RU2820776C2 - Coating for intraluminal expanding catheter, providing contact transfer of microreservoirs with medicinal products - Google Patents

Abstract

FIELD: medical devices.

SUBSTANCE: group of inventions relates to medicinal product delivery through expandable catheters. The following is presented: a catheter comprising an expandable part on an elongated body; and a coating on the outer surface of the expandable part. The said coating contains a lipophilic matrix with at least one lipid, more than one microreservoir, including only a crystalline active agent dispersed in the lipophilic matrix. The lipophilic matrix is configured to adhere to the intraluminal surface when the expandable portion is inflated and transfer at least a part from more than one microreservoir to the intraluminal surface. More than one microreservoir is uniform in size and has a maximum particle size of 10 μm, and less than 5% of the more than one microreservoir has a diameter of 1 μm or less. A method of coating an expandable part of a catheter and a method of treating a condition at a treatment site are also described.

EFFECT: maximum therapeutic effect is achieved with minimal toxicity of high doses of medicinal products.

45 cl, 8 dwg, 20 tbl, 14 ex

Description

Technical field

[0001] The present description relates to the field of drug delivery through expandable catheters.

Description of the prior art

[0002] Balloon angioplasty is an established method of treating vascular disease by physically widening the area of atherosclerosis, stenosis, or reducing the intraluminal diameter in the affected blood vessel. Angioplasty is usually performed using a catheter, which can be inserted into the affected area within the circulatory system. The catheter has a balloon at the distal end, which is inflated to dilate and widen the area of stenosis. In many cases, such as coronary arteries, the stent is also placed on the outside of the balloon. The balloon expands into the area of atherosclerosis, and the stent remains in place after deflation and removal of the balloon to maintain the dilated state of the lumen.

[0003] To achieve physical expansion of the area of the vessel to be treated, large forces are applied to the tissue of the vessel wall while inflating the balloon with high pressure. This physical expansion leads to injury to the vessel, including damage to the endothelium, fragmentation of the internal elastic layer, and dissection of the middle part of the vessel lining. Damage often extends to the outer adventitia. The vascular biological response progresses through a thrombotic phase over 0 to 3 days involving platelet activation and adhesion and thrombus formation. The thrombotic phase is followed by a cellular recruitment phase for 3 to 8 days, which involves the infiltration of inflammatory cells, macrophages, and lymphocytes at the site of vascular injury. The release of growth factors and cytokines from inflammatory cells leads to a proliferative phase of 8 to 14 days, in which dormant smooth muscle cells in the medial portion of the vessel lining are stimulated to proliferate. Subsequently, migration of proliferating smooth muscle cells into the tunica interna and luminal thrombus caused by injury leads to neointimal hyperplasia, the primary component of restenosis. Although cell proliferation ceases after 14 days, continued production of extracellular matrix by smooth muscle cells in the injured area continues to increase the degree of neointimal hyperplasia and restenosis. Restenosis effectively reverses dilatation treatment and potentially poses a critical threat to the patient. Clinical studies have shown that restenosis generally occurs between 1 and 3 months after balloon angioplasty, and restenosis usually peaks at approximately 3 months.

[0004] Although balloon angioplasty provides a much-needed dramatic increase in blood flow in the affected vessels, restenosis occurs due to the degree of mechanical damage involved. One strategy to reduce the restenosis response is to release drugs into the vessel in combination with balloon dilatation treatment to control inflammation and promote a healing response. Approaches include coating the balloon with drugs such as paclitaxel and sirolimus (rapamycin), which limit cell proliferation. It is believed that during contact of the balloon with the intraluminal surface of the vessel, the use of an auxiliary coating facilitates the transfer of the drug to the site of vessel damage. These methods attempt to ensure that the drug concentration in the vessel wall after balloon expansion is sufficient to reduce restenosis caused by cell proliferation, while at the same time low enough to minimize toxicity to the vessel that could lead to injury or pathology. vessel. It is believed that it is desirable to maintain an effective drug concentration for a period of time sufficient to minimize restenosis.

[0005] In practice, delivery of drugs to the tissues of the vessel wall using drug-coated balloons, as described in the art, is limited to the short period of time during which the balloon can be brought into contact with the vessel. Typically, inflation of the balloon during angioplasty is performed for about 30 to about 120 seconds to limit cardiac ischemia and possible complications and discomfort for the patient. This short-term balloon inflation and drug delivery may be sufficient for the anticancer drug paclitaxel, which has been shown to inhibit neointimal formation in animals after a few minutes of onset time. However, to ensure maximum therapeutic effect and minimize the potential toxicity of high doses to the vessel, it would be desirable to ensure delivery of drugs to the vessel over an extended period of time, ideally longer than the duration of balloon inflation. In addition, drugs such as sirolimus and its analogues have both antiproliferative and anti-inflammatory activity, which may provide benefit beyond the acute period of restenosis when delivered over an extended period of time.

[0006] Many coated drug canisters described in the prior art use high initial levels of active agent and multiple treatments to create a high initial concentration, but then the concentration drops rapidly. This is undesirable since most of the active agent on the device is lost due to possible embolization of particles into the bloodstream or by diffusion from the treatment site.

[0007] Many of the drug-containing coatings described in the prior art contain hydrophilic polymers and excipients, or excipients, that are liquid at body temperature. Such hydrophilic coating compositions provide a hydrophilic matrix for hydrophobic drug particles and can be effective in transporting the drug to the vessel wall. However, such coatings do not provide significant resistance to blood washout either during transport of the balloon to the treatment site or after transfer of the drug to the surface of the vessel.

BRIEF DESCRIPTION OF THE INVENTION

[0008] Some embodiments provide a coating for an expandable portion of a catheter comprising a hydrophobic matrix and a dispersed phase, wherein the dispersed phase comprises a plurality of microreservoirs dispersed in the hydrophobic matrix, wherein the plurality of microreservoirs contains a first active agent mixed or dispersed in a first biodegradable or biodegradable polymer. In some embodiments, a coating is provided in which the dispersed phase comprises a plurality of microreservoirs dispersed in a hydrophobic matrix, wherein some of the plurality of microreservoirs comprise a first active agent and a first biodegradable or biodegradable polymer.

