Drug-coated medical devices and manufacturing methods

Abstract

Disclosed herein are aspects of drug coatings and methods of making drug-coated medical devices. Methods of making drug-coated medical devices can include applying a drug coating onto the exterior surface of a medical device, including both implantable and non-implantable devices, that is used in the body during interventional procedures and, in some cases, remains in place after these procedures. The drug coating can include an anti-fibrotic drug, a kinase inhibitor, a phosphodiesterase inhibitor, or a combination thereof.

Description

[Technical Field]

[0001] FIELD OF THE DISCLOSURE The present disclosure relates generally to coatings for medical devices, and more particularly to drug-eluting stents and drug-coated balloon catheters. [Background technology]

[0002] By way of background, drug-device combination products provide a synergistic effect between the function of the bare device and the efficacy of a pharmaceutical agent. 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 various medical conditions by introducing drug-coated medical devices into the vascular system or other lumens of a human or veterinary patient, such as the esophagus, trachea, colon, bile duct, bronchial passages, sinus passages, 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, cannulae, and the like. While these medical devices appear to be initially successful, their benefits are often negated by the occurrence of complications such as late thrombosis or recurrence of disease such as stenosis (restenosis) after such treatment.

[0004] Combining drugs with medical devices is a complex technical area. It involves the usual formulation challenges of oral or injectable pharmaceuticals, along with the additional challenge of maintaining drug adhesion 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. Furthermore, the coating must not impair functional performance, such as the balloon's burst pressure and compliance. Coating thickness must also be kept to a minimum, as thick coatings increase the profile of the medical device, leading to reduced trackability and deliverability. These coatings generally contain little to no liquid chemicals, which are often used to stabilize drugs. Therefore, formulations that work well for ingestible tablets and capsules or injections may not work at all for medical device coatings.

[0005] Furthermore, the drug coating must meet a release profile dictated by the properties of the underlying device. For example, balloons are typically placed temporarily within a patient, requiring the ability to rapidly deliver the drug coating. Furthermore, balloons are often delivered to a desired location by moving along the lumen of a blood vessel from an insertion point, which is often distal to the area where the drug coating is desired. Therefore, the drug coating must be prevented or protected from premature delivery so that the intended maximum localized drug delivery is achieved in the intended area of ​​the blood vessel. While the balloon can provide sustained release of the drug, the drug coating layer itself must be safely and reliably deposited on the vessel wall while the balloon is inflated in place.

[0006] Stents also have specific requirements for drug coatings that are significantly different from balloons. For example, because stents are typically placed permanently or semi-permanently within a subject, the requirement for immediate or rapid delivery of the coating to the vessel wall is less stringent. The long life of the stent allows for a more dynamic release profile that can accommodate any period of time, allowing the coating to remain on the surface of the stent and allowing for time-controlled release therefrom rather than requiring rapid migration of the coating into the vessel. Stents also allow for the use of more biodegradable polymers in the drug coating, allowing for slower and more sustained drug release as the polymer slowly degrades from the surface of the stent.

[0007] Furthermore, if the drug is released or eluted from the device too easily, it may be lost during device delivery before being deposited at the target site, or it may suddenly detach from the device during the early stages of expansion and be washed away before it can be pressed into contact with the target tissue in the body lumen wall. If the drug is attached too tightly, the device may be removed before the drug can be released and absorbed in the target tissue. Summary of the Invention [Problem to be solved by the invention]

[0008] In the development of new generation interventional devices, there is an unmet need for reducing or eliminating restenosis after interventional procedures. The implantation of conventional interventional devices, such as stents, balloon catheters, and stent grafts, generally causes vessel wall injury and endothelial denudation, followed by abnormal proliferation and migration of vascular smooth muscle cells (VSMCs), chronic inflammation, and neointimal hyperplasia. In an attempt to address restenosis, drug-eluting devices have been developed that locally deliver antiproliferative agents to blood vessels.

[0009] Current anti-proliferative drug coating therapies have proven effective in reducing restenosis through the inhibition of VSMC migration and proliferation. However, these current therapies act through nonspecific anti-proliferative effects that also significantly inhibit endothelial cell (EC) proliferation, thereby leading to delayed endothelial recovery and late thrombosis. As a result, there is a need for alternative anti-restenotic agents, particularly for drug-coated devices for peripheral arterial disease. [Means for solving the problem]

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

[0011] A 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 on an exterior surface of the medical device, the coating layer comprising a phosophodiesterase (PDE) inhibitor and / or a kinase inhibitor in combination 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] A third aspect, alone or in combination with any other aspect herein, is the PDE inhibitor is a xanthine, aminophylline, sildenafil, tadalafil, vardenafil, udenafil, avanafil, dipyridamole, quinazoline, paraxanthine, papaverine, mesembrenone, rolipram, ibudilast, piclamilast, luteolin, drotaverine, roflumilast, apremilast, crisaborole, inamrinone, milrinone, enoximone, anagrelide, cilostazol, pimobendan, erythro-9-(2-hydroxybenzoates), ... theophylline, (9-(6-phenyl-2-oxohex-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. 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 free base, free acid, crystalline, or salt form.

[0015] A 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 salt, acetate salt, phosphate and / or diphosphate salt, pamoate or hemipamoate salt, lipophilic salt, chloride salt, potassium salt, maleate salt, calcium salt, citrate salt, mesylate salt, nitrate salt, tartrate salt, aluminum salt, stearate salt, dioctyl sulfosuccinate salt, or gluconate salt.

[0016] 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, sunitinib, regorafenib, sorafenib, vandetanib, dasatinib, pazopanib, Y27632, CA3, verteporfin, VGLL4 peptide, nintedanib, avapritinib, abemaciclib, erdafitinib, fedratinib, palbociclib, and pemigatinib.

[0017] 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. 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 free base, free acid, crystalline, or salt form.

[0018] A tenth aspect, alone or in combination with any other aspect herein, relates to the medical device of the ninth aspect, wherein the salt is hydrochloride, sodium salt, sulfate salt, acetate salt, phosphate and / or diphosphate salt, pamoate or hemipamoate salt, lipophilic salt, chloride salt, potassium salt, maleate salt, calcium salt, citrate salt, mesylate salt, nitrate salt, tartrate salt, aluminum salt, stearate salt, dioctyl sulfosuccinate salt, or gluconate salt.

[0019] An 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(vinylidene fluoride hexafluoropropylene) (PVDF-HFP), polyethylene terephthalate (PET), nylon 6,6, polyurethane (PU), polytetrafluoroethylene (PTFE), polyethylene, polysiloxane (silicone), and poly(methyl methacrylate) (PMMA), and combinations thereof.

[0020] 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 fluoride hexafluoropropylene) (PVDF-HFP).

[0021] 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 biodurable polymer to PDE inhibitor is from 1:1 to 10:1.

[0022] 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 biodurable polymer to kinase inhibitor is from 1:1 to 10:1.

[0023] A 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 polymer, polycaprolactone (PCL), polylactic-co-glycolic acid (PLGA), and poly(ethylene glycol) methyl ether-block-poly(lactic-co-glycolic acid) (PLGA-b-mPEG).

[0024] 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. A 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, a 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.

[0025] 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. 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.

[0026] A 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. A 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), 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, butylhydroxytoluene, vitamin E, vitamin E succinate, tannic acid, polyethylene glycol, N-isopropylacrylamide, and sorbitol esters.

[0027] A 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. A 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 butylhydroxytoluene.

[0028] A 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, cerebrovasculature, esophagus, airway, paranasal sinuses, trachea, colon, bile duct, urinary tract, prostate, and brain passages.

[0029] A twenty-fifth aspect, alone or in combination with any other aspect herein, is a balloon catheter for delivering a therapeutic agent to a blood vessel, comprising: an elongate member having a lumen and a distal end; an expandable balloon attached to the distal end of the elongate member and in fluid communication with the lumen; and a coating layer on an exterior 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 agent, or a mixture thereof, and the biodegradable polymer is selected from the group consisting of polylactic acid polymer, polycaprolactone (PCL), polylactic-co-glycolic acid (PLGA), and poly(ethylene glycol). The excipients are selected from fatty acids, fatty acid esters, polylactic acids (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 20), Tween 80, TPGS, SLS, butylhydroxytoluene, vitamin E, vitamin E succinate, tannic acid, polyethylene glycol, N-isopropylacrylamide, and sorbitol esters.

[0030] A twenty-sixth aspect, alone or in combination with any other aspect herein, is the twenty-sixth aspect wherein the PDE inhibitor is a xanthine, aminophylline, sildenafil, tadalafil, vardenafil, udenafil, avanafil, dipyridamole, quinazoline, paraxanthine, papaverine, mesembrenone, rolipram, ibudilast, piclamilast, luteolin, drotaverine, roflumilast, apremilast, crisaborole, inamrinone, milrinone, enoximone, anagrelide, cilostazol, pimobendan, erythro-9-(2-hydroxybenzoates), ... The twenty-fifth aspect relates to a balloon catheter in which the hydroxybenzoate is selected from (2-[(3,4-dimethoxyphenyl)methyl]-7-[(1R)-1-hydroxyethyl]-4-phenylbutyl]-5-methyl-imidazo[5,1-f][1,2,4]triazin-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.

[0031] A 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.

[0032] A 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 free base, crystalline, free acid, or salt form.

[0033] A 29th aspect, alone or in combination with any other aspect herein, relates to the balloon catheter of the 28th aspect, wherein the salt is hydrochloride, sodium salt, sulfate salt, acetate salt, phosphate and / or diphosphate salt, pamoate or hemipamoate salt, chloride salt, potassium salt, maleate salt, calcium salt, citrate salt, mesylate salt, nitrate salt, tartrate salt, aluminum salt, stearate salt, dioctyl sulfosuccinate salt, or gluconate salt.

[0034] A 30th aspect, alone or in combination with any other aspect herein, relates to the balloon catheter of the 25th 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, avapritinib, abemaciclib, erdafitinib, fedratinib, palbociclib, and pemigatinib.

[0035] A 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. A 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 free base, free acid, crystalline, or salt form.

[0036] A 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 hydrochloride, sodium salt, sulfate salt, acetate salt, phosphate and / or diphosphate salt, pamoate or hemipamoate salt, lipophilic salt, chloride salt, potassium salt, maleate salt, calcium salt, citrate salt, mesylate salt, nitrate salt, tartrate salt, aluminum salt, stearate salt, dioctyl sulfosuccinate salt, or gluconate salt.

[0037] A thirty-fourth aspect, alone or in combination with any other aspect herein, relates to the balloon catheter of the twenty-fifth aspect, wherein the antifibrotic agent is selected from triamciclone, tranilast, halofuginone, montelukast, zafirlukast, pirfenidone, nintedanib, and combinations thereof.

[0038] A 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 biodegradable polymer to therapeutic agent is 1:10 to 5:1.

[0039] A 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. A 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.

[0040] A 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. A 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, butylhydroxytoluene (BHT), ascorbic acid, beta-carotene, lycopene, lutein, retinol, manganese, selenium, flavonoids, flavones, catechins, polyphenols, and / or zeaxanthin.

[0041] A fortieth aspect, alone or in combination with any other aspect herein, is 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 on the device body, 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 agent, or a mixture thereof, and wherein the biodurable polymer is selected from the group consisting of poly(vinylidene fluoride hexafluoropropylene) (PVDF-HFP), polyethylene terephthalate (PET), nylon 6,6, polyurethane (PU), polytetrafluoroethylene (PT), FE), 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), 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 20), Tween 80, TPGS, SLS, butylhydroxytoluene, vitamin E, vitamin E succinate, and sorbitol esters.

[0042] A forty-first aspect, alone or in combination with any other aspect herein, is the invention wherein the PDE inhibitor is a xanthine, aminophylline, sildenafil, tadalafil, vardenafil, udenafil, avanafil, dipyridamole, quinazoline, paraxanthine, papaverine, mesembrenone, rolipram, ibudilast, piclamilast, luteolin, drotaverine, roflumilast, apremilast, 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]triazin-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.

[0043] A 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.

[0044] A 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 free base, crystalline, free acid, or salt form.

[0045] A 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 hydrochloride, sodium salt, sulfate salt, acetate salt, phosphate and / or diphosphate salt, pamoate or hemipamoate salt, chloride salt, potassium salt, maleate salt, calcium salt, citrate salt, mesylate salt, nitrate salt, tartrate salt, aluminum salt, stearate salt, dioctylsulfosuccinate salt, or gluconate salt.

[0046] A forty-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 fortieth 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, avapritinib, abemaciclib, erdafitinib, fedratinib, palbociclib, and pemigatinib.

[0047] A 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.

[0048] A 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 free base, free acid, crystalline, or salt form.

[0049] A 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 hydrochloride, sodium salt, sulfate salt, acetate salt, phosphate and / or diphosphate salt, pamoate or hemipamoate salt, lipophilic salt, chloride salt, potassium salt, maleate salt, calcium salt, citrate salt, mesylate salt, nitrate salt, tartrate salt, aluminum salt, stearate salt, dioctylsulfosuccinate salt, or gluconate salt.

[0050] A forty-ninth 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 anti-fibrotic agent is selected from triamcinolone, tranilast, halofuginone, montelukast, zafirlukast, pirfenidone, nintedanib, and combinations thereof.

[0051] A 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.

[0052] A 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 biodurable polymer to therapeutic agent is between 1:1 and 10:1.

[0053] A 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.

[0054] A 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.

[0055] A 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.

[0056] A 55th 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 54th aspect, wherein the antioxidant is selected from probucol, vitamin E, vitamin E succinate, butylhydroxytoluene (BHT), ascorbic acid, beta-carotene, lycopene, lutein, retinol, manganese, selenium, flavonoids, flavones, catechins, polyphenols, tannic acid, and / or zeaxanthin.

[0057] A kinase inhibitor, a PDE inhibitor, and / or an anti-fibrotic agent for use in a method for alleviating stenosis in a target tissue and / or preventing restenosis and / or late lumen loss in a body lumen, wherein the kinase inhibitor and / or anti-fibrotic agent is delivered to the target tissue by the medical device of any one of Aspects 1 to 55.

