromethane. The polymer loading was 293 μg. The stent was dried. Drug release experiments were performed using a rolling bottle apparatus (RBA) as well as a tube apparatus, and the release was monitored by HPLC.

[0164] Stent 11c was spray coated with a 0.09% w / v polyvinylpyrrolidone (K12) solution in methanol and tirofiban HCl (polymer-drug ratio 3:1 w / w). Tirofiban HCl loading was 48 μg. The stent was dried. It was then spray coated with a 0.09% w / v poly-ε-caprolactone (IV1.07) solution in dichloromethane-methanol (90:10 v / v) and tirofiban HCl (polymer-drug ratio 3:1 w / w). Tirofiban HCl loading was 42 μg. The stent was dried. It was then spray coated with a 0.09% w / v poly-ε-caprolactone (IV1.9) solution in dichloromethane. Polymer loading was 273 μg. The stent was dried. Drug release experiments were performed using a rolling bottle apparatus (RBA) as well as a tube apparatus, and the release was monitored by HPLC.

[0165] The cumulative release of drug as a function of time for these three stents is shown in FIG.

[0166] Example 12 Stent 12 was spray coated with four layers of polymer. The first layer was deposited by spraying a 0.09% w / v polyvinylpyrrolidone (K12) solution in methanol and tirofiban HCl (polymer-drug ratio 3:1). The tirofiban HCl loading was (42 μg). After drying the stent, the second layer was deposited by spraying a 0.09% w / v poly-ε-caprolactone (IV1.07) solution in dichloromethane-methanol (90:10 v / v) and tirofiban HCl (polymer-drug ratio 3:1). The tirofiban HCl loading was (49 μg). The third layer was spray coated with a 0.09% w / w poly-ε-caprolactone (1.9IV) solution in dichloromethane. The polymer loading was 292 μg. The fourth layer was spray coated with 0.09% w / v poly(D,L-lactide-co-glycolide) (75:25) (MW-75000) solution in dichloromethane and sirolimus (polymer-drug ratio 3:1). The sirolimus loading was (93 μg). The stents were allowed to dry. Drug release experiments were performed using a rolling bottle apparatus (RBA) and a tube apparatus, and drug release was monitored by HPLC. The cumulative release of drug as a function of time is shown in FIG. 14.

[0167] Example 13 Stent 13 was spray coated with four layers of polymer. The stent was first coated with a 0.09% w / v solution of polyvinylpyrrolidone (K90) in methanol and tirofiban HCl (polymer-drug ratio 3:1). The tirofiban HCl loading was (41 μg). The stent was allowed to dry. It was then spray coated with a 0.09% w / v solution of poly-ε-caprolactone (IV1.07) in dichloromethane-methanol (90:10 v / v) and aspirin (polymer-drug ratio 3:1). The aspirin loading was (39 μg). The stent was allowed to dry. The third layer was spray coated with a 0.09% w / v solution of poly-ε-caprolactone (1.9IV) in dichloromethane. The stent was allowed to dry. The fourth layer was spray coated with 0.09 wt / vol% poly(D,L-lactide-co-glycolide) (75:25) copolymer (MW-75000) solution in dichloromethane and sirolimus (polymer-drug ratio 3:1). Sirolimus loading was (75-100 μg). The stents were allowed to dry. Drug release experiments were performed using a rolling bottle apparatus (RBA) and a tube apparatus, and drug release was monitored by HPLC. The cumulative drug release as a function of time is shown in Figure 15.

[0168] Example 14 Stents 14 were spray coated with a single layer of polymer-drug composition using 0.09% w / v poly(L-lactide-co-caprolactone, 80:20, IV-1.12) solution in dichloromethane, and the drugs used were tirofiban HCl and everolimus (5:3 ratio). The polymer-drug ratio was 3:1. The tirofiban HCl loading was 150 μg and the everolimus loading was 90 μg. The stents were allowed to dry. Drug release experiments were performed using a rolling bottle apparatus (RBA) and a tube apparatus, and drug release was monitored by HPLC. The cumulative drug release as a function of time is shown in FIG. 16.

[0169] Example 15: Following the teachings from Example 10, stents coated with multiple polymer layers were manufactured. The release data of sirolimus and tirofiban HCl from the rolling bottle apparatus is shown in Figure 17. The stents were also implanted in a porcine model for a subchronic study to study the effect for up to 28 days. The details of the implantation and histopathological observations are given below.