[0009] In some embodiments, a catheter is provided including an expandable portion on an elongated body and a coating on the expandable portion. The coating includes a lipophilic matrix, wherein the lipophilic matrix includes at least one lipid, a plurality of microreservoirs are dispersed in the lipophilic matrix, wherein the plurality of microreservoirs contains an active agent, and the lipophilic matrix is configured to provide adhesion to an intraluminal surface when the expandable portion is inflated, and transfer at least part of a plurality of microreservoirs onto the luminal surface.

[0010] In some embodiments, a catheter is provided including an expandable portion on an elongated body, and a coating as described herein on the expandable portion. In some embodiments, the catheter further includes a release layer between the expandable portion and the cover, wherein the release layer is configured to release the cover from the expandable portion. In some embodiments, the catheter further includes a protective coating over the coating.

[0011] In some embodiments, a catheter expandable portion coating composition is provided, comprising a solid portion and a liquid portion. The solid portion contains a plurality of microreservoirs and at least one hydrophobic compound. The plurality of microreservoirs contains a first active agent and a first biodegradable or biodegradable polymer.

[0012] In some embodiments, a catheter expandable portion coating composition is provided comprising a plurality of microreservoirs containing an active agent and at least one lipid.

[0013] In some embodiments, a method of coating an expandable portion of a catheter is provided, comprising applying a coating composition as described herein to the surface of an inflated expandable portion of a catheter, evaporating the liquid, and deflating the expandable portion.

[0014] In some embodiments, a method of treating or preventing a condition at a treatment site is provided, comprising introducing a catheter comprising an expandable portion to the treatment site, wherein the expandable portion is coated with a coating described herein, inflating the expandable portion to ensure contact between the coating and tissue at the treatment site, deflation of the expandable part and removal of the catheter.

BRIEF DESCRIPTION OF THE DRAWINGS

[0015] Features and aspects and advantages of embodiments of the present invention are described in detail below with reference to the accompanying drawings of various embodiments, which are intended to be illustrative and not limiting of the present invention. These drawings depict only some embodiments of the present invention in accordance with the present description and should not be construed as limiting the scope thereof.

[0016] Figure 1 depicts one embodiment of a balloon catheter with a coating on the expandable portion of the catheter.

[0017] Figure 2 illustrates one embodiment of a balloon catheter with a separating layer between the cover and the expandable portion of the catheter.

[0018] Figure 3 depicts one embodiment of a balloon catheter with a protective layer on the cover.

[0019] Figure 4 is a photomicrograph of the intraluminal surface of a vessel treated with one embodiment of a balloon catheter.

[0020] Figure 5 is a photomicrograph of the intraluminal surface of a vessel treated with one embodiment of a balloon catheter.

[0021] Figure 6 is a micrograph of the surface of a coated balloon at 100x magnification showing the coating containing a crystalline microreservoir containing sirolimus.

[0022] Figure 7 is a micrograph of an artery surface at 50x magnification showing adherent material.

[0023] Figure 8 is a micrograph of the surface of an artery at 1000x magnification showing adherent material.

Detailed Description of the Preferred Embodiment

[0024] To overcome the limitations of the prior art, embodiments disclosed herein provide coatings for the expandable portion of a catheter that contain sustained-release drug microreservoirs mixed with or dispersed in the coating of a balloon that can be placed against the intraluminal surface of the vessel for 30 to about 120 seconds of balloon inflation time. This approach provides sustained and controlled drug release over a longer period of time, which can be tailored by microreservoir design to the characteristics of the specific drug or the pathology of the affected vessel. In addition to providing sustained release, the coating described herein can also be resistant to blood washout, which simultaneously improves drug transport efficiency and patient safety regarding excess particle production.

Coating

[0025] Disclosed herein is a coating for an expandable portion of a catheter or catheter system. The catheter is intended to be introduced into a living body to deliver at least one active agent locally. The coating is formulated and designed for minimal solubilization and dispersion in the bloodstream when the catheter is placed in the target vessel for treatment, or after the coating is transferred to the tissue of the vessel wall. In some embodiments, an active agent or drug is delivered to the vessel to prevent or minimize restenosis after balloon angioplasty. In some embodiments, the expandable portion may be a balloon of a balloon catheter.

[0026] Based on FIG. 1, in some embodiments, the coating 12 for the expandable portion 11 of the catheter 10 includes two phases, a hydrophobic matrix 14 and a dispersed phase 13. The dispersed phase 13 is dispersed in the hydrophobic matrix 14. The dispersed phase 13 includes a plurality of microreservoirs, and the plurality of microreservoirs includes a first active agent and a first biodegradable or biodegradable polymer. In some embodiments, the first active agent is mixed with or dispersed in the first biodegradable or biodegradable polymer. In some embodiments, some microreservoirs may contain a first active agent and a biodegradable or biodegradable polymer. In some embodiments, the plurality of microreservoirs also include a second active agent. In some embodiments, the plurality of microreservoirs may further include a second biodegradable or biodegradable polymer. In some embodiments, the first and second biodegradable or biodegradable polymers may be the same or different. In some embodiments, a plurality of microreservoirs may comprise only one type of microreservoir. In some embodiments, coating 12 comprises from about 10% to about 75%, from about 20% to about 65%, or from about 30% to about 55% by weight of the plurality of microreservoirs. In some embodiments, coating 12 has a surface concentration of from about 1 μg/mm ² to about 10 μg/mm ² , from about 2 μg/mm ² to about 9 μg/mm ² , or from about 3 μg/mm ² to about 8 μg /mm ² on the expandable part of the catheter 10.

[0027] The hydrophobic matrix 14 contains a combination of materials selected for their desired adhesive properties to the intraluminal surface. The preferred hydrophobic matrix 14 contains a combination of hydrophobic compounds that are resistant to dissolution in the blood but provide uniform distribution of the microreservoir composition when applied to the surface of the balloon. In some embodiments, the hydrophobic matrix 14 contains at least one hydrophobic compound selected from the group consisting of sterols, lipids, phospholipids, fats, fatty acids, surfactants, and derivatives thereof. Particularly suitable formulations are a combination of a sterol and a fatty acid or phospholipid. The sterol may be a sterol that utilizes the body's natural clearance mechanism, for example by forming complexes with serum lipids or aggregates with serum apolipoproteins, to allow transport to the liver for metabolic processing. In some embodiments, the sterol may be cholesterol. Due to the natural compatibility of cholesterol and fatty acids and phospholipids, such combinations can provide a homogeneous mixture for coating 12 and provide a homogeneous coating on the surface of the balloon. The coating 12 formed by such combinations is homogeneous without the formation of micelles or liposomes in the hydrophobic matrix 14.

