Drug coated medical devices and methods of manufacture

Abstract

In the disclosure, aspects of drug coatings and methods of making drug coated medical devices are disclosed. The methods of making drug-coated medical devices may include applying a drug coating to an outer surface of medical devices that are used in vivo during interventional procedures and may reside after those procedures, including implantable devices and non-implantable devices. The drug coating may include an anti-fibrotic drug, a kinase inhibitor, a phosphodiesterase inhibitor, or a combination thereof.

Description

Technical Field

[0001] The disclosure relates generally to coatings for medical devices, and more particularly to drug eluting stents and drug-coated balloon catheters. Background Art

[0002] By way of background, drug and device combination products provide a synergy of bare device functionality and the effects of the pharmaceutical agents. Two examples of combination devices include drug-coated medical devices, including drug-eluting stents and drug-coated balloon catheters.

[0003] It has become increasingly common to treat a variety of medical conditions by introducing drug-coated medical devices into the vasculature or other lumens of a human or veterinary patient, such as the esophagus, trachea, colon, bile duct, bronchial passages, sinuses, nasal passages, renal arteries, or urinary tract. For example, medical devices that can be coated and used to treat vascular disease include stents, stent grafts, catheters, balloon catheters, guidewires, cannulas, and the like. Although these medical devices appear to be successful initially, the benefits are often compromised by the development of complications (such as late thrombosis) or recurrence of disease (such as stenosis (restenosis)) following such treatment.

[0004] Combining drugs and medical devices is a complex technical field. It involves the usual formulation challenges, such as those of oral or injectable drugs, and the additional challenge of maintaining the adhesion of the drug to the medical device until it reaches the target site and then delivering the drug to the target tissue with the desired release and absorption kinetics. In addition, the coating must not compromise functional properties, such as the burst pressure and compliance of the balloon. The coating thickness must also be kept to a minimum, as thick coatings increase the medical device profile and result in poor traceability and deliverability. These coatings often contain almost no liquid chemicals that are typically used to stabilize drugs. Therefore, a formulation that works for ingestible tablets and capsules or for injectables may not work at all for coatings of medical devices.

[0005] In addition, the drug coating must meet the release curve required by the properties of the underlying device. For example, the balloon is usually temporarily placed in the patient's body, thereby requiring the ability to quickly deliver the drug coating. The balloon is also usually fed to the appropriate position by moving along the lumen of the blood vessel from the insertion point (usually distal to the area where the drug coating is required). Therefore, it is necessary to shield the drug coating or protect the drug coating from premature delivery of the drug coating so that the maximum expected local drug delivery is achieved at the expected area in the vessel. Although the balloon can provide sustained release of the drug, the drug coating still needs to be safely and firmly deposited on the vessel wall when the balloon is expanded in situ.

[0006] Stents also have special requirements for drug coatings that are very different from balloons. For example, stents are usually permanently or semi-permanently placed in the subject's body, so the requirements for immediate or rapid delivery of the coating to the vessel wall are less stringent. The length of the stent also allows for a more dynamic release profile that can be adapted to any time period, allowing the coating to remain on the surface of the stent and allow for timed release therefrom without requiring rapid transfer of the coating to the vessel. Stents also allow for the use of more biodegradable polymers in the drug coating, allowing for a slower, more sustained release of the drug as the polymer slowly degrades from the stent surface.

[0007] Additionally, if the drug is released or eluted from the device too easily, the drug may be lost during device delivery before it can be deployed at the target site, or the drug may burst from the device during the initial expansion phase of the device and be washed away before being pressed into contact with the target tissue of the body lumen wall. If the drug adheres too strongly, the device may be withdrawn before the drug can be released at the target tissue and absorbed by the tissue. Summary of the invention

[0008] Reducing or eliminating restenosis after interventional procedures remains an unmet need for the development of new generation interventional devices. Implantation of conventional interventional devices (such as stents, balloon catheters, and stent grafts) often results in vessel wall damage and endothelial denudation, followed by abnormal proliferation and migration of vascular smooth muscle cells (VSMCs), chronic inflammation, and neointimal hyperplasia. In an effort to combat restenosis, drug eluting devices have been developed that deliver antiproliferative agents locally to blood vessels.

[0009] Current antiproliferative drug coating therapies have proven themselves to be effective in reducing restenosis by inhibiting VSMC migration and proliferation. However, these existing therapies act with nonspecific antiproliferative effects that also significantly inhibit endothelial cell (EC) growth, which leads to delayed endothelial recovery and late thrombosis. Therefore, there is a need for alternative anti-restenotic agents for drug-coated devices, particularly for peripheral arterial disease.

[0010] In some aspects, the disclosure meets these needs by providing drug coatings and methods for coating medical devices, which include therapeutic agents that do not inhibit endothelial cells or cause delayed endothelial recovery or late thrombosis. In some aspects, the therapeutic agent can have one or more kinase inhibitors, which are used in the coating of the interventional device to prevent restenosis. In certain aspects, the therapeutic agent can be one or more receptor tyrosine kinase inhibitors, which are used in the coating of the interventional device to prevent restenosis.

[0011] The first aspect, alone or in combination with any other aspect herein, relates to a medical device for delivering a therapeutic agent to a tissue, the medical device comprising: a coating layer covering an outer surface of the medical device, wherein the coating layer comprises a phosphodiesterase (PDE) inhibitor and / or a kinase inhibitor together with one or more excipients.

[0012] A second aspect, alone or in combination with any other aspect herein, relates to the medical device of the first aspect, wherein the excipient comprises a biodurable polymer, a biodegradable polymer, or a combination thereof.

[0013] The third aspect, alone or in combination with any other aspect herein, relates to the medical device of the first aspect, wherein the PDE inhibitor is selected from the group consisting of xanthine, aminophylline, sildenafil, tadalafil, vardenafil, udenafil, avanafil, dipyridamole, quinazoline, paraxanthine, papaverine, mesembryantrine, rolipram, ibudilast, picamilast, luteolin, drotaverine, roflumilast, apremilast, crisaborole, crisaborole), inamrinone, milrinone, enoximone, anagrelide, cilostazol, pimobendan, erythro-9-(2-hydroxy-3-nonyl)adenine), (2-[(3,4-dimethoxyphenyl)methyl]-7-[(1R)-1-hydroxyethyl]-4-phenylbutyl]-5-methyl-imidazo[5,1-f][1,2,4]triazine-4(1H)-one), oxindole, (9-(6-phenyl-2-oxohexan-3-yl)-2-(3,4-dimethoxybenzyl)-purin-6-one), 3-isobutyl-1-methylxanthine, pentoxifylline, theobromine and theophylline.

[0014] A fourth aspect, alone or in combination with any other aspect herein, relates to the medical device of the first aspect, wherein the PDE inhibitor is tadalafil or sildenafil.

[0015] A fifth aspect, alone or in combination with any other aspect herein, relates to the medical device of the first aspect, wherein the PDE inhibitor is in the form of a free base, a free acid, crystals or a salt.

[0016] The sixth aspect, alone or in combination with any other aspect herein, relates to the medical device of the fifth aspect, wherein the salt is a hydrochloride, sodium salt, sulfate, acetate, phosphate and / or diphosphate, pamoate or hemi-pamoate salt, a lipophilic salt, a chloride salt, a potassium salt, a maleate, a calcium salt, a citrate, a methanesulfonate, a nitrate, a tartrate, an aluminum salt, a stearate, dioctylsulfosuccinate or a gluconate salt.

[0017] A seventh aspect, alone or in combination with any other aspect herein, relates to the medical device of the first aspect, wherein the kinase inhibitor is selected from bosutinib, ceritinib, crizotinib, gefitinib, ruxolitinib, imatinib, axitinib, nilotinib, trametinib, afatinib, ibrutinib, cabozantinib, imatinib, lenvatinib, inib), sunitinib, regorafenib, sorafenib, vandetanib, dasatinib, pazopanib, Y27632, CA3, verteporfin, VGLL4 peptide, nintedanib, avapritinib, abemaciclib, erdafitinib, fedratinib, palbociclib, and pemigatinib.

[0018] An eighth aspect, alone or in combination with any other aspect herein, relates to the medical device of the first aspect, wherein the kinase inhibitor is sunitinib.

[0019] A ninth aspect, alone or in combination with any other aspect herein, relates to the medical device of the first aspect, wherein the kinase inhibitor is in the form of a free base, a free acid, a crystal or a salt.

[0020] The tenth aspect, alone or in combination with any other aspect herein, relates to the medical device of the ninth aspect, wherein the salt is a hydrochloride, sodium salt, sulfate, acetate, phosphate and / or diphosphate, pamoate or hemipamoate, a lipophilic salt, chloride salt, potassium salt, maleate, calcium salt, citrate, methanesulfonate, nitrate, tartrate, aluminum salt, stearate, dioctylsulfosuccinate, or gluconate.

[0021] The eleventh aspect, alone or in combination with any other aspect herein, relates to the medical device of the second aspect, wherein the biodurable polymer is selected from poly(vinylidenehexafluoropropylene) (PVDF-HFP), polyethylene terephthalate (PET), nylon 6,6, polyurethane (PU), polytetrafluoroethylene (PTFE), polyethylene, polysiloxane (silicone) and poly(methyl methacrylate) (PMMA) and combinations thereof.

[0022] A twelfth aspect, alone or in combination with any other aspect herein, relates to the medical device of the second aspect, wherein the biodurable polymer is poly(vinylidene hexafluoropropylene) (PVDF-HFP).

[0023] A thirteenth aspect, alone or in combination with any other aspect herein, relates to the medical device of the second aspect, wherein the weight ratio of the biodurable polymer to the PDE inhibitor is from 1:1 to 10:1.

[0024] A fourteenth aspect, alone or in combination with any other aspect herein, relates to the medical device of the second aspect, wherein the weight ratio of the biodurable polymer to the kinase inhibitor is from 1:1 to 10:1.

[0025] The fifteenth aspect, alone or in combination with any other aspect herein, relates to the medical device of the second aspect, wherein the biodegradable polymer is selected from polylactic acid polymers, polycaprolactone (PCL), polylactic-co-glycolic acid (PLGA) and poly(ethylene glycol) methyl ether-block-poly(lactide-co-glycolide), PLGA-b-mPEG.

[0026] A sixteenth aspect, alone or in combination with any other aspect herein, relates to the medical device of the second aspect, wherein the biodegradable polymer is PLGA.

[0027] The seventeenth aspect, alone or in combination with any other aspect herein, relates to the medical device of the first aspect, wherein the medical device is selected from a balloon catheter, an perfusion balloon catheter, an infusion catheter, a cutting balloon catheter, a scoring balloon catheter, a laser catheter, an atherectomy device, a debulking catheter, a stent, a filter, a stent graft, a covered stent, a patch, a wire and a valve.

[0028] An eighteenth aspect, alone or in combination with any other aspect herein, relates to the medical device of the first aspect, wherein the medical device is a stent or a stent graft.

[0029] A nineteenth aspect, alone or in combination with any other aspect herein, relates to the medical device of the first aspect, wherein the medical device is a balloon catheter.

[0030] The twentieth aspect, alone or in combination with any other aspect herein, relates to the medical device of the first aspect, wherein the coating layer comprises one or more additional excipients.

[0031] The twenty-first aspect, alone or in combination with any other aspect herein, relates to the medical device of the twentieth aspect, wherein the one or more additional excipients are selected from polylactic acid (PLLA, PDLA, PDLLA), polycaprolactone (PCL), sodium docusate, PLGA, PLGA-b-mPEG, polyglutamic acid, polyacrylic acid, hyaluronic acid, alginate, PVA, PVP, Pluronic (PEO-PPO-PEO), cellulose, CMC, HPC, starch, chitosan, human serum albumin (HSA), phospholipids, fatty acids, fatty acid esters, triglycerides, beeswax, cyclodextrin, Tween 20, Tween 80, TPGS, SLS, butylated hydroxytoluene, vitamin E, vitamin E succinate, tannic acid, polyethylene glycol, N-isopropylacrylamide and sorbitan esters.

[0032] The twenty-second aspect, alone or in combination with any other aspect herein, relates to the medical device of the first aspect, further comprising an antioxidant.

[0033] The twenty-third aspect, alone or in combination with any other aspect herein, relates to the medical device of the twenty-second aspect, wherein the antioxidant is butylated hydroxytoluene.

[0034] The twenty-fourth aspect, alone or in combination with any other aspect herein, relates to the medical device of the first aspect, wherein the tissue comprises tissue of one of the coronary vasculature, peripheral vasculature, cerebral vasculature, esophagus, airway, sinus, trachea, colon, bile duct, urinary tract, prostate, and brain passage.

[0035] The twenty-fifth aspect, alone or in combination with any other aspect herein, relates to a balloon catheter for delivering a therapeutic agent to a blood vessel, the balloon catheter comprising: an elongated member having an inner cavity and a distal end; an expandable balloon attached to the distal end of the elongated member and in fluid communication with the inner cavity; and a coating layer covering the outer surface of the balloon, the coating layer comprising a therapeutic agent and at least one of a biodegradable polymer and an excipient, wherein: the therapeutic agent comprises a PDE inhibitor, a kinase inhibitor, an anti-fibrotic drug or a mixture thereof, and the biodegradable polymer is selected from a polylactic acid polymer, polycaprolactone (PCL), a polylactic-co-glycolic acid copolymer (PLGA) and a poly(ethylene glycol) methyl ether-block-polylactic-co-glycolic acid copolymer (PLGA). and the excipient is selected from fatty acids, fatty acid esters, polylactic acid (PLLA, PDLA, PDLLA), polycaprolactone (PCL), docusate sodium, PLGA-b-mPEG, polyglutamic acid, polyacrylic acid, hyaluronic acid, alginate, PVA, PVP, Pluronic (PEO-PPO-PEO), cellulose, CMC, HPC, starch, chitosan, human serum albumin (HSA), phospholipids, fatty acids, fatty acid esters, triglycerides, beeswax, cyclodextrin, Tween 20, Tween 80, TPGS, SLS, butylated hydroxytoluene, vitamin E, vitamin E succinate, tannic acid, polyethylene glycol, N-isopropylacrylamide and sorbitol esters.

[0036] The twenty-sixth aspect, alone or in combination with any other aspect herein, relates to the balloon catheter of the twenty-fifth aspect, wherein the PDE inhibitor is selected from the group consisting of xanthine, aminophylline, sildenafil, tadalafil, vardenafil, udenafil, avanafil, dipyridamole, quinazoline, paraxanthine, papaverine, mesembranose, rolipram, ibudilast, pyramilast, luteolin, drotaverine, roflumilast, apremilast, criborole, amrinone, milrinone, enoximone, anagrelide, cilostazol, pimobendan, erythro-9-(2-hydroxy-3-nonyl)adenine), (2-[(3,4-dimethoxyphenyl)methyl]-7-[(1R)-1-hydroxyethyl]-4-phenylbutyl]-5-methyl-imidazo[5,1-f][1,2,4]triazine-4(1H)-one), oxindole, (9-(6-phenyl-2-oxohexan-3-yl)-2-(3,4-dimethoxybenzyl)-purin-6-one), 3-isobutyl-1-methylxanthine, pentoxifylline, theobromine and theophylline.

[0037] The twenty-seventh aspect, alone or in combination with any other aspect herein, relates to the balloon catheter of the twenty-fifth aspect, wherein the PDE inhibitor is tadalafil or sildenafil.

[0038] The twenty-eighth aspect, alone or in combination with any other aspect herein, relates to the balloon catheter of the twenty-fifth aspect, wherein the PDE inhibitor is in the form of a free base, crystals, a free acid, or a salt.

[0039] The twenty-ninth aspect, alone or in combination with any other aspect herein, relates to the balloon catheter of the twenty-eighth aspect, wherein the salt is a hydrochloride, sodium salt, sulfate, acetate, phosphate and / or diphosphate, pamoate or hemipamoate, chloride, potassium, maleate, calcium salt, citrate, methanesulfonate, nitrate, tartrate, aluminum salt, stearate, dioctylsulfosuccinate or gluconate.

[0040] The thirtieth aspect, alone or in combination with any other aspect herein, relates to the balloon catheter of the twenty-fifth aspect, wherein the kinase inhibitor is selected from bosutinib, ceritinib, crizotinib, gefitinib, ruxolitinib, imatinib, axitinib, nilotinib, trametinib, afatinib, ibrutinib, cabozantinib, imatinib, lenvatinib, sunitinib, regorafenib, sorafenib, vandetanib, dasatinib, pazopanib, Y27632, CA3, verteporfin, VGLL4 peptide, nintedanib, afatinib, abemaciclib, erdafitinib, fitrinib, palbociclib and pemitinib.

[0041] The thirty-first aspect, alone or in combination with any other aspect herein, relates to the balloon catheter of the twenty-fifth aspect, wherein the kinase inhibitor is sunitinib.

[0042] The thirty-second aspect, alone or in combination with any other aspect herein, relates to the balloon catheter of the twenty-fifth aspect, wherein the kinase inhibitor is in the form of a free base, a free acid, a crystal, or a salt.

[0043] The thirty-third aspect, alone or in combination with any other aspect herein, relates to the balloon catheter of the thirty-second aspect, wherein the salt is a hydrochloride, sodium salt, sulfate, acetate, phosphate and / or diphosphate, pamoate or hemipamoate, a lipophilic salt, a chloride salt, a potassium salt, a maleate, a calcium salt, a citrate, a methanesulfonate, a nitrate, a tartrate, an aluminum salt, a stearate, dioctylsulfosuccinate, or a gluconate.

[0044] The thirty-fourth aspect, alone or in combination with any other aspect herein, relates to the balloon catheter of the twenty-fifth aspect, wherein the anti-fibrotic drug is selected from triamciclone, tranilast, halofuginone, montelukast, zafirlukast, pirfenidone, nintedanib and combinations thereof.

[0045] The thirty-fifth aspect, alone or in combination with any other aspect herein, relates to the balloon catheter of the twenty-fifth aspect, wherein the weight ratio of the biodegradable polymer to the therapeutic agent is from 1:10 to 5:1.

[0046] The thirty-sixth aspect, alone or in combination with any other aspect herein, relates to the balloon catheter of the twenty-fifth aspect, wherein the biodegradable polymer is PLGA.

[0047] The thirty-seventh aspect, alone or in combination with any other aspect herein, relates to the balloon catheter of the twenty-fifth aspect, wherein the excipient is docusate sodium.

[0048] The thirty-eighth aspect, alone or in combination with any other aspect herein, relates to the balloon catheter of the twenty-fifth aspect, further comprising an antioxidant.

[0049] The thirty-ninth aspect, alone or in combination with any other aspect herein, relates to the balloon catheter of the thirty-eighth aspect, wherein the antioxidant is selected from probucol, vitamin E, vitamin E succinate, butylated hydroxytoluene (BHT), ascorbic acid, beta-carotene, lycopene, lutein, retinol, manganese, selenium, flavonoids, flavonoids, catechins, polyphenols and / or zeaxanthin.

[0050] The fortieth aspect, alone or in combination with any other aspect herein, relates to a stent, stent graft or other permanent or semi-permanent medical device for delivering a therapeutic agent to a blood vessel, comprising a device body and a drug coating thereon, wherein the drug coating comprises: a therapeutic agent and at least one of a biodurable polymer and an excipient, wherein: the therapeutic agent comprises a PDE inhibitor, a kinase inhibitor, an anti-fibrotic drug and a mixture thereof, and the biodurable polymer is selected from poly(vinylidene hexafluoropropylene) (PVDF-HFP), polyethylene terephthalate (PET), nylon 66, polyurethane (PU), polytetrafluoroethylene (PTFE), polyethylene, polysiloxane (silicone) and poly(methyl methacrylate) and the excipient is selected from fatty acids, fatty acid esters, polylactic acid (PLLA, PDLA, PDLLA), polycaprolactone (PCL), docusate sodium, PLGA, PLGA-b-mPEG, polyglutamic acid, polyacrylic acid, hyaluronic acid, alginate, PVA, PVP, Pluronic (PEO-PPO-PEO), cellulose, CMC, HPC, starch, chitosan, human serum albumin (HSA), phospholipids, fatty acids, fatty acid esters, triglycerides, beeswax, cyclodextrin, Tween 20, Tween 80, TPGS, SLS, butylated hydroxytoluene, vitamin E, vitamin E succinate, and sorbitan esters.