[0058] These and other features, aspects, and advantages of the present disclosure will become better understood with reference to the following description and appended claims. Additional features and advantages of the embodiments described herein will be set forth in the detailed description which follows, and in part will be readily apparent to those skilled in the art from that description, or may be learned by practicing the embodiments described herein, including the following detailed description, the claims, and the accompanying drawings.

[0059] It is to 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 characteristics 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. [Brief explanation of the drawings]

[0060] [Figure 1] 1 is a schematic diagram of an exemplary embodiment of a medical device, particularly a balloon catheter, according to the present disclosure. [Figure 2A] 2 is a cross-sectional view of an embodiment of the distal end of the balloon catheter of FIG. 1 taken along line AA, including a drug coating layer on the outer surface of the balloon. [Figure 2B] 2 is a cross-sectional view of an embodiment of the distal end of the balloon catheter of FIG. 1 taken along line AA, including an intermediate layer between the outer surface of the balloon and the drug coating layer. [Figure 3] 1 is a schematic diagram of an exemplary embodiment of a medical device, particularly a stent, according to the present disclosure. [Figure 4] 4 is a cross-sectional view of an embodiment of the distal end of the balloon catheter of FIG. 3 taken along line AA, including a drug coating layer on the outer surface of the stent. [Figure 5] 1 is an optical microscope image of sample stent 1. [Figure 6] 1 is an optical microscope image of sample stent 2. [Figure 7] 1 shows cumulative release profiles of Sample Stent 1 and Sample Stent 2. [Figure 8] 1 is a graph of the in vivo release profile and tissue PK (pharmacokinetics) over a period up to 90 days after stent implantation. [Figure 9] 1 shows cross-sectional views of blood vessels of Comparative Examples A and C and Samples 1 and 2. [Figure 10] 1 shows in vivo pharmacokinetic data for sunitinib, tadalafil, colchicine, and roflumilast at 7 and 28 days after stenting. [Figure 11] 1 shows arterial cross-sections and stent endothelialization 60 days after implantation of stents with drug coatings of colchicine, tadalafil, roflumilast, sunitinib, and PVDF alone. [Figure 12] 1 shows arterial cross-sections and stent endothelialization 90 days after implantation of stents with drug coatings of colchicine, tadalafil, roflumilast, sunitinib, and PVDF alone. [Figure 13] Representative scanning electron microscope images of PLGA / sunitinib malate microparticles prepared using the oil-in-water emulsion evaporation method are shown, showing spherical morphology at low (top panel) and high (bottom panel) magnification. DETAILED DESCRIPTION OF THE INVENTION

[0061] 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 present subject matter to those skilled in the art. Unless otherwise specified, all molecular weights herein are reported in Daltons (g / mol). Molecular weights of polymeric materials are reported as weight average molecular weights.

[0062] 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, for example, vapor deposition, spray coating, dip coating, lamination, adhesion, micropatterning, molding, painting, spin coating, sputtering, immersion coating, plasma-assisted deposition, or vacuum deposition.

[0063] The terms "coated" and "applied" as verbs may be used interchangeably herein. Unless otherwise specified, references to a "substrate coated with a particular material" or the like are equivalent to a "substrate having a particular material applied to a surface or portion of a surface of the substrate using any conventional application or deposition method, such as, for example, vapor deposition, spray coating, dip coating, painting, spin coating, sputtering, immersion coating, plasma-assisted deposition, or vacuum deposition.

[0064] Drug Coating In some aspects, the present disclosure relates to one or more drug coatings for medical devices and their uses. Medical devices may include angioplasty balloons, catheters, guidewires, balloons, filters, stents, stent grafts, vascular grafts, aneurysm filling coils, meshes, prosthetic heart valves, pacemaker leads, ports, needles, clips, and any other device having a drug coating. In some aspects, the drug coatings of the present disclosure may be applied to the exterior surface of expandable medical devices, including, by way of non-limiting example, balloon catheters and stents. Exemplary methods for preparing medical devices and coatings thereon, as well as exemplary data from expandable medical devices comprising the drug coatings described herein, are described herein. In some aspects, the drug coating may itself be a therapeutic agent. In other aspects, the drug coating may include a therapeutic agent and an additive. In further aspects, the drug coating may be a therapeutic agent and two or more additives. In some aspects, the additive may include a polymer.

[0065] As mentioned above, currently available drug-coated devices can effectively reduce restenosis by inhibiting VSMC migration and proliferation, but they also act with sufficient nonspecificity to inhibit endothelial cell (EC) growth and / or proliferation, delay endothelial recovery, and cause late-stage thrombosis. Collectively, these nonspecific and undesirable effects increase the long-term mortality risk in patients.

[0066] In another aspect, the present disclosure provides a drug coating for a medical device that may include an antifibrotic drug, a kinase inhibitor, a phosphodiesterase inhibitor, or a combination thereof. One additional nonspecific effect observed with some current drug-coated devices is the promotion of fibrin production, which can lead to fibrosis. One drawback of current coated angioplasty balloons is that the included drugs can act nonspecifically and antiproliferatively, shed, and migrate to other parts of the body. Therefore, residues of the nonspecific and antiproliferative drugs can migrate downstream from the inserted device into the body, potentially leading to unintended consequences. For example, the shed drugs can migrate to the lungs, where they can cause fibrotic scarring. Including an antifibrotic drug in the device coating as described herein prevents the potential for promoting fibrin production or inducing fibrotic tissue.

[0067] In some aspects, the presently described drug coatings may enable effective and efficient delivery of therapeutic agents, drugs, or bioactive materials directly to localized tissue regions during or after a medical procedure to treat or prevent vascular and non-vascular diseases, such as restenosis. The presently described drug coatings may enable the release of therapeutic agents in an effective and efficient manner at desired target locations, where the therapeutic agents can penetrate the target tissue and treat the disease, e.g., alleviate stenosis and prevent restenosis and late lumen loss of a body cavity. In some further aspects, the presently described drug coatings may enable the release of therapeutic agents in an effective and efficient manner for the treatment of pulmonary fibrosis. Furthermore, the presently described drug coatings may enable effective treatment without significant endothelial cell (EC) inhibition.

[0068] In some embodiments, the drug coating comprises at least one therapeutic agent present thereon at a desired concentration density. In some embodiments, the concentration of the at least one therapeutic agent in the drug coating is about 0.1 μg / mm2 ~about 10μg / mm 2 and may be about 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 0.55, 0.6, 0.65, 0.7, 0.75, 0.8, 0.85, 0.9, 0.95, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, and 9.9 μg / mm 2 In other embodiments, the concentration of the at least one therapeutic agent in the drug coating is about 0.1 μg / mm 2 ~about 8μg / mm 2 , about 0.1μg / mm 2 ~approximately 6 μg / mm 2 , about 0.1μg / mm 2 ~about 4μg / mm 2 , about 0.1μg / mm 2 ~approximately 2 μg / mm 2 , about 0.1μg / mm 2 ~Approx. 1μg / mm 2 , about 1μg / mm 2 ~about 10μg / mm 2 , about 1μg / mm 2 ~about 8μg / mm 2 , about 1μg / mm 2 ~approximately 6 μg / mm 2 , about 1μg / mm 2 ~about 4μg / mm 2 , about 1μg / mm 2 ~approximately 2 μg / mm 2 , approximately 2 μg / mm 2 ~about 10μg / mm 2, approximately 2 μg / mm 2 ~about 8μg / mm 2 , approximately 2 μg / mm 2 ~approximately 6 μg / mm 2 , approximately 2 μg / mm 2 ~about 4μg / mm 2 , about 4μg / mm 2 ~about 10μg / mm 2 , about 4μg / mm 2 ~about 8μg / mm 2 , about 4μg / mm 2 ~approximately 6 μg / mm 2 , approximately 6 μg / mm 2 ~about 10μg / mm 2 , approximately 6 μg / mm 2 ~about 8μg / mm 2 , or about 8 μg / mm 2 ~about 10μg / mm 2 In some embodiments, the concentration of the at least one therapeutic agent in the drug coating can be about 0.5 μg / mm 2 ~about 5μg / mm 2 It could be.

[0069] In some aspects described herein, the drug coating can include a polymer or two or more polymers. In some embodiments, the weight ratio of polymer to therapeutic agent in the drug coating is from about 1:1 to about 10:1, from about 1:1 to about 9:1, from about 1:1 to about 8:1, from about 1:1 to about 7:1, from about 1:1 to about 6:1, from about 1:1 to about 5:1, from about 1:1 to about 4:1, from about 1:1 to about 3:1, from about 1:1 to about 2:1, from about 2:1 to about 10:1, from about 2:1 to about 9:1, from about 2:1 to about 8:1, from about 2:1 to about 7:1, from about 2:1 to about 6:1, from about 2:1 to about 5:1, from about 2:1 to about 4:1, from about 2:1 to about 3:1, from about 3:1 to about 10:1, from about 3:1 to about 9:1, from about 3:1 to about 8:1, from about 3:1 to about 7:1, from about 3:1 to about 3:1, :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 The polymer to therapeutic agent (by weight) ratio can be 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 (by weight) ratio is too low, the drug may be released prematurely; if the ratio is too high, the drug may not elute or be absorbed into the tissue sufficiently rapidly upon placement at the target site. For example, a low ratio may lead to faster release, and a high ratio may lead to slower release.

[0070] In some aspects, the drug coating may include a biodurable polymer. As described herein, a biodurable polymer may include a polymer that exhibits good tolerance and / or is non-reactive when in contact with a subject or its immunoreactive cells, and that resists erosion and / or enzymatic degradation and / or dissolution within a subject or its circulatory system (see, e.g., Nathanael et al., Polymer, 2020, Vol. 12, p. 3061; doi:10.3390 / polym12123061; Shalaby et al., eds., Polymers for Vascular and Urogenital Applications, CRC Press, 2017; and Mishra, ed., Concise Encyclopedia of Biomedical Polymers and Polymeric Biomaterials, CRC Press, 2017). By way of example, biodurable polymers include polyethylene terephthalate (PET), nylon 6,6, polyurethane (PU), polytetrafluoroethylene (PTFE), polyethylene (PE, low density and high density and ultra-high molecular weight (UHMW)), polysiloxane (silicone), and poly(methyl methacrylate) (PMMA), and poly(vinylidene fluoride-co-hexafluoropropylene) (PVDF-HFP). In some embodiments, the biodurable polymer can be PVDF-HFP.

[0071] In other aspects, the drug coating may comprise a biodegradable polymer. As described herein, the biodegradable polymer may include a polymer that is well tolerated and / or non-reactive when in contact with a subject or its immunoreactive cells, and that is susceptible to erosion and / or enzymatic degradation and / or dissolution over time within a subject or its circulatory system. (See, e.g., Nathanael et al., Polymer, 2020, Vol. 12, p. 3061; doi:10.3390 / polym12123061; Shalaby et al., eds., Polymers for Vascular and Urogenital Applications, CRC Press, 2017; and Mishra, ed., Concise Encyclopedia of Biomedical Polymers and Polymeric Biomaterials, CRC Press, 2017.) Biodegradable polymers allow for the 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-poly(lactic-co-glycolic acid) (PLGA-b-mPEG).

[0072] In some embodiments, the drug coating is configured for the underlying medical device. For example, in some embodiments, the medical device is a stent, and in other embodiments, the medical device is a balloon. Thus, the drug coating may be tailored to the properties of a temporary device that is delivered along the vessel wall, or the drug coating may be tailored for a permanent or semi-permanent device that can release the drug directly from its surface when the device is within the vessel.

[0073] In some aspects, the present disclosure relates to drug coatings for balloons or inflatable devices intended to inflate and exert pressure from the inside to the outside of a blood vessel. Due to the occlusive nature of the expansion, these devices are only deployed for a short period of time. Due to such constraints, it will be apparent that the drug coating must be configured for rapid delivery to the vessel wall. In some aspects, the balloon can deliver the drug coating in a manner that either releases the coating into the vessel wall or allows for rapid absorption by the vessel wall. In some aspects, the drug coating can be configured with excipients and / or drug solvates to facilitate migration to the interior of the vessel wall. In some aspects, the excipients can include those described herein. In other embodiments, 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, butyryltrihexyl citrate (BTHC), N-isopropylacrylamide (P-NIPAAm), or a combination thereof. In some embodiments, the drug coating may be a specific formulation of the therapeutic agent, such as crystals and / or microparticles thereof, or a salt and / or microparticles thereof. In some embodiments, the salt may be a malate salt. In some embodiments, the drug coating may include a polymer, such as a biodegradable polymer and / or a bioerodible polymer, as described herein, or a combination thereof. In some embodiments, the drug coating may include PLA, PGA, and / or PLGA. In some embodiments, the drug coating may be in the free base form. In some embodiments, the drug coating may be of an excipient, a salt of a therapeutic agent, and a biodegradable and / or bioerodible polymer.

[0074] In other aspects, drug coatings are configured for stents, stent grafts, or other longer-lasting medical devices, such as perfusion balloon catheters, infusion catheters, cutting balloon catheters, scoring balloon catheters, laser catheters, atherectomy devices, debulking catheters, filters, stent grafts, covered stents, patches, wires, and valves. Due to the permanent or semi-permanent nature of stents, drug coatings do not need to transfer the active ingredient with the same urgency and can be configured to remain on the surface or outer region of the stent and provide the drug release profile needed in some situations. For example, combining a therapeutic agent with a biodurable, biodegradable, and / or bioerodible polymer can embed the therapeutic agent, allowing for sustained and / or delayed release as the polymer erodes. Such polymers may include PLA, PGA, PLGA, polyvinylidene fluoride (PVD or PVDF), polyvinylidene fluoride-hexafluoropropylene (PVDF-HFP or PVD-HFP), poly(n-butyl methacrylate (PBMA), polystyrene-b-polyisobutylene-b-polystyrene (SIBS), or combinations thereof. In some embodiments, the drug coating may contain 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.