[0028] In some embodiments, the hydrophobic matrix 14 contains cholesterol and a fatty acid. In some embodiments, the cholesterol to fatty acid weight ratio ranges from about 1:2 to about 3:1, from about 1:1.5 to about 2.5:1, or from about 1:1 to about 2:1. The cholesterol component of the formulation may include cholesterol, chemically modified cholesterol, or a cholesterol conjugate. In some embodiments, the cholesterol is dimethylaminoethane-carbamoyl cholesterol (DC-cholesterol). For physiological compatibility, preferred fatty acids are fatty acids typically found in blood serum or cell membranes. In some embodiments, the fatty acid is selected from the group consisting of lauric acid, lauroleic acid, tetradecadienoic acid, octanoic acid, myristic acid, myristoleic acid acid, decenoic acid, decanoic acid, hexadecenoic acid, palmitoleic acid, palmitic acid, linolenic acid, linoleic acid, oleic acid, vaccenic acid, stearic acid, eicosapentaenoic acid, arachidonic acid, midic acid, arachidic acid, docosahexaenoic acid, docosapentaenoic acid, docosatetraenoic acid, docosenoic acid, tetracosanoic acid, hexacosenoic acid, pristanic acid, phytanic acid and nervonic acid.

[0029] In some embodiments, the hydrophobic matrix 14 contains cholesterol and a phospholipid. In some embodiments, the cholesterol to phospholipid weight ratio is in the range of about 1:2 to about 3:1, about 1:1.5 to about 2.5:1, or about 1:1 to about 2:1. The cholesterol component of the formulation may include cholesterol, chemically modified cholesterol, or a cholesterol conjugate. In some embodiments, the cholesterol is DC cholesterol. Preferred phospholipids are those typically found in blood serum or cell membranes. In some embodiments, the phospholipid is selected from the group consisting of phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, or phosphatidylinositol. In some embodiments, the phospholipid has an acyl chain length of from about 20 to about 34 carbon atoms. In some embodiments, the hydrophobic matrix 14 may further include a third active agent, which may be the same or different from the first active agent in the plurality of microreservoirs.

[0030] In some embodiments of the present disclosure, the hydrophobic matrix 14 contains only hydrophobic components, such as lipids, sterols, and fatty acids. That is, in some embodiments, the hydrophobic matrix does not contain hydrophilic polymers or hydrophilic excipients. In some embodiments of the present disclosure, the hydrophobic matrix 14 contains only hydrophobic components, such as lipids, sterols and fatty acids, and no amphiphilic components are present. Preferably, the coating 12 and its components have limited solubility in blood or analogs such as plasma or phosphate buffered saline solution. The use of cationic cholesterol or cationic phospholipid in the formulation may provide additional chemical affinity of the hydrophobic matrix 14 to the surface of the vessel and potentially to the surface of the microreservoirs to enhance transfer of the coating 12 and resistance to dissolution in the blood after transfer. Suitable cationic forms of cholesterol are modified at carbon 3 to attach a tertiary or quaternary amine side chain and include DC-cholesterol. Suitable cationic forms of phospholipids include natural phospholipids and synthetic modifications of phospholipids such as phosphatidylethanolamine, dioleoylphosphatidylethanolamine (DOPE) and amino derivatives of phosphatidylcholine such as ethylphosphatidylcholine.

[0031] In some embodiments, the length of the acyl chain and the degree of unsaturation of the phospholipid component of the hydrophobic matrix 14 can be used to tailor the physicochemical properties of the hydrophobic matrix 14. In some embodiments, the length of the large acyl chain is selected to increase the hydrophobicity of the phospholipid for adhesion to a surface vessel and reduce solubility and leaching due to exposure to the bloodstream. The length of the acyl chain of fatty acids and the fatty acid portion of phospholipids are described in abbreviation as the number of carbon atoms followed by a colon and the number of carbon-carbon double bonds. In the following description of phospholipids, both the generic and generic name, stereospecific numbering and abbreviation are used to first describe the compound. Acyl chain lengths of 20 to 34 carbon atoms (C20 to C34) are suitable for use as a component of coating 12, acyl chain lengths of 20 to 24 carbon atoms (C20 to C24) are particularly preferred. Although the present invention also works with saturated acyl chains, one or more sites of unsaturation may provide increased chain flexibility. Examples of preferred phospholipids include dieicosenoylphosphatidylcholine (1,2-dieicosenoyl-sn-glycero-3-phosphocholine, C20:1 PC), diarachidonoylphosphatidylcholine (1,2-diarachidoyl-sn-glycero-3-phosphocholine, C20:0 PC), dierucoylphosphatidylcholine ( 1,2-dierucoyl-sn-glycero-3-phosphocholine, C22:1 PC), didocosahexaenoylphosphatidylcholine (1,2-didocosahexaenoyl-sn-glycero-3-phosphocholine, C22:6 PC), heneicosenoylphosphatidylcholine (1,2-heneicosenoyl- sn-glycero-3-phosphocholine, C21:1 PC) and dinervonoyl-phosphatidylcholine (1,2-dinervonoyl-sn-glycero-3-phosphocholine, C24:1 PC). In some embodiments, the phospholipids have a transition temperature at or above ambient temperature (20°C), such that the hydrophobic matrix 14 is a solid upon storage.

[0032] The plurality of microreservoirs contain an active agent and a polymer. The active agent may be referred to as a first active agent or a second active agent. The active agent is bound to the polymer in such a way as to provide a slow or sustained release of the active agent from the microreservoirs. In some embodiments, the active agent is mixed with or dispersed in a biodegradable or biodegradable polymer. In some embodiments, the active agent may be encapsulated with a biodegradable or biodegradable polymer. In some embodiments, the plurality of microreservoirs may comprise a first active agent. In some embodiments, the plurality of microreservoirs may further include a second active agent. A suitable active agent may include antiproliferative or anti-inflammatory agents such as paclitaxel, sirolimus (rapamycin), and chemical derivatives or analogs thereof , which are mTOR inhibitors, inhibitory RNA, inhibitory DNA, steroids and complement inhibitors. In some embodiments, the active agent is selected from the group consisting of paclitaxel, sirolimus, a paclitaxel derivative, a sirolimus derivative, paclitaxel analogs, sirolimus analogs, inhibitory RNA, inhibitory DNA, steroids, and complement inhibitors. In some embodiments, the active agent constitutes from about 10% to about 50%, from about 15% to about 45%, from about 20% to about 40%, or from about 25% to about 35% by weight of the plurality of microreservoirs. Microreservoirs may include microparticles or microspheres. In some embodiments, polylactic-co-glycolic acid (PLGA) microspheres are well suited to incorporate an active agent to continuously release up to about 50% by weight of the active agent in the microsphere.