[0051] The forty-first aspect, alone or in combination with any other aspect herein, relates to the stent, stent graft, or other permanent or semi-permanent medical device of the fortieth aspect, wherein the PDE inhibitor is selected from the group consisting of xanthine, aminophylline, sildenafil, tadalafil, vardenafil, udenafil, avanafil, dipyridamole, quinazoline, paraxanthine, papaverine, mesembryone, rolipram, ibudilast, pyramilast, luteolin, drotaverine, roflumilast, apremilast, criborole, amrinone, milrinone, enoximone, anagrelide, Cilostazol, pimobendan, erythro-9-(2-hydroxy-3-nonyl)adenine), (2-[(3,4-dimethoxyphenyl)methyl]-7-[(1R)-1-hydroxyethyl]-4-phenylbutyl]-5-methyl-imidazo[5,1-f][1,2,4]triazine-4(1H)-one), oxindole, (9-(6-phenyl-2-oxohex-3-yl)-2-(3,4-dimethoxybenzyl)-purin-6-one), 3-isobutyl-1-methylxanthine, pentoxifylline, theobromine and theophylline.

[0052] The forty-second aspect, alone or in combination with any other aspect herein, relates to the stent, stent graft, or other permanent or semi-permanent medical device of the fortieth aspect, wherein the PDE inhibitor is tadalafil or sildenafil.

[0053] The forty-third aspect, alone or in combination with any other aspect herein, relates to the stent, stent graft, or other permanent or semi-permanent medical device of the fortieth aspect, wherein the PDE inhibitor is in the form of a free base, crystals, free acid, or salt.

[0054] The forty-fourth aspect, alone or in combination with any other aspect herein, relates to the stent, stent graft, or other permanent or semi-permanent medical device of the forty-third aspect, wherein the salt is a hydrochloride, sodium salt, sulfate, acetate, phosphate and / or diphosphate, pamoate or hemipamoate, chloride, potassium, maleate, calcium salt, citrate, methanesulfonate, nitrate, tartrate, aluminum salt, stearate, dioctylsulfosuccinate, or gluconate.

[0055] The 45th aspect, alone or in combination with any other aspect herein, relates to the stent, stent graft, or other permanent or semi-permanent medical device of the 40th aspect, wherein the kinase inhibitor is selected from bosutinib, ceritinib, crizotinib, gefitinib, ruxolitinib, imatinib, axitinib, nilotinib, trametinib, afatinib, ibrutinib, cabozantinib, imatinib, lenvatinib, sunitinib, regorafenib, sorafenib, vandetanib, dasatinib, pazopanib, Y27632, CA3, verteporfin, VGLL4 peptide, nintedanib, afatinib, abemaciclib, erdafitinib, fitratinib, palbociclib and pemitinib.

[0056] The forty-sixth aspect, alone or in combination with any other aspect herein, relates to the stent, stent graft, or other permanent or semi-permanent medical device of the fortieth aspect, wherein the kinase inhibitor is sunitinib.

[0057] The forty-seventh aspect, alone or in combination with any other aspect herein, relates to the stent, stent graft, or other permanent or semi-permanent medical device of the fortieth aspect, wherein the kinase inhibitor is in the form of a free base, a free acid, a crystal, or a salt.

[0058] The forty-eighth aspect, alone or in combination with any other aspect herein, relates to the stent, stent graft, or other permanent or semi-permanent medical device of the forty-seventh aspect, wherein the salt is a hydrochloride, sodium salt, sulfate, acetate, phosphate and / or diphosphate, pamoate or hemipamoate, a lipophilic salt, chloride salt, potassium salt, maleate, calcium salt, citrate, methanesulfonate, nitrate, tartrate, aluminum salt, stearate, dioctylsulfosuccinate, or gluconate.

[0059] The 49th aspect, alone or in combination with any other aspect herein, relates to the stent, stent graft or other permanent or semi-permanent medical device of the 40th aspect, wherein the anti-fibrotic drug is selected from triamcinolone, tranilast, halofuginone, montelukast, zafirlukast, pirfenidone, nintedanib and combinations thereof.

[0060] The fiftieth aspect, alone or in combination with any other aspect herein, relates to the stent, stent graft, or other permanent or semi-permanent medical device of the fortieth aspect, wherein the biodurable polymer is PVDF-HFP.

[0061] The fifty-first aspect, alone or in combination with any other aspect herein, relates to the stent, stent graft, or other permanent or semi-permanent medical device of the fortieth aspect, wherein the weight ratio of the biodurable polymer to the therapeutic agent is from 1:1 to 10:1.

[0062] The fifty-second aspect, alone or in combination with any other aspect herein, relates to the stent, stent graft, or other permanent or semi-permanent medical device of the fortieth aspect, wherein the biodegradable polymer is PLGA.

[0063] The fifty-third aspect, alone or in combination with any other aspect herein, relates to the stent, stent graft, or other permanent or semi-permanent medical device of the fortieth aspect, wherein the excipient is docusate sodium.

[0064] The fifty-fourth aspect, alone or in combination with any other aspect herein, relates to the stent, stent graft, or other permanent or semi-permanent medical device of the fortieth aspect, further comprising an antioxidant.

[0065] The fifty-fifth aspect, alone or in combination with any other aspect herein, relates to the stent, stent graft, or other permanent or semi-permanent medical device of the fifty-fourth aspect, wherein the antioxidant is selected from probucol, vitamin E, vitamin E succinate, butylated hydroxytoluene (BHT), ascorbic acid, beta-carotene, lycopene, lutein, retinol, manganese, selenium, flavonoids, flavonoids, catechins, polyphenols, tannic acid and / or zeaxanthin.

[0066] A kinase inhibitor, a PDE inhibitor and / or an anti-fibrotic agent for use in a method of alleviating stenosis in a target tissue and / or preventing restenosis and / or late lumen loss of a body lumen, wherein the kinase inhibitor and / or the anti-fibrotic agent is delivered to the target tissue by a medical device according to any one of aspects 1 to 55.

[0067]

[0011] These and other features, aspects and advantages of the disclosure will become better understood with reference to the following description and appended claims.

[0068] Additional features and advantages of the aspects described herein will be set forth in the following detailed description, and some features and advantages will be readily apparent to those skilled in the art from the description or may be recognized by practicing the aspects described herein, including the following detailed description, claims, and accompanying drawings. BRIEF DESCRIPTION OF THE DRAWINGS

[0069] It should be understood that both the foregoing general description and the following detailed description describe various aspects and are intended to provide an overview or framework for understanding the nature and character of the claimed subject matter. The accompanying drawings are included to provide a further understanding of the various aspects and are incorporated into and constitute a part of this specification. The drawings illustrate various aspects described herein and, together with the description, serve to explain the principles and operation of the claimed subject matter.

[0070] Figure 1 is a schematic diagram of exemplary aspects of a medical device, particularly a balloon catheter, according to the disclosure.

[0071] Figure 2A yes Figure 1 A cross-sectional view of an aspect of the distal portion of a balloon catheter taken along line AA, including a drug coating on the outer surface of the balloon.

[0072] Figure 2B yes Figure 1 A cross-sectional view of an aspect of the distal portion of the balloon catheter taken along line AA, including an intermediate layer between the outer surface of the balloon and the drug coating layer.

[0073] Figure 3is a schematic diagram of exemplary aspects of a medical device, particularly a stent, according to the disclosure.

[0074] Figure 4 yes Figure 3 A cross-sectional view of an aspect of the distal portion of the balloon catheter taken along line AA, including a drug coating layer on the outer surface of the stent.

[0075] Figure 5 is an optical microscope image of sample holder 1.

[0076] Figure 6 is an optical microscope image of sample holder 2.

[0077] Figure 7 is the cumulative release curve of sample holder 1 and sample holder 2.

[0078] Figure 8 In vivo release profiles and tissue PK graphs over a time course of up to 90 days after stent insertion.

[0079] Fig. 9 Vessel cross-sectional views of Comparative Examples A and C and Samples 1 and 2 are shown.

[0080] Fig.10 In vivo pharmacokinetic data for sunitinib, tadalafil, colchicine, and roflumilast at 7 and 28 days after stent insertion are shown.

[0081] Fig.11 Shown are arterial cross sections and stent endothelialization 60 days after stent insertion with drug coatings of colchicine, tadalafil, roflumilast, sunitinib, and PVDF alone.

[0082] Fig.12 Shown are arterial cross sections and stent endothelialization 90 days after stent insertion with drug coatings of colchicine, tadalafil, roflumilast, sunitinib, and PVDF alone.

[0083] Fig.13 Shown are representative scanning electron microscopy images of PLGA / sunitinib malate microparticles prepared using the O / W emulsion evaporation method, showing the spherical morphology at low magnification (upper panel) and high magnification (lower panel). DETAILED DESCRIPTION

[0084] Specific aspects of the present application will now be described. These aspects are provided so that this disclosure will be thorough and complete, and will fully convey the scope of the subject matter to those skilled in the art.

[0085] Unless otherwise indicated, all molecular weights herein are reported in Daltons (g / mol). Molecular weights of polymeric materials are reported as weight average molecular weight.

[0086] As used herein, the interchangeable terms "coating" and "layer" refer to a material that is or has been applied to a surface or portion of a surface of a substrate using any conventional application or deposition method, such as vapor deposition, spraying, dipping, laminating, bonding, micropatterning, molding, painting, spin coating, sputtering, immersion plating, plasma-assisted deposition, or vacuum evaporation.

[0087] The terms "coating" and "applying" as verbs are used interchangeably herein. Unless otherwise specified, references to "a substrate coated with a material" and the like are equivalent to "a substrate to which a material has been applied" (applied to a surface or portion of a surface of a substrate) using any conventional application or deposition method, such as vapor deposition, spraying, dipping, painting, spin coating, sputtering, immersion plating, plasma-assisted deposition, or vacuum evaporation.

[0088] Drug coating

[0089] In some aspects, the disclosure relates to one or more drug coatings for medical devices and methods of using the same. Medical devices may include angioplasty balloons, catheters, guidewires, balloons, filters, stents, stent grafts, vascular grafts, aneurysm filling embolic coils, meshes, artificial heart valves, pacemaker wires, ports, needles, clips, and all other devices with drug coatings. In some aspects, the drug coating disclosed in the present invention may be applied to the outer surface of an expandable medical device, which, as a non-limiting example, includes a balloon catheter and a stent. Exemplary methods for preparing medical devices and coatings thereon, as well as exemplary data from expandable medical devices including the drug coatings described herein, are described herein. In some aspects, the drug coating may have a therapeutic agent itself. In other aspects, the drug coating may include a therapeutic agent and an additive. In other aspects, the drug coating may have a therapeutic agent and two or more additives. In some aspects, the additive may include a polymer.

[0090] As previously mentioned, currently commercialized drug-coated devices, while effective in reducing restenosis by inhibiting VSMC migration and proliferation, act in a sufficiently nonspecific manner that they also result in inhibition of endothelial cell (EC) growth and / or proliferation, delayed endothelial recovery, and late thrombosis. Taken together, these nonspecific and undesirable effects increase the long-term risk of patient mortality.

[0091] In other aspects, the disclosure provides a drug coating for a medical device that may include an anti-fibrotic drug, a kinase inhibitor, a phosphodiesterase inhibitor, or a combination thereof. Another nonspecific effect that can be seen in some current drug-coated devices includes stimulating the production of fibrin, which can lead to fibrosis. One disadvantage of current coated angioplasty balloons is that the contained drugs act in an indiscriminate anti-proliferative manner and can become displaced and move to other parts of the body. Therefore, when nonspecific anti-proliferative drug residues move downstream from the inserted device in the body, unexpected consequences may result. For example, the displaced drug can migrate to the lungs and cause fibrotic scarring therein. By including an anti-fibrotic drug in the coating of the device as described herein, the possibility of stimulating fibrin production or inducing fibrotic tissue is prevented.

[0092] In some aspects, the drug coating described in the present invention can allow therapeutic agents, drugs or bioactive materials to be effectively and efficiently delivered directly to local tissue areas during or after medical procedures to treat or prevent vascular and non-vascular diseases, such as restenosis. The drug coating described in the present invention can allow therapeutic agents to be released at the desired target location in an effective and efficient manner, wherein the therapeutic agent can penetrate the target tissue to treat the disease, for example, to relieve stenosis and prevent restenosis and late lumen loss of the body lumen. In some other aspects, the drug coating described in the present invention can allow therapeutic agents to be released in an effective and efficient manner to treat pulmonary fibrosis. In addition, the drug coating described in the present invention can allow effective treatment without significantly inhibiting endothelial cells (EC).

[0093] In some aspects, the drug coating comprises at least one therapeutic agent present thereon at a desired concentration density. In some aspects, the concentration density of the at least one therapeutic agent in the drug coating can be about 0.1 μg / mm 2 About 10 μg / mm 2 , including about 0.2μg / mm 2 , 0.25μg / mm 2 , 0.3μg / mm 2 , 0.35μg / mm 2 , 0.4μg / mm 2 , 0.45μg / mm 2 , 0.5μg / mm 2 , 0.55μg / mm 2 , 0.6μg / mm 2 , 0.65μg / mm 2 , 0.7μg / mm 2 , 0.75μg / mm 2 , 0.8μg / mm 2 , 0.85μg / mm2 、0.9μg / mm 2 、0.95μg / mm 2 、1.0μg / mm 2 、1.1μg / mm 2 、1.2μg / mm 2 、1.3μg / mm 2 、1.4μg / mm 2 、1.5μg / mm 2 、1.6μg / mm 2 、1.7μg / mm 2 、1.8μg / mm 2 、1.9μg / mm 2 、2.0μg / mm 2 、2.1μg / mm 2 、2.2μg / mm 2 、2.3μg / mm 2 、2.4μg / mm 2 、2.5μg / mm 2 、2.6μg / mm 2 、2.7μg / mm 2 、2.8μg / mm 2 、2.9μg / mm 2 、3.0μg / mm 2 、3.1μg / mm 2 、3.2μg / mm 2 、3.3μg / mm 2 、3.4μg / mm 2 、3.5μg / mm 2 、3.6μg / mm 2 、3.7μg / mm 2 、3.8μg / mm 2 、3.9μg / mm 2 、4.0μg / mm 2 、4.1μg / mm 2 、4.2μg / mm 2 、4.3μg / mm 2 、4.4μg / mm 2 、4.5μg / mm 2 、4.6μg / mm 2 、4.7μg / mm 2 、4.8μg / mm 2 、4.9μg / mm 2 、5.0μg / mm 2 、5.1μg / mm 2 、5.2μg / mm 2、5.3μg / mm 2 、5.4μg / mm 2 、5.5μg / mm 2 、5.6μg / mm 2 、5.7μg / mm 2 、5.8μg / mm 2 、5.9μg / mm 2 、6.0μg / mm 2 、6.1μg / mm 2 、6.2μg / mm 2 、6.3μg / mm 2 、6.4μg / mm 2 、6.5μg / mm 2 、6.6μg / mm 2 、6.7μg / mm 2 、6.8μg / mm 2 、6.9μg / mm 2 、7.0μg / mm 2 、7.1μg / mm 2 、7.2μg / mm 2 、7.3μg / mm 2 、7.4μg / mm 2 、7.5μg / mm 2 、7.6μg / mm 2 、7.7μg / mm 2 、7.8μg / mm 2 、7.9μg / mm 2 、8.0μg / mm 2 、8.1μg / mm 2 、8.2μg / mm 2 、8.3μg / mm 2 、8.4μg / mm 2 、8.5μg / mm 2 、8.6μg / mm 2 、8.7μg / mm 2 、8.8μg / mm 2 、8.9μg / mm 2 、9.0μg / mm 2 、9.1μg / mm 2 、9.2μg / mm 2 、9.3μg / mm 2 、9.4μg / mm 2 、9.5μg / mm 2 、9.6μg / mm 2 、9.7μg / mm 2 、9.8μg / mm2 and 9.9 μg / mm 2 In other aspects, the concentration density of the at least one therapeutic agent in the drug coating can be about 0.1 μg / mm 2 About 8 μg / mm 2 , about 0.1μg / mm 2 About 6 μg / mm 2 , about 0.1μg / mm 2 About 4 μg / mm 2 , about 0.1μg / mm 2 About 2 μg / mm 2 , about 0.1μg / mm 2 About 1 μg / mm 2 , about 1μg / mm 2 About 10 μg / mm 2 , about 1μg / mm 2 About 8 μg / mm 2 , about 1μg / mm 2 About 6 μg / mm 2 , about 1μg / mm 2 About 4 μg / mm 2 , about 1μg / mm 2 About 2 μg / mm 2 , 2μg / mm 2 About 10 μg / mm 2 , 2μg / mm 2 About 8 μg / mm 2 , 2μg / mm 2 About 6 μg / mm 2 , 2μg / mm 2 About 4 μg / mm 2 , 4μg / mm 2 About 10 μg / mm 2 , 4μg / mm 2 About 8 μg / mm 2 , 4μg / mm 2 About 6 μg / mm 2 , 6μg / mm 2 About 10 μg / mm 2 , 6μg / mm 2 About 8 μg / mm 2 or about 8 μg / mm 2 About 10 μg / mm 2 In some aspects, the concentration density of the at least one therapeutic agent in the drug coating can be about 0.5 μg / mm 2 About 5 μg / mm 2 .

[0094] In some aspects, as described herein, the drug coating can include one polymer or two or more polymers. In some aspects, the weight ratio of polymer to therapeutic agent in the drug coating can be about 1:1 to about 10:1, about 1:1 to about 9:1, about 1:1 to about 8:1, about 1:1 to about 7:1, about 1:1 to about 6:1, about 1:1 to about 5:1, about 1:1 to about 4:1, about 1:1 to about 3:1, about 1:1 to about 2:1, about 2:1 to about 10:1, about 2:1 to about 9:1, about 2:1 to about 8:1, about 2:1 to about 7:1, about 2:1 to about 6:1, about 2:1 to about 5:1, about 2:1 to about 4:1, about 2:1 to about 3:1, about 1:1 to about 2:1, about 2:1 to about 10:1, about 2:1 to about 9:1, about 2:1 to about 8:1, about 2:1 to about 7:1, about 2:1 to about 6:1, about 2:1 to about 5:1, about 2:1 to about 4:1, about 2:1 to about 3:1, about 3:1 to about 10:1, about 3:1 to about 9:1, about 3:1 to about 8:1, about 3:1 to about 7:1, about 3:1 to about 1 to about 6:1, about 3:1 to about 5:1, about 3:1 to about 4:1, about 4:1 to about 10:1, about 4:1 to about 9:1, about 4:1 to about 8:1, about 4:1 to about 7:1, about 4:1 to about 6:1, about 4:1 to about 5:1, about 5:1 to about 10:1, about 5:1 to about 9:1, about 5:1 to about 8:1, about 5:1 to about 7:1, about 5:1 to about 6:1, about 6:1 to about 10:1, about 6:1 to about 9:1, about 6:1 to about 8:1, about 6:1 to about 7:1, about 7:1 to about 10:1, about 7:1 to about 9:1, about 7:1 to about 8:1, about 8:1 to about 10:1, about 8:1 to about 9:1, or about 9:1 to about 10:1. If the polymer to therapeutic agent ratio (weight ratio) is too low, the drug may be released prematurely, and if the ratio is too high, the drug may not elute quickly enough or be absorbed by the tissue when deployed at the target site. For example, a low ratio may result in faster release, and a high ratio may result in slower release.

[0095] In some aspects, the drug coating may include a biodurable polymer. As described herein, a biodurable polymer may include a polymer that is well tolerated and / or non-reactive when in contact with a subject or its immune response cells and resists erosion and / or enzymatic degradation and / or dissolution in a subject or its circulatory system. (See, for example, Nathanael et al. Polymer 2020, 12, 3061; doi: 10.3390 / polym12123061; "Polymers for Vascular and Urogenital Applications", Shalaby et al. eds. CRC Pres, 2017 and "Concise Encyclopedia of Biomedical Polymers and Polymeric Biomaterials", Mishra et al. eds. CRC Press 2017). By way of example, biodurable polymers include polyethylene terephthalate (PET), nylon 66, polyurethane (PU), polytetrafluoroethylene (PTFE), polyethylene (PE, low density and high density and ultra high molecular weight UHMW), polysiloxanes (silicones) and poly (methyl methacrylate) (PMMA) and poly (vinylidene fluoride-co-hexafluoropropylene) (PVDF-HFP). In some aspects, the biodurable polymer can be PVDF-HFP.

[0096] In other aspects, the drug coating may include a biodegradable polymer. As described herein, a biodegradable polymer may include a polymer that is well tolerated and / or non-reactive when in contact with a subject or its immune response cells and is susceptible to erosion and / or enzymatic degradation and / or dissolution over time in a subject or its circulatory system. (See, for example, Nathanael et al. Polymer 2020, 12, 3061; doi: 10.3390 / polym12123061; "Polymers for Vascular and Urogenital Applications", Shalaby et al. eds. CRC Pres, 2017 and "Concise Encyclopedia of Biomedical Polymers and Polymeric Biomaterials", Mishra et al. eds. CRC Press 2017). Biodegradable polymers allow for reduction or elimination of incomplete drug release. Examples of biodegradable polymers include polylactic acid polymers (PLA, PLLA, PDLA, PDLLA), polycaprolactone (PCL), polylactic-co-glycolic acid (PLGA), and poly(ethylene glycol) methyl ether-block-polylactic-co-glycolic acid (PLGA-b-mPEG).