[0075] Many aspects of the present disclosure may be particularly useful for treating vascular disease and reducing stenosis and late lumen loss, or for the manufacture of devices for that purpose or methods of treating that class of disease. While the examples described 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 containing therapeutic agents and additives, such as those described above with respect to stents and balloon catheters. Such other medical devices include, but are not limited to, stent grafts, scoring balloon catheters, and recanalization catheters.

[0076] Treatment drugs In some embodiments, the drug coating of a medical device may comprise at least one therapeutic agent. The therapeutic agent may comprise a small molecule compound in an uncharged or neutral state, its anion, its cation, its salt, its derivative, and / or its crystalline or crystalline form. In some embodiments, the drug coating of a medical device may comprise a therapeutic agent and at least one additive. In some embodiments, the drug coating may comprise an antifibrotic agent, a kinase inhibitor, or a combination thereof, which may be a viable target for treating restenosis with improved specificity and fewer adverse effects compared to nonspecific antiproliferative agents.

[0077] As used herein, a "derivative" may refer to a chemically or biologically modified version of a compound that is structurally similar to and derivable (actually or theoretically) from a parent compound (e.g., dexamethasone). A derivative may or may not have different chemical or physical properties than the parent compound. For example, a derivative may be more hydrophilic or have altered reactivity compared to the parent compound. Derivatization (i.e., modification) may involve the substitution of one or more moieties within a molecule (e.g., a change in functional group). For example, hydrogen may be replaced with a halogen, such as fluorine or chlorine, or a hydroxyl group (-OH) may be replaced with a carboxylic acid moiety (-COOH). The term "derivative" may also include conjugates of a parent compound and prodrugs (i.e., chemically modified derivatives that can be converted into the original compound under physiological conditions). For example, a prodrug may be an inactive form of an active ingredient. Under physiological conditions, a prodrug may be converted into the active form of the compound, for example, via phase I and / or phase II of a metabolic pathway. Prodrugs may be formed, for example, by replacing one or two hydrogen atoms on the 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 Fleisher et al., Advanced Drug Delivery Reviews, Vol. 19 (1996), p. 115; Bundgaard, ed., Design of Prodrugs, Elsevier, 1985; or H. Bundgaard, Drugs of the Future, Vol. 16 (1991), p. 443. The term "derivative" is also used to describe all solvates, such as hydrates or adducts (e.g., adducts with alcohols), active metabolites, and salts of the parent compound. The type of salt that can be prepared depends on the nature of the moiety in the compound.For example, acidic groups, such as carboxylic acid groups, can form alkali metal or alkaline earth metal salts (e.g., sodium, potassium, magnesium, and calcium salts, as well as salts with physiologically acceptable quaternary ammonium ions, and acid addition salts with ammonia and physiologically acceptable organic amines, such as triethylamine, ethanolamine, or tris-(2-hydroxyethyl)amine). Basic groups can form acid addition salts with inorganic acids, such as hydrochloric acid, sulfuric acid, or phosphoric acid, or organic carboxylic 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 embodiments, the organic acid can include fatty acids, such as stearic acid and / or dioctyl sulfosuccinic acid. In some embodiments, the organic acid can include those with biological activity, such as oleanolic acid, betulinic acid, ursolic acid, and / or vaprolic acid. In other embodiments, the organic acid can include those with antioxidant properties, such as ascorbic acid, tannic acid, and vitamin E succinate. In some embodiments, the organic acid can include pamoic acid. Compounds that simultaneously contain a basic group, such as a carboxyl group, and an acidic group in addition to a basic nitrogen atom can exist as zwitterions. Salts can be obtained by conventional methods known to those skilled in the art, for example, by combining the compound with an inorganic or organic acid or base in a solvent or diluent, or by cation or anion exchange from another salt.

[0078] As used herein, "analog" or "analogue" may refer to a compound that is structurally similar to another compound but differs slightly in composition (e.g., certain atoms are replaced by atoms of different elements, or certain functional groups are present, etc.), and may or may not be derivable from the parent compound. A "derivative" may differ from an "analog" or "analogue" in that the parent compound may be the starting material for making a "derivative," while the parent compound may not necessarily be used as the starting material for making an "analog."

[0079] In some aspects of the present disclosure, the therapeutic agent or substance may comprise a drug or biologically active material. The drug may be in various physical states, such as, for example, molecular dispersion, crystalline 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 inhibitors and / or antifibrotic agents and / or kinase inhibitors and / or tyrosine kinase inhibitors and / or receptor tyrosine kinase inhibitors. Further examples of drugs include bosutinib, ceritinib, crizotinib, gefitinib, ruxolitinib, imatinib, axitinib, nilotinib, trametinib, afatinib, ibrutinib, cabozantinib, imatinib, lenvatinib, sunitinib, regorafenib, sorafenib, vandetanib, dasatinib, pazopanib, triamcinolone, tranilast, halofuginone, montegravir, and the like. Lukast, zafirlukast, pirfenidone, Y27632, CA3, verteporfin, VGLL4 peptide, nintedanib, avapritinib, abemaciclib, erdafitinib, fedratinib, nilotinib, nintendanib, palbociclib, pemigatinib, xanthine, aminophylline, sildenafil, tadalafil, vardenafil, udenafil, avanafil, dipyridone Damor, quinazoline, paraxanthine, papaverine, mesembrenone, rolipram, ibudilast, piclamilast, luteolin, drotaverine, roflumilast, apremilast, 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]triazin-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.In certain aspects, these drugs may be suitable for use in coatings on expandable medical devices used to treat tissue in the vasculature.

[0080] In some embodiments, the therapeutic agent may include a protein kinase inhibitor, also referred to as a multi-target tyrosine kinase inhibitor (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 enzymatic cascade of phosphorylation events. Tyrosine kinase refers to the tyrosine amino acid involved in the phosphorylation of specific enzymes or receptors and the resulting enzymatic activity, while serine and threonine amino acids are other key amino acids for kinase activation and signal transduction. One example is the receptor protein tyrosine kinase platelet-derived growth factor receptor (PDGFR), which, upon binding to endogenous platelet-derived growth factor (PDGF or platelet-derived growth hormone PDGH), can initiate a cascade of events leading to the migration and proliferation of vascular smooth muscle cells (VSMCs). Increased expression of PDGF and PDGFR has been reported in damaged vascular tissue. In addition, it has been demonstrated that vascular endothelial growth factor (VEGF) and its tyrosine kinase receptor VEGFR are also highly involved in the pathological progression of restenosis. Examples of PDGFR and / or VEGFR inhibitors, including inhibitors of downstream enzymes of PDGFR and / or VEGFR inhibitors, include imatinib, nintedanib, sorafenib, sunitinib, and pazopanib, ROCK inhibitors (Y27632), YAP / TAZ inhibitors (CA3 and verteporfin), YAP / TAZ-TEAD interaction inhibitors (verteporfin, VGLL4 peptide), and SRC inhibitors (dasatinib). Additionally, kinase modulators derived from bioactive products may be included, such as resveratrol, quercetin, curcumin, chrysin, myricetin, luteolin, apigenin, anthrocyanins, genistein, epigallocatechin gallate, fisetin, astaxanthin, tetrahydrocurcumin, and / or combinations thereof.

[0081] Thus, inhibition of activation of PDGF and / or VEGF, and / or their tyrosine kinase receptors (i.e., VEGFR and / or PDGFR), offers a more selective approach than common cytotoxic agents for preventing the formation of neointimal hyperplasia without equally suppressing both vascular smooth muscle cells (VSMCs) and / or normal cells. Furthermore, tyrosine kinase inhibitors, such as sunitinib, target proliferating smooth muscle cells in a more selective manner than drugs currently used in drug-coated interventional devices. In some embodiments, local delivery of kinase inhibitors using the interventional devices described herein, followed by sustained drug release, may enable the inhibition of restenosis without causing systemic toxicity. Additionally, kinase inhibitors generally offer good chemical stability, as they do not readily degrade during typical storage conditions of the medical devices described herein.

[0082] Kinase inhibitors are typically weak bases that are protonated under physiological conditions. As a result, tyrosine kinase inhibitors have higher water solubility. In some embodiments, the drug coating has a concentration 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 8 mg / mL, or about 8 mg / mL. The therapeutic agent may have a water solubility of about 10 mg / mL to about 10 mg / mL, about 6 mg / mL to about 20 mg / mL, about 8 mg / mL to about 25 mg / mL, about 10 mg / mL to about 25 mg / mL, about 10 mg / mL to about 30 mg / mL, about 15 mg / mL to about 35 mg / mL, about 20 mg / mL to about 40 mg / mL, about 30 mg / mL to about 45 mg / mL, about 30 mg / mL to about 50 mg / mL, about 35 mg / mL to about 50 mg / mL, about 40 mg / mL to about 50 mg / mL, about 45 mg / mL to about 50 mg / mL, about 10 mg / mL to about 50 mg / mL, or about 1 mg / mL to about 50 mg / mL. For example, the water solubility of sunitinib malate is about 25 mg / mL. In some aspects, high solubility can be a challenge for sustained release formulations, but the use of lipophilic excipients within the coating matrix can slow or inhibit drug dissolution.

[0083] In some embodiments, the kinase inhibitor may be coated directly onto the medical device as a free base or free acid, hi other embodiments, the kinase inhibitor may be protonated or in the form of a salt such as hydrochloride, sodium, sulfate, acetate, phosphate and / or diphosphate, pamoate or hemipamoate, chloride, potassium, maleate, calcium, citrate, mesylate, nitrate, tartrate, aluminum, or gluconate.

[0084] Conventionally, systemic administration of kinase inhibitors can require relatively high doses, potentially causing severe side effects. In some present embodiments, the concentration of the kinase inhibitor in the drug coating is about 0.1 μg / mm 2 ~about 10μg / mm 2 , about 0.1μg / mm 2 ~about 8μg / mm 2 , about 0.1μg / mm 2 ~approximately 6 μg / mm 2 , about 0.1μg / mm 2 ~about 4μg / mm 2 , about 0.1μg / mm 2 ~approximately 2 μg / mm 2 , about 0.1μg / mm 2 ~Approx. 1μg / mm 2 , about 1μg / mm 2 ~about 10μg / mm 2 , about 1μg / mm 2 ~about 8μg / mm 2 , about 1μg / mm 2 ~approximately 6 μg / mm 2 , about 1μg / mm 2 ~about 4μg / mm 2 , about 1μg / mm 2 ~approximately 2 μg / mm 2 , approximately 2 μg / mm 2 ~about 10μg / mm 2 , approximately 2 μg / mm 2 ~about 8μg / mm 2 , approximately 2 μg / mm 2 ~approximately 6 μg / mm 2 , approximately 2 μg / mm 2 ~about 4μg / mm 2 , about 4μg / mm 2 ~about 10μg / mm 2 , about 4μg / mm 2 ~about 8μg / mm 2 , about 4μg / mm 2 ~approximately 6 μg / mm 2 , approximately 6 μg / mm 2 ~about 10μg / mm 2 , approximately 6 μg / mm 2 ~about 8μg / mm 2 , or about 8 μg / mm 2 ~about 10μg / mm 2In some embodiments, the concentration of the at least one therapeutic agent in the drug coating can be about 0.5 μg / mm 2 ~about 5μg / mm 2 It could be.

[0085] In some embodiments, the therapeutic agent can be an anti-fibrotic agent.The pharmacological mechanism of action of anti-fibrotic agents includes inhibiting and / or reducing local inflammation and reducing and / or inhibiting the formation of fibrotic tissue growth factors.Anti-fibrotic agents can include, for example, triamcinolone, tranilast, halofuginone, montelukast, zafirlukast, pirfenidone, and nintedanib.For example, therapeutic agents such as pirfenidone and nintedanib can slow the progression of scar tissue accumulation.

[0086] In some embodiments, the therapeutic agent of the drug coating may be 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 embodiments, the therapeutic agent may include at least one of cabozantinib, imatinib, lenvatinib, sunitinib, regorafenib, sorafenib, vandetanib, dasatinib, pazopanib, triamcinolone, tranilast, halofuginone, montelukast, zafirlukast, pirfenidone, nintedanib, a ROCK inhibitor (Y27632), a YAP / TAZ inhibitor (CA3 and verteporfin), a YAP / TAZ-TEAD interaction inhibitor (verteporfin, VGLL4 peptide), an SRC inhibitor (dasatinib), or a salt thereof, or a crystalline or crystalline form thereof, or a derivative thereof.

[0087] In some embodiments, the therapeutic agent can be a phosphodiesterase (PDE) inhibitor. PDE inhibitors refer to a class of pharmaceuticals characterized by their ability to inhibit PDE enzyme activity. PDE enzymes are a class of enzymes that catalyze the cleavage of phosphodiester bonds in cyclic nucleotide compounds, such as cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). Multiple isoforms of PDE exist, and each specific protein receives a numerical identifier. In some embodiments, application of a PDE inhibitor can prevent the cleavage of cAMP and / or cGMP. In some embodiments, application of a PDE inhibitor can increase the levels of cAMP and / or cGMP. Thus, PDE inhibitors may provide a more selective approach to preventing the formation of neointimal hyperplasia without negatively inhibiting other surrounding cells. In some embodiments, local delivery of PDE inhibitors using the interventional devices described herein, followed by sustained drug release, can enable the inhibition of restenosis without causing systemic toxicity.

[0088] Some PDE inhibitors, or at least salts thereof, are weak bases that are typically protonated under physiological conditions and therefore have higher water solubility. In some embodiments, the drug coating has 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, about 4 mg / mL to about 6 mg / mL, about 6 ... The composition may comprise a therapeutic agent having a water solubility of about 10 mg / mL to about 15 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.

[0089] In some embodiments, the therapeutic agent may include a non-selective PDE inhibitor, which may inhibit more than one PDE enzyme. Examples of non-selective PDE inhibitors may include xanthine, caffeine, aminophylline, 3-isobutyl-1-methylxanthine, pentoxifylline, theobromine, and theophylline.