[0033] In some embodiments, the hydrophobic matrix 14 may be a lipophilic matrix, and the dispersed phase 13 is dispersed in the lipophilic matrix. In some embodiments, the lipophilic matrix may include at least one lipid. In some embodiments, the lipid may be a phospholipid, sphingolipids, ceramides, terpenes, terpenoids, monoglycerides, diglycerides, triglycerides, phytosterols, prostaglandins, vegetable oils (e.g., amaranth, apricot kernel, argan, almond, avocado, coconut, grapeseed) kernels, palm, safflower, sesame, soybean, sunflower and wheat germ oils), vegetable waxes (for example, beeswax, jojoba oil and shea butter), paraffin, fat-soluble vitamins and provitamins (for example, carotenes and vitamins A, D, E, K), steroids, squalene. In some embodiments, the phospholipid is a cationic phospholipid. In some embodiments, the lipophilic matrix may further include a sterol, such as cholesterol. The described lipophilic matrix is designed to adhere to an intraluminal surface when the expandable portion of the catheter is expanded into a lumen, such as a blood vessel. As the expandable portion of the catheter expands into the lumen, at least a portion of the plurality of microreservoirs is transferred to the intraluminal surface along with at least a portion of the lipophilic matrix.

[0034] Dispersed phase 13 includes a plurality of microreservoirs. In some embodiments, the plurality of microreservoirs include a first active agent. In some embodiments, the plurality of microreservoirs include a first active agent and a first biodegradable or biodegradable polymer. In some embodiments, the first active agent is mixed with or dispersed in the first biodegradable or biodegradable polymer. In some embodiments, some microreservoirs may include only a first active agent, and some microreservoirs may include a first active agent mixed with or dispersed within a first biodegradable or biodegradable polymer. In other embodiments, the first active agent may be crystalline. In some embodiments, a plurality of microreservoirs may comprise only one type of microreservoir.

[0035] In some embodiments, coating 12 comprises from about 10% to about 75%, from about 20% to about 65%, or from about 30% to about 55% by weight of the plurality of microreservoirs. In some embodiments, coating 12 has a surface concentration of from about 1 μg/mm ² to about 10 μg/mm ² , from about 2 μg/mm ² to about 9 μg/mm ² , or from about 3 μg/mm ² to about 8 μg /mm ² on the expandable part of the catheter 10.

[0036] In some embodiments, the microreservoirs contain microparticles of the active agent. In some embodiments, the active agent, such as sirolimus, may be a crystallized powder from the manufacturer, or may be recrystallized in a controlled manner. For example, sirolimus microparticles can be prepared by grinding crystalline powder for 2 hours in Novec 7100 hydrofluorocarbon solvent. By selecting grinding ball size and hardness and grinding speed and time, crystalline sirolimus can be reduced to micron-sized particles or smaller. Grinding can be done dry or wet in a sirolimus antisolvent such as water, hexane or hydrofluorocarbons, which are then removed by drying or vacuum. Alternative mechanical grinding methods include miniature hammer mills, automatic mortar and pestle, ultrasonic homogenization, electrohydraulic (arc cavitation) homogenization, or any mechanical method that leaves the crystals intact without dissolving them in a solvent.

[0037] In some embodiments, the crushed crystalline sirolimus can then be sieved to remove large particles. For example, an ASTM E-11 number 100 sieve (150 µm mesh) could be used on this sample of sirolimus, and particles that did not pass through were returned to the planetary ball mill for further grinding.

[0038] In some embodiments, microparticles of a certain size range may be selected using any size sorting techniques. For example, passing particles in an antisolvent through sieves of gradually decreasing size. In some embodiments, optional additional size reduction may be provided by an ultrasonic homogenization sensor, electrohydraulic lithotripsy, or other high shear cavitation sources known in the art. In some embodiments, a recirculation loop may be designed to continue to crush particles to sizes less than red blood cells.

[0039] In some embodiments, once the maximum particle size is reduced to less than about 10 micrometers, particle uniformity can be further improved by stream grading, such as screening, to remove smaller particles that may produce too much of a "blast" effect. In some embodiments, the particles can be circulated in an antisolvent (water, heptane, hydrofluorocarbon) and, by controlling the geometry and flow rate, the desired particle size can be collected through sedimentation.

[0040] In some embodiments, the plurality of microreservoirs have an average diameter of from about 0.5 micrometers to about 10 micrometers, from about 1 micrometer to about 10 micrometers, from about 0.5 micrometers to about 8 micrometers, from about 1.8 micrometers to about 8 micrometers, about 2 micrometers to about 6 micrometers, or about 3 micrometers to about 5 micrometers. In some embodiments, the microreservoirs are desirably of a size large enough to provide continuous release of the active agent, approximately 1.5 micrometers or more in diameter, or an average cross-sectional size for non-uniformly sized microparticles. Smaller microreservoir sizes typically have an increased surface area to volume ratio and a reduced diffusion path for the active agent, which does not provide sufficient sustained release. The maximum size of microreservoirs is approximately the size of red blood cells, from about 6 micrometers to about 8 micrometers, to prevent capillary embolization due to any microreservoirs released into the bloodstream during or after treatment. In some embodiments, the plurality of microreservoirs do not contain nano-sized particles. In some embodiments, less than about 5%, less than about 8%, less than about 10%, less than about 15%, less than about 20%, less than about 25%, less than about 30%, less than about 40%, less than about 50% of the plurality microreservoirs have a diameter of 1.5 micrometers or less. In some embodiments, less than about 5%, less than about 8%, less than about 10%, less than about 15%, less than about 20%, less than about 25%, less than about 30%, less than about 40%, less than about 50% of the plurality of microreservoirs have a diameter of 1 micrometer or less. In some embodiments, the microreservoirs do not necessarily have affinity or adhesion to the surface of the vessel.