[0097] In some aspects, the drug coating is configured for an underlying medical device. For example, in some aspects, the medical device is a stent, and in other aspects, the medical device is a balloon. Thus, the drug coating can be tailored to suit the properties of a transient device that is fed along a vessel wall, and the drug coating can be tailored for a permanent or semi-permanent device that can release the drug directly from the surface while it resides in the vessel.

[0098] In some aspects, the disclosure relates to a drug coating for a balloon or inflatable device that is intended to inflate and apply pressure from the inside of a vessel to the outside of the vessel. Due to the obstructive nature of the circulation caused by inflation, these devices can only be deployed for a shortened time period. Due to such constraints, it is obviously necessary to configure the drug coating to be delivered quickly to the vessel wall. In some aspects, the balloon can deliver the drug coating in a manner that the coating is released to the vessel wall or allows the vessel wall to absorb quickly. In some aspects, the drug coating can be configured with an excipient and / or drug solvation to promote transfer to the inside of the vessel wall. In some aspects, the excipient may include an excipient as described herein. In other aspects, the excipient may include polyethylene glycol (PEG), urea, polylactic acid (PLA), polyglycolic acid (PGA), polylactic-co-glycolic acid (PLGA), shellac, dimethyl sulfoxide (DMSO), polysorbate, docusate sodium, sorbitol, tri-n-hexyl butyryl citrate (BTHC), N-isopropylacrylamide (P-NIPAAm) or a combination thereof. In some aspects, the drug coating can have a specific formulation of a therapeutic agent, such as crystals and / or microparticles thereof, or salts and / or microparticles thereof. In some aspects, the salt can be a malate. In some aspects, the drug coating can include a polymer, such as a biodegradable and / or bioerodible polymer or a combination thereof as described herein. In some aspects, the drug coating can include PLA, PGA, and / or PLGA. In some aspects, the drug coating can be in the form of a free alkali. In some aspects, the drug coating can have an excipient, a salt of a therapeutic agent, and a biodegradable and / or bioerodible polymer.

[0099] In other aspects, drug coating is configured for stent, stent graft or other medical devices that stay longer, such as perfusion balloon catheter, infusion catheter, cutting balloon catheter, scoring balloon catheter, laser catheter, atherectomy equipment, volume reduction catheter, filter, stent graft, stent graft, patch, line and valve.Due to the permanent or semi-permanent nature of stent, drug coating does not need to transfer active agent with the same urgency, and can be configured to remain on the surface of stent or external area to provide the drug release curve required for disease.For example, therapeutic agent and biodurable polymer, biodegradable and / or bioerodible polymer combination can be embedded therapeutic agent, and allow to continue and / or delay release when polymer erosion.Such polymer can include PLA, PGA, PLGA, polyvinylidene fluoride (PVD or PVDF), polyvinylidene fluoride-hexafluoropropylene (PVDF-HFP or PVD-HFP), poly methacrylate n-butyl ester (PBMA), polystyrene-b-polyisobutylene-b-polystyrene (SIBS) or its combination. In some aspects, the drug coating may include the therapeutic agent in one or more formulations to provide a preferred release profile, such as different loadings within the polymer, different particle sizes, and combinations of salt / crystalline / free base forms of the therapeutic agent.

[0100] Many aspects of the disclosure may be particularly useful for treating vascular disease and for reducing stenosis and late lumen loss, or for making devices for such purposes or for methods of treating such diseases. Although the examples set forth herein are described only with respect to stents and balloon catheters, it should be understood that, in addition to stents and balloon catheters, other medical devices (particularly other expandable medical devices) may be coated with drug coatings including therapeutic agents and additives, such as those previously described with respect to stents and balloon catheters. Such other medical devices include, but are not limited to, stent grafts, scored balloon catheters, and recanalization catheters.

[0101] Therapeutic agents

[0102] In some aspects, the drug coating of the medical device may include at least one therapeutic agent. The therapeutic agent may include a small molecule chemical compound, an anion thereof, a cation thereof, a salt thereof, a derivative thereof, and / or a crystal or a crystalline form thereof in an uncharged or neutral state. In some aspects, the drug coating of the medical device may include a therapeutic agent and at least one additive. In some aspects, the drug coating may include an anti-fibrotic drug, a kinase inhibitor, or a combination thereof, which may be a feasible target for treating restenosis with improved specificity and fewer side effects compared to nonspecific antiproliferative drugs.

[0103] As used herein, "derivative" may refer to a chemical or biologically modified form of a chemical compound, which is structurally similar to a parent compound and (actually or theoretically) may be derived from the parent compound (e.g., dexamethasone). A derivative may or may not have chemical or physical properties different from the parent compound. For example, a derivative may be more hydrophilic or it may have a changed reactivity compared to the parent compound. Derivatization (i.e., modification) may involve substitution of one or more parts within a molecule (e.g., a change in a functional group). For example, hydrogen may be substituted by a halogen (such as fluorine or chlorine), or a hydroxyl group (—OH) may be substituted by a carboxylic acid moiety (—COOH). The term "derivative" may also include conjugates and prodrugs (i.e., chemically modified derivatives that may be converted into the original compound under physiological conditions) of the parent compound. For example, a prodrug may be an inactive form of an active agent. Under physiological conditions, a prodrug may be converted into an active form of a compound, such as by phase I and / or phase II of a metabolic pathway. Prodrugs can be formed, for example, by replacing one or two hydrogen atoms on a nitrogen atom with an acyl group (acyl prodrug) or a carbamate group (carbamate prodrug). More detailed information on prodrugs can be found, for example, in the following literature: Fleisher et al., Advanced Drug Delivery Reviews 19 (1996) 115; Design of Prodrugs, H. Bundgaard (ed.), Elsevier, 1985 or H. Bundgaard, Drugs of the Future 16 (1991) 443. The term "derivative" is also used to describe all solvates of the parent compound, for example, hydrates or adducts (for example, adducts with alcohols), active metabolites and salts. The type of salt that can be prepared depends on the nature of the moiety within the compound. For example, acidic groups (e.g., carboxylic acid groups) can form alkali metal salts or alkaline earth metal salts (e.g., sodium salts, potassium salts, magnesium salts and calcium salts), and salts with physiologically tolerable quaternary ammonium ions, and with ammonia and physiologically tolerable organic amines such as triethylamine, ethanolamine or tri-(2-hydroxyethyl) amine acid addition salts. Basic groups can form acid addition salts with, for example, inorganic acids such as hydrochloric acid, sulfuric acid or phosphoric acid or with organic carboxylic acids and sulfonic acids such as acetic acid, citric acid, benzoic acid, maleic acid, fumaric acid, tartaric acid, methanesulfonic acid or p-toluenesulfonic acid. In some aspects, organic acids can include fatty acids, such as stearic acid and / or dioctyl sulfosuccinic acid. In some aspects, organic acids can include those with biological activity, such as oleanolic acid, betulinic acid, ursolic acid and / or valproic acid. In other aspects, organic acids can include those with antioxidant properties, such as ascorbic acid, tannic acid and vitamin E succinate. In some aspects, the organic acid can include pamoic acid.Compounds containing both basic and acidic groups (e.g., carboxyl groups in addition to basic nitrogen atoms) may exist as zwitterions. Salts may be obtained by conventional methods known to those skilled in the art, for example, by mixing the compound with an inorganic or organic acid or base in a solvent or diluent, or by cation exchange or anion exchange from other salts.

[0104] As used herein, an "analog" or "like" may refer to a chemical compound that is similar in structure to another but slightly different in composition (such as one atom is replaced by an atom of a different element or in the presence of a particular functional group) and may or may not be derived from a parent compound. A "derivative" may differ from an "analog" or "like" in that a parent compound may be the starting material for generating a "derivative", while a parent compound may not necessarily be used as a starting material for generating an "analog".

[0105] In some aspects of the disclosure, the therapeutic agent or substance may include a drug or a bioactive material. The drug may have various physical states, such as molecular distribution, crystal form, cluster form, or a combination thereof. Examples of drugs that may exhibit specific antiproliferative effects and / or lack nonspecific inhibition of endothelial cell growth and / or proliferation or endothelialization may include phosphodiesterase inhibitor drugs and / or antifibrotic drugs and / or kinase inhibitors and / or tyrosine kinase inhibitors and / or receptor tyrosine kinase inhibitors. Other examples of drugs may include one or more of the following: bosutinib, ceritinib, crizotinib, gefitinib, ruxolitinib, imatinib, axitinib, nilotinib, trametinib, afatinib, ibrutinib, cabozantinib, imatinib, lenvatinib, sunitinib, regorafenib, sorafenib, vandetanib, dasatinib, pazopanib, triamcinolone ... Nilast, Halofuginone, Montelukast, Zafirlukast, Pirfenidone, Y27632, CA3, Verteporfin, VGLL4 peptide, Nintedanib, Afatinib, Abemacili, Erdatinib, Fidrazolidinib, Nilotinib, Nintedanib, Palbociclib, Pemitinib, Xanthine, Aminophylline, Sildenafil, Tadalafil, Vardenafil, Udenafil, Avanafil, Dipyridamole, Quinazoline, paraxanthine, papaverine, mesembryone, rolipram, ibudilast, pyramilast, luteolin, drotaverine, roflumilast, apremilast, crisaborole, amrinone, milrinone, enoximone, anagrelide, cilostazol, pimobendan, erythro-9-(2-hydroxy-3-nonyl)adenine), (2-[(3,4-dimethoxyphenyl)methyl]-7-[(1R)-1-hydroxyethyl]-4-phenylbutyl]-5-methyl-imidazo[5,1-f][1,2,4]triazine-4(1H)-one), oxindole, (9-(6-phenyl-2-oxohexan-3-yl)-2-(3,4-dimethoxybenzyl)-purin-6-one), 3-isobutyl-1-methylxanthine, pentoxifylline, theobromine, and theophylline. In certain aspects, these drugs may be suitable for use in coatings on expandable medical devices for treating vasculature tissue.

[0106] In some aspects, therapeutic agents may include protein kinase inhibitors, which may also be referred to as multi-target tyrosine kinase inhibitors (MTK), such as cabozantinib, imatinib, lenvatinib, sunitinib, regorafenib, sorafenib, vandetanib, dasatinib and pazopanib. Protein kinases are a large family of enzymes that regulate biological responses (including cell proliferation and inflammation) through an enzyme cascade of phosphorylation events. Tyrosine kinases refer to tyrosine amino acids that participate in the phosphorylation of specific enzymes or receptors and the resulting enzymatic activity, wherein serine and threonine are other major amino acids for kinase activation and signal transduction. An example is the receptor protein tyrosine kinase platelet-derived growth factor receptor (PDGFR), which, after binding to endogenous platelet-derived growth factor (PDGF or platelet-derived growth hormone PDGH), can initiate a cascade reaction, leading to vascular smooth muscle cell (VSMC) migration and proliferation. It is reported that PDGF and PDGFR expression are upregulated in damaged vascular tissue. In addition, vascular endothelial growth factor (VEGF) and its tyrosine kinase receptor VEGFR are also confirmed to be highly involved in the pathological progression of restenosis. The example of PDGFR and / or VEGFR inhibitor (including the inhibitor of its downstream enzyme) includes imatinib, nintedanib, sorafenib, sunitinib and pazopanib, ROCK inhibitor (Y27632), YAP / TAZ inhibitor (CA3 and verteporfin), YAP / TAZ-TEAD interaction inhibitor (verteporfin, VGLL4 peptide), SRC inhibitor (dasatinib). In addition, the kinase regulator derived from biologically active products can be included, such as resveratrol, quercetin, curcumin, chrysin, myricetin, luteolin, apigenin, anthocyanidin, genistein, epigallocatechin gallate, fisetin, astaxanthin, tetrahydrocurcumin and / or its combination.

[0107] Thus, inhibition of PDGF and / or VEGF and / or activation of their tyrosine kinase receptors (i.e., VEGFR and / or PDGFR) provides a more selective approach than general cytotoxic agents for preventing the formation of neointimal hyperplasia without equally inhibiting vascular smooth muscle cells (VSMC) and / or normal cells. In addition, tyrosine kinase inhibitors (such as sunitinib) target proliferative smooth muscle cells in a more selective manner than drugs currently used for drug-coated interventional devices. In some aspects, local delivery of kinase inhibitors using the interventional devices described herein, followed by sustained release of the drug, can allow inhibition of restenosis without causing systemic toxicity. In addition, in general, kinase inhibitors have good chemical stability because they are not easily degraded during typical storage conditions of the medical devices set forth herein.

[0108] Kinase inhibitors are generally weak bases that are protonated under physiological conditions. Therefore, tyrosine kinase inhibitors have high water solubility. In some aspects, the drug coating can include a therapeutic agent having a water solubility of about 0.1 mg / mL to about 50 mg / mL, about 0.1 mg / mL to about 8 mg / mL, about 0.1 mg / mL to about 6 mg / mL, about 0.1 mg / mL to about 4 mg / mL, about 0.1 mg / mL to about 2 mg / mL, about 2 mg / mL to about 10 mg / mL, about 2 mg / mL to about 8 mg / mL, about 2 mg / mL to about 6 mg / mL, about 2 mg / mL to about 4 mg / mL, about 4 mg / mL to about 10 mg / mL, about 4 mg / mL to about 8 mg / mL, about 4 mg / mL to about 6 mg / mL, about 6 mg / mL to about 10 mg / mL, about 6 mg / mL to about 10 mg / mL. In some aspects, the water solubility of sunitinib malate is about 25 mg / mL. In some aspects, although high solubility may pose a challenge to sustained release formulations, the use of lipophilic excipients in coating matrices can slow down or inhibit drug dissolution.

[0109] In some aspects, the kinase inhibitor can be applied directly to the medical device as a free base or free acid. In other aspects, the kinase inhibitor can be protonated or in the form of a salt, such as a hydrochloride, sodium salt, sulfate, acetate, phosphate and / or diphosphate, pamoate or hemipamoate, chloride, potassium, maleate, calcium salt, citrate, methanesulfonate, nitrate, tartrate, aluminum salt or gluconate.

[0110] In conventional methods, systemic administration of kinase inhibitors may require relatively high doses, which may lead to serious side effects. In some current aspects, the concentration density of the kinase inhibitor in the drug coating may be: about 0.1 μg / mm 2 About 10 μg / mm 2 , about 0.1μg / mm 2 About 8 μg / mm 2 , about 0.1μg / mm2 About 6 μg / mm 2 , about 0.1μg / mm 2 About 4 μg / mm 2 , about 0.1μg / mm 2 About 2 μg / mm 2 , about 0.1μg / mm 2 About 1 μg / mm 2 , about 1μg / mm 2 About 10 μg / mm 2 , about 1μg / mm 2 About 8 μg / mm 2 , about 1μg / mm 2 About 6 μg / mm 2 , about 1μg / mm 2 About 4 μg / mm 2 , about 1μg / mm 2 About 2 μg / mm 2 , about 2μg / mm 2 About 10 μg / mm 2 , about 2μg / mm 2 About 8 μg / mm 2 , about 2μg / mm 2 About 6 μg / mm 2 , about 2μg / mm 2 About 4 μg / mm 2 , about 4μg / mm 2 About 10 μg / mm 2 , about 4μg / mm 2 About 8 μg / mm 2 , about 4μg / mm 2 About 6 μg / mm 2 , about 6μg / mm 2 About 10 μg / mm 2 , about 6μg / mm 2 About 8 μg / mm 2 or about 8 μg / mm 2 About 10 μg / mm 2 In some aspects, the concentration density of the at least one therapeutic agent in the drug coating can be about 0.5 μg / mm 2 About 5 μg / mm 2 .

[0111] In some aspects, therapeutic agent can be anti-fibrosis drug.Anti-fibrosis pharmacological mechanism of action includes suppressing and / or reducing local inflammation, and reducing and / or suppressing the formation of fibrous tissue growth factor.Anti-fibrosis drug can include, for example, triamcinolone, tranilast, halofuginone, montelukast, zafirlukast, pirfenidone and nintedanib.For example, therapeutic agent such as pirfenidone and nintedanib can slow down the progress of scar tissue accumulation.

[0112] In some aspects, the therapeutic agent of the drug coating can have at least one tyrosine kinase inhibitor, at least one receptor tyrosine kinase inhibitor, at least one anti-fibrotic agent or any combination thereof. In some aspects, the therapeutic agent may include at least one of the following items: cabozantinib, imatinib, lenvatinib, sunitinib, regorafenib, sorafenib, vandetanib, dasatinib, pazopanib, triamcinolone, tranilast, halofuginone, montelukast, zafirlukast, pirfenidone, nintedanib, ROCK inhibitor (Y27632), YAP / TAZ inhibitor (CA3 and verteporfin), YAP / TAZ-TEAD interaction inhibitor (verteporfin, VGLL4 peptide), SRC inhibitor (dasatinib), or its salt or its crystal or crystalline form or its derivative.

[0113] In some aspects, therapeutic agent can be phosphodiesterase (PDE) inhibitor. PDE inhibitor refers to a class of drugs characterized by its activity of inhibiting PDE enzyme activity. PDE enzyme is an enzyme that catalyzes the cleavage of phosphodiester bonds in a class of cyclic nucleotide compounds (such as cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP)). PDE has a variety of subtypes, and each specific protein accepts a digital identifier. In some aspects, applying PDE inhibitors can prevent the cracking of cAMP and / or cGMP. In some aspects, applying PDE inhibitors can increase the level of cAMP and / or cGMP. Therefore, PDE inhibitors can provide a more selective method to prevent the formation of new intimal hyperplasia without negative inhibition of other surrounding cells. In some aspects, using the interventional device described herein to locally deliver PDE inhibitors, followed by sustained release of drugs, can allow inhibition of restenosis without causing systemic toxicity.

[0114] Some PDE inhibitors, or at least salts thereof, are generally weak bases that are protonated under physiological conditions and therefore have a high water solubility. In some aspects, the drug coating can include a therapeutic agent having a water solubility of about 0.1 mg / mL to about 25 mg / mL, about 0.1 mg / mL to about 8 mg / mL, about 0.1 mg / mL to about 6 mg / mL, about 0.1 mg / mL to about 4 mg / mL, about 0.1 mg / mL to about 2 mg / mL, about 2 mg / mL to about 10 mg / mL, about 2 mg / mL to about 8 mg / mL, about 2 mg / mL to about 6 mg / mL, about 2 mg / mL to about 4 mg / mL, about 4 mg / mL to about 10 mg / mL, about 4 mg / mL to about 8 mg / mL. / mL to about 6 mg / mL, about 6 mg / mL to about 10 mg / mL, about 6 mg / mL to about 8 mg / mL, about 8 mg / mL to about 10 mg / mL, about 6 mg / mL to about 15 mg / mL, about 8 mg / mL to about 15 mg / mL, about 10 mg / mL to about 20 mg / mL, about 10 mg / mL to about 25 mg / mL, about 15 mg / mL to about 20 mg / mL, about 15 mg / mL to about 25 mg / mL, about 20 mg / mL to about 25 mg / mL, about 10 mg / mL to about 25 mg / mL, or about 1 mg / mL to about 25 mg / mL.

[0115] In some aspects, the therapeutic agent may include a non-selective PDE inhibitor, wherein the therapeutic agent may inhibit two or more PDE enzymes. Examples of non-selective PDE inhibitors may include xanthine, caffeine, aminophylline, 3-isobutyl-1-methylxanthine, pentoxifylline, theobromine, and theophylline.

[0116] In some aspects, the PDE inhibitor can be a selective PDE inhibitor, wherein the therapeutic agent preferentially targets one PDE enzyme subtype. For example, in some aspects, the PDE inhibitor can be a PDE2 inhibitor, such as erythro-9-(2-hydroxy-3-nonyl)adenine), (2-[(3,4-dimethoxyphenyl)methyl]-7-[(1R)-1-hydroxyethyl]-4-phenylbutyl]-5-methyl-imidazo[5,1-f][1,2,4]triazine-4(1H)-one), oxindole and / or 9-(6-phenyl-2-oxohex-3-yl)-2-(3,4-dimethoxybenzyl)-purine-6-one. In some aspects, the PDE inhibitor is a PDE3 inhibitor, such as amrinone, milrinone, enoximone, anagrelide, cilostazol and / or pimobendan. In some aspects, the PDE inhibitor is a PDE4 inhibitor, such as mesembryone, rolipram, ibudilast, pyramilast, luteolin, drotaverine, roflumilast, apremilast and / or criborole. In some aspects, the PDE inhibitor is a PDE5 inhibitor, such as sildenafil, tadalafil, vardenafil, udenafil, avanafil and / or dipyridamole. In some aspects, the PDE inhibitor is a PDE7 inhibitor, such as quinazoline. In some aspects, the PDE inhibitor is a PDE9 inhibitor, such as paraxanthine. In some aspects, the PDE inhibitor is a PDE10 inhibitor, such as papaverine.