[0090] In some embodiments, the PDE inhibitor can be a selective PDE inhibitor, where the therapeutic agent preferentially targets one isoform of PDE enzyme.For example, in some embodiments, 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]triazin-4(1H)-one), oxindole, and / or 9-(6-phenyl-2-oxohex-3-yl)-2-(3,4-dimethoxybenzyl)-purin-6-one.In some embodiments, the PDE inhibitor is a PDE3 inhibitor such as inamrinone, milrinone, enoximone, anagrelide, cilostazol, and / or pimobendan. In some embodiments, the PDE inhibitor is a PDE4 inhibitor such as mesembrenone, rolipram, ibudilast, piclamilast, luteolin, drotaverine, roflumilast, apremilast, and / or crisaborole. In some embodiments, the PDE inhibitor is a PDE5 inhibitor such as sildenafil, tadalafil, vardenafil, udenafil, avanafil, and / or dipyridamole. In some embodiments, the PDE inhibitor is a PDE7 inhibitor such as quinazoline. In some embodiments, the PDE inhibitor is a PDE9 inhibitor such as paraxanthine. In some embodiments, the PDE inhibitor is a PDE10 inhibitor such as papaverine.

[0091] In some present embodiments, the concentration of the PDE inhibitor in the drug coating is about 0.1 μg / mm 2 ~about 10μg / mm 2 , about 0.1μg / mm 2 ~about 8μg / mm 2 , about 0.1μg / mm 2 ~approximately 6 μg / mm 2 , about 0.1μg / mm 2 ~about 4μg / mm 2 , about 0.1μg / mm 2 ~approximately 2 μg / mm 2 , about 0.1μg / mm 2 ~Approx. 1μg / mm 2, about 1μg / mm 2 ~about 10μg / mm 2 , about 1μg / mm 2 ~about 8μg / mm 2 , about 1μg / mm 2 ~approximately 6μg / mm 2 , about 1μg / mm 2 ~about 4μg / mm 2 , about 1μg / mm 2 ~approximately 2 μg / mm 2 , approximately 2 μg / mm 2 ~about 10μg / mm 2 , approximately 2 μg / mm 2 ~about 8μg / mm 2 , approximately 2 μg / mm 2 ~approximately 6μg / mm 2 , approximately 2 μg / mm 2 ~about 4μg / mm 2 , about 4μg / mm 2 ~about 10μg / mm 2 , about 4μg / mm 2 ~about 8μg / mm 2 , about 4μg / mm 2 ~approximately 6 μg / mm 2 , approximately 6 μg / mm 2 ~about 10μg / mm 2 , approximately 6 μg / mm 2 ~about 8μg / mm 2 , or about 8 μg / mm 2 ~about 10μg / mm 2 In some embodiments, the concentration of the at least one therapeutic agent in the drug coating can be about 0.5 μg / mm 2 ~about 5μg / mm 2 It could be.

[0092] In some embodiments, the therapeutic agent is a combination of a kinase inhibitor and an anti-fibrotic agent. In some embodiments, the selected therapeutic agent comprises a combination of a kinase inhibitor and a PDE inhibitor. In some embodiments, the selected therapeutic agent comprises a combination of an anti-fibrotic agent and a PDE inhibitor. In some embodiments, the selected therapeutic agent comprises at least one kinase inhibitor, at least one anti-fibrotic agent, and at least one PDE inhibitor.

[0093] In some aspects, the therapeutic agent may be applied to the exterior surface of the medical device or a coating thereon. In some aspects, the therapeutic agent may be applied directly. In other aspects, the therapeutic agent may be applied after combining with a coating solvent. Those skilled in the art will appreciate that a combination of approaches for coating a therapeutic agent may also be utilized to coat a medical device.

[0094] In some embodiments, other therapeutic compounds may be included in the drug coatings of the present disclosure. Such other drugs may 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 useful in some embodiments of the present disclosure are polynucleotides, antisense, RNAi, or siRNA that inhibit inflammation and / or smooth muscle cell or fibroblast proliferation, contractility, or migration, including lipid nanoparticles encapsulating these. Antiplatelet agents may include drugs such as aspirin and dipyridamole. Aspirin is classified as an analgesic, antipyretic, anti-inflammatory, and antiplatelet agent. Dipyridamole is a drug similar to aspirin in that it has antiplatelet properties. Dipyridamole is also classified as a coronary vasodilator. Anticoagulants used in some embodiments of the present 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, flavones, catechins, polyphenols, and / or zeaxanthin. Antiproliferative agents may include drugs such as amlodipine and doxazosin. Antimitotic agents and antimetabolites that may be used in some embodiments of the present disclosure include drugs such as methotrexate, azathioprine, vincristine, adriamycin, and mutamycin. Antibiotics used in some embodiments of the present disclosure include penicillin, cefoxitin, oxacillin, tobramycin, and gentamicin. Suitable antioxidants for use in some embodiments of the present disclosure include probucol. Additionally, in embodiments of the present disclosure, genes or nucleic acids, or portions thereof, may be used as therapeutic agents.Photosensitizers for photodynamic therapy or radiotherapy, including various porphyrin compounds such as porfimers, are also useful as drugs in aspects of the present disclosure.

[0095] In some embodiments of the present disclosure, drug combinations may also be used. Some combinations have different mechanisms and therefore have additive and / or superadditive effects. In some embodiments, the additive effect may be advantageous for use in the drug coatings described herein. For example, in some embodiments, the additive effect may allow for a reduction in the drug dose. In some embodiments, the combination of therapeutic agents may reduce complications associated with the use of high doses of therapeutic agents.

[0096] In some embodiments of the present disclosure, the therapeutic agent is rapidly released from the drug coating and readily absorbed after the medical device contacts tissue. For example, certain embodiments of the devices of the present disclosure include drug-coated expandable medical devices that deliver high drug concentrations of proliferative pharmaceutical agents to vascular tissue through brief, direct pressure contact during balloon angioplasty. The therapeutic agent is preferentially retained in the target tissue at the delivery site, where it inhibits hyperplasia and restenosis while allowing endothelialization. In these embodiments, the coating formulations of the present disclosure not only promote rapid drug release from the balloon surface and drug migration to the target tissue during deployment, but also prevent the drug from diffusing from the device before reaching the target site while passing through tortuous arterial anatomical structures and from explosively peeling off from the device during the initial phase of balloon inflation before the drug coating is pressed against and directly contacts the surface of the vessel wall.

[0097] excipients In some embodiments, the drug coating may be of a therapeutic agent and one or more additives. In some embodiments, the additives may be excipients. In addition to a therapeutic agent or combination of therapeutic agents, the drug coating according to some embodiments may include at least one excipient. In one embodiment, the drug coating may include multiple excipients, for example, two, three, four, or more excipients. Such combinations of excipients may be useful for purposes of the present disclosure.

[0098] The selection of an excipient or excipient combination may be based on the therapeutic agent, coating solvent, and / or coating solvent used. As described in more detail below, in some embodiments, an excipient or excipient combination may be mixed with a therapeutic agent or a therapeutic agent and a coating solvent (or a mixture of coating solvents) to form a coating mixture, which is coated onto the exterior surface of a medical device. Alternatively, or additionally, some embodiments of the present disclosure may include applying the excipient to the exterior surface of a medical device separately from the therapeutic agent dissolved in the coating solvent. In some embodiments, the excipient or excipient combination may be applied to the medical device before the therapeutic agent and / or before the therapeutic agent dissolved in the coating solvent. In some embodiments, the excipient or excipient combination may be applied to the medical device after the therapeutic agent and / or the therapeutic agent dissolved in the coating solvent. Without being bound by theory, the selected excipient or excipient combination, when mixed with the therapeutic agent, coating solvent, and / or multiple coating solvents, may form a coating mixture that adheres to the medical device such that coating particles do not shed during handling and interventional procedures. Alternatively or additionally, the selected excipient or combination of excipients, when applied before or after the therapeutic agent, coating solvent, and / or coating solvents, should adhere to the medical device such that the coating particles do not shed during handling and interventional procedures.

[0099] The relative amounts of therapeutic agent and one or more excipients in a drug coating can vary depending on the application. The optimal amount of one or more excipients can depend, for example, on the particular therapeutic agent and other excipients selected, the critical micelle concentration of the surface modifier if it forms micelles, the hydrophilic-lipophilic balance (HLB) of the excipient, the octanol-water partition coefficient (P) of the one or more excipients, the melting point of the excipient, the water solubility of the excipient and / or therapeutic agent, the surface tension of aqueous solutions of the surface modifier, etc. Other considerations also influence the selection of specific ratios of excipients. These considerations include the degree of biocompatibility of the excipients and the desired dose of therapeutic agent to be provided.

[0100] In some embodiments, the excipient may comprise a polymer. In some embodiments, the polymer may be an anionic polymer. Examples of anionic polymers include polyglutamic acid or any block polymer containing this segment, polyacrylic acid or any block polymer containing this segment, polymethylacrylic acid or any block polymer containing this segment, polystyrene sulfonic acid or any block polymer containing this segment, heparin, hyaluronic acid, and alginic acid. Without being bound by theory, due to the cationic nature of therapeutic agents such as sunitinib malate, drug coatings containing anionic polymers may be able to retain the therapeutic agent for sustained drug release.

[0101] In further embodiments, the excipient can be a biodurable polymer. A biodurable polymer can refer to a polymer that exhibits good resistance and / or is resistant to erosion or enzymes when placed within the human body, including within the lumen of a blood vessel. Biodurable polymers include polyethylene terephthalate (PET), nylon 6,6, polyurethane (PU), polytetrafluoroethylene (PTFE), polyethylene (PE, low density, high density, and ultra-high molecular weight (UHMW)), polysiloxane (silicone), and poly(methyl methacrylate) (PMMA), N-isopropylacrylamide (P-NIPAAm), and poly(vinylidene fluoride-co-hexafluoropropylene) (PVDF-HFP). In some embodiments, the excipient can be PVDF-HFP. Without being bound by theory, the use of a biodurable polymer can reduce or eliminate incomplete drug release. In further embodiments, the excipient can be a biodegradable polymer. Biodegradable polymers can include polymers that are well tolerated and decompose over a period of time when introduced into the human body, including into the lumen of a blood vessel. 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-poly(lactide-co-glycolide) (PLGA-b-mPEG).

[0102] In some embodiments, 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 embodiments, the ratio is 1:1. In other embodiments, the ratio is 2:1. In some embodiments, 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 embodiments, the ratio is from about 2:1 to about 8:1. In some embodiments, the ratio is about 3:1. In other embodiments, the ratio is about 3:1 to about 5:1 or about 8:1, including about 3:1 to about 4:1, about 3:1 to about 5:1, about 3:1 to about 6:1, and about 3:1 to about 7:1. In some embodiments, the ratio is about 4:1 to about 8:1. In some embodiments, the ratio is 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 8:1, about 6:1 to about 7:1, or about 7:1 to about 8:1.

[0103] Suitable excipients that may be used in some embodiments of the present disclosure include, but are not limited to, excipients already described or listed herein, organic and inorganic pharmaceutical excipients, natural products and their derivatives (such as sugars, vitamins, amino acids, peptides, proteins, fatty acid esters, and fatty acids), surfactants (anionic, cationic, nonionic, and ionic), and mixtures thereof. The following list of excipients useful in the present disclosure is provided for illustrative purposes only and is not intended to be comprehensive. Many other excipients may be useful for the purposes of the present disclosure, such as polyglutamic acid, polyacrylic acid, hyaluronic acid, alginic acid, 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, polysorbates, polyethylene glycol, polyvinylpyrrolidone (PVP), and aliphatic polyesters.

[0104] In some embodiments, the excipient may have a drug affinity moiety. The drug affinity moiety includes affinity for a therapeutic agent through hydrogen bonding and / or van der Waals interactions. For example, the drug affinity moiety of the excipient may bind the excipient to an antifibrotic agent, a kinase inhibitor, a tyrosine kinase inhibitor, a PDE inhibitor, or a combination thereof. The excipient of embodiments of the present disclosure may include a hydrophilic moiety. As is well known in the art, the terms "hydrophilic" and "hydrophobic" are relative terms. To function as an excipient in exemplary embodiments of the present disclosure, the excipient may be a compound containing a polar or charged hydrophilic portion and a non-polar hydrophobic (lipophilic) portion. The hydrophilic portion or portions can facilitate the diffusion of the therapeutic agent and increase its penetration into tissues. The hydrophilic portion of the excipient may facilitate the rapid migration or transfer of the therapeutic agent from the surface of the expandable medical device during deployment at the target site by preventing hydrophobic drug molecules from accumulating with each other and on the device, thereby increasing drug solubility in the interstitial space and / or facilitating the passage of the drug through the polar headgroup into the lipid bilayer of the cell membrane of the target tissue.

[0105] A commonly used empirical parameter 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 oil, 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 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 embodiments, the HLB value of an excipient is in the range of 0.0 to 40. In certain embodiments of the present disclosure, higher HLB values ​​may be preferred, as increased hydrophilicity may facilitate release of a therapeutic agent from the surface of a device. In one embodiment, the HLB of the excipient is greater than 10. In another embodiment, the HLB of the excipient may be greater than 14. Alternatively, excipients with lower HLB values ​​may be preferred, for example, when used in a separate topcoat on a drug layer with a very hydrophilic additive to prevent drug loss prior to placement of the device at the target site. It should be understood that the HLB values ​​of excipients are merely rough guides commonly used to enable the preparation of, for example, industrial, pharmaceutical, and cosmetic emulsions. With these inherent difficulties in mind and using the HLB value as a guide, excipients with hydrophilic or hydrophobic properties suitable for use in some embodiments of the present disclosure can be identified, as described herein.