[0041] A biodegradable or biodegradable polymer can provide controlled and sustained release of the active agent. The biodegradable or biodegradable polymer may be referred to as a first biodegradable or biodegradable polymer or a second biodegradable or biodegradable polymer. The polymer acts as a barrier to drug diffusion, thereby providing a release profile tailored to the pharmacokinetics of the active agent acting on the vessel being treated. For example, the active agent may be mixed and distributed throughout the polymer in solid solution. The polymer may provide controlled release by reducing the diffusion of the active agent or by a combination of drug release and biodegradation, dissolution or biodegradation of the polymer. In some embodiments, the biodegradable or biodegradable polymer is selected from the group consisting of polylactic acid, polyglycolic acid and copolymers thereof, polydioxanone, polycaprolactone, polyphosphazine, collagen, gelatin, chitosan, glycosaminoglycans, and combinations thereof. In some embodiments, the microreservoirs may also be microspheres or microparticles containing at least one active agent that treats inflammation or induces a healing response. In some embodiments, the plurality of microreservoirs may include a first biodegradable or biodegradable polymer. In some embodiments, the plurality of microreservoirs may include a second biodegradable or biodegradable polymer.

[0042] Once the coating 12 contacts the vessel wall, the release kinetics of the active agent is controlled by the release of the active agent from the microreservoirs into the environment, thereby allowing long-term elution of the active agent to penetrate the vessel wall. To provide a significant amount of active agent during the initial period of high risk of restenosis after dilatation, it is preferable that the active agent in coating 12 is continuously released with release kinetics with a half-life of about 2 weeks to about 6 weeks or more. In some embodiments, the plurality of microreservoirs have active agent release kinetics with a half-life of at least 14 days.

[0043] The kinetics of release of the active agent can be tailored to the characteristics of the microreservoirs. In the coating 12, two or more types of microreservoirs with different active agents or different release kinetics for the same active agent can be prepared to tailor the therapeutic effect. In some embodiments, certain active agents may be included in the coating composition outside of the microreservoirs to provide rapid initial release of the active agent to the walls of the vessel, allowing the microreservoirs to provide sufficient amounts of the active agent to maintain an effective concentration of the active agent in tissues over an extended period of time. Since healing and resolution of inflammation in the area of dilatation typically takes 4-12 weeks, it is desirable for the microreservoirs and coating 12 to elute the active agent to provide therapeutic levels in the tissue for at least about 4 weeks until about 12 weeks after treatment. In some applications, such as very long vessels with extensive lesions, maintaining active agent levels for more than 4 to 12 weeks may be desirable to provide additional protection against the effects of less common late restenosis.

[0044] The release of an active agent mixed with or dispersed in a solid has been shown to follow Higuchi kinetics, with the release of the active agent decreasing over time. For spherical particles with the active agent dispersed in the polymer, the release kinetics of the active agent also follows a power law of decreasing release rate, the Korsmeyer-Peppas kinetic model, similar to the Higuchi equation. (J.Siepmanna J, Peppas NA, Modeling of active agent release from delivery systems based on hydroxypropyl methylcellulose (HPMC), Advanced Drug Delivery Reviews 48 (2001) 139-157). The kinetics of release of the active agent from such microreservoirs is well suited for the treatment of the vessel wall after dilatation. The design and selection of microreservoirs with an appropriate release constant provides rapid initial release of the active agent with continuous release of the active agent and prolonged residence of the active agent in the vessel wall for longer periods of time compared to prior art devices. The release rate of the active agent can be adjusted by adjusting the solubility of the active agent in the microreservoir material and by adjusting the microporosity of the microreservoir. The duration of effective delivery of the active agent can be selected by selecting the size of the microreservoir, the solubility of the active agent in the microreservoir material, and the amount of active agent loaded into the microreservoirs. The total amount of active agent to be delivered is determined by the number of microreservoirs in the coating composition and their active agent loading level. As a result, the coating 12 can be formulated to have an active agent concentration ranging from about 0.3 to about 3 μg per mm ² of the surface of the expandable portion 11. The desired kinetics of release of the active agent from the coating 12 can be achieved by one type of microreservoir or alternatively, a mixture of microreservoirs with different sizes or release characteristics to provide the desired release profile into the vessel wall.

[0045] In some embodiments, coating 12 further includes a PEG lipid to increase hemocompatibility. Because the coating 12 described herein is intended to be transferred to the surface of a blood vessel and remain there to release drug during the healing period of the vessel, hemocompatibility of the coating 12 is necessary. In addition to preventing the coating 12 from dissolving into the bloodstream before the vessel has healed, it is necessary to prevent the initiation of significant clotting and attachment of fibrin and platelets to the surface of the coating exposed to blood after transfer. The addition of a PEG lipid to a cholesterol-phospholipid or fatty acid composition can be used to provide increased hemocompatibility of the composition. PEG-cross-linked polymer surfaces showed improved blood contact characteristics primarily due to reduced surface free energy and steric hindrance of hydrated PEG chains on the surface. Without wishing to be bound by a particular theory of action, it is believed that a small amount of PEG-lipid conjugate added to the composition may migrate to the blood interface after transfer, especially for PEG-lipids with a relatively low molecular weight. Thus, PEG chains are able to reduce the surface free energy at the interface with blood. Since the coating material at the blood interface represents a small portion of the total coating, a relatively small amount of PEG lipid is required.

[0046] In some embodiments, the PEG lipid is selected from the group consisting of 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-methoxy(polyethylene glycol)-350 (DSPE-mPEG350), 1,2-dipalmitoyl- sn-glycero-3-phosphoethanolamine-methoxy(polyethylene glycol)-350 (DPPE-mPEG350), 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine-N-methoxy(polyethylene glycol)-350 (DOPE-mPEG350), 1, 2-distearoyl-sn-glycero-3-phosphoethanolamine-N-methoxy(polyethylene glycol)-550 (DSPE-mPEG550), 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine-N-methoxy(polyethylene glycol)-550 (DPPE -mPEG550) and 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine-N-methoxy(polyethylene glycol)-500 (DOPE-mPEG550). In some embodiments, the PEG lipid comprises from about 1% to about 30% by weight of the hydrophobic matrix 14 consisting of a combination of cholesterol, fatty acid, or phospholipid and the PEG lipid. In other embodiments, the PEG lipid comprises from about 2% to about 25%, from about 3% to about 20%, or from about 5% to about 10% by weight of the hydrophobic matrix 14. In some embodiments, the amount of PEG lipid is from approximately 12% or less.