[0170] animal transplant 1. Clinically healthy adult male Ankamali pigs weighing 53.4 Kg were transferred to restraining cages 7 days prior to the implantation date for acclimatization and kept under standard maintenance protocols.

[0171] 2. A first whole blood sample was collected prior to stent implantation for baseline hematology / biochemistry and for assessment of baseline coagulation parameters - platelet count, clotting time (CT) and bleeding time (BT).

[0172] 3. Transplantation was performed under systemic heparinization at 3 mg (300 IU) per kg of body weight.

[0173] 4. Heparin was not reversed after the procedure.

[0174] 5.Dual antiplatelet therapy (DAPT) or low molecular weight heparin was not administered during the observation period.

[0175] 6. A second blood sample was taken on the postoperative day (10 days follow-up) for evaluation of hematology / biochemistry and coagulation parameters such as CT, BT, APTT, ACT and platelet count.

[0176] At the end of the 7.28 day period, animals were anesthetized and transitioned to OT.

[0177] 8. A third blood sample was taken on postoperative day 28 (28-day follow-up) for evaluation of hematology / biochemistry and coagulation parameters such as bleeding time (BT) and clotting time (CT).

[0178] 9. A confirmatory angiogram was performed under heparin (1.5 mg / Kg) to assess vascular patency.

[0179] 10. Animals were euthanized using an overdose of the intravenous anesthetic thiopentone sodium.

[0180] 11. Hearts were perfusion-fixed in situ.

[0181] 12. A detailed autopsy was performed and the stented vessel segments were subjected to histopathological and histomorphometric evaluation according to standard protocols.

[0182] The effects of tirofiban HCl so administered are summarized below. [Table 1]

[0183] When tirofiban HCl is administered intravenously, clotting and bleeding times are usually increased 3-4 times. In this case, the increase in clotting and bleeding times was 30-40%.

[0184] Images of implanted stents after 10 days (A, B) in the right coronary artery (RC Proximal) of a porcine model show the absence of neointimal growth (Figure 18). The absence of a new endothelial cell layer indicates activity of sirolimus in the abluminal region. Images of implanted stents after 28 days (C, D) in the right coronary artery (RC Proximal) of a porcine model. The growth of a new endothelial cell layer indicates the absence of sirolimus in the abluminal region. The inner surface of the stent is open to blood flow. The absence of thrombus or clots at the end of 10 days indicates release of tirofiban in the luminal region preventing thrombus formation. By the end of 28 days, new cell growth appears in the luminal region indicating endothelialization of the stent.

[0185] The results of the histopathological and histomorphometric evaluations are shown in FIG.

[0186] The embodiments have been chosen and described to best explain the principles of the invention and its practical application, thereby enabling others skilled in the art to best utilize the invention and its various embodiments, with various modifications suited to the particular uses intended.

[0187] It is understood that various omissions and substitutions of equivalents are contemplated as circumstances may suggest or render expedient, but they are intended to cover applications or implementations without departing from the scope of the invention.

Claims

1. A multi-polymer layer coating for the directed and temporary release of a drug, comprising a hydrophilic drug in a polymer layer selected from a) a hydrophobic polymer layer and b) a hydrophilic polymer layer, and a hydrophobic drug in a hydrophobic polymer layer, wherein the polymer layer containing the hydrophilic drug is coated on the luminal side of a biomedical device, and the polymer layer containing the hydrophobic drug is coated on the abluminal side of the biomedical device.

2. 10. A multi-polymer layer coating for the directed and temporary release of a drug according to claim 1 selected from a stent, a graft, a balloon, a catheter, a filter or a mesh-like structure.

3. 10. A multi-polymer layer coating for directional and transient release of a drug as described in claim 1, comprising: a) a layer having a hydrophobic polymer layer coated on the biomedical device, followed by b) a layer having a hydrophobic polymer layer coated on a), followed by a layer having a hydrophobic polymer and a hydrophobic drug coated on b), wherein less than 1% of the hydrophobic drug is released in the luminal region for up to 24 hours.

4. A multi-polymer layer coating for the directional and temporary release of a drug as described in claim 3, wherein 32 to 74% of the hydrophobic drug is released into the abluminal region over 21 days.

5. A multi-polymer layer coating for the directed and temporary release of a drug as described in claim 3, wherein 68 to 98% of the hydrophilic drug is released into the luminal region over a period of 9 days.