[0106] In medicinal chemistry, a commonly used empirical parameter to characterize the relative hydrophilicity and hydrophobicity of a pharmaceutical compound is the partition coefficient P, which is the ratio of the concentrations of the non-ionized compound in the two phases of a mixture of two immiscible solvents, usually octanol and water, where P = ([solute] octanol / [solute] water). Compounds with higher log P are more hydrophobic, and compounds with lower log P are more hydrophilic. Lipinski's law suggests that pharmaceutical compounds with log P < 5 are typically more membrane permeable. For purposes of certain embodiments of the present disclosure, it is preferred that the excipient have a log P lower than that of the formulated drug (e.g., paclitaxel has a log P of 7.4). A larger difference in log P between the therapeutic agent and the excipient can facilitate phase separation of the therapeutic agent. For example, if the log P of an excipient is much lower than the log P of the drug, the excipient may accelerate the release of the therapeutic agent in an aqueous environment from the surface of the device to which the therapeutic agent may have been firmly attached, thereby accelerating drug delivery to tissue during brief placement at the intervention site. In certain embodiments of the present disclosure, the log P of the excipient is negative. In other embodiments, the log P of the excipient is less than the log P of the therapeutic agent. While the octanol / water partition coefficient, P, or log P of a compound is useful as a measure of relative hydrophilicity and hydrophobicity, it is merely a rough guide that may be useful in defining suitable excipients for use in some embodiments of the present disclosure.

[0107] Exemplary excipients for use in some embodiments of the present disclosure may include compounds having one or more hydroxyl, amino, carbonyl, carboxyl, acid, amide, or ester moieties. In certain embodiments, hydrophilic compounds having one or more hydroxyl, amino, carbonyl, carboxyl, acid, amide, or ester moieties with a molecular weight of less than 5,000-10,000 are preferred. In other embodiments, the molecular weight of excipients having one or more hydroxyl, amino, carbonyl, carboxyl, acid, amide, or ester moieties is preferably less than 1,000-5,000, or more preferably less than 750-1,000, or most preferably less than 750. In these embodiments, it may be preferred that the molecular weight of the excipient is less than the molecular weight of the therapeutic agent to be delivered.

[0108] Excipients according to some embodiments may include amino alcohols, alcohols, amines, acids, amides, and hydroxy acids in both cyclic and linear aliphatic and aromatic groups. Examples include L-ascorbic acid and its salts, D-glucoscorbic acid and its salts, tromethamine, triethanolamine, diethanolamine, meglumine, glucamine, amine alcohols, glucoheptonic acid, gluconic acid, hydroxyketones, hydroxylactones, gluconolactone, glucoheptonolactone, glucoctanoic acid lactone, gulonic acid lactone, mannonic acid lactone, ribonic acid lactone, lactobionic acid, glucosamine, glutamic acid, benzyl alcohol, benzoic acid, hydroxybenzoic acid, propyl 4-hydroxybenzoate, lysine acetate, gentisic acid, lactobionic acid, lactitol, sorbitol, glucitol, sugar phosphates, glucopyranose phosphates, sugar sulfates, sugar alcohols, sinapic acid, vanillic acid, vanillin, methylparaben, propylparaben, xylitol, 2-ethoxyethanol ol, sugars, 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, multiglycerol, 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 compounds described herein having one or more hydroxyl, amine, carbonyl, carboxyl, amide, or ester moieties are highly stable under heat, survive ethylene oxide sterilization processes, and / or do not react with therapeutic agents during sterilization.

[0109] In some embodiments, the excipient may comprise an amino acid and its salt. 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. Certain amino acids, in their zwitterionic and / or salt forms with monovalent or polyvalent ions, have polar groups and relatively high octanol / water partition coefficients and are useful in some embodiments of the present disclosure. In the context of the present disclosure, a "low-solubility amino acid" refers to an amino acid with a solubility of less than about 4% (40 mg / ml) in unbuffered water. These include cystine, tyrosine, tryptophan, leucine, isoleucine, phenylalanine, asparagine, aspartic acid, glutamic acid, and methionine.

[0110] Amino acid dimers, glycoconjugates, and other derivatives may also be useful. Hydrophilic molecules may be attached to hydrophobic amino acids, or hydrophobic molecules may be attached to hydrophilic amino acids, via simple reactions well known to those skilled in the art, to create additional excipients useful in some embodiments of the present disclosure. Catecholamines such as dopamine, levodopa, carbidopa, and DOPA may also be useful as excipients.

[0111] In some embodiments, the excipient may be a liquid additive. One or more liquid excipients may be used in medical device coatings to improve coating integrity. Without being bound by theory, the liquid excipient may improve compatibility of the therapeutic agent in the coating mixture. The liquid excipient used in some embodiments of the present disclosure is not a solvent. Solvents such as ethanol, methanol, dimethyl sulfoxide, and acetone evaporate after the coating dries. In other words, the solvent does not remain in the coating after it dries. In contrast, the liquid excipient in some embodiments of the present disclosure may remain in the coating after it dries. The liquid excipient is a liquid or semi-liquid at room temperature and 1 atmosphere. The liquid excipient may form a gel at room temperature. The liquid excipient may include a hydrophilic portion and a drug-affinity portion, where the drug-affinity portion is at least one of a hydrophobic portion, a portion having affinity for the therapeutic agent through hydrogen bonding, and a portion having affinity for the therapeutic agent through van der Waals interactions. In some embodiments, the liquid excipient may be a nonionic surfactant. Examples of liquid excipients include the above-mentioned PEG-fatty acids and esters, PEG-oil transesterification products, polyglyceryl fatty acids and esters, propylene glycol fatty acid esters, PEG sorbitan fatty acid esters, and PEG alkyl ethers. Some examples of liquid excipients are Tween 80, Tween 81, Tween 20, Tween 40, Tween 60, Solutol HS 15, Cremophor RH40, PEG, N-PIAAm, and Cremophor EL&ELP.

[0112] In some embodiments, the excipient may be a surfactant, a compound having one or more hydroxyl, amine, carbonyl, carboxyl, amide, or ester moieties, or both.Exemplary surfactants include PEG fatty acid esters, PEG omega-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, 60), p-isononylphenoxypolyglycidol, 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, PEG sorbitan monooleate, PEG sorbitan stearate, PEG oleyl ether, PEG lauryl ether, Tween 20, Tween 40, Tween 60 60), Tween 80, docusate sodium, octoxynol, monoxynol, tyloxapol, sucrose monopalmitate, sucrose monolaurate, decanoyl-N-methylglucamide, n-decyl-β-D-glucopyranoside, n-decyl-β-D-maltopyranoside, n-dodecyl-β-D-glucopyranoside, n-dodecyl-β-D-maltoside, heptanoyl-N-methylglucamide The alkyl esters may be selected from n-heptyl-β-D-glucopyranoside, n-heptyl-β-D-thioglucoside, n-hexyl-β-D-glucopyranoside, nonanoyl-N-methylglucamide, n-nonyl-β-D-glucopyranoside, octanoyl-N-methylglucamide, n-octyl-β-D-glucopyranoside, octyl-β-D-thioglucopyranoside, and derivatives thereof.

[0113] In some embodiments, using a therapeutic agent with one or more surfactants or water-soluble small molecules (compounds having one or more hydroxyl, amine, carbonyl, carboxyl, amide, or ester moieties) can, in some cases, be superior to using only a therapeutic agent and a single excipient. By incorporating one or more additional excipients, embodiments of the drug coating can exhibit improved stability during transit and rapid drug release when pressed against the tissue of the lumen wall at the target site of therapeutic intervention, when compared to some formulations containing only a therapeutic agent and one excipient. Furthermore, the miscibility and compatibility of the therapeutic agent with the excipient, or the drug coating with the medical device, is generally improved by the presence of one or more additional excipients. For example, a surfactant may be able to improve the uniformity and integrity of the coating.

[0114] In one embodiment, the drug coating may include multiple excipients, where one excipient may be more hydrophilic than one or more of the other excipients. In another embodiment, the drug coating may include multiple excipients, where one excipient may have a different structure than one or more of the other excipients. In another embodiment, the drug coating may include multiple excipients, where one excipient may have a different HLB value than one or more of the other excipients. In yet another embodiment, the drug coating may include multiple excipients, where one excipient may have a different LogP value than one or more of the other excipients.

[0115] Some embodiments of the present disclosure may include a combination of at least two additional excipients, for example, one or more surfactants and one or more compounds having one or more hydroxyl, amine, carbonyl, carboxyl, amide, or ester moieties. For example, a therapeutic agent may bind more weakly to a highly water-soluble small molecule than to a surfactant, which may lead to suboptimal coating uniformity and integrity. When used in some embodiments of the present disclosure, some surfactants adhere too strongly to the therapeutic agent and the surface of the medical device, preventing the therapeutic agent from being rapidly 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 too weakly to the medical device, releasing the therapeutic agent into the serum before reaching the target site, for example, during passage of a coated balloon catheter to the targeted site for intervention. By incorporating a mixture of multiple excipients, some embodiments of the drug coating may have improved properties over formulations containing only one excipient.

[0116] In some embodiments, one or more additional excipients may include an antioxidant. Antioxidants are molecules capable of slowing or preventing the oxidation of other molecules. Oxidative reactions can generate free radicals and / or peroxides, which can initiate chain reactions and lead to the degradation of sensitive therapeutic agents, such as sunitinib and its derivatives. Antioxidants terminate these chain reactions by scavenging free radicals and / or peroxides, and further inhibit the oxidation of active agents by being oxidized themselves. In some embodiments, antioxidants are used as one or more additional excipients to prevent or slow the oxidation of therapeutic agents in coatings for medical devices. Antioxidants are a type of free radical scavenger. In some embodiments, antioxidants may be used alone or in combination with other additional excipients and may prevent the degradation of active therapeutic agents during sterilization or storage prior to use. Some representative examples of antioxidants that may be used in the drug coatings of the present disclosure include, but are not limited to, oligomeric or polymeric proanthocyanidins, polyphenols, polyphosphates, polyazomethines, high sulfate agar oligomers, chitooligosaccharides obtained by partial hydrolysis of chitosan, polyfunctional oligomeric thioethers having sterically bulky phenols, sterically hindered amines such as p-phenylenediamine, trimethyldihydroquinolone, and alkylated diphenylamines, substituted phenolic compounds having one or more bulky functional groups such as tertiary butyl (sterically hindered phenols), arylamines, phosphites, hydroxylamines, and benzofuranones. Aromatic amines such as p-phenylenediamine, diphenylamine, and N,N'-disubstituted p-phenylenediamines may also 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, rosmanol, isorosmanol, rosmaridiphenol, propyl gallate, gallic acid, tannic acid, caffeic acid, p-coumaric acid, p-hydroxybenzoic acid, astaxanthin, ferulic acid, dehydrozingerone, chlorogenic acid, ellagic acid, propylparaben, sinapic acid, daidzin, glycitin, genistin, daidzein, glycitein, genistein, isoflavones, and tertiary butylhydroquinone. Some examples of phosphites include di(stearyl)pentaerythritol diphosphite, tris(2,4-di-tert-butylphenyl)phosphite, dilaurylthiodipropionate, and bis(2,4-di-tert-butylphenyl)pentaerythritol diphosphite. Some examples of sterically hindered phenols include, but are not limited to, octadecyl-3,5,di-tert-butyl-4-hydroxycinnamate, tetrakis-methylene-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-tertiary butylphenol, propyl gallate, catechin, catechin gallate, and quercetin. Preferred antioxidants are butylated hydroxytoluene (BHT) and butylated hydroxyanisole (BHA).

[0117] In some embodiments, the excipient may be present in an amount relative to the amount of one or more therapeutic agents, hi some embodiments, the ratio of excipient to therapeutic agent may 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.

[0118] Coating Solvent The solvent for preparing the drug coating, referred to herein as the "coating solvent," is used to dissolve the therapeutic agent and additives. Together, the therapeutic agent and additives dissolved in the coating solvent constitute the "coating mixture" that is coated onto the medical device.

[0119] The coating solvent can be any solvent or combination of solvents suitable for dissolving the selected therapeutic agent, including, by way of example, 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, iso-butanol, n-butanol, tertiary butanol, diethylamide, ethylene glycol monoethyl ether, Trascultol, and benzyl alcohol; ethers such as dioxane, dimethyl ether, ethyl ether, diethyl ether, di-n-propyl ether, diisopropyl ether, t-butyl methyl ether, petroleum ether, and tetrahydrofuran; methyl acetate, ethyl acetate, and the like. ketones such as acetone, acetonitrile, diethyl ketone, cyclohexanone, and methyl ethyl ketone, methyl isobutyl ketone; chlorinated hydrocarbons such as chloroform, dichloromethane, ethylene dichloride, carbon tetrachloride, and chlorobenzene; dioxane; tetrahydrofuran; dimethylformamide; acetonitrile; dimethyl sulfoxide; 1,6-dioxane; N,N-dimethylacetamide (DMA); diethylene glycol; diglyme; 1,2-dimethoxyethane; hexamethylphosphoramide; and any combination of one or more of the following mixtures: water / ethanol, water / acetone, water / methanol, water / tetrahydrofuran, and the like.

[0120] The therapeutic agent and / or additive or additives may be dispersed, solubilized, or otherwise mixed in the coating solvent. The weight percentage of the therapeutic agent, additive, and optionally one or more additional additives in the coating solvent may be in the range of about 0.1% to about 80% by weight, or about 0.1% to about 60% by weight, about 0.1% to about 40% by weight, about 0.1% to about 20% by weight, about 0.1% to about 1% by weight, about 1% to about 80% by weight, about 1% to about 60% by weight, about 1% to about 40% by weight, about 1% to about 20% by weight, about 20% to about 80% by weight, about 20% to about 60% by weight, about 20% to about 40% by weight, about 40% to about 80% by weight, about 40% to about 60% by weight, or about 60% to about 80% by weight.

[0121] In methods of preparing drug-coated medical devices, particularly balloon catheters or stents, for example, a coating solution or suspension is prepared that includes at least one coating solvent, a therapeutic agent, and optionally one or more additional additives. In some embodiments, the therapeutic agent, coating solvent, additive, and optionally one or more additional additives can be combined to produce a coating mixture.