[0047] In some embodiments, coating 12 further includes one or more additives. In some embodiments, one or more additives are independently selected from penetration enhancers and stabilizers. For example, coating 12 may further contain additives to enhance activity, such as permeation enhancers. A permeation enhancer can promote diffusion of the active agent to the vessel wall and maximize delivery of the active agent to the tissue. Suitable penetration enhancers may include surfactants, cationic excipients and cationic lipids. In some embodiments, the additive may be added to the hydrophobic matrix, the microreservoirs, or both. In some embodiments, stabilizers may be added to protect the drug during sterilization of the balloon catheter system and its subsequent storage prior to use. Stabilizers may include antioxidants and free radical scavengers. Examples of stabilizers include gallic acid, propyl gallate, tocopherols and tocotrienols (vitamin E), butylated hydroxytoluene, butylated hydroxyanisole, ascorbic acid, thioglycolic acid, ascorbyl palmitate and EDTA.

[0048] In some embodiments, coating 12 further comprises a third active agent, wherein the third active agent is located outside of the microreservoirs or in the hydrophobic matrix 14. The third active agent may be the same or different from the first or second active agent in the plurality of microreservoirs. However, since the active agent(s) are primarily contained in microreservoirs rather than in direct contact with the hydrophobic matrix 14, there is no need to solubilize or emulsify the active agent in the hydrophobic matrix 14 itself. Since the active agent(s) are primarily contained in microreservoirs and do not come into contact with the hydrophobic matrix 14, the need to include an amphiphilic component or an active agent affinity component in the hydrophobic matrix 14 is eliminated. Thus, the hydrophobic matrix 14 can be optimized for suitable properties for resistance to blood washout and adhesion to the surface of the coating transfer vessel 12.

Catheter

[0049] With reference to FIG. 2, also provided herein is a catheter 10 that includes an expandable portion 11 on the elongated body 17, a cover 12 as described above on the expandable portion 11, and a separating layer 15 between the expandable portion 11 and the cover. 12. In some embodiments, the release layer 15 is configured to release the cover 12 from the expandable portion 11. The release layer 15, which is not mixed with the cover 12, is preferred for maintaining separate layers. In some embodiments, PEG conjugated lipids are used as the release layer 15 because the degree of hydrophilicity and miscibility with the active agent coating 12 can be adjusted by selecting the length of the lipid and the length of the PEG chain. In some embodiments, release layer 15 is 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-(methoxy(polyethylene glycol)-350) (DSPE-mPEG350) or 1,2-distearoyl-sn-glycero-3 -phosphoethanolamine-N-(methoxy(polyethylene glycol)-550) (DSPE-mPEG550). In some embodiments, the release layer 15 has a surface concentration of from about 0.1 μg/mm ² to about 5 μg/mm ² , from 0.25 μg/mm ² to about 3 μg/mm ² , or from 0.5 μg/mm ² to approximately 2 μg/mm ² .

[0050] Referring to FIG. 3, in some embodiments, catheter 10 further includes a protective layer 16 over cover 12 as a top cover. In some embodiments, the protective layer 16 includes a hydrophilic polymer, a carbohydrate, or an amphiphilic polymer. In some embodiments, the protective layer 16 is a glycosaminoglycan or crystallized sugar. Examples of glycosaminoglycans include dextran sulfate, chondroitin sulfate, heparan sulfate and hyaluronic acid. Examples of crystallized sugars include mannitol, sorbitol, erythritol and xylitol. The crystalline nature of these sugars provides a hard surface that protects the underlying microreservoirs. The thickness of the protective layer 16 can be adjusted so that the protective layer 16 is washed away during the travel time required to advance the catheter 10 to the target site. In some embodiments, the protective layer 16 has a surface concentration of from about 0.1 μg/mm ² to about 5 μg/mm ² , from about 0.2 μg/mm ² to about 4 μg/mm ² , or from about 0.3 μg /mm ² to approximately 3 µg/mm ² .

[0051] The expandable portion 11 of the catheter 10 may be a balloon that acts as a base for the cover 12. In some embodiments, the balloon may be of low pressure construction using an elastomeric material such as polyisoprene, polystyrene copolymers, polysiloxane, or polyurethane. In some embodiments, the cylinder may also have a high-pressure design using high tensile strength polymers such as polyvinyl chloride, polyethylene, polyethylene terephthalate, or nylon. In some embodiments, the expandable portion 11 may be made of nylon 12. The cover 12 may be sufficiently adherent to the expandable portion 11 but readily blend into the lumen of the vessel upon contact. In such cases, the separating layer may be omitted. In addition, nylon 12 has sufficient strength so that the balloon can additionally act as a post-dilatation balloon (if necessary) in a subsequent procedure after transferring the coating 12.

[0052] In some embodiments, the expandable portion 11 under the cover 12 can be used to expand the target vessel. In some embodiments, the vessel may be pre-dilated with another balloon catheter 10 prior to treatment with the coated balloon in accordance with the present embodiments.

Coating composition

[0053] Also described herein is a coating composition for the expandable portion 11 of the catheter 10. The composition includes a solid portion and a liquid. The solid portion includes a plurality of microreservoirs and at least one hydrophobic compound. The liquid acts to disperse or solubilize the at least one hydrophobic compound. In some embodiments, the liquid can disperse some hydrophobic compounds and solubilize other hydrophobic compounds. The microreservoirs are dispersed and suspended in the resulting mixture of liquid medium to obtain a coating composition. The liquid mixture is prepared to form a homogeneous mixture of hydrophobic compounds, which does not separate during drying, resulting in a uniform uniform coating of the hydrophobic matrix 14. The coating composition is characterized by the mass of the solid part, which refers to all non-volatile components of the coating composition, but excludes the liquid, which then evaporates during drying of the coating.

[0054] The microreservoirs include an active agent and a polymer. The active agent may be referred to as a first active agent or a second active agent, as described herein. The polymer may be a first biodegradable or biodegradable polymer or a second biodegradable or biodegradable polymer described herein. In some embodiments, the active agent is mixed or dispersed in a biodegradable or biodegradable polymer described herein. In some embodiments, the formulation may include more than one type of microreservoir. For example, the plurality of microreservoirs may include a first active agent and a first biodegradable or biodegradable polymer. In some embodiments, the plurality of microreservoirs may further include a second active agent. In some embodiments, the plurality of microreservoirs may also include a second biodegradable or biodegradable polymer.