[0117] In some current aspects, the concentration density of the PDE inhibitor in the drug coating may be: about 0.1 μg / mm 2 About 10 μg / mm 2 , about 0.1μg / mm 2 About 8 μg / mm 2 , about 0.1μg / mm 2 About 6 μg / mm 2 , about 0.1μg / mm 2 About 4 μg / mm 2 , about 0.1μg / mm 2 About 2 μg / mm 2 , about 0.1μg / mm 2 About 1 μg / mm 2 , about 1μg / mm 2 About 10 μg / mm 2 , about 1μg / mm 2 About 8 μg / mm 2 , about 1μg / mm 2 About 6 μg / mm 2 , about 1μg / mm 2 About 4 μg / mm 2 , about 1μg / mm 2About 2 μg / mm 2 , about 2μg / mm 2 About 10 μg / mm 2 , about 2μg / mm 2 About 8 μg / mm 2 , about 2μg / mm 2 About 6 μg / mm 2 , about 2μg / mm 2 About 4 μg / mm 2 , about 4μg / mm 2 About 10 μg / mm 2 , about 4μg / mm 2 About 8 μg / mm 2 , about 4μg / mm 2 About 6 μg / mm 2 , about 6μg / mm 2 About 10 μg / mm 2 , about 6μg / mm 2 About 8 μg / mm 2 or about 8 μg / mm 2 About 10 μg / mm 2 In some aspects, the concentration density of the at least one therapeutic agent in the drug coating can be about 0.5 μg / mm 2 About 5 μg / mm 2 .

[0118] In some aspects, the therapeutic agent is a combination of a kinase inhibitor and an anti-fibrotic drug. In some aspects, the selected therapeutic agent includes a combination of a kinase inhibitor and a PDE inhibitor. In some aspects, the selected therapeutic agent includes a combination of an anti-fibrotic drug and a PDE inhibitor. In some aspects, the selected therapeutic agent includes at least one kinase inhibitor and at least one anti-fibrotic drug and at least one PDE inhibitor.

[0119] In some aspects, the therapeutic agent can be applied to the outer surface of the medical device or a coating thereon. In some aspects, the therapeutic agent can be applied directly. In other aspects, the therapeutic agent can be applied after being combined with a coating solvent. Those skilled in the art will appreciate that a combination of methods of applying the therapeutic agent can also be used to coat the medical device.

[0120] In some aspects, other therapeutic compounds can be included together with the drug coating of the open text. Such other drugs can include but are not limited to glucocorticoids (e.g., cortisol, betamethasone), hirudin, angiopeptin, aspirin, growth factors, antisense agents, anticancer agents, antiproliferative agents, oligonucleotides, and more generally, antiplatelet agents, anticoagulants, antimitotic agents, antioxidants, antimetabolites, antichemotactic agents and anti-inflammatory agents. Also available in some aspects of the open text are polynucleotides, antisense, RNAi or siRNA, such as those that inhibit inflammation and / or smooth muscle cells or fibroblast proliferation, contractility or mobility, including lipid nanoparticles that wrap them. Antiplatelet agents can include drugs such as aspirin and dipyridamole. Aspirin is classified as analgesic, antipyretic, anti-inflammatory and antiplatelet drugs. Dipyridamole is a drug similar to aspirin because it has antiplatelet properties. Dipyridamole is also classified as a coronary vasodilator. Anticoagulants used in some aspects of the disclosure may include drugs such as heparin, protamine, hirudin and tick anticoagulant protein. Antioxidants may include probucol, vitamin E, vitamin E succinate, butylated hydroxytoluene (BHT), ascorbic acid, beta-carotene, lycopene, lutein, retinol, manganese, selenium, flavonoids, flavonoids, catechins, polyphenols and / or zeaxanthin. Antiproliferative agents may include drugs such as amlodipine and doxazosin. Antimitotic agents and antimetabolites used in some aspects of the disclosure may include drugs such as methotrexate, azathioprine, vincristine, doxorubicin and mutamycin. Antibiotic agents used in some aspects of the disclosure may include penicillin, cefoxitin, oxacillin, tobramycin and gentamicin. Suitable antioxidants used in some aspects of the disclosure may include probucol. In addition, genes or nucleic acids or portions thereof may be used as therapeutic agents in aspects of the disclosure. Photosensitizers used in photodynamic or radiotherapy (eg, including various porphyrin compounds such as porphimers) may also be used as drugs in aspects of the disclosure.

[0121] In some aspects of the disclosure, a combination of medicines can also be used. Some combinations have additional effects and / or super additional effects because they have different mechanisms. In some aspects, the additional effect can be advantageous for using in drug coatings as described herein. For example, in some aspects, due to the additional effect, the dosage of medicine can be reduced. In some aspects, the combination of therapeutic agents can reduce complications caused by using high-dose therapeutic agents.

[0122] In some aspects of the disclosure, the therapeutic agent is rapidly released from the drug coating after the medical device contacts the tissue and is easily absorbed. For example, certain aspects of the device of the disclosure include a drug-coated expandable medical device that delivers a proliferative drug to vascular tissue during balloon angioplasty by brief, direct pressure contact at high drug concentrations. The therapeutic agent is preferentially retained in the target tissue at the delivery site, where it inhibits hyperplasia and restenosis, but allows endothelialization. In these aspects, the coating formulation of the disclosure not only promotes the rapid release of the drug from the balloon surface and the transfer of the drug to the target tissue during deployment, but also prevents the drug from diffusing out of the device before reaching the target site during transportation through the tortuous arterial anatomy, and bursting from the device before the drug coating is pressed into direct contact with the surface of the vascular wall during the initial stage of balloon inflation.

[0123] excipient

[0124] In some aspects, the drug coating can have a therapeutic agent and one or more additives. In some aspects, the additive can be an excipient. In addition to the therapeutic agent or therapeutic agent combination, according to some aspects, the drug coating can include at least one excipient. In one aspect, the drug coating can include a variety of excipients, for example, two, three, four or more excipients. Such combinations of excipients can be used for the purpose of the disclosure.

[0125] The selection of excipient or excipient combination can be based on the therapeutic agent used, one or more coating solvents. As explained in more detail later, in some aspects, excipient or excipient combination can be mixed with therapeutic agent or with therapeutic agent and coating solvent (or a mixture of multiple coating solvents) to form a coating mixture, and the coating mixture is applied on the outer surface of the medical device. Alternatively or additionally, some aspects of the disclosure can include excipient and the therapeutic agent dissolved in the coating solvent are separately applied to the outer surface of the medical device. In some aspects, excipient or excipient combination can be applied to the medical device before the therapeutic agent and / or before the therapeutic agent is dissolved in the coating solvent. In some aspects, excipient or excipient combination can be applied to the medical device after the therapeutic agent and / or after the therapeutic agent is dissolved in the coating solvent. Without being bound by theory, when mixed with therapeutic agent, one or more coating solvents, selected excipient or excipient combination can form a coating mixture that adheres to the medical device so that the coating particles will not fall off during processing and intervention procedures. Alternatively or additionally, when applied before or after the therapeutic agent, coating solvent(s), the selected excipient or excipient combination should adhere to the medical device so that coating particles are not dislodged during handling and interventional procedures.

[0126] The relative amount of therapeutic agent and one or more excipients in the drug coating can be different according to applicable environment.The optimum amount of one or more excipients can depend on, for example, the critical micelle concentration (if it forms micelles) of selected specific therapeutic agent and other excipients, surface modifier, the hydrophilic-lipophilic balance (HLB) of excipient, the octanol-water partition coefficient (P) of one or more excipients, the fusing point of excipient, the water solubility of excipient and / or therapeutic agent, the surface tension of the aqueous solution of surface modifier etc.Other considerations will further affect the selection of the specific ratio of excipient.These considerations include the biological acceptance degree of excipient and the expected dose of therapeutic agent to be provided.

[0127] In some aspects, the excipient may include a polymer. In some aspects, the polymer may be an anionic polymer. Examples of anionic polymers include polyglutamic acid or any block polymer containing the fragment, polyacrylic acid or any block polymer containing the fragment, polymethacrylic acid or any block polymer containing the fragment, polystyrene sulfonate or any block polymer containing the fragment, heparin, hyaluronic acid and alginate. Without being bound by theory, due to the cationic nature of the therapeutic agent (such as sunitinib malate), the drug coating including anionic polymers may allow the therapeutic agent to be retained for sustained drug release.

[0128] In other aspects, the excipient can be a biodurable polymer. Biodurable polymers can refer to well-tolerated and / or anti-erosion or anti-enzyme polymers when placed in the human body (including in the lumen of a blood vessel). Biodurable polymers include polyethylene terephthalate (PET), nylon 66, polyurethane (PU), polytetrafluoroethylene (PTFE), polyethylene (PE, low density and high density and ultra-high molecular weight UHMW), polysiloxanes (silicone) and poly (methyl methacrylate) (PMMA), N-isopropylacrylamide (P-NIPAAm) and poly (vinylidene fluoride-to-hexafluoropropylene) (PVDF-HFP). In some aspects, the excipient can be PVDF-HFP. Without being bound by theory, biodurable polymers are utilized to allow reduction or elimination of incomplete drug release. In other aspects, the excipient can be a biodegradable polymer. Biodegradable polymers can include well-tolerated and degradable polymers when introduced into the human body (including in the lumen of a blood vessel) over a period of time. Examples of biodegradable polymers include polylactic acid polymers (PLA, PLLA, PDLA, PDLLA), polycaprolactone (PCL), polylactic-co-glycolic acid (PLGA), polyethylene glycol (PEG), and poly(ethylene glycol) methyl ether-block-polylactic-co-glycolic acid (PLGA-b-mPEG).

[0129] In some aspects, the weight ratio of polymer to therapeutic agent can be from about 0.5:1 to about 8:1, including about 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, and 7:1. In some aspects, the ratio is 1:1. In other aspects, the ratio is 2:1. In some aspects, the ratio is from about 1:1 to about 8:1 or from about 1:1 to about 7:1 or from about 1:1 to about 6:1 or from about 1:1 to about 5:1 or from about 1:1 to about 4:1 or from about 1:1 to about 3:1 or from about 1:1 to about 2:1. In some aspects, the ratio is from about 2:1 to about 8:1. In some aspects, the ratio is about 3:1. In other aspects, the ratio is from about 3:1 to about 5:1 or to about 8:1, including from about 3:1 to about 4:1, from about 3:1 to about 5:1, from about 3:1 to about 6:1, from about 3:1 to about 7:1. In some aspects, the ratio is from about 4: 1 to about 8: 1. In some aspects, the ratio is from about 5: 1 to about 8: 1, from about 5: 1 to about 7: 1, from about 5: 1 to about 6: 1, from about 6: 1 to about 8: 1, from about 6: 1 to about 7: 1, or from about 7: 1 to about 8: 1.

[0130] Suitable excipients that can be used in some aspects of the disclosure include but are not limited to those excipients, organic and inorganic pharmaceutical excipients, natural products and derivatives thereof (such as sugar, vitamins, amino acids, peptides, proteins, fatty acid esters and fatty acids) described or listed herein, surfactants (anions, cations, nonionic and ions) and mixtures thereof. The excipients that can be used for the disclosure listed below are provided only for exemplary purposes, are not intended to be comprehensively encompassed. Many other excipients can be used for the purpose of the disclosure, such as polyglutamic acid, polyacrylic acid, hyaluronic acid, alginate, PVA, PVP, Pluronic (PEO-PPO-PEO), cellulose, PEG, P-NIPAAm, CMC, HPC, starch, chitosan, human serum albumin (HSA), phospholipids, fatty acids, fatty acid esters, triglycerides, beeswax, cyclodextrins, polysorbate, polyethylene glycol, polyvinylpyrrolidone (PVP) and aliphatic polyesters.

[0131] In some aspects, the excipient may have a drug affinity portion. The drug affinity portion includes affinity for the therapeutic agent through hydrogen bonds and / or van der Waals interactions. For example, the drug affinity portion of the excipient may bond the excipient to an anti-fibrotic drug, a kinase inhibitor, a tyrosine kinase inhibitor, a PDE inhibitor, or a combination thereof. The excipients of the disclosure may include a hydrophilic portion. As is well known in the art, the terms "hydrophilic" and "hydrophobic" are relative terms. In exemplary aspects of the disclosure, in order to be used as an excipient, the excipient may have a compound including a polar or charged hydrophilic portion and a non-polar hydrophobic (lipophilic) portion. The hydrophilic portion or component may accelerate diffusion and increase the penetration of the therapeutic agent into the tissue. The hydrophilic portion of the excipient can facilitate rapid movement or transfer of the therapeutic agent off the surface of the expandable medical device during deployment at the target site by preventing hydrophobic drug molecules from aggregating together and onto the device, thereby increasing the solubility of the drug in the interstitial space, and / or accelerating the passage of the drug through the polar head group to the lipid bilayer of the cell membrane of the target tissue.

[0132] An empirical parameter commonly used to characterize the relative hydrophilicity and hydrophobicity of an excipient is the hydrophilic-lipophilic balance ("HLB" value). Excipients with lower HLB values ​​are more hydrophobic and have greater solubility in oils, while surfactants with higher HLB values ​​are more hydrophilic and have greater solubility in aqueous solutions. Using the HLB value as a rough guide, hydrophilic excipients are generally considered to be those compounds with an HLB value greater than about 10, as well as anionic, cationic or zwitterionic compounds for which the HLB scale is generally not applicable. Similarly, hydrophobic excipients are compounds with an HLB value less than about 10. In certain aspects, the HLB value of the excipient is in the range of 0.0 to 40. In certain aspects of the disclosure, higher HLB values ​​may be preferred because increased hydrophilicity may promote release of therapeutic agents from the surface of the device. In one aspect, the HLB of the excipient is greater than 10. In another aspect, the excipient HLB may be greater than 14. Alternatively, excipients with lower HLBs may be preferred when used to prevent drug loss prior to deployment of the device at the target site, such as in a separate top coating over a drug layer with a very hydrophilic additive. It should be understood that the HLB value of an excipient is only a rough guide commonly used to achieve formulations such as industrial, pharmaceutical, and cosmetic emulsions. Keeping these inherent difficulties in mind and using the HLB value as a guide, excipients with suitable hydrophilicity or hydrophobicity for use in some aspects of the disclosure can be identified, as described herein.

[0133] An empirical parameter commonly used in medicinal chemistry to characterize the relative hydrophilicity and hydrophobicity of a drug compound is the partition coefficient, P, which is the ratio of the concentrations of the unionized compound in the two phases of a mixture of two immiscible solvents (usually octanol and water) such that P = ([solute] octanol / [solute] water). Compounds with higher log P are more hydrophobic, while compounds with lower log P are more hydrophilic. Lipinski's rule states that drug compounds with log P < 5 generally have higher membrane permeability. For the purposes of certain aspects of the disclosure, it is preferred that the log P of the excipient is less than the log P of the drug to be formulated (as an example, the log P of paclitaxel is 7.4). A greater difference in log P between the therapeutic agent and the excipient can promote phase separation of the therapeutic agent. For example, if the log P of the excipient is much lower than the log P of the drug, the excipient can accelerate the release of the therapeutic agent from the device surface (to which the therapeutic agent may otherwise be tightly adhered) in an aqueous environment, thereby accelerating drug delivery to the tissue during the brief deployment period at the intervention site. In certain aspects of the disclosure, the log P of the excipient is negative. In other aspects, the log P of the excipient is less than the log P of the therapeutic agent. Although the octanol-water partition coefficient P or log P of a compound can be used as a measure of relative hydrophilicity and hydrophobicity, it is only a rough guide that can be used to define suitable excipients for use in some aspects of the disclosure.

[0134] Exemplary excipients for use in some aspects of the disclosure may include chemical compounds with one or more hydroxyl, amino, carbonyl, carboxyl, acid, amide or ester moieties. In certain aspects, hydrophilic chemical compounds with one or more hydroxyl, amino, carbonyl, carboxyl, acid, amide or ester moieties and a molecular weight less than 5,000 to 10,000 are preferred. In other aspects, the molecular weight of the excipient with one or more hydroxyl, amino, carbonyl, carboxyl, acid, amide or ester moieties is preferably less than 1000 to 5,000, or more preferably less than 750 to 1,000, or most preferably less than 750. In these aspects, the molecular weight of the excipient may preferably be less than the molecular weight of the therapeutic agent to be delivered.

[0135] Excipients according to some aspects can include amino alcohols, alcohols, amines, acids, amides and hydroxy acids in both cyclic and linear aliphatic and aromatic groups. Examples are L-ascorbic acid and its salts, D-glucoscorbic acid and its salts, tromethamine, triethanolamine, diethanolamine, meglumine, glucosamine, amino alcohols, glucoheptonic acid, gluconic acid, hydroxyketones, hydroxylactones, gluconolactone, gluconolactone, glucooctanolactone, gulonic acid lactone, mannolactone, ribonolactone, lactobionic acid, glucosamine, glutamic acid, benzyl alcohol, benzoic acid, hydroxybenzoic acid, 4-hydroxybenzoic acid propyl ester, lysine acetate, gentisic acid, lactobionic acid, lactitol, sorbitol, glucitol, phosphate sugars, phosphate glucopyranose, sulfate sugars, sugar alcohols, sinapinic acid, vanillic acid, vanillin, methyl p-hydroxybenzoate, p-hydroxybenzoic acid acid propyl ester, xylitol, 2-ethoxyethanol, sugar, galactose, glucose, ribose, mannose, xylose, sucrose, lactose, maltose, arabinose, lyxose, fructose, cyclodextrin, (2-hydroxypropyl)-cyclodextrin, acetaminophen, ibuprofen, retinoic acid, lysine acetate, gentisic acid, catechin, catechin gallate, tiletamine, ketamine, propofol, lactic acid, acetic acid, salts of any of the above organic acids and amines, polyglycidol, glycerol, polyglycerol, galactitol, di(ethylene glycol), tri(ethylene glycol), tetra(ethylene glycol), penta(ethylene glycol), di(propylene glycol), tri(propylene glycol), tetra(propylene glycol) and penta(propylene glycol), and combinations thereof. Some of the chemical compounds described herein having one or more hydroxyl, amine, carbonyl, carboxyl, amide, or ester moieties are very stable under heat, survive ethylene oxide sterilization, and / or do not react with therapeutic agents during sterilization.

[0136] In some aspects, the excipient may include amino acids and salts thereof. For example, the excipient may be one or more of alanine, arginine, asparagine, aspartic acid, cysteine, cystine, glutamic acid, glutamine, glycine, histidine, proline, isoleucine, leucine, lysine, methionine, phenylalanine, serine, threonine, tryptophan, tyrosine, valine and derivatives thereof. Some amino acids (in their zwitterionic form and / or in the form of salts with monovalent or multivalent ions) have polar groups, relatively high octanol-water partition coefficients, and may be used in some aspects of the disclosure. In the context of the disclosure, "low solubility amino acids" refer to amino acids having a solubility of less than about 4% (40 mg / ml) in non-buffered water. These include cystine, tyrosine, tryptophan, leucine, isoleucine, phenylalanine, asparagine, aspartic acid, glutamic acid and methionine.

[0137] Amino acid dimers, sugar conjugates and other derivatives may also be useful. Hydrophilic molecules may be linked to hydrophobic amino acids, or hydrophobic molecules may be linked to hydrophilic amino acids, by simple reactions well known in the art, to prepare additional excipients that may be used in some aspects of the disclosure. Catecholamines such as dopamine, levodopa, carbidopa and DOPA may also be used as excipients.

[0138] In some aspects, the excipient can be a liquid additive. One or more liquid excipients can be used in the medical device coating to improve the integrity of the coating. Without being bound by theory, the liquid excipient can improve the compatibility of the therapeutic agent in the coating mixture. The liquid excipient used in some aspects of the disclosure is not a solvent. After the coating is dried, solvents such as ethanol, methanol, dimethyl sulfoxide and acetone will be evaporated. In other words, after the coating is dried, the solvent will not remain in the coating. In contrast, after the coating is dried, the liquid excipient in some aspects of the disclosure can be retained in the coating. The liquid excipient is liquid or semi-liquid at room temperature and one atmosphere. The liquid excipient can form a gel at room temperature. The liquid excipient can include a hydrophilic part and a drug affinity part, wherein the drug affinity part is at least one of a hydrophobic part, a part having affinity for the therapeutic agent through hydrogen bonds, and a part having affinity for the therapeutic agent through van der Waals interactions. In some aspects, the liquid excipient can be a nonionic surfactant. Examples of liquid excipients include PEG-fatty acids and esters, PEG-oil transesterification products, polyglycerol fatty acids and esters, propylene glycol fatty acid esters, PEG sorbitan fatty acid esters, and PEG alkyl ethers, as described above. Some examples of liquid excipients are Tween 80, Tween 81, Tween 20, Tween 40, Tween 60, Solutol HS15, Cremophor RH40, PEG, N-PIAAm, and Cremophor EL & ELP.