[0122] In embodiments where the coating solution comprises at least one coating solvent, a therapeutic agent, and optionally one or more additional additives, the content of the therapeutic agent in the coating solution may range from about 0.05% to about 50% by weight, about 0.05% to about 40% by weight, about 0.05% to about 30% by weight, about 0.05% to about 20% by weight, about 0.05% to about 10% by weight, about 0.05% to about 1% by weight, about 1% to about 50% by weight, about The coating solvent may be 1% to about 40% by weight, about 1% to about 30% by weight, about 1% to about 20% by weight, about 1% to about 10% by weight, about 10% to about 50% by weight, about 10% to about 40% by weight, about 10% to about 30% by weight, about 10% to about 20% by weight, about 20% to about 50% by weight, about 20% to about 40% by weight, about 20% to about 30% by weight, about 30% to about 50% by weight, about 30% to about 40% by weight, or about 40% to about 50% by weight. The amount of coating solvent used depends on the coating process and viscosity, as even though the coating solvent evaporates, the amount of solvent may affect the uniformity of the drug coating.

[0123] In embodiments where the coating solution comprises at least one coating solvent, a therapeutic agent, an additive, and optionally one or more additional additives, the content of the therapeutic agent in the coating solution may range from about 0.1% to about 50% by weight, about 0.1% to about 40% by weight, about 0.1% to about 30% by weight, about 0.1% to about 20% by weight, about 0.1% to about 10% by weight, about 0.1% to about 1% by weight, about 1% to about 50% by weight, about The coating solvent may be 1% to about 40% by weight, about 1% to about 30% by weight, about 1% to about 20% by weight, about 1% to about 10% by weight, about 10% to about 50% by weight, about 10% to about 40% by weight, about 10% to about 30% by weight, about 10% to about 20% by weight, about 20% to about 50% by weight, about 20% to about 40% by weight, about 20% to about 30% by weight, about 30% to about 50% by weight, about 30% to about 40% by weight, or about 40% to about 50% by weight. The amount of coating solvent used depends on the coating process and viscosity, as even though the coating solvent evaporates, the amount of solvent may affect the uniformity of the drug coating. The content of the additive in the coating solution is, based on the total weight of the solution, about 0.5% by weight to about 50% by weight, about 0.5% by weight to about 40% by weight, about 0.5% by weight to about 30% by weight, about 0.5% by weight to about 20% by weight, about 0.5% by weight to about 10% by weight, about 0.5% by weight to about 1% by weight, about 1% by weight to about 50% by weight, about 1% by weight to about 40% by weight, about 1% by weight to about 30% by weight, about 1 ... The coating solvent may be about 20% by weight, about 1% to about 10% by weight, about 10% to about 50% by weight, about 10% to about 40% by weight, about 10% to about 30% by weight, about 10% to about 20% by weight, about 20% to about 50% by weight, about 20% to about 40% by weight, about 20% to about 30% by weight, about 30% to about 50% by weight, about 30% to about 40% by weight, or about 40% to about 50% by weight. The amount of coating solvent used depends on the coating process and viscosity, as even though the coating solvent evaporates, the amount of solvent may affect the uniformity of the drug coating.

[0124] In other embodiments, more than one solvent, more than one therapeutic agent, more than one additive, or optionally, more than one additional additive may be used in the coating solution or coating mixture. In certain embodiments, polymeric materials may be used as additives in the coating mixture.

[0125] Kinase inhibitors and PDE inhibitors may, in some cases, be lipid-soluble weak bases that are insoluble in commonly used organic solvents. Furthermore, the presence of kinase inhibitors in the formulation may alter the surface energy of the drug / excipient droplets formed by spraying, causing the droplets to bead up and not spread immediately upon reaching the device surface. This can lead to uneven coating or an uncoated surface. In some embodiments, using a combination of solvents can alleviate this problem. In some embodiments, the solvent mixture used may contain two, three, or more solvents. In some embodiments, the solvent mixture used may contain ethyl acetate, acetone, and DMF.

[0126] Various techniques may be used to apply the coating solution or mixture to the medical device, including metering, casting, spinning, spraying, dipping, rolling, inkjet printing, 3D printing, electrostatic techniques, plasma etching, vapor deposition, and combinations of these processes. The choice of application technique depends primarily on the viscosity and surface tension of the coating solution or mixture. In some embodiments of the present disclosure, metering, dipping, and spraying may be preferred because they provide easier control over the uniformity of the thickness and concentration of the therapeutic agent in the drug coating applied to the medical device. Whether the coating solution or mixture is applied by spraying, dipping, or other methods or combinations of methods, additional coating layers may be applied to the medical device in multiple application steps to control the uniformity and amount of therapeutic substance and additive applied to the medical device.

[0127] Each applied coating layer may have a thickness of 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 embodiments, only one layer is applied to the medical device. In some embodiments, 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 It may be 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.

[0128] In addition to the coating layer containing the drug coating, the medical device may include one or more intermediate or top layers. In some embodiments, the intermediate or top layer may be advantageous to promote adhesion of the drug coating to the medical device, to be an additional layer containing additives, or to prevent premature loss during the device delivery process prior to placement at the target site.

[0129] As mentioned above, in some embodiments, the additive may be mixed with the therapeutic agent and / or coating solvent (or mixture of coating solvents) to form a coating mixture that is coated on the exterior surface of the medical device. Alternatively or additionally, some embodiments may include applying the additive to the exterior surface of the medical device separately from the therapeutic agent or therapeutic agent dissolved in the coating solvent. In some embodiments, the additive may be applied to the medical device before the therapeutic agent or therapeutic agent dissolved in the coating solvent. In some embodiments, the additive may be applied to the medical device after the therapeutic agent or therapeutic agent dissolved in the coating solvent.

[0130] In one exemplary embodiment, an application device that can be used is a paint jar attached to an airbrush, such as a Badger Model 150, supplied with a pressurized air source via a regulator (Norgren, 0-160 psi). When using such an application device, air can be applied when the brush hose is attached to the compressed air source downstream of the regulator. The pressure can be adjusted to approximately 15 psi to 25 psi, and the nozzle status can be confirmed by depressing the trigger. Prior to spraying, both ends of a relaxed expandable medical device can be fastened to a fixture with two elastic retainers, i.e., alligator clips, and the distance between the clips can be adjusted so that the expandable medical device remains in a relaxed state, e.g., contracted, folded, or in an expanded or partially expanded, unfolded state. The rotor can then be energized, and the rotational speed can be adjusted to the desired coating speed, approximately 40 rpm. With the expandable medical device rotating in a substantially horizontal plane, the nozzle may be adjusted so that the distance from the nozzle to the expandable medical device is approximately 0.51 centimeters to 10.16 centimeters (0.2 inches to 4 inches). First, the coating solution or mixture may be sprayed substantially horizontally in a sweeping motion by guiding the brush along the expandable medical device from the distal end to the proximal end, and then from the proximal end to the distal end, at a rate such that one spray cycle occurs over approximately three revolutions of the expandable medical device. The expandable medical device may be repeatedly sprayed with the coating solution, with subsequent drying, until an effective amount of drug is deposited on the expandable medical device. It should be understood that this description of application devices, fixtures, and spraying techniques is merely exemplary. Any other suitable spraying or other techniques may be used for coating expandable medical devices, particularly coating balloons of balloon catheters or stent delivery systems or stents.

[0131] In one aspect of the present disclosure, the expandable medical device may be expanded, e.g., inflated or partially expanded, and a coating solution or mixture may be applied to the expanded expandable medical device, e.g., by spraying, after which the expandable medical device may be allowed to dry and then relaxed or collapsed to an unexpanded configuration or shape. For example, if the expandable medical device is a balloon, the balloon is dried, deflated, and folded. Drying may be performed under vacuum.

[0132] After spraying the coating solution or mixture onto the medical device, the coated medical device may be subjected to drying to evaporate the coating solvent. 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 above for about 24 hours or more, e.g., up to 48 or 72 hours. Another example may include air drying. Any other suitable method of drying the coating solution may also be used. The time and temperature may vary depending on the particular additive and therapeutic agent.

[0133] medical devices We now describe embodiments of medical devices, including, by way of non-limiting example, balloon catheters and stents, in which a drug coating is applied to the exterior surface of the medical device. This is followed by a description of several embodiments of methods for preparing the exemplary medical devices.

[0134] Balloon catheter In some embodiments, the medical device is a balloon catheter. Referring to the exemplary drawing of FIG. 1 , balloon catheter 10 has a proximal end 18 and a distal end 20. Balloon catheter 10 can be any suitable catheter for the desired application, including conventional balloon catheters known to those of skill in the art. For example, balloon catheter 10 can be a rapid-exchange catheter or an over-the-wire catheter. In some particular examples, the balloon catheter can be a ClearStream™ peripheral catheter available from BD Peripheral Intervention. Balloon catheter 10 can be made of any suitable biocompatible material. The balloon 12 of the balloon catheter can comprise a polymeric 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 a variety of other suitable materials that will be apparent to those of skill in the art.

[0135] 2A and 2B show various embodiments of the balloon catheter 10 of FIG. 1, shown in cross-sectional views along line AA in FIG. 1. Referring to FIGS. 1, 2A, and 2B together, the balloon catheter 10 includes an expandable balloon 12 and an elongate member 14. The elongate member 14 extends between a proximal end 18 and a distal end 20 of the balloon catheter 10. The elongate member 14 has at least one lumen 26a, 26b and a distal end 20. The elongate member 14 may be a flexible member that is a tube made of a suitable biocompatible material. The elongate member 14 may have one lumen or, as shown in FIGS. 1, 2A, and 2B, more than one lumen 26a, 26b. For example, the elongate member 14 may include a guidewire lumen 26b extending from a guidewire port 15 at the proximal end 18 of the balloon catheter 10 to the distal end 20 of the balloon catheter 10. The elongate 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 expandable balloon 12 to allow for inflation of the expandable balloon 12. Although the elements of Figures 1, 2A, and 2B show the inflation lumen 26a and the guidewire lumen 26b as side-by-side lumens, it should be understood that one or more lumens present within the elongate member 14 may be configured in any manner suitable for the lumen's intended purpose, including, for example, introduction of an inflation medium and / or introduction of a guidewire. Many such configurations are known in the art.

[0136] The expandable balloon 12 is attached to a distal mounting end 22 of the elongate member 14. The expandable balloon 12 has an outer surface 25 and is inflatable. The expandable balloon 12 is in fluid communication with an inner lumen (e.g., inflation lumen 26a) of the elongate member 14. At least one lumen of the elongate member 14 is configured to receive an inflation medium and deliver such medium to the expandable balloon 12 for inflation of the expandable balloon 12. Examples of inflation medium include air, saline, and contrast medium.

[0137] 1 , in one aspect, the balloon catheter 10 includes a handle assembly, such as a hub 16. The hub 16 may be attached to the balloon catheter 10 at a proximal end 18 thereof. The hub 16 may be connected to and / or receive one or more suitable medical devices, such as a source of inflation media (e.g., air, saline, or contrast media) or a guidewire. For example, a source of inflation media (not shown) may be connected to an inflation port 17 of the hub 16 (e.g., through inflation lumen 26 a), and a guidewire (not shown) may be introduced into the guidewire port 15 of the hub 16 (e.g., through guidewire lumen 26 b).

[0138] In some examples, cross section AA in FIG. 1 may be as illustrated in FIG. 2A , in which drug coating layer 30 is applied directly onto outer surface 25 of balloon 12. The specific compositions of drug coating layer 30 itself, according to various embodiments, are also described in more detail below. In other examples, cross section AA in FIG. 1 may be as illustrated in FIG. 2B , in which drug coating layer 30 is applied onto intermediate layer 40 on outer surface 25 of balloon 12. In some embodiments, outer surface 25 may undergo a surface modification. In some embodiments in which outer surface 25 is a modified outer surface, outer surface 25 is subjected to a surface modification, such as a fluorine plasma treatment, to reduce the surface free energy of outer surface 25 prior to application of drug coating layer 30. Applying a surface modification to the outer surface reduces the surface free energy of the outer surface prior to application of the coating layer, which may 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 in the therapeutic layer within the coating layer, and the drug distribution on the surface.

[0139] In embodiments where cross section AA of Figure 1 is as illustrated in accordance with Figure 2A, balloon catheter 10 includes a drug coating layer 30 applied onto outer surface 25 of balloon 12. Drug coating layer 30 itself includes a therapeutic agent and an additive. In one particular embodiment, drug coating layer 30 includes a kinase inhibitor, a tyrosine kinase inhibitor, a PDE inhibitor, or an antifibrotic therapeutic agent, a polymer, and one or more additional additives. In further embodiments, drug coating layer 30 does not include a polymer.

[0140] In other embodiments, two or more therapeutic agents are used in combination with the drug coating layer. In other embodiments, the device may include a top layer (not shown) overlying drug coating layer 30. In some embodiments, the top coat layer may be advantageous to prevent premature loss during the device delivery process prior to placement at the target site.

[0141] Drug-eluting stents In some embodiments, the medical device is a drug-eluting stent 100. Referring to the example depicted in FIG. 3 , 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 application, including conventional stents known to those skilled 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 embodiments, the shape-memory properties of Nitinol may allow the base stent 102 to self-expand when placed in a tubular vessel at normal body temperature.

[0142] Various embodiments of the drug-eluting stent 100 of FIG. 3 are shown in FIG. 4 through a cross section taken along line BB in FIG. 3 . In some examples, cross section BB in FIG. 3 may be as illustrated in accordance with FIG. 4 , in which a drug coating layer 110 is applied directly onto the outer surface 107 of the base stent 102. In some embodiments described below, the outer surface 107 may undergo a surface modification. In embodiments in which the outer surface 107 is a modified outer surface, the outer surface 107 is subjected to a surface modification, such as a fluorine plasma treatment, to reduce the surface free energy of the outer surface 107 prior to application of the drug coating layer 110. The surface modification of the outer surface reduces the surface free energy of the outer surface prior to application of the coating layer, and may 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 in the therapeutic layer within the coating layer, and the drug distribution on the surface.