[0055] Microreservoirs can be made by any of the known methods of producing particles, including spray drying, coacervation, micromolding and milling. All such methods begin by dissolving the active agent and polymer together in a suitable solvent, such as acetonitrile or dichloromethane, after which the solvent is removed in a controlled manner, creating uniform particles. The particles can be further shaped by mechanical means. Methods that produce particles with a size distribution with coefficients of variation of 10% or less are particularly suitable for providing more consistent release rates of the active agent. Methods for producing microspheres of uniform size are described by emulsifying the microsphere material and extruding the emulsion through a substrate with controlled through holes, as described in US Patents US 7,972,543 and US 8,100,348. Alternatively, microspheres can be prepared by spray drying polymer solutions, as described in US Patents US 6560897 and US 20080206349.

[0056] The coating liquid may contain water, an organic solvent, perfluorocarbon liquids, or a mixture of such liquids. In some embodiments, the liquid is selected from the group consisting of pentane, hexane, heptane, a mixture of heptane and a fluorocarbon, a mixture of an alcohol and a fluorocarbon, and a mixture of an alcohol and water. Liquids that readily solubilize the active agent or microreservoir polymer are not preferred since they may extract the active agent from the microreservoirs. Such undesirable liquids include acetic acid, acetonitrile, acetone, dichloromethane, ethyl formate, cyclohexanone, DMSO and chloroform. Optionally, the liquid/liquid mixture may be selected to saturate at the desired level of extracted active agent. An additional active agent, the same as that found in the microreservoirs, can be added to the liquid in advance to pre-saturate the solution, thereby reducing extraction from the microreservoirs during coating processing.

[0057] In some embodiments, the at least one hydrophobic compound is selected from the group consisting of sterols, lipids, phospholipids, fats, fatty acids and surfactants and derivatives thereof. In some embodiments, the at least one hydrophobic compound comprises cholesterol and a fatty acid, as described herein. In other embodiments, the at least one hydrophobic compound comprises cholesterol and a phospholipid, as described herein. In some embodiments, the formulation may also include a PEG lipid, as described herein. In some embodiments, the formulation may further include additives such as penetration enhancers and stabilizers.

[0058] In some embodiments, the solid portion further contains a third active agent outside the plurality of microreservoirs. In other words, the coating composition may provide a hydrophobic matrix 14 that further contains a third active agent. The active agent outside the microreservoirs may be the same or different from the active agent(s) in the microreservoirs. In some embodiments, the solid portion may further comprise a PEG lipid. In some embodiments, the solid portion may also further comprise an additive described herein.

[0059] In some embodiments, the percentage solids concentration by weight in the coating composition is from about 1% to about 90%. In some embodiments, the solids content of the coating composition has a concentration of from about 2% to about 80% by weight, from about 3% to about 70% by weight, or from about 4% to about 60% by weight. In some spray coating embodiments, the solid portion of the coating composition has a concentration of from about 2% to about 7% by weight. The solid portion of the coating composition comprises from about 10% to about 75%, from about 20% to about 65%, or from about 30% to about 55% by weight of the plurality of microreservoirs.

Coating method

[0060] The present invention also relates to a method for coating an expandable portion 11 of a catheter 10. These steps include: applying the composition described herein to the surface of an inflated expandable portion 11 of a catheter 10, evaporating the liquid components of the coating composition, and deflating the expandable portion 11 Applying the composition to the surface of the inflated expandable portion 11 involves applying the composition to the surface of the inflated expandable portion 11. In some embodiments, the composition may be applied to or over the inflated expandable portion 11 by spray coating, dip coating, roll coating, electrostatic deposition, printing, pipetting or dispensing.

[0061] The coating composition is prepared by mixing the coating components in a liquid medium as described herein. In some embodiments, the microreservoirs are dispersed in a liquid composition. Once completely mixed, the coating composition can be applied to the surface of the inflated expandable portion 11, such as a balloon, and dried to form coating 12. Application of the coating composition can be repeated as necessary to apply the desired amount of coating 12, typically in the range of about 5 mg to about 9 mg coating 12 per mm ² surface of the cylinder. Cover 12 is dried and the balloon is deflated and collapsed to allow insertion into the vascular system.

[0062] In some embodiments, the method may further include applying a release layer to the surface of the inflated expandable portion 11. Essentially, a coating composition is applied to the release layer, wherein the release layer is applied to the surface of the inflated expandable portion 11. The release layer is described above.

A method of treating or preventing a condition

[0063] Also described herein is a method for treating or preventing a condition at a treatment site. The method includes the steps of introducing a catheter 10 containing an expandable portion 11 to the treatment site, inflating the expandable portion 11 to provide contact between the coating 12 and tissue at the treatment site, deflating the expandable portion 11, and removing the catheter 10. The expandable portion 11 is coated with a coating described herein. In some embodiments, the contact between the fabric and the cover 12 causes at least a portion of the cover on the expandable portion 11 to be transferred to the treatment site through contact for a period of about 30 to about 120 seconds.

[0064] A catheter 10 with an expandable portion 11, such as a coated balloon catheter, is used in the present invention to demonstrate the concept of delivering an active agent or combination of active agents to a vessel. The coated balloon catheter is inserted into the vessel with the folded expandable portion 11 to provide a small cross-sectional profile and to facilitate percutaneous insertion of the catheter 10, for example, using the well-known Seldinger technique. After introducing the expandable portion 11 of the catheter 10 to the affected area of the vessel for treatment, the balloon is inflated and the coating 12 is in close contact with the lumen of the vessel. The coating is manufactured in such a way that it has an affinity for the surface of the intraluminal tissue, which leads to adhesion of the coating layer to the lumen of the vessel. The expandable portion 11 may be inflated or expanded for 30 seconds to 2 minutes to promote adhesion and allow initial penetration of the active agent into the vessel. The expandable portion 11 can be deflated and inflation repeated as needed for treatment to control the time period and risks of vessel occlusion or tissue ischemia. The coating is adhesively transferred into the lumen of the vessel when the balloon is inflated and the surface of the balloon is in firm contact with the surface of the lumen of the vessel. The adhesion of the coating to the surface of the vessel thereby transfers the microreservoirs and moves them to the surface of the vessel.

[0065] In some embodiments, the condition is selected from the group consisting of atherosclerosis, stenosis or reduction in luminal diameter in the affected blood vessel, restenosis, and in-stent restenosis. In some embodiments, an additional separating layer, as described herein, is located between the expandable portion 11 and the cover 12.