[0139] In some aspects, the excipient can be a surfactant; a chemical compound having one or more hydroxyl, amine, carbonyl, carboxyl, amide, or ester moieties; or both. Exemplary surfactants can be selected from PEG fatty acid esters, PEG ω-3 fatty acid esters and alcohols, glycerol fatty acid esters, sorbitan fatty acid esters, PEG glyceryl fatty acid esters, PEG sorbitan fatty acid esters, sugar fatty acid esters, PEG sugar esters, Tween 20, Tween 40, Tween 60, p-isononylphenoxy polyglycidol, PEG laurate, PEG oleate, PEG stearate, PEG glyceryl laurate, PEG glyceryl oleate, PEG glyceryl stearate, polyglyceryl laurate, polyglyceryl oleate, polyglyceryl myristate, polyglyceryl palmitate, polyglyceryl-6 laurate, polyglyceryl-6 oleate, polyglyceryl-6 myristate, polyglyceryl-6 palmitate, polyglyceryl-10 laurate, polyglyceryl-10 oleate, polyglyceryl-10 myristate, polyglyceryl-10 palmitate, PEG sorbitan monolaurate, PEG sorbitan monolaurate, Sugar alcohol monolaurate, PEG sorbitan monooleate, PEG sorbitan stearate, PEG oleyl ether, PEG lauryl ether, Tween 20, Tween 40, Tween 60, Tween 80, docusate sodium, octoxynol, nonoxynol, tyloxapol, sucrose monopalmitate, sucrose monolaurate, decanoyl-N-methylglucamide, n-decyl-β-D-pyranoglucoside, n-decyl-β-D-maltopyranoside, n-dodecyl-β-D -Glucopyranoside, n-dodecyl-β-D-maltoside, heptanoyl-N-methylglucose amide, n-heptyl-β-D-glucopyranoside, n-heptyl-β-D-thioglucoside, n-hexyl-β-D-glucopyranoside, nonanoyl-N-methylglucose amide, n-nonyl-β-D-glucopyranoside, octanoyl-N-methylglucose amide, n-octyl-β-D-glucopyranoside, octyl-β-D-thioglucopyranoside and their derivatives.

[0140] In some respects, surfactant or little water-soluble molecule (chemical compound with one or more hydroxyl, amine, carbonyl, carboxyl, amide or ester part) together with therapeutic agent is better than only utilizing therapeutic agent and single excipient in some cases.Compared with some preparations including therapeutic agent and only a kind of excipient, by combining one or more additional excipients, the aspect of drug coating can have the stability of increase during transportation, and when the tissue of inner cavity wall is pressed against at the target site of treatment intervention, the aspect of drug coating can have fast drug release.In addition, the miscibility and compatibility of therapeutic agent and excipient or drug coating and medical device are improved usually by the presence of one or more additional excipients.For example, surfactant can realize improved coating uniformity and integrity.

[0141] In one aspect, drug coating can have multiple excipients, wherein one excipient is more hydrophilic than one or more excipients in other excipients. In another aspect, drug coating can have multiple excipients, wherein one excipient has a structure different from one or more excipients in other excipients. In another aspect, drug coating can include multiple excipients, wherein one excipient has an HLB value different from one or more excipients in other excipients. In another aspect, drug coating can include multiple excipients, wherein one excipient has a Log P value different from one or more excipients in other excipients.

[0142] Some aspects of the disclosure may include a mixture of at least two additional excipients, for example, a combination of one or more surfactants and one or more chemical compounds having one or more hydroxyl, amine, carbonyl, carboxyl, amide or ester moieties. For example, therapeutic agents may bind to extremely water-soluble small molecules more poorly than they bind to surfactants, which may result in suboptimal coating uniformity and integrity. When used in some aspects of the disclosure, some surfactants adhere very firmly to the surfaces of the therapeutic agent and the medical device, so that the therapeutic agent cannot be quickly released from the surface of the medical device at the target site. On the other hand, some water-soluble small molecules (having one or more hydroxyl, amine, carbonyl, carboxyl, amide or ester moieties) adhere very poorly to the medical device, so that they release the therapeutic agent before the medical device reaches the target site, for example, releasing the therapeutic agent into the serum during the transport of the coated balloon catheter to the intervention target site. By combining a mixture of multiple excipients, some aspects of the drug coating may have improved properties relative to formulations comprising only one excipient.

[0143] In some aspects, one or more additional excipients may include antioxidants.Antioxidants are molecules that can slow down or prevent the oxidation of other molecules.Oxidation reactions can produce free radicals and / or peroxides that start chain reactions and can cause degradation of sensitive therapeutic agents (e.g., sunitinib and its derivatives).Antioxidants terminate these chain reactions by removing free radicals and / or peroxides, and they further inhibit the oxidation of active agents by self-oxidation.In some aspects, antioxidants are used as one or more additional excipients to prevent or slow down the oxidation of therapeutic agents in medical device coatings.Antioxidants are free radical scavengers of a type.In some aspects, antioxidants can be used alone or in combination with other additional excipients, and can prevent degradation of active therapeutic agents during sterilization or storage before use. Some representative examples of antioxidants that can be used in the drug coating of the disclosure include, but are not limited to, oligomeric or polymeric proanthocyanidins, polyphenols, polyphosphates, polyazomethine, high sulfate agar oligomers, chitosan oligosaccharides obtained by partial hydrolysis of chitosan, polyfunctional oligomeric thioethers with sterically hindered phenols, hindered amines such as, but not limited to, p-phenylenediamine, trimethyldihydroquinolone and alkylated diphenylamine, substituted phenolic compounds (hindered phenols) with one or more bulky functional groups such as tert-butyl, arylamines, phosphites, hydroxylamines and benzofuranones. In addition, aromatic amines such as p-phenylenediamine, diphenylamine and N,N' disubstituted p-phenylenediamine can be used as free radical scavengers. Other examples include, but are not limited to, butylated hydroxytoluene ("BHT"), butylated hydroxyanisole ("BHA"), L-ascorbic acid (vitamin C), vitamin E, tannic acid, the herb rosemary, sage extract, glutathione, resveratrol, ethoxyquin, rosmarinol, isosmarinol, rosmarinol, propyl gallate, gallic acid, tannic acid, caffeic acid, p-coumaric acid, p-hydroxybenzoic acid, astaxanthin, ferulic acid, dehydrogingerone, chlorogenic acid, ellagic acid, propylparaben, sinapinic acid, daidzin, glycitein, genistin, daidzein, glycitein, genistein, isoflavones, and t-butylhydroquinone. Some examples of phosphites include di(stearyl)pentaerythritol diphosphite, tris(2,4-di-tert-butylphenyl)phosphite, dilauryl thiodipropionate, and bis(2,4-di-tert-butylphenyl)pentaerythritol diphosphite. Some examples of hindered phenols include, but are not limited to, octadecyl-3,5-di-tert-butyl-4-hydroxycinnamate, tetramethylene-3-(3',5'-di-tert-butyl-4-hydroxyphenyl)propionate methane, 2,5-di-tert-butylhydroquinone, ionol, pyrogallol, retinol, and octadecyl-3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionate. Antioxidants may include glutathione, lipoic acid, melatonin, tocopherols, tocotrienols, thiols, beta-carotene, retinoic acid, cryptoxanthin, 2,6-di-tert-butylphenol, propyl gallate, catechins, catechin gallate, and quercetin.Preferred antioxidants are butylated hydroxytoluene (BHT) and butylated hydroxyanisole (BHA).

[0144] In some aspects, the excipient can be present in an amount relative to the amount of one or more therapeutic agents. In some aspects, the ratio of excipient to therapeutic agent can be from about 1:20 to about 10:1, including 1:15, 1:10, 1:5, 1:3, 1:2, 1:1, 2:18, 2:16, 2:14, 2:12, 2:1, 3:18, 3:15, 3:10, 3:9, 3:7, 3:5, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1 and 10:1.

[0145] Coating solvent

[0146] The solvent used to prepare the drug coating (which is referred to herein as the "coating solvent") is used to dissolve the therapeutic agent and additives. The dissolved therapeutic agent and additives in the coating solvent together constitute the "coating mixture" which is applied to the medical device.

[0147] The coating solvent can be any solvent or combination of solvents suitable for dissolving the selected therapeutic agent. As an example, the coating solvent can include any combination of one or more of the following: water; alkanes such as pentane, cyclopentane, hexane, cyclohexane, heptane, and octane; aromatic solvents such as benzene, toluene, and xylene; alcohols such as methanol, ethanol, 2,2,2-trifluoroethanol, propanol and isopropanol, isobutanol, n-butanol, tert-butanol, diethylamine, ethylene glycol monoethyl ether, diethylene glycol monoethyl ether (trascutol), and benzyl alcohol; ethers such as dioxane, dimethyl ether, ethyl ether, diethyl ether, di-n-propyl ether, diisopropyl ether, tert-butyl methyl ether, petroleum ether, and tetrahydrofuran; esters / acetates , such as methyl acetate, ethyl acetate, isobutyl acetate, isopropyl acetate and n-butyl acetate; ketones such as acetone, acetonitrile, diethyl ketone, cyclohexanone and methyl ethyl ketone, methyl isobutyl ketone; chlorinated hydrocarbons such as chloroform, dichloromethane, dichloroethane; carbon tetrachloride and chlorobenzene; dioxane; tetrahydrofuran; dimethylformamide; acetonitrile; dimethyl sulfoxide; 1,6-dioxane; N,N-dimethylacetamide (DMA); diethylene glycol; diethylene glycol dimethyl ether; 1,2-dimethoxyethane; hexamethylphosphoramide; and mixtures such as water / ethanol, water / acetone, water / methanol, water / tetrahydrofuran.

[0148] Therapeutic agent and / or one or more additives can be dispersed, dissolved or otherwise mixed in the coating solvent. The weight percentage of therapeutic agent, additive and optional one or more additional additives in the coating solvent can be in the following ranges: about 0.1 wt % to about 80 wt %, or about 0.1 wt % to about 60 wt %, about 0.1 wt % to about 40 wt %, about 0.1 wt % to about 20 wt %, about 0.1 wt % to about 1 wt %, about 1 wt % to about 80 wt %, about 1 wt % to about 60 wt %, about 1 wt % to about 40 wt %, about 1 wt % to about 20 wt %, about 20 wt % to about 80 wt %, about 20 wt % to about 60 wt %, about 20 wt % to about 40 wt %, about 40 wt % to about 80 wt %, about 40 wt % to about 60 wt % or about 60 wt % to about 80 wt %.

[0149] In the method for preparing a medical device coated with a drug, such as a balloon catheter or a stent in particular, a coating solution or suspension comprising at least one coating solvent, a therapeutic agent, and optionally one or more additional additives is prepared. In some aspects, the therapeutic agent, the coating solvent, the additive, and optionally one or more additional additives can be combined to produce a coating mixture.

[0150] In aspects where the coating solution includes at least one coating solvent, a therapeutic agent, and optionally one or more additional additives, the amount of the therapeutic agent in the coating solution can be from about 0.05 wt % to about 50 wt %, from about 0.05 wt % to about 40 wt %, from about 0.05 wt % to about 30 wt %, from about 0.05 wt % to about 20 wt %, from about 0.05 wt % to about 10 wt %, from about 0.05 wt % to about 1 wt %, from about 1 wt % to about 50 wt %, from about 1 wt % to about 40 wt %, based on the total weight of the solution. %, about 1 wt % to about 30 wt %, about 1 wt % to about 20 wt %, about 1 wt % to about 10 wt %, about 10 wt % to about 50 wt %, about 10 wt % to about 40 wt %, about 10 wt % to about 30 wt %, about 10 wt % to about 20 wt %, about 20 wt % to about 50 wt %, about 20 wt % to about 40 wt %, about 20 wt % to about 30 wt %, about 30 wt % to about 50 wt %, about 30 wt % to about 40 wt %, or about 40 wt % to about 50 wt %. The amount of coating solvent used depends on the coating process and viscosity, as the amount of solvent can affect the uniformity of the drug coating, even if the coating solvent will be evaporated.

[0151] In aspects where the coating solution includes at least one coating solvent, a therapeutic agent, an additive, and optionally one or more additional additives, the amount of the therapeutic agent in the coating solution can be about 0.1 wt % to about 50 wt %, about 0.1 wt % to about 40 wt %, about 0.1 wt % to about 30 wt %, about 0.1 wt % to about 20 wt %, about 0.1 wt % to about 10 wt %, about 0.1 wt % to about 1 wt %, about 1 wt % to about 50 wt %, about 1 wt % to about 40 wt %, based on the total weight of the solution. %, about 1 wt % to about 30 wt %, about 1 wt % to about 20 wt %, about 1 wt % to about 10 wt %, about 10 wt % to about 50 wt %, about 10 wt % to about 40 wt %, about 10 wt % to about 30 wt %, about 10 wt % to about 20 wt %, about 20 wt % to about 50 wt %, about 20 wt % to about 40 wt %, about 20 wt % to about 30 wt %, about 30 wt % to about 50 wt %, about 30 wt % to about 40 wt %, about 40 wt % to about 50 wt %. The amount of coating solvent used depends on the coating process and viscosity, as the amount of solvent can affect the uniformity of the drug coating, even if the coating solvent will be evaporated. The content of the additive in the coating solution can be about 0.5 wt % to about 50 wt %, about 0.5 wt % to about 40 wt %, about 0.5 wt % to about 30 wt %, about 0.5 wt % to about 20 wt %, about 0.5 wt % to about 10 wt %, about 0.5 wt % to about 1 wt %, about 1 wt % to about 50 wt %, about 1 wt % to about 40 wt %, about 1 wt % to about 30 wt %, about 1 wt % to about 20 wt %, about 1 wt % to about 10 wt %, about 10 wt % to about 50 wt %, about 10 wt % to about 40 wt %, about 10 wt % to about 30 wt %, about 10 wt % to about 20 wt %, about 20 wt % to about 50 wt %, about 20 wt % to about 40 wt %, about 20 wt % to about 30 wt %, about 30 wt % to about 50 wt %, about 30 wt % to about 40 wt %, or about 40 wt % to about 50 wt %. The amount of coating solvent used depends on the coating process and viscosity, as the amount of solvent can affect the uniformity of the drug coating even if the coating solvent will evaporate.

[0152] In other aspects, two or more solvents, two or more therapeutic agents, two or more additives or optionally two or more additional additives may be used in the coating solution or coating mixture. In certain aspects, a polymeric material may be used as an additive in the coating mixture.

[0153] In some cases, kinase inhibitors and PDE inhibitors can be lipophilic weak bases that are insoluble in common organic solvents. In addition, the presence of kinase inhibitors in the preparation can change the surface energy of the drug / excipient droplets formed by atomization, which form beads but do not spread immediately when they arrive at the device surface. This may result in uneven coatings or uncovered surfaces. In some aspects, a combination of solvents can alleviate this problem. In some aspects, the mixture of solvents utilized can include two, three or more solvents. In some aspects, the mixture of solvents utilized can include ethyl acetate, acetone and DMF.

[0154] The coating solution or coating mixture can be applied to the medical device using various techniques, such as metering, casting, spin coating, spraying, dipping (immersion), roller coating, inkjet printing, 3D printing, electrostatic technology, plasma etching, vapor deposition and combinations of these processes. The selection of the application technique depends primarily on the viscosity and surface tension of the coating solution or coating mixture. In some aspects of the disclosure, metering, dipping and spraying may be preferred because it makes it easier to control the uniformity of the thickness of the drug coating and the concentration of the therapeutic agent applied to the medical device. Whether the coating solution or coating mixture is applied by spraying or by dipping or by another method or combination of methods, additional coating layers can be applied to the medical device in multiple application steps to control the uniformity and amount of the therapeutic substance and additives applied to the medical device.

[0155] The thickness of each applied coating layer can be about 0.1 μm to about 15 μm, about 0.1 μm to about 10 μm, about 0.1 μm to about 5 μm, about 0.1 μm to about 1 μm, about 1 μm to about 15 μm, about 1 μm to about 10 μm, about 1 μm to about 5 μm, about 5 μm to about 15 μm, about 5 μm to about 10 μm, or about 10 μm to about 15 μm. The total number of coating layers applied to the medical device is in the range of about 1 to about 50, about 1 to about 40, about 1 to about 30, about 1 to about 20, about 1 to about 10, about 10 to about 50, about 10 to about 40, about 10 to about 30, about 10 to about 20, about 20 to about 50, about 20 to about 40, about 20 to about 30, about 30 to about 40, or about 40 to about 50. In some aspects, only one layer is applied to the medical device. In some aspects, more than one layer is applied to the medical device. The total thickness of the coating may be from about 0.1 μm to about 200 μm, from about 0.1 μm to about 150 μm, from about 0.1 μm to about 100 μm, from about 0.1 μm to about 50 μm, from about 0.1 μm to about 10 μm, from about 0.1 μm to about 1 μm, from about 1 μm to about 200 μm, from about 1 μm to about 150 μm, from about 1 μm to about 100 μm, from about 1 μm to about 50 μm, from about 1 μm to about 10 μm. m to about 10 μm, about 10 μm to about 200 μm, about 10 μm to about 150 μm, about 10 μm to about 100 μm, about 10 μm to about 50 μm, about 50 μm to about 200 μm, about 50 μm to about 150 μm, about 50 μm to about 100 μm, about 100 μm to about 200 μm, about 100 μm to about 150 μm, or about 150 μm to about 200 μm.

[0156] In addition to the coating layer including the drug coating, the medical device may include one or more intermediate or top layers. In some aspects, the intermediate or top layers may be advantageous in order to promote adhesion of the drug coating to the medical device, as an additional layer including additives, or to prevent premature drug loss prior to deployment at the target site during the device delivery process.

[0157] As previously described, in some aspects, the additive can be mixed with the therapeutic agent and / or the coating solvent (or a mixture of multiple coating solvents) to form a coating mixture, and the coating mixture is applied to the outer surface of the medical device. Alternatively or additionally, some aspects can include applying the additive to the outer surface of the medical device separately from the therapeutic agent or the therapeutic agent dissolved in the coating solvent. In some aspects, the additive can be applied to the medical device before the therapeutic agent or before the therapeutic agent is dissolved in the coating solvent. In some aspects, the additive can be applied to the medical device after the therapeutic agent or after the therapeutic agent is dissolved in the coating solvent.

[0158] In one exemplary aspect, the application device that can be used is a paint can attached to an air brush (such as Badger Model 150), which is supplied with a pressurized air source through a regulator (Norgren, 0psi to 160psi). When using such an application device, air can be applied once the brush hose is connected to the compressed air source downstream of the regulator. The pressure can be adjusted to approximately 15psi to 25psi, and the nozzle condition can be checked by pressing the trigger. Before spraying, the two ends of the relaxed inflatable medical device can be fastened to the fixture by two elastic retainers (i.e., alligator clips), and the distance between the clips can be adjusted so that the inflatable medical device remains in a relaxed state, for example, a vented, folded, or inflated or partially inflated, unfolded state. Then, the rotor can be energized and the rotational speed can be adjusted to the desired coating speed, about 40rpm. As the inflatable medical device rotates in a substantially horizontal plane, the spray nozzle can be adjusted so that the distance between the nozzle and the inflatable medical device is approximately 0.2 inches to 4 inches. First, the coating solution or coating mixture can be sprayed substantially horizontally, with the brush directed from the distal end of the inflatable medical device to the proximal end and then from the proximal end to the distal end in a sweeping motion along the inflatable medical device at a speed such that one spraying cycle occurs in about three rotations of the inflatable medical device. The inflatable medical device can be repeatedly sprayed with the coating solution and then dried until an effective amount of the drug is deposited on the inflatable medical device. It should be understood that the description of the application apparatus, fixture, and spraying technique is merely exemplary. Any other suitable spraying or other technique can be used to coat the inflatable medical device, particularly for coating the balloon of a balloon catheter or a stent delivery system or stent.

[0159] In one aspect of the disclosure, an inflatable medical device can be expanded (such as inflated or partially inflated), and a coating solution or coating mixture can be applied to the inflated inflatable medical device, for example by spraying, and the inflatable medical device can then be dried and subsequently relaxed or collapsed to an unexpanded form or shape. For example, if the inflatable medical device is a balloon, the balloon is dried, deflated, and folded. Drying can be performed under vacuum.

[0160] After spraying the medical device with the coating solution or coating mixture, the coated medical device can be subjected to drying, in which the coating solvent is evaporated. This produces a coating matrix containing the therapeutic agent and additives on the expandable medical device. One example of a drying technique may include placing the coated expandable medical device in an oven at about 20° C. or higher for about 24 hours or longer, such as up to 48 hours or 72 hours. Another example may include air drying. Any other suitable method of drying the coating solution may be used. The time and temperature may vary depending on the specific additives and therapeutic agents.