[0143] In embodiments where cross section BB of FIG. 3 is as illustrated in accordance with FIG. 4, drug-eluting stent 100 includes drug coating layer 110 applied onto outer surface 107 of base stent 102. Drug coating layer 110 itself includes a therapeutic agent and an additive. In one particular embodiment, drug coating layer 110 includes a kinase inhibitor or tyrosine kinase inhibitor, a PDE inhibitor, an antifibrotic therapeutic agent, a polymer, and one or more additional additives. In further embodiments, drug coating layer 110 does not include a polymer.

[0144] In other embodiments, two or more therapeutic agents are combined in drug coating layer 110. In other embodiments, the device may include a top layer (not shown) overlying drug coating layer 100. In some embodiments, the top coat layer may be advantageous to prevent premature loss during the device delivery process prior to placement at the target site. [Example]

[0145] Example 1 In Example 1, two formulations were prepared as described below and are summarized in Table 1. 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, followed by 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. This mixture was bath sonicated for 15 minutes to completely dissolve the solid PVDF-HFP. Next, 18 mL of the PVDF-HFP / acetone solution was transferred and mixed with the prepared sunitinib / DMF solution, followed by the addition of 36 mL of methyl acetate. This formulation was stored at 4°C before spray coating.

[0146] 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, followed by 5 minutes of bath sonication to form a clear yellow solution. Separately, 300 mg of PVDF-HFP was added to 24 mL of acetone containing 3 mg of BHT, followed by 15 minutes of bath sonication to completely dissolve the solid PVDF-HFP. Next, 16.8 mL of the 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. This formulation was stored at 4°C before spray coating.

[0147] [Table 1]

[0148] Formulations 1 and 2 were then coated onto Life Stents® using a Sono-Tek Extracoat ultrasonic spray coating system using the parameters summarized in Table 2. Formulations 1 and 2 were used to prepare Sample Stents 1 and 2, respectively. The primer was 5 mg / mL PBMA in a mixed solvent (acetone / cyclohexanone = 9:1).

[0149] [Table 2]

[0150] As shown in Figures 5 and 6, Sample Stent 1 and Sample Stent 2 had smooth, uniform coatings formed on the struts without any noticeable coating defects.

[0151] To evaluate the in vitro drug release profiles of Sample Stent 1 and Sample Stent 2, a drug elution test was carried out at 37°C in 1x phosphate buffered saline (pH 7.3-7.4) as the elution medium. The results are shown in Figure 7.

[0152] As shown in Figure 7, both Formulation 1 and Formulation 2 exhibited a burst release followed by sustained release kinetics for over 45 days. Formulation 1 exhibited a slower release rate, with approximately 20% of unreleased sunitinib remaining on the stent after 45 days of elution.

[0153] Example 2 Stents of size 5x40 and size 6x40 were prepared using Formulation 1 or Formulation 2 as described above, inserted into peripheral arteries of healthy Yorkshire pigs, and examined at various time points.

[0154] The effect on vessel cross-sectional area was evaluated 28 days after stenting and compared with several other models: Comparative Example A was a bare metal stent, Comparative Example B was an Orsiro stent (sirolimus-eluting stent) commercially available from Biotronik, and Comparative Example C was an Eluvia stent (paclitaxel-eluting stent) commercially available from Boston Scientific.

[0155] The results of the study are shown below in Tables 3 and 4.

[0156] [Table 3]

[0157] [Table 4]

[0158] As shown in Tables 3 and 4, the overall mean stenosis rates for Samples 1 and 2 were minimal (e.g., Sample 2, stenosis rate = 21.62 ± 6.68%), comparable to the results obtained with the other comparative stents A, B, and C tested in the same animal model. In Sample 2, mild to moderate fibrin was observed in 64.97 ± 20.84% ​​of the struts, with a mean fibrin score of 1.56 ± 0.83, and essentially no intimal / medial inflammation. Granulomas were absent, and giant cells were minimal. Sample 2 also showed no significant peri-strut bleeding, no calcification, and no adventitial inflammation. The percentage of uncovered struts was 10.47 ± 12.13%. There was minimal endothelial loss (mean endothelial loss score = 0.44 ± 0.52%). In contrast, vessels treated with comparative sample C containing paclitaxel had poor endothelial coverage, with a mean endothelial loss score of 1.81±0.24%.

[0159] The study was then extended to 60 and 90 days, after which histological and pharmacokinetic profile analyses were performed. Formulation 1 was prepared with a dose density of 1 μg / mm and a total dose of 425 μg / stent, and Formulation 2 was prepared with a dose density of 2 μg / mm and a total dose of 750 μg / stent. Figure 8 shows both the release and pharmacokinetic (PK) profiles at 7, 28, 60, and 90 days after stent implantation. Additionally, morphometric vessel cross-sectional area was measured at 60 and 90 days, as described above, and compared with Comparative Examples A and C above. Tables 5 and 6 show the results at 60 days, and Tables 7 and 8 show the results at 90 days.

[0160] [Table 5]

[0161] [Table 6]

[0162] [Table 7]

[0163] [Table 8]

[0164] As shown in Tables 5-8, the overall mean restenosis rates for Samples 1 and 2 remained minimal at 60 and 90 days, whereas Comparative Examples A and C experienced a significant increase in stenosis. In Sample 2, fibrin decreased from the early time points, as did the fibrin score, but intimal / medial inflammation only increased slightly. There was no granuloma development and no malapposition. Both the bare stent (Comparative Example A) and the paclitaxel stent (Comparative Example B) exhibited significant malapposition. Similarly, Samples 1 and 2 did not exhibit uncovered struts, while the paclitaxel stent exhibited a 16.22% incidence. Figure 9 shows cross-sectional views of Comparative Examples A and C and Samples 1 and 2, with the paclitaxel stent demonstrating malapposition accompanied by fibrin and delayed healing. In contrast, both Samples 1 and 2 exhibited no malapposition, no fibrin, and normal healing with complete endothelialization.

[0165] Example 3 Drug elution from balloons was also studied to determine the release profile. PLGA was selected as the biopolymer, and sunitinib was selected as the tyrosine kinase inhibitor. The tyrosine kinase inhibitor was studied in both particulate and crystalline forms, in the presence of one or more excipients. The tyrosine kinase inhibitor was also studied as the free base and in ionized forms with maleate and hemipamoate salts. The combination of PLGA with sunitinib malate and sodium doxanate as excipients was studied to determine how different PLGA compositions might affect the elution profile.

[0166] To prepare the drug coating, microparticles containing sunitinib malate and PLGA (PLGA / sunitinib microparticles) were prepared in polyvinyl alcohol by emulsion evaporation / extraction using a homogenizer, followed by centrifugation and vacuum drying.

[0167] Table 9 shows the elution profiles of sunitinib from the identified drug coating compositions.

[0168] [Table 9]

[0169] As shown in Table 9, the presence of greater amounts of sodium doxanate increased the ability to load higher tyrosine kinase inhibitors into PLGA microparticles, suggesting that excipients can assist in increasing the drug loading of the drug coating.

[0170] Drug coatings containing crystalline forms of tyrosine kinase inhibitors were also investigated. Sunitinib was again selected as the candidate drug, and pamoate crystals were prepared by recrystallization in ethanol, or in ethanol and DMF for the hemipamoate salt. Sunitinib as a free base has a solubility of 26.4 μmol / L in PBS, while the malate salt has a solubility of 1231 μmol / L. The pamoate salt further reduces the solubility of the free base, with pamoate crystals having a solubility of 9.6 μmol / L and the hemipamoate salt having a solubility of 6.02 μmol / L.

[0171] Example 4 In Example 4, a formulation for stent drug coating was prepared as described below, and then implanted in the femoral artery of a porcine model, and histological data were obtained at 7, 28, 60, and 90 days of in vivo testing.

[0172] A total of five formulations were used: a PVDF-only control prepared at 5 mg / mL in a solution of 90% acetone and 10% cyclohexane; a colchicine coating prepared at 5 mg / mL in a 5:1 PVDF:colchicine ratio in 90% acetone and 10% DMF; a roflumilast coating prepared at 7.5 mg / mL in a solution of 42.5% ethyl acetate, 50% acetone, and 7.5% DMF; a tadalafil coating prepared at 5 mg / mL in a 3:1 PVDF:tadalafil ratio in a solution of 30% ethyl acetate, 60% acetone, and 10% DMF; and a sunitinib coating prepared at 5 mg / mL in a 3:1 PVDF:sunitinib malate ratio in a solution of 60% methyl acetate, 30% acetone, and 10% DMF. Coatings were applied to 5 x 40 mm and 6 x 40 mm stents. Fill concentrations were evaluated before and after ETO (ethylene oxide) sterilization, and no discernible change was observed due to this process.

[0173] Figure 10 shows some preliminary pharmacokinetic data obtained from the prepared stents at 7 and 28 days after implantation in pigs. Colchicine and roflumilast showed the expected target range, while tadalafil showed values ​​lower than expected based on comparison with oral bioavailability.

[0174] Histological examination was then performed at days 60 and 90. Table 10 provides some observational data for each of the five test groups.

[0175] [Table 10]

[0176] From these data, it appears that the stenosis rates between sunitinib and tadalafil were similar, and colchicine showed an accelerated amount of stenosis. Figure 11 shows a general cross-sectional view and a magnified view of the amount of inflammation observed. Table 11 provides a further summary of the relevant histological data.

[0177] [Table 11]

[0178] These data were repeated at day 90. Table 12 shows the same data collected as Table 10, and Table 13 shows the same data collected as Table 11.

[0179] [Table 12]

[0180] [Table 13]

[0181] These data show that both tadalafil and sunitinib result in an improvement in the amount of restenosis observed. Similar cross-sectional images are shown in FIG. Example 5 In Example 5, a formulation having tadalafil and sildenafil was prepared as a balloon coating as described below.

[0182] To prepare PLGA / tadalafil microparticles, an oil-in-water emulsion and evaporation method was used. PLGA755S was mixed with tadalafil in DMSO at the desired ratio. For example, for a 4:1 ratio, 60 mg of tadalafil and 240 mg of PLGA755S were added to 1 mL of DMSO and 8 mL of dichloromethane (DCM). The organic solution was added to an aqueous solution of 5% polyvinyl alcohol (PVA) in water pre-saturated with DCM. The mixture was then emulsified for 1 minute to form an emulsion (VWR 250 homogenizer with a VWR Saw-Tooth Generator Probe, 20 x 11 mm). The emulsion was added to 250 mL of 2% PVA and continuously stirred (500 rpm) overnight to evaporate the organic solvent. The resulting suspension was centrifuged (at 4000 g) and washed three times with deionized water. The microparticles were dried in a vacuum oven at room temperature.

[0183] For sildenafil microparticles, a similar method was used, with the additional step of encapsulating the more water-soluble sildenafil before adding it to the organic solvent. 120 mg of sildenafil citrate and 120 mg of sodium doxanoate were dissolved in 1.5 mL of water, and 240 mg of PLGA753H was prepared in 6 mL of water and then combined. The resulting solution was vortexed for 1 minute, then poured into 300 mL of 1% PVA in water, and then left overnight to allow the solvent to evaporate. The resulting microparticles were washed with water, centrifuged (4000 g for 8 minutes), and dried in a vacuum oven.

[0184] For comparison, microparticles containing roflumilast, sunitinib, and colchicine were also prepared using the same method. Representative scanning electron microscope images of microparticles prepared with sunitinib and PLGA are shown in Figure 13. These were prepared using the oil-in-water emulsion evaporation method described. As shown, the microparticles exhibit a spherical morphology at low magnification (upper panel of Figure 13) and high magnification (lower panel of Figure 13).

[0185] While particular aspects have been illustrated 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. Moreover, although various aspects of the claimed subject matter have been described herein, such aspects need not be used in combination. It is therefore intended that the appended claims encompass all such changes and modifications that are within the scope of the claimed subject matter.

Claims

1. 1. A medical device for delivering a therapeutic agent to a tissue, comprising: a coating layer on an exterior surface of the medical device; the coating layer comprises a kinase inhibitor in combination with one or more excipients; Medical devices.

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

3. 2. The medical device of claim 1, 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, avapritinib, abemaciclib, erdafitinib, fedratinib, palbociclib, and pemigatinib.

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 free base, free acid, crystalline, or salt form.

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

7. 3. The medical device of claim 2, wherein the biodurable polymer is selected from poly(vinylidene fluoride hexafluoropropylene) (PVDF-HFP), polyethylene terephthalate (PET), nylon 6,6, polyurethane (PU), polytetrafluoroethylene (PTFE), polyethylene, polysiloxane (silicone), and poly(methyl methacrylate) (PMMA), and combinations thereof.

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

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

1.

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

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

12. 10. The medical device of claim 1, selected from a balloon catheter, a 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.

13. The medical device of claim 1 , which is a stent or a stent-graft.

14. The medical device of claim 1 which is a balloon catheter.

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

16. 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, butylhydroxytoluene, vitamin E, vitamin E succinate, tannic acid, polyethylene glycol, N-isopropylacrylamide, and sorbitol esters.

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

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

19. 10. The medical device of claim 1, wherein the tissue comprises tissue of one of the coronary vasculature, peripheral vasculature, cerebrovasculature, esophagus, airway, paranasal sinuses, trachea, colon, bile duct, urinary tract, prostate, and brain passageways.

20. 1. A balloon catheter for delivering a therapeutic agent to a blood vessel, comprising: an elongated member having a lumen and a distal end; an expandable balloon attached to the distal end of the elongate member and in fluid communication with the lumen; a coating layer on an exterior surface of the balloon, the coating layer comprising a therapeutic agent and at least one of a biodegradable polymer and an excipient; Including, the therapeutic agent comprises a kinase inhibitor, an anti-fibrotic agent, or a mixture thereof; the biodegradable polymer is selected from polylactic acid polymer, polycaprolactone (PCL), polylactic-co-glycolic acid (PLGA), and poly(ethylene glycol) methyl ether-block-poly(lactic-co-glycolic acid) (PLGA-b-mPEG); 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, butylhydroxytoluene, vitamin E, vitamin E succinate, tannic acid, polyethylene glycol, N-isopropylacrylamide, and sorbitol esters. Balloon catheter.