6. A multi-polymer layer coating for directional and temporary release of a drug as described in claim 1, comprising: a) a layer having a hydrophilic drug and a hydrophobic polymer coated on the device; b) a hydrophobic polymer layer coated on a); and c) a layer having a hydrophobic polymer and a hydrophobic drug coated on b), wherein 40-46% of the hydrophilic drug is released into the luminal region over 30 days.

7. A multi-polymer layer coating for the directional and temporary release of a drug as described in claim 5, wherein 40 to 65% of the hydrophobic drug is released into the abluminal region over a 30 day period.

8. 10. The multi-polymer layer coating for directional and transient release of a drug as described in claim 1, comprising: a) a layer having a hydrophilic drug and a hydrophobic polymer coated on the biomedical device; b) a layer having a hydrophilic drug and a hydrophobic polymer layer coated on a); and c) a layer having a hydrophobic polymer and a hydrophobic drug coated on b), wherein the hydrophilic drug is not released into the abluminal region.

9. A multi-polymer layer coating for directional and temporary release of a drug as described in claim 1, comprising: a) a layer containing a hydrophilic drug and a hydrophilic polymer coated on the device; b) a layer containing a hydrophilic drug and a hydrophobic polymer coated on b); c) a hydrophobic polymer layer coated on b); and d) a layer containing a hydrophobic drug and a hydrophobic polymer coated on c), wherein the hydrophobic drug is not released into the luminal region for at least 24 hours.

10. A multi-polymer layer coating for the directed and temporary release of a drug as described in claim 1, wherein 75% of the hydrophobic drug is released to the abluminal region over a period of 30 days.

11. A multi-polymer layer coating for the directed and temporary release of a drug as described in claim 8, wherein 64% of the hydrophilic drug is released into the luminal region over a 30 day period.

12. A multi-polymer coating for the directed and temporary release of a drug as described in claim 1, wherein the hydrophilic drug in the hydrophilic polymer layer is different from the hydrophilic drug in the hydrophobic polymer layer.

13. A multi-polymer layer coating for the directional and temporary release of a drug as described in claim 1, wherein the hydrophobic polymer is selected from poly-ε-caprolactone (PCL), polylactide-co-ε-caprolactone (PLCL), polylactic acid (PLA), polylactide-co-glycolide (PLGA), and blends thereof.

14. A multi-polymer layer coating for the directed and temporary release of a drug as described in claim 3, wherein the hydrophilic polymer is polyvinylpyrrolidone.

15. A multi-polymer layer system for the directed and temporary release of a drug as described in claim 12, comprising: a) a layer having a hydrophobic polymer and a hydrophilic drug coated on a biomedical device; and b) a layer having a hydrophobic polymer blend and a hydrophobic drug coated on a), wherein the biomedical device, when administered to a mammal, inhibits thrombus formation for up to at least 10 days.

16. A multi-polymer system for the directed and temporary release of drugs as described in claim 15, wherein the hydrophobic drug is selected from the classes of antiproliferative agents, anti-inflammatory agents, antibiotics, bioactive molecules, vasodilators and vasorelaxants.

17. A multi-polymer system for the directed and temporary release of drugs as described in claim 16, wherein a) the antiproliferative drug is selected from sirolimus (rapamycin), everolimus, tacrolimus, pimecrolimus, paclitaxel and docetaxel and pharmaceutically acceptable salts thereof; and b) the anti-inflammatory drug, if used, is selected from aspirin, celecoxib, rofecoxib, piroxicam, ibuprofen, ketoprofen, indomethacin, diclofenac, dexamethasone, betamethasone, prednisolone, prednisone, triamcinolone, methylprednisolone and pharmaceutically acceptable salts thereof.

18. A multi-polymer coating for the directional and temporary release of a drug as described in claim 15, wherein the hydrophilic drug is selected from the classes of antithrombotic agents, antiplatelet agents, thrombin inhibitors, glycoprotein IIb / IIIa (GPIIbIIIa) inhibitors, and adenosine diphosphate (ADP) inhibitors.

19. The multi-polymer coating for the directed and temporary release of a drug according to claim 18, wherein the antithrombotic drug is selected from aspirin, clopidogrel, tirofiban HCl, and argatroban, and pharmaceutically acceptable salts thereof.

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