[0161] Medical Devices

[0162] Aspects of medical devices will now be described, including balloon catheters and stents as non-limiting examples. In the medical devices, a drug coating is applied to the outer surface of the medical device. Some aspects of methods for preparing exemplary medical devices will then be described.

[0163] Balloon Catheter

[0164] In some aspects, the medical device is a balloon catheter. Figure 1 , a balloon catheter 10 has a proximal end 18 and a distal end 20. The balloon catheter 10 can be any suitable catheter for the desired use, including conventional balloon catheters known to those of ordinary skill in the art. For example, the balloon catheter 10 can be a rapid exchange or over-the-wire catheter. In some specific examples, the balloon catheter can be a ClearStream 100 available from BD Peripheral Intervention. TM Peripheral catheter. The balloon catheter 10 can be made of any suitable biocompatible material. The balloon 12 of the balloon catheter can include a polymer material, such as, by way of example only, polyvinyl chloride (PVC), polyethylene terephthalate (PET), polyethylene, nylon, PEBAX (i.e., a copolymer of polyether and polyamide), polyurethane, polystyrene (PS), polyethylene terephthalate (PETP), or various other suitable materials that will be apparent to one of ordinary skill in the art.

[0165] pass Figure 2A and Figure 2B Along the Figure 1 The cross section of line A-A shows Figure 1 Various aspects of the balloon catheter 10. Common References Figure 1 , Figure 2A and Figure 2B The balloon catheter 10 includes an expandable balloon 12 and an elongated member 14. The elongated member 14 extends between a proximal end 18 and a distal end 20 of the balloon catheter 10. The elongated member 14 has at least one lumen 26a, 26b, and a distal end 20. The elongated member 14 may be a flexible member that is a tubular member made of a suitable biocompatible material. The elongated member 14 may have one lumen, or may have a Figure 1 , Figure 2A and Figure 2BAs shown, there are more than one lumen 26a, 26b therein. For example, the elongated member 14 may include a guidewire lumen 26b extending from the guidewire port 15 at the proximal end 18 of the balloon catheter 10 to the distal end 20 of the balloon catheter 10. The elongated member 14 may also include an inflation lumen 26a extending from the inflation port 17 of the balloon catheter 10 to the interior of the inflatable balloon 12 to enable the inflatable balloon 12 to be inflated. Figure 1 , Figure 2A and Figure 2B Even though the inflation lumen 26a and the guidewire lumen 26b are shown as side-by-side lumens, it should be understood that the one or more lumens present in the elongated member 14 may be configured in any manner suitable for the intended purpose of the lumen, including, for example, the introduction of an inflation medium and / or the introduction of a guidewire. Many such configurations are known in the art.

[0166] The expandable balloon 12 is attached to the distal attachment end 22 of the elongated member 14. The expandable balloon 12 has an outer surface 25 and is inflatable. The expandable balloon 12 is in fluid communication with the lumen of the elongated member 14 (e.g., in fluid communication with the inflation lumen 26a). At least one lumen of the elongated member 14 is configured to receive an inflation medium and pass such medium to the expandable balloon 12 to inflate it. Examples of inflation media include air, saline, and contrast media.

[0167] Still reference Figure 1 In one aspect, the balloon catheter 10 includes a handle assembly, such as a hub 16. The hub 16 can be attached to the balloon catheter 10 at the proximal end 18 of the balloon catheter 10. The hub 16 can be connected to and / or receive one or more suitable medical devices, such as an inflation medium (e.g., air, saline, or contrast agent) source or a guidewire. For example, an inflation medium source (not shown) can be connected to an inflation port 17 of the hub 16 (e.g., through an inflation lumen 26a), and a guidewire (not shown) can be introduced into the guidewire port 15 of the hub 16 (e.g., through a guidewire lumen 26b).

[0168] In some examples, Figure 1 The cross section A-A can be as follows Figure 2A As depicted, the drug coating layer 30 is applied directly to the outer surface 25 of the balloon 12. According to various aspects, the specific composition of the drug coating layer 30 itself will also be described in more detail later. In other examples, Figure 1 The cross section A-A can be as follows Figure 2B1, wherein the drug coating layer 30 is applied to the intermediate layer 40 covering the outer surface 25 of the balloon 12. In some aspects, the outer surface 25 can undergo surface modification. In some aspects where the outer surface 25 is a modified outer surface, the outer surface 25 has been subjected to surface modification, such as fluorine plasma treatment, which reduces the surface free energy of the outer surface 25 before applying the drug coating layer 30. Subjecting the outer surface to surface modification can reduce the surface free energy of the outer surface before applying the coating layer and affect the release kinetics of the drug in the coating layer from the balloon, the crystallinity of the drug layer, the surface morphology and particle shape of the coating, or the particle size of the drug of the therapeutic agent layer in the coating layer, the distribution of the drug on the surface.

[0169] In it Figure 1 The cross section A-A is as follows Figure 2A In the depicted aspect, the balloon catheter 10 includes a drug coating 30 applied to the outer surface 25 of the balloon 12. The drug coating 30 itself includes a therapeutic agent and an additive. In a specific aspect, the drug coating 30 includes a kinase inhibitor, a tyrosine kinase inhibitor, a PDE inhibitor or an anti-fibrotic therapeutic agent, a polymer and one or more additional additives. In other aspects, the drug coating 30 does not include a polymer.

[0170] In other aspects, two or more therapeutic agents are used in combination in the drug coating. In other aspects, the device may include a top layer (not shown) covering the drug coating 30. In some aspects, the top coating may be advantageous in order to prevent premature drug loss prior to deployment at the target site during the device delivery process.

[0171] Drug-eluting stents

[0172] In some aspects, the medical device is a drug eluting stent 100. Figure 3 In the example set forth in , the drug eluting stent 100 has a proximal end 180 and a distal end 200. The drug eluting stent 100 may include any suitable base stent 102 for the desired use, including conventional stents known to those of ordinary skill in the art. The base stent 102 may be made of any suitable biocompatible metal alloy. Examples of biocompatible metal alloys may include stainless steel, Nitinol, or Elgiloy. In some aspects, the shape memory properties of Nitinol may allow the base stent 102 to self-expand at normal body temperature when placed in a tubular body vessel.

[0173] pass Figure 4 Along the Figure 3 The cross section of line B-B shows Figure 3 Various aspects of the drug eluting stent 100. In some examples, Figure 3 The cross section B-B can be as follows Figure 4107 is depicted, where the drug coating layer 110 is applied directly to the outer surface 107 of the base stent 102. In some aspects described subsequently, the outer surface 107 can undergo surface modification. In aspects where the outer surface 107 is a modified outer surface, the outer surface 107 has been subjected to surface modification, such as fluorine plasma treatment, which reduces the surface free energy of the outer surface 107 before applying the drug coating layer 110. Subjecting the outer surface to surface modification can reduce the surface free energy of the outer surface before applying the coating layer, and affect the release kinetics of the drug in the coating layer from the balloon, the crystallinity of the drug layer, the surface morphology and particle shape of the coating, or the particle size of the drug of the therapeutic agent layer in the coating layer, the distribution of the drug on the surface.

[0174] In it Figure 3 The cross section B-B is as follows Figure 4 In the depicted aspect, the drug eluting stent 100 includes a drug coating 110 applied to the outer surface 107 of the base stent 102. The drug coating 110 itself includes a therapeutic agent and an additive. In a specific aspect, the drug coating 110 includes a kinase inhibitor or a tyrosine kinase inhibitor, a PDE inhibitor, an anti-fibrotic drug therapeutic agent, a polymer, and one or more additional additives. In other aspects, the drug coating 110 does not include a polymer.

[0175] In other aspects, two or more therapeutic agents are used in combination in the drug coating 110. In other aspects, the device can include a top layer (not shown) covering the drug coating 100. In some aspects, a top coating can be advantageous in order to prevent premature drug loss prior to deployment at the target site during the device delivery process.

[0176] Example

[0177] Example 1

[0178] In Example 1, two formulations were prepared as described subsequently and summarized in Table 1.

[0179] To prepare Formulation 1, 50 mg of sunitinib malate was weighed and dissolved in 5.14 mL of N,N-dimethylformamide (DMF) (HPLC grade) in an amber vial, which was then subjected to water bath sonication for 5 minutes to form a clear yellow solution. Separately, 300 mg of PVDF-HFP was added to 21.6 mL of acetone containing 1.8 mg of BHT. The mixture was water bath sonicated for 15 minutes to completely dissolve the solid PVDF-HFP. Next, 18 mL of PVDF-HFP / acetone solution was transferred and mixed with the prepared sunitinib / DMF solution, followed by the addition of 36 mL of methyl acetate. The formulation was stored at 4 ° C before spraying.

[0180] To prepare formulation 2, 70 mg of sunitinib malate was weighed and dissolved in 5.6 mL of DMF (HPLC grade) in an amber vial, which was then subjected to water bath sonication for 5 minutes to form a clear yellow solution. Separately, 300 mg of PVDF-HFP was added to 24 mL of acetone containing 3 mg of BHT, which was subjected to water bath sonication for 15 minutes to completely dissolve the solid PVDF-HFP. Next, 16.8 mL of PVDF-HFP / acetone solution was transferred and mixed with the prepared sunitinib / DMF solution, followed by the addition of 33.6 mL of methyl acetate. The formulation was stored at 4 ° C before spraying.

[0181] Table 1. Formulation 1 and Formulation 2.

[0182]

[0183] Then, Formulation 1 and Formulation 2 were coated on the bare stent using a Sono-Tek Extracoat ultrasonic spray system, the parameters of which are summarized in Table 2. Formulation 1 and Formulation 2 were used to produce sample stent 1 and sample stent 2, respectively. The primer was 5 mg / mL PBMA in a mixed solvent (acetone / cyclohexanone=9:1).

[0184] Table 2. Coating parameters of sample holder 1 and sample holder 2.

[0185]

[0186]

[0187] like Figure 5 and Figure 6 As shown, sample holder 1 and sample holder 2 formed a smooth, uniform coating on the pillars without obvious coating defects.

[0188] In order to evaluate the in vitro drug release profiles of sample holder 1 and sample holder 2, a drug elution test was performed at 37°C using 1x phosphate buffered saline (pH between 7.3 and 7.4) as the elution medium. Figure 7 shown.

[0189] like Figure 7 As shown, a burst release was observed for both Formulation 1 and Formulation 2, followed by sustained release kinetics over 45 days. A slower release rate was observed in Formulation 1, with approximately 20% of the unreleased sunitinib remaining on the stent after 45 days of elution.

[0190] Example 2

[0191] Stents with sizes of 5×40 and 6×40 were prepared using the above-mentioned Formulation 1 or Formulation 2, and were inserted into the peripheral arteries of healthy Yorkshire pigs and tested at different time points.

[0192] The effect on vessel cross-sectional area was evaluated 28 days after stent insertion and compared with several other models. Comparative A was a bare metal stent, Comparative B was an Orsiro stent (sirolimus eluting stent) commercially available from Biotronik, and Comparative C was an Eluvia stent (paclitaxel eluting stent) commercially available from Boston Scientific.

[0193] The research results are then presented in Tables 3 and 4.

[0194] Table 3. Comparison of vessel cross-sectional area and morphology of neointimal response in coronary arteries treated with sample stents 1 and 2 and comparative example stents A, B and C.

[0195]

[0196] EEL = external elastic lamina, IEL = internal elastic lamina, lumen area = cross-sectional area of ​​the vascular lumen, Med area = EEL area - IEL area, Neoint area = IEL area - lumen area (indicates the cross-sectional area composed of neointimal tissue), % stenosis = [1 - (lumen area / IEL area)] * 100

[0197] Table 4. Semi-quantitative scoring of arterial injury, fibrin, malapposition, hemorrhage, and endothelial cell loss in coronary artery tissue sections treated with sample scaffolds 1 and 2 and comparative scaffolds A, B, and C.

[0198]

[0199]

[0200] The P values ​​shown were calculated based on all data from the four groups in the table. Numbers below 0.05 indicate significant differences between the means of the four groups.

[0201] As shown in Tables 3 and 4, the overall average stenosis percentages of samples 1 and 2 were minimal (e.g., for sample 2, stenosis % = 21.62 ± 6.68), which is comparable to the results obtained for other comparative example stents A, B, and C tested in the same animal model. For sample 2, mild to moderate fibrin was found in 64.97 ± 20.84% ​​of the struts, with an average fibrin score of 1.56 ± 0.83, and intimal / medial inflammation was essentially absent. No granulomas occurred, and there were very few giant cells. Also for sample 2, bleeding around the struts was not obvious, and there was no calcification, and no adventitial inflammation occurred. The percentage of uncovered struts was 10.47 ± 12.13%. There was minimal endothelial loss (average endothelial loss score = 0.44 ± 0.52%). In contrast, in vessels treated with comparative example sample C including paclitaxel, endothelial coverage was poor, with an average endothelial loss score of 1.81 ± 0.24%.

[0202] The study was then extended to 60 and 90 days, followed by histology and pharmacokinetic profile analysis.Formulation 1 was prepared at a dose density of 1 μg / mm and a total dose of 425 μg / stent, and Formulation 2 was prepared at a dose density of 2 μg / mm and a total dose of 750 μg / stent. Figure 8 Release profiles and pharmacokinetic (PK) profiles at 7, 28, 60, and 90 days after stent insertion are shown. In addition, as described above, morphometric vessel cross-sectional area was measured at 60 and 90 days and compared with Comparative Examples A and C described above. Tables 5 and 6 show the results at 60 days, and Tables 7 and 8 show the results at 90 days. Table 5: Morphological comparison of vessel cross-sectional area and neointimal response of coronary arteries treated for 60 days with sample stents 1 and 2 and comparative example stents A and C.

[0203]

[0204] The P values ​​shown were calculated based on all data from the four groups in the table. Numbers below 0.05 indicate significant differences between the means of the four groups.

[0205] Table 6. Semi-quantitative scoring of arterial injury, fibrin, malapposition, hemorrhage, and endothelial cell loss in coronary artery tissue sections treated with Sample Scaffolds 1 and 2 and Comparative Scaffolds A and C at 60 days.

[0206]

[0207]

[0208] Table 7: Comparison of vessel cross-sectional area and morphology of neointimal response in coronary arteries treated with sample stents 1 and 2 and comparative stents A and C for 90 days.

[0209]

[0210] Table 8. Semi-quantitative scoring of arterial injury, fibrin, malapposition, hemorrhage, and endothelial cell loss in coronary artery tissue sections treated with Sample Scaffolds 1 and 2 and Comparative Scaffolds A and C at 90 days.

[0211]

[0212]

[0213] The P values ​​shown were calculated based on all data from the four groups in the table. Numbers below 0.05 indicate significant differences between the means of the four groups.

[0214] As shown in Tables 5 to 8, the overall average restenosis percentages for Samples 1 and 2 remained minimal at 60 and 90 days, while for Comparative Examples A and C, stenosis increased significantly. In Sample 2, fibrin was reduced from the early time point, the fibrin score was also reduced, and intimal / medial inflammation increased only slightly. No granulomas occurred, and no malapposition was identified. Both the bare stent (Comparative Example A) and the paclitaxel stent (Comparative Example B) showed significant dislocation. Similarly, Samples 1 and 2 showed no uncovered struts, while the paclitaxel stent showed an incidence of 16.22%. Fig. 9 Comparative Examples A and C and Samples 1 and 2 are shown in cross-sectional views, showing that the paclitaxel stent had malapposition, fibrin, and delayed healing. In contrast, both Samples 1 and 2 showed normal healing, no malapposition, no fibrin, and were fully endothelialized.

[0215] Example 3

[0216] The drug elution from the balloon was also examined to determine the release profile. PLGA was selected as the biopolymer and sunitinib as the tyrosine kinase inhibitor. The tyrosine kinase inhibitor was examined in microparticle form, crystalline form, and in the presence of one or more excipients. The tyrosine kinase was also examined as a free base and in an ionized form with malic acid and hemipamoic acid. The combination of PLGA and sunitinib malate with docusate sodium as an excipient was studied to understand how different PLGA compositions might affect the elution profile.

[0217] To prepare the drug coating, microparticles containing sunitinib malate and PLGA (PLGA / sunitinib microparticles) were prepared by emulsion evaporation / extraction in polyvinyl alcohol using a homogenizer, followed by centrifugation and vacuum drying.

[0218] Table 10 shows the elution profiles of sunitinib from the identified drug coating compositions.

[0219] Table 10: Loading properties of various PLGA / sunitinib / docusate sodium compositions.

[0220]

[0221] As shown in Table 10, the ability of PLGA microparticles to load more tyrosine kinase inhibitors increased when the amount of docusate sodium was higher. These indicate that excipients can help increase the drug loading of the drug coating.

[0222] Drug coatings with tyrosine kinase inhibitors in crystalline form were also examined. Sunitinib was again selected as a candidate drug and the crystalline pamoate salt was prepared by recrystallization in ethanol or ethanol and DMF to obtain hemipamoic acid. The solubility of sunitinib as a free base in PBS is 26.4 μmol / L, while the solubility of the malate salt is 1231 μmol / L. Pamoate further reduced the solubility of the free base, with the solubility of the pamoate salt crystals being 9.6 μmol / L and the solubility of the hemipamoate salt being 6.02 μmol / L.

[0223] Example 4

[0224] In Example 4, formulations for stent drug coatings were prepared as described subsequently, and histological data were subsequently obtained from in vivo studies at 7, 28, 60, and 90 days when implanted in the femoral artery of a porcine model.

[0225] A total of five formulations were used: a PVDF-only control, prepared at a concentration of 5 mg / mL in a solution of 90% acetone and 10% cyclohexane; a colchicine coating, prepared at a 5:1 PVDF:colchicine ratio, provided at 5 mg / mL into 90% acetone and 10% DMF; a roflumilast coating, prepared at a 5:1 PVDF:roflumilast ratio, provided at 7.5 mg / mL into a solution of 42.5% EtOAc, 50% acetone, and 7.5% DMF; a tadalafil coating, prepared at a 3:1 PVDF:tadalafil ratio, provided at 5 mg / mL into a solution of 30% EtOAc, 60% acetone, and 10% DMF; and a sunitinib coating, provided at a 3:1 PVDF:sunitinib malate, prepared at 5 mg / mL in a solution of 60% MeOAc, 30% acetone, and 10% DMF. The coating was provided to 5 x 40 mm and 6 x 40 mm stents. The loading concentration was evaluated before and after ETO (ethylene oxide) sterilization and no discernible changes were observed with the process.

[0226] Fig.10Some preliminary pharmacokinetic data obtained from the fabricated scaffolds at 7 and 28 days after implantation in pigs are presented. Colchicine and roflumilast showed expected target ranges, while tadalafil was lower than expected (based on comparison with oral bioavailability).

[0227] Histological studies were then performed at days 60 and 90. Table 11 provides some observational data from each of the five study groups.

[0228] Table 11 (Area, unit: mm 2 )

[0229]

[0230] From these data, the percentage of stenosis was similar between sunitinib and tadalafil, with colchicine demonstrating what appeared to be an accelerated amount of stenosis. Fig.11 Gross cross-sectional views and magnified views of the amount of inflammation seen are shown. Table 12 provides a further summary of relevant histological data.

[0231] Table 12

[0232]

[0233] These data were also repeated at 90 days. Table 13 sets forth the same data collected as Table 11 and Table 14 sets forth the same data collected as Table 12.

[0234] Table 13

[0235]

[0236] Table 14

[0237]

[0238]

[0239] These data reflect that both tadalafil and sunitinib provided improvements in the amount of restenosis observed. Fig.12 Similar cross-sectional images are illustrated in .

[0240] Example 5

[0241] In Example 5, a formulation containing tadalafil and sildenafil was prepared as a balloon coating as described subsequently.

[0242] In order to prepare PLGA / tadalafil microparticles, an oil / water emulsion evaporation method is used. PLGA 755S is mixed with tadalafil in DMSO at a desired ratio. For example, for a ratio of 4: 1, 60mg tadalafil and 240mg PLGA 755S are added to 1mL DMSO and 8mL dichloromethane (DCM). The organic solution is added to an aqueous solution of 5% polyvinyl alcohol (PVA) in water that has been pre-saturated with DCM. The mixture is then emulsified (VWR 250 homogenizer, VWR sawtooth generator probe is 20×11mm) for 1 minute to form an emulsion. The emulsion is added to 250mL of 2% PVA, and it is continuously stirred overnight (500rpm) to evaporate the organic solvent. The resulting suspension is centrifuged (4000g) and washed three times with deionized water. The microparticles are dried at room temperature in a vacuum oven.