21. 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, avapritinib, abemaciclib, erdafitinib, fedratinib, palbociclib, and pemigatinib.

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

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

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

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

26. 21. 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. 21. The balloon catheter of claim 20, wherein the biodegradable polymer is PLGA.

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

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

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

31. 1. 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 on the device body, the drug coating comprising: a therapeutic agent and at least one of a biodurable polymer and an excipient. Including, the therapeutic agent comprises a kinase inhibitor, an anti-fibrotic agent, or a mixture thereof; the biodurable polymer is selected from poly(vinylidene fluoride hexafluoropropylene) (PVDF-HFP), polyethylene terephthalate (PET), nylon 6,6, polyurethane (PU), polytetrafluoroethylene (PTFE), polyethylene, polysiloxane (silicone), and poly(methyl methacrylate) (PMMA), and combinations thereof; 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, butylhydroxytoluene, vitamin E, vitamin E succinate, and sorbitol esters. Stents, stent grafts, or other permanent or semi-permanent medical devices.

32. The kinase inhibitors include bosutinib, ceritinib, crizotinib, gefitinib, ruxolitinib, imatinib, axitinib, nilotinib, trametinib, afatinib, ibrutinib, cabozantinib, imatinib, lenvatinib, sunitinib, regorafenib, sorafenib, vandetanib, dasatinib, pazopanib, triamcinolone, tranilast, and halofuginib.

32. The stent, stent graft, or other permanent or semi-permanent medical device of claim 31, selected from non, montelukast, zafirlukast, pirfenidone, Y27632, CA3, verteporfin, VGLL4 peptide, nintedanib, avapritinib, abemaciclib, erdafitinib, fedratinib, palbociclib, and pemigatinib.

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

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

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

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

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

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

1.

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

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

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

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

43. 1. A medical device for delivering a therapeutic agent to a tissue, comprising: a coating layer on the exterior surface of the medical device Including, the coating layer comprises a phosphodiesterase (PDE) inhibitor in combination with one or more excipients; Medical devices.

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

45. PDE inhibitors include xanthines, aminophylline, sildenafil, tadalafil, vardenafil, udenafil, avanafil, dipyridamole, quinazoline, paraxanthine, papaverine, mesembrenone, rolipram, ibudilast, piclamilast, luteolin, drotaverine, roflumilast, apremilast, crisaborole, inamrinone, milrinone, enoximone, anagrelide, cilostazol, pimobendan, erythro-9-(2-hydroxy-3-nonyl)adenine, ( 44. The medical device of claim 43, wherein the hydroxybenzoate is selected from 2-[(3,4-dimethoxyphenyl)methyl]-7-[(1R)-1-hydroxyethyl]-4-phenylbutyl]-5-methyl-imidazo[5,1-f][1,2,4]triazin-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.

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

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

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

49. 45. The medical device of claim 44, wherein the biodurable polymer is selected from poly(vinylidene fluoride hexafluoropropylene) (PVDF-HFP), polyethylene terephthalate (PET), nylon 6,6, polyurethane (PU), polytetrafluoroethylene (PTFE), polyethylene, polysiloxane (silicone), and poly(methyl methacrylate) (PMMA), and combinations thereof.

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

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

1.

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

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

54. 44. The medical device of claim 43, selected from a balloon catheter, a 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.

55. 44. The medical device of claim 43, which is a stent or a stent-graft.

56. 44. The medical device of claim 43, which is a balloon catheter.

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

58. 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, butylhydroxytoluene, vitamin E, vitamin E succinate, tannic acid, polyethylene glycol, N-isopropylacrylamide, and sorbitol esters.

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

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

61. 44. The medical device of claim 43, wherein the tissue comprises tissue of one of the coronary vasculature, peripheral vasculature, cerebrovasculature, esophagus, airway, paranasal sinuses, trachea, colon, bile duct, urinary tract, prostate, and brain passageways.

62. 1. A balloon catheter for delivering a therapeutic agent to a blood vessel, comprising: an elongated member having a lumen and a distal end; an expandable balloon attached to the distal end of the elongate member and in fluid communication with the lumen; a coating layer on an exterior surface of the balloon, the coating layer comprising a therapeutic agent and at least one of a biodegradable polymer and an excipient; Including, the therapeutic agent comprises a PDE inhibitor, an anti-fibrotic agent, or a mixture thereof; the biodegradable polymer is selected from polylactic acid polymer, polycaprolactone (PCL), polylactic-co-glycolic acid (PLGA), and poly(ethylene glycol) methyl ether-block-poly(lactic-co-glycolic acid) (PLGA-b-mPEG); 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, butylhydroxytoluene, vitamin E, vitamin E succinate, tannic acid, polyethylene glycol, N-isopropylacrylamide, and sorbitol esters. Balloon catheter.

63. The PDE inhibitors include xanthines, aminophylline, sildenafil, tadalafil, vardenafil, udenafil, avanafil, dipyridamole, quinazoline, paraxanthine, papaverine, mesembrenone, rolipram, ibudilast, piclamilast, luteolin, drotaverine, roflumilast, apremilast, crisaborole, inamrinone, milrinone, enoximone, anagrelide, cilostazol, pimobendan, erythro-9-(2-hydroxy-3-nonyl)adenine, (2 63. The balloon catheter of claim 62, wherein the hydroxybenzoate is selected from the group consisting of 5-[(3,4-dimethoxyphenyl)methyl]-7-[(1R)-1-hydroxyethyl]-4-phenylbutyl]-5-methyl-imidazo[5,1-f][1,2,4]triazin-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.

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

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

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

67. 63. The balloon catheter of claim 62, wherein the antifibrotic agent is selected from triamcinolone, tranilast, halofuginone, montelukast, zafirlukast, pirfenidone, nintedanib, and combinations thereof.

68. 63. 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. 63. The balloon catheter of claim 62, wherein the biodegradable polymer is PLGA.

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

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

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

73. 1. 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 on the device body, the drug coating comprising: a therapeutic agent and at least one of a biodurable polymer and an excipient. Including, the therapeutic agent comprises a PDE inhibitor, an anti-fibrotic agent, or a mixture thereof; the biodurable polymer is selected from poly(vinylidene fluoride hexafluoropropylene) (PVDF-HFP), polyethylene terephthalate (PET), nylon 6,6, polyurethane (PU), polytetrafluoroethylene (PTFE), polyethylene, polysiloxane (silicone), and poly(methyl methacrylate) (PMMA), and combinations thereof; 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, butylhydroxytoluene, vitamin E, vitamin E succinate, and sorbitol esters. Stents, stent grafts, or other permanent or semi-permanent medical devices.

74. The PDE inhibitors include xanthines, aminophylline, sildenafil, tadalafil, vardenafil, udenafil, avanafil, dipyridamole, quinazoline, paraxanthine, papaverine, mesembrenone, rolipram, ibudilast, piclamilast, luteolin, drotaverine, roflumilast, apremilast, crisaborole, inamrinone, milrinone, enoximone, anagrelide, cilostazol, pimobendan, erythro-9-(2-hydroxy-3-nonyl)adenine, (2-[(3,4-dimethoxyphenyl)-2-methyl-2-propanol]-4-one, erythro-9-(2-hydroxy-3-nonyl)adenine, (2-[(3,4-dimethoxyphenyl)-2-methyl ...

74. The stent, stent graft, or other permanent or semi-permanent medical device of claim 73, wherein the active ingredient is selected from (9-(6-phenyl-2-oxohex-3-yl)-2-(3,4-dimethoxybenzyl)-purin-6-one), oxindole, (9-(6-phenyl-2-oxohex-3-yl)-2-(3,4-dimethoxybenzyl)-purin-6-one), 3-isobutyl-1-methylxanthine, pentoxifylline, theobromine, and theophylline.

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

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

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

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

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

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

1.

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

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

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

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

85. 1. A medical device for delivering a therapeutic agent to a tissue, comprising: a coating layer on the exterior surface of the medical device Including, the coating layer comprises a phosphodiesterase (PDE) inhibitor and a kinase inhibitor in combination with one or more excipients; Medical devices.

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

87. PDE inhibitors include xanthines, aminophylline, sildenafil, tadalafil, vardenafil, udenafil, avanafil, dipyridamole, quinazoline, paraxanthine, papaverine, mesembrenone, rolipram, ibudilast, piclamilast, luteolin, drotaverine, roflumilast, apremilast, crisaborole, inamrinone, milrinone, enoximone, anagrelide, cilostazol, pimobendan, erythro-9-(2-hydroxy-3-nonyl)adenine, ( 86. The medical device of claim 85, wherein the hydroxybenzoate is selected from 2-[(3,4-dimethoxyphenyl)methyl]-7-[(1R)-1-hydroxyethyl]-4-phenylbutyl]-5-methyl-imidazo[5,1-f][1,2,4]triazin-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.

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

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

90. 86. The medical device of claim 85, 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, avapritinib, abemaciclib, erdafitinib, fedratinib, palbociclib, and pemigatinib.

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

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

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

94. 87. The medical device of claim 86, wherein the biodurable polymer is selected from poly(vinylidene fluoride hexafluoropropylene) (PVDF-HFP), polyethylene terephthalate (PET), nylon 6,6, polyurethane (PU), polytetrafluoroethylene (PTFE), polyethylene, polysiloxane (silicone), and poly(methyl methacrylate) (PMMA), and combinations thereof.

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

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

1.

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

1.

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

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

100. 86. The medical device of claim 85, selected from a balloon catheter, a 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.

101. 86. The medical device of claim 85, which is a stent or a stent-graft.

102. 86. The medical device of claim 85, which is a balloon catheter.

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

104. 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, butylhydroxytoluene, vitamin E, vitamin E succinate, tannic acid, polyethylene glycol, N-isopropylacrylamide, and sorbitol esters.

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

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

107. 86. The medical device of claim 85, wherein the tissue comprises tissue of one of the coronary vasculature, peripheral vasculature, cerebrovasculature, esophagus, airway, paranasal sinuses, trachea, colon, bile duct, urinary tract, prostate, and brain passageways.

108. 1. A balloon catheter for delivering a therapeutic agent to a blood vessel, comprising: an elongated member having a lumen and a distal end; an expandable balloon attached to the distal end of the elongate member and in fluid communication with the lumen; a coating layer on an exterior surface of the balloon, the coating layer comprising a therapeutic agent and at least one of a biodegradable polymer and an excipient; Including, the therapeutic agent comprises a PDE inhibitor, a kinase inhibitor, an anti-fibrotic agent, or a mixture thereof; the biodegradable polymer is selected from polylactic acid polymer, polycaprolactone (PCL), polylactic-co-glycolic acid (PLGA), and poly(ethylene glycol) methyl ether-block-poly(lactic-co-glycolic acid) (PLGA-b-mPEG); 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, butylhydroxytoluene, vitamin E, vitamin E succinate, tannic acid, polyethylene glycol, N-isopropylacrylamide, and sorbitol esters. Balloon catheter.

109. The PDE inhibitors include xanthines, aminophylline, sildenafil, tadalafil, vardenafil, udenafil, avanafil, dipyridamole, quinazoline, paraxanthine, papaverine, mesembrenone, rolipram, ibudilast, piclamilast, luteolin, drotaverine, roflumilast, apremilast, crisaborole, inamrinone, milrinone, enoximone, anagrelide, cilostazol, pimobendan, erythro-9-(2-hydroxy-3-nonyl)adenine, (2 109. The balloon catheter of claim 108, wherein the hydroxybenzoate is selected from the group consisting of 5-[(3,4-dimethoxyphenyl)methyl]-7-[(1R)-1-hydroxyethyl]-4-phenylbutyl]-5-methyl-imidazo[5,1-f][1,2,4]triazin-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.

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

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

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

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, avapritinib, abemaciclib, erdafitinib, fedratinib, palbociclib, and pemigatinib.

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

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

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

117. 109. 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. 109. The balloon catheter of claim 108, wherein the biodegradable polymer is PLGA.

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

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

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

122. 1. 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 on the device body, the drug coating comprising: a therapeutic agent and at least one of a biodurable polymer and an excipient. Including, the therapeutic agent comprises a PDE inhibitor, a kinase inhibitor, an anti-fibrotic agent, or a mixture thereof; the biodurable polymer is selected from poly(vinylidene fluoride hexafluoropropylene) (PVDF-HFP), polyethylene terephthalate (PET), nylon 6,6, polyurethane (PU), polytetrafluoroethylene (PTFE), polyethylene, polysiloxane (silicone), and poly(methyl methacrylate) (PMMA), and combinations thereof; 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, butylhydroxytoluene, vitamin E, vitamin E succinate, and sorbitol esters. Stents, stent grafts, or other permanent or semi-permanent medical devices.

123. The PDE inhibitors include xanthines, aminophylline, sildenafil, tadalafil, vardenafil, udenafil, avanafil, dipyridamole, quinazoline, paraxanthine, papaverine, mesembrenone, rolipram, ibudilast, piclamilast, luteolin, drotaverine, roflumilast, apremilast, crisaborole, inamrinone, milrinone, enoximone, anagrelide, cilostazol, pimobendan, erythro-9-(2-hydroxy-3-nonyl)adenine, (2-[(3,4-dimethoxyphenyl)-2-methyl-2-propanol]-4-one, erythro-9-(2-hydroxy-3-nonyl)adenine, (2-[(3,4-dimethoxyphenyl)-2-methyl ...

123. The stent, stent graft, or other permanent or semi-permanent medical device of claim 122, wherein the active ingredient is selected from (9-(6-phenyl-2-oxohex-3-yl)-2-(3,4-dimethoxybenzyl)-purin-6-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. 123. The stent, stent graft, or other permanent or semi-permanent medical device of claim 122, wherein the PDE inhibitor is tadalafil or sildenafil.

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

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

127. 123. 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, avapritinib, abemaciclib, erdafitinib, fedratinib, palbociclib, and pemigatinib.

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

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

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

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

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

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

1.

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

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

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

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

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

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