[0243] For sildenafil microparticles, a similar method was used, wherein before being added to the organic solvent, a step of encapsulating the more water-soluble sildenafil was added. 120 mg of sildenafil citrate and 120 mg of docusate sodium were dissolved in 1.5 mL, and 6 mL of a solution of 240 mg of PLGA 753H was prepared at the same time, and then the two were combined. The resulting solution was vortexed for 1 mL, then poured into 300 mL of a 1% PVA aqueous solution, and then the solvent was allowed to evaporate overnight. The resulting microparticles were washed with water, centrifuged (4000 g, 8 minutes) and vacuum dried.

[0244] For comparison, microparticles with roflumilast, sunitinib, and colchicine were also prepared in a similar manner. Fig.13 Representative scanning electron microscopy images of microparticles prepared with sunitinib and PLGA can be seen in . These were prepared using the oil-in-water emulsion evaporation method. As shown, the microparticles show a spherical morphology at low magnification ( Fig.13 The spherical shape at high magnification ( Fig.13 (see figure below).

[0245] Although specific aspects have been shown and described herein, it should be understood that various other changes and modifications may be made without departing from the spirit and scope of the claimed subject matter. In addition, although various aspects of the claimed subject matter have been described herein, such aspects need not be utilized in combination. Therefore, the appended claims are intended to cover all such changes and modifications that fall within the scope of the claimed subject matter.

Claims

1. A medical device for delivering a therapeutic agent to a tissue, the medical device comprising: a coating layer covering the outer surface of the medical device, wherein the coating comprises a kinase inhibitor together with one or more excipients.

2. The medical device of claim 1, wherein the excipient comprises a biodurable polymer, a biodegradable polymer, or a combination thereof.

3. The medical device of claim 1, wherein the kinase inhibitor is selected from the group consisting of bosutinib, ceritinib, crizotinib, gefitinib, ruxolitinib, imatinib, axitinib, nilotinib, trametinib, afatinib, ibrutinib, cabozantinib, imatinib, lenvatinib, sunitinib, regorafenib, sorafenib, vandetanib, dasatinib, pazopanib, Y27632, CA3, verteporfin, VGLL4 peptide, nintedanib, afatinib, abemaciclib, erdafitinib, fitrinib, palbociclib and pemitinib.

4. The medical device of claim 1, wherein the kinase inhibitor is sunitinib.

5. The medical device of claim 1, wherein the kinase inhibitor is in the form of a free base, a free acid, a crystal, or a salt.

6. The medical device of claim 5, wherein the salt is a hydrochloride, sodium salt, sulfate, acetate, phosphate and / or diphosphate, pamoate or hemipamoate, a lipophilic salt, chloride salt, potassium salt, maleate, calcium salt, citrate, methanesulfonate, nitrate, tartrate, aluminum salt, stearate, dioctylsulfosuccinate or gluconate.

7. The medical device of claim 2, wherein the biodurable polymer is selected from the group consisting of poly(vinylidene hexafluoropropylene) (PVDF-HFP), polyethylene terephthalate (PET), nylon 66, polyurethane (PU), polytetrafluoroethylene (PTFE), polyethylene, polysiloxane (silicone) and poly(methyl methacrylate) (PMMA), and combinations thereof.

8. The medical device of claim 2, wherein the biodurable polymer is poly(vinylidene hexafluoropropylene) (PVDF-HFP).

9. The medical device of claim 2, wherein the weight ratio of the biodurable polymer to the kinase inhibitor is from 1:1 to 10:

1.

10. The medical device of claim 2, wherein the biodegradable polymer is selected from the group consisting of polylactic acid polymers, polycaprolactone (PCL), polylactic-co-glycolic acid (PLGA), and poly(ethylene glycol) methyl ether-block-polylactic-co-glycolic acid (PLGA-b-mPEG).

11. The medical device of claim 2, wherein the biodegradable polymer is PLGA.

12. The medical device of claim 1, wherein the medical device is selected from the group consisting of a balloon catheter, an infusion balloon catheter, an infusion catheter, a cutting balloon catheter, a scoring balloon catheter, a laser catheter, an atherectomy device, a volume reduction catheter, a stent, a filter, a stent graft, a covered stent, a patch, a wire, and a valve.

13. The medical device of claim 1, wherein the medical device is a stent or a stent graft.

14. The medical device of claim 1, wherein the medical device is a balloon catheter.

15. The medical device of claim 1, wherein the coating layer comprises one or more additional excipients.

16. The medical device of claim 15, wherein the one or more additional excipients are selected from polylactic acid (PLLA, PDLA, PDLLA), polycaprolactone (PCL), docusate sodium, PLGA, PLGA-b-mPEG, polyglutamic acid, polyacrylic acid, hyaluronic acid, alginate, PVA, PVP, Pluronic (PEO-PPO-PEO), cellulose, CMC, HPC, starch, chitosan, human serum albumin (HSA), phospholipids, fatty acids, fatty acid esters, triglycerides, beeswax, cyclodextrin, Tween 20, Tween 80, TPGS, SLS, butylated hydroxytoluene, vitamin E, vitamin E succinate, tannic acid, polyethylene glycol, N-isopropylacrylamide and sorbitan esters.

17. The medical device of claim 1 further comprising an antioxidant.

18. The medical device of claim 17, wherein the antioxidant is butylated hydroxytoluene.

19. The medical device of claim 1, wherein the tissue comprises tissue of one of the coronary vasculature, peripheral vasculature, cerebral vasculature, esophagus, airways, sinuses, trachea, colon, bile duct, urinary tract, prostate, and brain passages.

20. A balloon catheter for delivering a therapeutic agent to a blood vessel, the balloon catheter comprising: an elongated member having an inner lumen and a distal end; an expandable balloon attached to the distal end of the elongated member and in fluid communication with the lumen; and a coating layer covering the outer surface of the balloon, the coating layer comprising a therapeutic agent and at least one of a biodegradable polymer and an excipient, in: The therapeutic agent comprises a kinase inhibitor, an anti-fibrotic drug or a mixture thereof, The biodegradable polymer is selected from polylactic acid polymer, polycaprolactone (PCL), polylactic acid-co-glycolic acid (PLGA) and poly(ethylene glycol) methyl ether-block-polylactic acid-co-glycolic acid (PLGA-b-mPEG); as well as The excipient is selected from fatty acids, fatty acid esters, polylactic acid (PLLA, PDLA, PDLLA), polycaprolactone (PCL), docusate sodium, PLGA, PLGA-b-mPEG, polyglutamic acid, polyacrylic acid, hyaluronic acid, alginate, PVA, PVP, Pluronic (PEO-PPO-PEO), cellulose, CMC, HPC, starch, chitosan, human serum albumin (HSA), phospholipids, fatty acids, fatty acid esters, triglycerides, beeswax, cyclodextrin, Tween 20, Tween 80, TPGS, SLS, butylated hydroxytoluene, vitamin E, vitamin E succinate, tannic acid, polyethylene glycol, N-isopropylacrylamide and sorbitan esters.

21. The balloon catheter of claim 20, wherein the kinase inhibitor is selected from bosutinib, ceritinib, crizotinib, gefitinib, ruxolitinib, imatinib, axitinib, nilotinib, trametinib, afatinib, ibrutinib, cabozantinib, imatinib, lenvatinib, sunitinib, regorafenib, sorafenib, vandetanib, dasatinib, pazopanib, Y27632, CA3, verteporfin, VGLL4 peptide, nintedanib, afatinib, abemaciclib, erdafitinib, fitrinib, palbociclib and pemitinib.

22. The balloon catheter of claim 20, wherein the kinase inhibitor is sunitinib.

23. The balloon catheter of claim 20, wherein the kinase inhibitor is in the form of a free base, a crystal, a free acid, or a salt.

24. The balloon catheter of claim 23, wherein the salt is a hydrochloride, sodium salt, sulfate, acetate, phosphate and / or diphosphate, pamoate or hemipamoate, chloride, potassium, maleate, calcium salt, citrate, methanesulfonate, nitrate, tartrate, aluminum salt, stearate, dioctylsulfosuccinate or gluconate.

25. The balloon catheter of claim 20, wherein the anti-fibrotic drug is selected from the group consisting of triamcinolone, tranilast, halofuginone, montelukast, zafirlukast, pirfenidone, nintedanib, and combinations thereof.

26. The balloon catheter of claim 20, wherein the weight ratio of the biodegradable polymer to the therapeutic agent is 1:10 to 5:

1.

27. The balloon catheter of claim 20, wherein the biodegradable polymer is PLGA.

28. The balloon catheter of claim 20, wherein the excipient is docusate sodium.

29. The balloon catheter of claim 20, further comprising an antioxidant.

30. The balloon catheter of claim 29, wherein the antioxidant is selected from probucol, vitamin E, vitamin E succinate, butylated hydroxytoluene (BHT), ascorbic acid, beta-carotene, lycopene, lutein, retinol, manganese, selenium, flavonoids, flavonoids, catechins, polyphenols and / or zeaxanthin.

31. A stent, stent graft or other permanent or semi-permanent medical device for delivering a therapeutic agent to a blood vessel, comprising a device body and a drug coating thereon, wherein the drug coating comprises: a therapeutic agent and at least one of a biodurable polymer and an excipient, in: The therapeutic agent comprises a kinase inhibitor, an anti-fibrotic drug or a mixture thereof, The biodurable polymer is selected from the group consisting of poly(vinylidene hexafluoropropylene) (PVDF-HFP), polyethylene terephthalate (PET), nylon 66, polyurethane (PU), polytetrafluoroethylene (PTFE), polyethylene, polysiloxane (silicone) and poly(methyl methacrylate) (PMMA), and combinations thereof; and The excipient is selected from fatty acids, fatty acid esters, polylactic acid (PLLA, PDLA, PDLLA), polycaprolactone (PCL), docusate sodium, PLGA, PLGA-b-mPEG, polyglutamic acid, polyacrylic acid, hyaluronic acid, alginate, PVA, PVP, Pluronic (PEO-PPO-PEO), cellulose, CMC, HPC, starch, chitosan, human serum albumin (HSA), phospholipids, fatty acids, fatty acid esters, triglycerides, beeswax, cyclodextrin, Tween 20, Tween 80, TPGS, SLS, butylated hydroxytoluene, vitamin E, vitamin E succinate, and sorbitan esters.

32. The stent, stent graft or other permanent or semi-permanent medical device of claim 31 , wherein the kinase inhibitor is selected from bosutinib, ceritinib, crizotinib, gefitinib, ruxolitinib, imatinib, axitinib, nilotinib, trametinib, afatinib, ibrutinib, cabozantinib, imatinib, lenvatinib, sunitinib, regorafenib, sorafenib, vandetanib, dasatinib, pazopanib, triamcinolone, tranilast, halofuginone, montelukast, zafirlukast, pirfenidone, Y27632, CA3, verteporfin, VGLL4 peptide, nintedanib, afatinib, abemaciclib, erdafitinib, fitrinib, palbociclib and pemitinib.

33. The stent, stent graft or other permanent or semi-permanent medical device of claim 31 , wherein the kinase inhibitor is sunitinib.

34. The stent, stent graft or other permanent or semi-permanent medical device of claim 31, wherein the kinase inhibitor is in the form of a free base, crystals, a free acid or a salt.

35. The stent, stent graft or other permanent or semi-permanent medical device of claim 34, wherein the salt is a hydrochloride, sodium salt, sulfate, acetate, phosphate and / or diphosphate, pamoate or hemipamoate, chloride, potassium, maleate, calcium salt, citrate, methanesulfonate, nitrate, tartrate, aluminum salt, stearate, dioctylsulfosuccinate or gluconate.

36. The stent, stent graft or other permanent or semi-permanent medical device of claim 31, wherein the anti-fibrotic drug is selected from the group consisting of triamcinolone, tranilast, halofuginone, montelukast, zafirlukast, pirfenidone, nintedanib and combinations thereof.

37. The stent, stent graft, or other permanent or semi-permanent medical device of claim 31 , wherein the biodurable polymer is PVDF-HFP.

38. The stent, stent graft, or other permanent or semi-permanent medical device of claim 31, wherein the weight ratio of the biodurable polymer to the therapeutic agent is from 1:1 to 10:

1.

39. The stent, stent graft, or other permanent or semi-permanent medical device of claim 31 , wherein the biodegradable polymer is PLGA.

40. The stent, stent graft, or other permanent or semi-permanent medical device of claim 31, wherein the excipient is docusate sodium.

41. The stent, stent graft, or other permanent or semi-permanent medical device of claim 31 , further comprising an antioxidant.

42. A stent, stent graft or other permanent or semi-permanent medical device according to claim 41, wherein the antioxidant is selected from probucol, vitamin E, vitamin E succinate, butylated hydroxytoluene (BHT), ascorbic acid, beta-carotene, lycopene, lutein, retinol, manganese, selenium, flavonoids, flavonoids, catechins, polyphenols, tannic acid and / or zeaxanthin.

43. A medical device for delivering a therapeutic agent to a tissue, the medical device comprising: a coating layer covering the outer surface of the medical device, The coating layer comprises a phosphodiesterase (PDE) inhibitor together with one or more excipients.

44. The medical device of claim 43, wherein the excipient comprises a biodurable polymer, a biodegradable polymer, or a combination thereof.

45. The medical device of claim 43, wherein the PDE inhibitor is selected from the group consisting of xanthine, aminophylline, sildenafil, tadalafil, vardenafil, udenafil, avanafil, dipyridamole, quinazoline, paraxanthine, papaverine, mesembranose, rolipram, ibudilast, piramilalast, luteolin, drotaverine, roflumilast, apremilast, criborole, amrinone, milrinone, enoximone, anagrelide, cilostazol, pimobendan, erythro-9-(2-hydroxy)- [0013] The compounds include 2-[(3,4-dimethoxyphenyl)methyl]-7-[(1R)-1-hydroxyethyl]-4-phenylbutyl]-5-methyl-imidazo[5,1-f][1,2,4]triazine-4(1H)-one), oxindole, (9-(6-phenyl-2-oxohexan-3-yl)-2-(3,4-dimethoxybenzyl)-purin-6-one), 3-isobutyl-1-methylxanthine, pentoxifylline, theobromine and theophylline.

46. ​​The medical device of claim 43, wherein the PDE inhibitor is tadalafil or sildenafil.

47. The medical device of claim 43, wherein the PDE inhibitor is in the form of a free base, a free acid, a crystal, or a salt.

48. The medical device of claim 47, wherein the salt is a hydrochloride, sodium salt, sulfate, acetate, phosphate and / or diphosphate, pamoate or hemipamoate, a lipophilic salt, chloride salt, potassium salt, maleate, calcium salt, citrate, methanesulfonate, nitrate, tartrate, aluminum salt, stearate, dioctylsulfosuccinate, or gluconate.

49. The medical device of claim 44, wherein the biodurable polymer is selected from the group consisting of poly(vinylidene hexafluoropropylene) (PVDF-HFP), polyethylene terephthalate (PET), nylon 66, polyurethane (PU), polytetrafluoroethylene (PTFE), polyethylene, polysiloxane (silicone) and poly(methyl methacrylate) (PMMA), and combinations thereof.

50. The medical device of claim 44, wherein the biodurable polymer is poly(vinylidene hexafluoropropylene) (PVDF-HFP).

51. The medical device of claim 44, wherein the weight ratio of the biodurable polymer to the PDE inhibitor is from 1:1 to 10:

1.

52. The medical device of claim 44, wherein the biodegradable polymer is selected from the group consisting of polylactic acid polymers, polycaprolactone (PCL), polylactic-co-glycolic acid (PLGA), and poly(ethylene glycol) methyl ether-block-polylactic-co-glycolic acid (PLGA-b-mPEG).

53. The medical device of claim 44, wherein the biodegradable polymer is PLGA.

54. The medical device of claim 43, wherein the medical device is selected from the group consisting of a balloon catheter, an irrigation balloon catheter, an infusion catheter, a cutting balloon catheter, a scoring balloon catheter, a laser catheter, an atherectomy device, a volume reduction catheter, a stent, a filter, a stent graft, a covered stent, a patch, a wire, and a valve.

55. The medical device of claim 43, wherein the medical device is a stent or a stent graft.

56. The medical device of claim 43, wherein the medical device is a balloon catheter.

57. The medical device of claim 43, wherein the coating layer comprises one or more additional excipients.

58. The medical device of claim 57, wherein the one or more additional excipients are selected from polylactic acid (PLLA, PDLA, PDLLA), polycaprolactone (PCL), docusate sodium, PLGA, PLGA-b-mPEG, polyglutamic acid, polyacrylic acid, hyaluronic acid, alginate, PVA, PVP, Pluronic (PEO-PPO-PEO), cellulose, CMC, HPC, starch, chitosan, human serum albumin (HSA), phospholipids, fatty acids, fatty acid esters, triglycerides, beeswax, cyclodextrin, Tween 20, Tween 80, TPGS, SLS, butylated hydroxytoluene, vitamin E, vitamin E succinate, tannic acid, polyethylene glycol, N-isopropylacrylamide, and sorbitan esters.

59. The medical device of claim 43, further comprising an antioxidant.

60. The medical device of claim 59, wherein the antioxidant is butylated hydroxytoluene.

61. The medical device of claim 43, wherein the tissue comprises tissue of one of the coronary vasculature, peripheral vasculature, cerebral vasculature, esophagus, airways, sinuses, trachea, colon, bile duct, urinary tract, prostate, and brain passages.

62. A balloon catheter for delivering a therapeutic agent to a blood vessel, the balloon catheter comprising: an elongated member having an inner lumen and a distal end; an expandable balloon attached to the distal end of the elongated member and in fluid communication with the lumen; and a coating layer covering the outer surface of the balloon, the coating layer comprising a therapeutic agent and at least one of a biodegradable polymer and an excipient, in: The therapeutic agent comprises a PDE inhibitor, an anti-fibrotic drug or a mixture thereof, The biodegradable polymer is selected from polylactic acid polymer, polycaprolactone (PCL), polylactic acid-co-glycolic acid (PLGA) and poly(ethylene glycol) methyl ether-block-polylactic acid-co-glycolic acid (PLGA-b-mPEG); as well as The excipient is selected from fatty acids, fatty acid esters, polylactic acid (PLLA, PDLA, PDLLA), polycaprolactone (PCL), docusate sodium, PLGA, PLGA-b-mPEG, polyglutamic acid, polyacrylic acid, hyaluronic acid, alginate, PVA, PVP, Pluronic (PEO-PPO-PEO), cellulose, CMC, HPC, starch, chitosan, human serum albumin (HSA), phospholipids, fatty acids, fatty acid esters, triglycerides, beeswax, cyclodextrin, Tween 20, Tween 80, TPGS, SLS, butylated hydroxytoluene, vitamin E, vitamin E succinate, tannic acid, polyethylene glycol, N-isopropylacrylamide and sorbitan esters.

63. The balloon catheter of claim 62, wherein the PDE inhibitor is selected from the group consisting of xanthine, aminophylline, sildenafil, tadalafil, vardenafil, udenafil, avanafil, dipyridamole, quinazoline, paraxanthine, papaverine, mesembranose, rolipram, ibudilast, pyramilast, luteolin, drotaverine, roflumilast, apremilast, criborole, amrinone, milrinone, enoximone, anagrelide, cilostazol, pimobendan, erythro-9-(2-hydroxy)- [0013] The compounds include 2-[(3,4-dimethoxyphenyl)methyl]-7-[(1R)-1-hydroxyethyl]-4-phenylbutyl]-5-methyl-imidazo[5,1-f][1,2,4]triazine-4(1H)-one), oxindole, (9-(6-phenyl-2-oxohexan-3-yl)-2-(3,4-dimethoxybenzyl)-purin-6-one), 3-isobutyl-1-methylxanthine, pentoxifylline, theobromine and theophylline.

64. The balloon catheter of claim 62, wherein the PDE inhibitor is tadalafil or sildenafil.

65. The balloon catheter of claim 62, wherein the PDE inhibitor is in the form of a free base, crystals, a free acid, or a salt.

66. The balloon catheter of claim 65, wherein the salt is a hydrochloride, sodium salt, sulfate, acetate, phosphate and / or diphosphate, pamoate or hemipamoate, chloride, potassium, maleate, calcium salt, citrate, methanesulfonate, nitrate, tartrate, aluminum salt, stearate, dioctylsulfosuccinate or gluconate.

67. The balloon catheter of claim 62, wherein the anti-fibrotic drug is selected from the group consisting of triamcinolone, tranilast, halofuginone, montelukast, zafirlukast, pirfenidone, nintedanib, and combinations thereof.

68. The balloon catheter of claim 62, wherein the weight ratio of the biodegradable polymer to the therapeutic agent is 1:10 to 5:

1.

69. The balloon catheter of claim 62, wherein the biodegradable polymer is PLGA.

70. The balloon catheter of claim 62, wherein the excipient is docusate sodium.

71. The balloon catheter of claim 62, further comprising an antioxidant.

72. The balloon catheter of claim 71, wherein the antioxidant is selected from probucol, vitamin E, vitamin E succinate, butylated hydroxytoluene (BHT), ascorbic acid, beta-carotene, lycopene, lutein, retinol, manganese, selenium, flavonoids, flavonoids, catechins, polyphenols and / or zeaxanthin.

73. A stent, stent graft or other permanent or semi-permanent medical device for delivering a therapeutic agent to a blood vessel, comprising a device body and a drug coating thereon, wherein the drug coating comprises: a therapeutic agent and at least one of a biodurable polymer and an excipient, in: The therapeutic agent comprises a PDE inhibitor, an anti-fibrotic drug or a mixture thereof, The biodurable polymer is selected from the group consisting of poly(vinylidene hexafluoropropylene) (PVDF-HFP), polyethylene terephthalate (PET), nylon 66, polyurethane (PU), polytetrafluoroethylene (PTFE), polyethylene, polysiloxane (silicone) and poly(methyl methacrylate) (PMMA) and combinations thereof; and The excipient is selected from fatty acids, fatty acid esters, polylactic acid (PLLA, PDLA, PDLLA), polycaprolactone (PCL), docusate sodium, PLGA, PLGA-b-mPEG, polyglutamic acid, polyacrylic acid, hyaluronic acid, alginate, PVA, PVP, Pluronic (PEO-PPO-PEO), cellulose, CMC, HPC, starch, chitosan, human serum albumin (HSA), phospholipids, fatty acids, fatty acid esters, triglycerides, beeswax, cyclodextrin, Tween 20, Tween 80, TPGS, SLS, butylated hydroxytoluene, vitamin E, vitamin E succinate, and sorbitan esters.

74. The stent, stent graft or other permanent or semi-permanent medical device of claim 73, wherein the PDE inhibitor is selected from the group consisting of xanthine, aminophylline, sildenafil, tadalafil, vardenafil, udenafil, avanafil, dipyridamole, quinazoline, paraxanthine, papaverine, mesembryone, rolipram, ibudilast, pyramilast, luteolin, drotaverine, roflumilast, apremilast, criborole, amrinone, milrinone, enoximone, anagrelide, cilostazol, pimostat, pyrimidine ... benzene, erythro-9-(2-hydroxy-3-nonyl)adenine), (2-[(3,4-dimethoxyphenyl)methyl]-7-[(1R)-1-hydroxyethyl]-4-phenylbutyl]-5-methyl-imidazo[5,1-f][1,2,4]triazine-4(1H)-one), oxindole, (9-(6-phenyl-2-oxohexan-3-yl)-2-(3,4-dimethoxybenzyl)-purin-6-one), 3-isobutyl-1-methylxanthine, pentoxifylline, theobromine and theophylline.

75. The stent, stent graft, or other permanent or semi-permanent medical device of claim 73, wherein the PDE inhibitor is tadalafil or sildenafil.

76. The stent, stent graft or other permanent or semi-permanent medical device of claim 73, wherein the PDE inhibitor is in the form of a free base, crystals, a free acid or a salt.

77. The stent, stent graft, or other permanent or semi-permanent medical device of claim 76, wherein the salt is a hydrochloride, sodium salt, sulfate, acetate, phosphate and / or diphosphate, pamoate or hemipamoate, chloride, potassium, maleate, calcium salt, citrate, methanesulfonate, nitrate, tartrate, aluminum salt, stearate, dioctylsulfosuccinate, or gluconate.

78. The stent, stent graft or other permanent or semi-permanent medical device of claim 73, wherein the anti-fibrotic drug is selected from the group consisting of triamcinolone, tranilast, halofuginone, montelukast, zafirlukast, pirfenidone, nintedanib and combinations thereof.

79. The stent, stent graft, or other permanent or semi-permanent medical device of claim 73, wherein the biodurable polymer is PVDF-HFP.

80. The stent, stent graft, or other permanent or semi-permanent medical device of claim 73, wherein the weight ratio of the biodurable polymer to the therapeutic agent is from 1:1 to 10:

1.

81. The stent, stent graft, or other permanent or semi-permanent medical device of claim 73, wherein the biodegradable polymer is PLGA.

82. The stent, stent graft, or other permanent or semi-permanent medical device of claim 73, wherein the excipient is docusate sodium.

83. The stent, stent graft, or other permanent or semi-permanent medical device of claim 73, further comprising an antioxidant.

84. A stent, stent graft or other permanent or semi-permanent medical device according to claim 83, wherein the antioxidant is selected from probucol, vitamin E, vitamin E succinate, butylated hydroxytoluene (BHT), ascorbic acid, beta-carotene, lycopene, lutein, retinol, manganese, selenium, flavonoids, flavonoids, catechins, polyphenols, tannic acid and / or zeaxanthin.

85. A medical device for delivering a therapeutic agent to a tissue, the medical device comprising: a coating layer covering the outer surface of the medical device, The coating comprises a phosphodiesterase (PDE) inhibitor and a kinase inhibitor together with one or more excipients.

86. The medical device of claim 85, wherein the excipient comprises a biodurable polymer, a biodegradable polymer, or a combination thereof.

87. The medical device of claim 85, wherein the PDE inhibitor is selected from the group consisting of xanthine, aminophylline, sildenafil, tadalafil, vardenafil, udenafil, avanafil, dipyridamole, quinazoline, paraxanthine, papaverine, mesembranose, rolipram, ibudilast, piramilalast, luteolin, drotaverine, roflumilast, apremilast, criborole, amrinone, milrinone, enoximone, anagrelide, cilostazol, pimobendan, erythro-9-(2-hydroxy)- [0013] The compounds include 2-[(3,4-dimethoxyphenyl)methyl]-7-[(1R)-1-hydroxyethyl]-4-phenylbutyl]-5-methyl-imidazo[5,1-f][1,2,4]triazine-4(1H)-one), oxindole, (9-(6-phenyl-2-oxohexan-3-yl)-2-(3,4-dimethoxybenzyl)-purin-6-one), 3-isobutyl-1-methylxanthine, pentoxifylline, theobromine and theophylline.

88. The medical device of claim 85, wherein the PDE inhibitor is tadalafil or sildenafil.

89. The medical device of claim 85, wherein the PDE inhibitor is in the form of a free base, a free acid, a crystal, or a salt.

90. The medical device of claim 85, wherein the kinase inhibitor is selected from the group consisting of bosutinib, ceritinib, crizotinib, gefitinib, ruxolitinib, imatinib, axitinib, nilotinib, trametinib, afatinib, ibrutinib, cabozantinib, imatinib, lenvatinib, sunitinib, regorafenib, sorafenib, vandetanib, dasatinib, pazopanib, Y27632, CA3, verteporfin, VGLL4 peptide, nintedanib, afatinib, abemaciclib, erdafitinib, fitrinib, palbociclib, and pemitinib.

91. The medical device of claim 85, wherein the kinase inhibitor is sunitinib.

92. The medical device of claim 85, wherein the kinase inhibitor is in the form of a free base, a free acid, a crystal, or a salt.

93. The medical device of claim 92, wherein the salt is a hydrochloride, sodium salt, sulfate, acetate, phosphate and / or diphosphate, pamoate or hemipamoate, a lipophilic salt, chloride salt, potassium salt, maleate, calcium salt, citrate, methanesulfonate, nitrate, tartrate, aluminum salt, stearate, dioctylsulfosuccinate, or gluconate.

94. The medical device of claim 86, wherein the biodurable polymer is selected from the group consisting of poly(vinylidene hexafluoropropylene) (PVDF-HFP), polyethylene terephthalate (PET), nylon 66, polyurethane (PU), polytetrafluoroethylene (PTFE), polyethylene, polysiloxane (silicone) and poly(methyl methacrylate) (PMMA), and combinations thereof.

95. The medical device of claim 86, wherein the biodurable polymer is poly(vinylidene hexafluoropropylene) (PVDF-HFP).

96. The medical device of claim 86, wherein the weight ratio of the biodurable polymer to the PDE inhibitor is from 1:1 to 10:

1.

97. The medical device of claim 86, wherein the weight ratio of the biodurable polymer to the kinase inhibitor is from 1:1 to 10:

1.

98. The medical device of claim 86, wherein the biodegradable polymer is selected from the group consisting of polylactic acid polymers, polycaprolactone (PCL), polylactic-co-glycolic acid (PLGA), and poly(ethylene glycol) methyl ether-block-polylactic-co-glycolic acid (PLGA-b-mPEG).

99. The medical device of claim 86, wherein the biodegradable polymer is PLGA.

100. The medical device of claim 85, wherein the medical device is selected from the group consisting of a balloon catheter, an infusion balloon catheter, an infusion catheter, a cutting balloon catheter, a scoring balloon catheter, a laser catheter, an atherectomy device, a volume reduction catheter, a stent, a filter, a stent graft, a covered stent, a patch, a wire, and a valve.

101. The medical device of claim 85, wherein the medical device is a stent or a stent graft.

102. The medical device of claim 85, wherein the medical device is a balloon catheter.

103. The medical device of claim 85, wherein the coating layer comprises one or more additional excipients.

104. The medical device of claim 103, wherein the one or more additional excipients are selected from polylactic acid (PLLA, PDLA, PDLLA), polycaprolactone (PCL), docusate sodium, PLGA, PLGA-b-mPEG, polyglutamic acid, polyacrylic acid, hyaluronic acid, alginate, PVA, PVP, Pluronic (PEO-PPO-PEO), cellulose, CMC, HPC, starch, chitosan, human serum albumin (HSA), phospholipids, fatty acids, fatty acid esters, triglycerides, beeswax, cyclodextrin, Tween 20, Tween 80, TPGS, SLS, butylated hydroxytoluene, vitamin E, vitamin E succinate, tannic acid, polyethylene glycol, N-isopropylacrylamide, and sorbitan esters.

105. The medical device of claim 85, further comprising an antioxidant.

106. The medical device of claim 105, wherein the antioxidant is butylated hydroxytoluene.

107. The medical device of claim 85, wherein the tissue comprises tissue of one of the coronary vasculature, peripheral vasculature, cerebral vasculature, esophagus, airways, sinuses, trachea, colon, bile duct, urinary tract, prostate, and brain passages.

108. A balloon catheter for delivering a therapeutic agent to a blood vessel, the balloon catheter comprising: an elongated member having an inner lumen and a distal end; an expandable balloon attached to the distal end of the elongated member and in fluid communication with the lumen; and a coating layer covering the outer surface of the balloon, the coating layer comprising a therapeutic agent and at least one of a biodegradable polymer and an excipient, in: The therapeutic agent comprises a PDE inhibitor, a kinase inhibitor, an anti-fibrotic drug or a mixture thereof, The biodegradable polymer is selected from the group consisting of polylactic acid polymer, polycaprolactone (PCL), polylactic-co-glycolic acid (PLGA), and poly(ethylene glycol) methyl ether-block-polylactic-co-glycolic acid (PLGA-b-mPEG); and The excipient is selected from fatty acids, fatty acid esters, polylactic acid (PLLA, PDLA, PDLLA), polycaprolactone (PCL), docusate sodium, PLGA, PLGA-b-mPEG, polyglutamic acid, polyacrylic acid, hyaluronic acid, alginate, PVA, PVP, Pluronic (PEO-PPO-PEO), cellulose, CMC, HPC, starch, chitosan, human serum albumin (HSA), phospholipids, fatty acids, fatty acid esters, triglycerides, beeswax, cyclodextrin, Tween 20, Tween 80, TPGS, SLS, butylated hydroxytoluene, vitamin E, vitamin E succinate, tannic acid, polyethylene glycol, N-isopropylacrylamide and sorbitan esters.

109. The balloon catheter of claim 108, wherein the PDE inhibitor is selected from the group consisting of xanthine, aminophylline, sildenafil, tadalafil, vardenafil, udenafil, avanafil, dipyridamole, quinazoline, paraxanthine, papaverine, mesembranose, rolipram, ibudilast, pyramilast, luteolin, drotaverine, roflumilast, apremilast, criborole, amrinone, milrinone, enoximone, anagrelide, cilostazol, pimobendan, erythro-9-(2- [0013] The compounds described herein include (1,2-[(3,4-dimethoxyphenyl)methyl]-7-[(1R)-1-hydroxyethyl]-4-phenylbutyl]-5-methyl-imidazo[5,1-f][1,2,4]triazine-4(1H)-one), oxindole, (9-(6-phenyl-2-oxohexan-3-yl)-2-(3,4-dimethoxybenzyl)-purin-6-one), 3-isobutyl-1-methylxanthine, pentoxifylline, theobromine and theophylline.

110. The balloon catheter of claim 108, wherein the PDE inhibitor is tadalafil or sildenafil.

111. The balloon catheter of claim 108, wherein the PDE inhibitor is in the form of a free base, crystals, a free acid, or a salt.

112. The balloon catheter of claim 111, wherein the salt is a hydrochloride, sodium salt, sulfate, acetate, phosphate and / or diphosphate, pamoate or hemipamoate, chloride, potassium, maleate, calcium salt, citrate, methanesulfonate, nitrate, tartrate, aluminum salt, stearate, dioctylsulfosuccinate or gluconate.

113. The balloon catheter of claim 108, wherein the kinase inhibitor is selected from bosutinib, ceritinib, crizotinib, gefitinib, ruxolitinib, imatinib, axitinib, nilotinib, trametinib, afatinib, ibrutinib, cabozantinib, imatinib, lenvatinib, sunitinib, regorafenib, sorafenib, vandetanib, dasatinib, pazopanib, Y27632, CA3, verteporfin, VGLL4 peptide, nintedanib, afatinib, abemaciclib, erdafitinib, fitrinib, palbociclib and pemitinib.

114. The balloon catheter of claim 108, wherein the kinase inhibitor is sunitinib.

115. The balloon catheter of claim 108, wherein the kinase inhibitor is in the form of a free base, crystals, a free acid, or a salt.

116. The balloon catheter of claim 108, wherein the anti-fibrotic drug is selected from the group consisting of triamcinolone, tranilast, halofuginone, montelukast, zafirlukast, pirfenidone, nintedanib, and combinations thereof.

117. The balloon catheter of claim 108, wherein the weight ratio of the biodegradable polymer to the therapeutic agent is 1:10 to 5:

1.

118. The balloon catheter of claim 108, wherein the biodegradable polymer is PLGA.

119. The balloon catheter of claim 108, wherein the excipient is docusate sodium.

120. The balloon catheter of claim 108, further comprising an antioxidant.

121. The balloon catheter of claim 120, wherein the antioxidant is selected from probucol, vitamin E, vitamin E succinate, butylated hydroxytoluene (BHT), ascorbic acid, beta-carotene, lycopene, lutein, retinol, manganese, selenium, flavonoids, flavonoids, catechins, polyphenols and / or zeaxanthin.

122. A stent, stent graft or other permanent or semi-permanent medical device for delivering a therapeutic agent to a blood vessel, comprising a device body and a drug coating thereon, wherein the drug coating comprises: a therapeutic agent and at least one of a biodurable polymer and an excipient, in: The therapeutic agent comprises a PDE inhibitor, a kinase inhibitor, an anti-fibrotic drug or a mixture thereof, The biodurable polymer is selected from the group consisting of poly(vinylidene hexafluoropropylene) (PVDF-HFP), polyethylene terephthalate (PET), nylon 66, polyurethane (PU), polytetrafluoroethylene (PTFE), polyethylene, polysiloxane (silicone) and poly(methyl methacrylate) (PMMA) and combinations thereof; and The excipient is selected from fatty acids, fatty acid esters, polylactic acid (PLLA, PDLA, PDLLA), polycaprolactone (PCL), docusate sodium, PLGA, PLGA-b-mPEG, polyglutamic acid, polyacrylic acid, hyaluronic acid, alginate, PVA, PVP, Pluronic (PEO-PPO-PEO), cellulose, CMC, HPC, starch, chitosan, human serum albumin (HSA), phospholipids, fatty acids, fatty acid esters, triglycerides, beeswax, cyclodextrin, Tween 20, Tween 80, TPGS, SLS, butylated hydroxytoluene, vitamin E, vitamin E succinate, and sorbitan esters.

123. The stent, stent graft or other permanent or semi-permanent medical device of claim 122, wherein the PDE inhibitor is selected from the group consisting of xanthine, aminophylline, sildenafil, tadalafil, vardenafil, udenafil, avanafil, dipyridamole, quinazoline, paraxanthine, papaverine, mesembryone, rolipram, ibudilast, pyramilast, luteolin, drotaverine, roflumilast, apremilast, criborole, amrinone, milrinone, enoximone, anagrelide, cilostazol, pitalopram, pyramilast, luteolin, drotaverine, roflumilast, apremilast, crisborole, amrinone, milrinone, enoximone, anagrelide, cilostazol, pitalopram, pyramilast, luteolin, drotaverine, roflumilast, apremilast, crisborole, amrinone, milrinone, enoximone, anagrelide, cilostazol, pitalopram, pyramilast, cilostazol, pitalopram, cilostazol ... mophenazine, erythro-9-(2-hydroxy-3-nonyl)adenine), (2-[(3,4-dimethoxyphenyl)methyl]-7-[(1R)-1-hydroxyethyl]-4-phenylbutyl]-5-methyl-imidazo[5,1-f][1,2,4]triazine-4(1H)-one), oxindole, (9-(6-phenyl-2-oxohex-3-yl)-2-(3,4-dimethoxybenzyl)-purin-6-one), 3-isobutyl-1-methylxanthine, pentoxifylline, theobromine and theophylline.

124. The stent, stent graft, or other permanent or semi-permanent medical device of claim 122, wherein the PDE inhibitor is tadalafil or sildenafil.

125. The stent, stent graft or other permanent or semi-permanent medical device of claim 122, wherein the PDE inhibitor is in the form of a free base, crystals, a free acid or a salt.

126. The stent, stent graft, or other permanent or semi-permanent medical device of claim 125, wherein the salt is a hydrochloride, sodium salt, sulfate, acetate, phosphate and / or diphosphate, pamoate or hemipamoate, chloride, potassium, maleate, calcium salt, citrate, methanesulfonate, nitrate, tartrate, aluminum salt, stearate, dioctylsulfosuccinate, or gluconate.

127. The stent, stent graft, or other permanent or semi-permanent medical device of claim 122, wherein the kinase inhibitor is selected from bosutinib, ceritinib, crizotinib, gefitinib, ruxolitinib, imatinib, axitinib, nilotinib, trametinib, afatinib, ibrutinib, cabozantinib, imatinib, lenvatinib, sunitinib, regorafenib, sorafenib, vandetanib, dasatinib, pazopanib, Y27632, CA3, verteporfin, VGLL4 peptide, nintedanib, afatinib, abemaciclib, erdafitinib, fitrinib, palbociclib, and pemitinib.

128. The stent, stent graft, or other permanent or semi-permanent medical device of claim 122, wherein the kinase inhibitor is sunitinib.

129. The stent, stent graft or other permanent or semi-permanent medical device of claim 122, wherein the kinase inhibitor is in the form of a free base, crystals, a free acid or a salt.

130. The stent, stent graft, or other permanent or semi-permanent medical device of claim 129, wherein the salt is a hydrochloride, sodium salt, sulfate, acetate, phosphate and / or diphosphate, pamoate or hemipamoate, chloride, potassium, maleate, calcium salt, citrate, methanesulfonate, nitrate, tartrate, aluminum salt, stearate, dioctylsulfosuccinate, or gluconate.

131. The stent, stent graft or other permanent or semi-permanent medical device of claim 122, wherein the anti-fibrotic drug is selected from the group consisting of triamcinolone, tranilast, halofuginone, montelukast, zafirlukast, pirfenidone, nintedanib and combinations thereof.

132. The stent, stent graft, or other permanent or semi-permanent medical device of claim 122, wherein the biodurable polymer is PVDF-HFP.

133. The stent, stent graft, or other permanent or semi-permanent medical device of claim 122, wherein the weight ratio of the biodurable polymer to the therapeutic agent is from 1:1 to 10:

1.

134. The stent, stent graft, or other permanent or semi-permanent medical device of claim 122, wherein the biodegradable polymer is PLGA.

135. The stent, stent graft, or other permanent or semi-permanent medical device of claim 122, wherein the excipient is docusate sodium.

136. The stent, stent graft, or other permanent or semi-permanent medical device of claim 122, further comprising an antioxidant.

137. A stent, stent graft or other permanent or semi-permanent medical device according to claim 136, wherein the antioxidant is selected from probucol, vitamin E, vitamin E succinate, butylated hydroxytoluene (BHT), ascorbic acid, beta-carotene, lycopene, lutein, retinol, manganese, selenium, flavonoids, flavonoids, catechins, polyphenols, tannic acid and / or zeaxanthin.

138. A kinase inhibitor, PDE inhibitor and / or anti-fibrotic agent for use in a method of alleviating stenosis in a target tissue and / or preventing restenosis and / or late lumen loss of a body lumen, wherein the kinase inhibitor and / or anti-fibrotic agent is delivered to the target tissue via a medical device according to any one of claims 1 to 137.

Images