[0066] Although the present disclosure is directed to the treatment of restenosis associated with balloon dilatation of blood vessels, the present invention can be used to deliver drugs to various other lumens and hollow structures of the body, such as structures of the respiratory system, gastrointestinal system, urinary system, reproductive system and lymphatic system. The coated device may be an inflatable balloon or other inflatable device. Alternatively, the coating delivery device of the present invention may be a non-inflatable device or any other type of expandable device that is used to treat a living body.

EXAMPLES

Example 1

[0067] Microreservoirs (microspheres) containing a drug were prepared by coacervation of a polylactic-co-glycolic acid copolymer, including sirolimus (rapamycin).

[0068] Microsphere Sample 1: 50% DL-lactide/50% glycolide copolymer, average diameter 3.1 µm, SD 0.44 µm, 39% rapamycin by weight

[0069] Microsphere Sample 2: 75% DL-lactide/25% glycolide copolymer, average diameter 3.2 µm, SD 0.76 µm, 40% rapamycin by weight

[0070] Microsphere sample 3: 50% DL-lactide/50% glycolide copolymer, average diameter 2.7 µm, SD 0.8 µm, 45% rapamycin by weight

[0071] Microsphere Sample 4: 75% DL-lactide/25% glycolide copolymer, average diameter 3.3 µm, SD 1.2 µm, 46% rapamycin by weight

[0072] Microsphere Sample 5: 75% DL-lactide/25% glycolide copolymer, average diameter 4.1 µm, SD 0.61 µm, 25% rapamycin by weight

[0073] Microsphere Sample 6: 75% DL-lactide/25% glycolide copolymer, average diameter 3.78 µm, SD 0.44 µm, 28.8% rapamycin by weight

[0074] Microsphere Sample 7: 75% DL-lactide/25% glycolide copolymer, average diameter 3.8 µm, SD 0.34 µm, 27.7% rapamycin by weight

[0075] Microsphere Sample 8: 75% DL-lactide/25% glycolide copolymer, average diameter 3.79 µm, SD 0.39 µm, 29.4% rapamycin by weight

[0076] The drug content of these microreservoirs was checked by a quantitative assessment method using HPLC. Typically, microreservoirs (1 to 5 mg) were weighed and dissolved in 1 mL acetonitrile, stirred gently at room temperature for several hours or 37°C for 1 hour, and diluted 50- to 200-fold with acetonitrile. Absorbance was tested at 278 nm and content was determined from linear calibration curves.

Example 2: Continuous drug release from microreservoirs under physiological conditions

[0077] The microreservoirs from Example 1 were tested for sustained drug release. Microreservoir samples weighing 2-5 mg were placed in 1.6 ml Eppendorf tubes with 1.2 ml phosphate buffered saline (PBS) to simulate a physiological environment. After an initial wash to remove any drug not included in the microreservoirs, the tubes were incubated at 37°C with gentle agitation at 250 rpm. PBS was withdrawn at time intervals and the released drug was quantified by reverse phase HPLC using a C18 column.

[0078] The microreservoirs were assayed for drug elution over a period of 5 hours. The resulting drug release followed the Korsmeyer-Peppas kinetic equation for drug release from a drug-dispersed polymer. The results of the Korsmeyer-Peppas model are shown in Table 1.

Table 1. Korsmeyer-Peppas simulation of drug release over 5 hours.

Q=a*x^b Microsphere 1 Microsphere 2 Microsphere 3 Microsphere 4 R (correlation coefficient) 0.9061 0.8778 0.8579 0.9016 SE estimates 0.0026 0.0025 0.0021 0.0033 a 0.0450 0.0382 0.0305 0.0506 b 0.5241 0.5204 0.5167 0.4502

[0079] Short-term delivery results demonstrate Korsmeyer-Peppas drug release constants typical of drug dispersed in a spherical polymer particle, likely with little contribution from polymer breakdown or degradation for microsphere samples 1, 2, and 3.

[0080] Sustained Drug Release Study: Microspheres were assayed for drug elution over 7 days using the methods described for 5 hour testing. The resulting drug release is shown in Table 2.

Table 2. Drug release testing over 7 days

Cumulative drug release, % total drug Time [days] Microsphere 1 Microsphere 2 Microsphere 3 Microsphere 4 0 0.9% 1.5% 2.3% 2.2% 1 1.8% 2.8% 3.3% 3.9% 2 2.3% 4.1% 4.0% 5.0% 3 4.2% 6.1% 4.6% 5.9% 4 5.7% 13.4% 5.2% 6.9% 5 7.5% 19.6% 5.8% 7.7% 6 10.0% 26.2% 6.4% 8.7% 7 11.9% 30.7% 7.0% 9.5%

[0081] Release rates based on 7-day delivery followed the Higuchi equation:

Q=A [D(2C - Cs)Cs t] ^1/2

Q=K _h (t) ^1/2

where Q is the amount of drug released per time t per unit area A, C is the initial drug concentration, Cs is the solubility of the drug in the polymer medium, and D is the diffusion coefficient of the drug in the microsphere polymer. In the generalized equation, K _h represents the Higuchi constant, including area, diffusion coefficient, and drug concentration coefficients.

[0082] The Higuchi equation was used to determine the half-life of the drug from the microreservoirs, as well as to estimate the half-life as a function of microsphere size. The resulting drug half-lives are presented in Table 3.

Table 3. Drug half-life according to the Higuchi model

Microsphere diameter [micrometers] t ^1/2 [days] Microsphere 1 Microsphere 2 Microsphere 3 Microsphere 4 0.5 0.14 0.02 0.42 0.11 1 2.29 0.34 6.65 1.70 1.5 11.58 1.71 33.66 8.61 2 36.60 5.42 106.38 27.22 3 185.29 27.43 538.53 137.81 4 585.62 86.71 1702.01 435.55 5 1429.74 211.69 4155.29 1063.36 6 2964.70 438.96 8616.42 2204.98 7 5492.48 813.22 15962.98 4084.99 8 9369.93 1387.32 27232.13 6968.81

[0083] The results obtained indicate that the half-life of a drug from microreservoirs can be tailored to the composition and size of the microreservoirs. It is estimated that a microsphere size of 1.5 micrometers in diameter or greater is required for a drug half-life of at least 14 days.

[0084] Sustained Release Verification: Microsphere sample 4 was assayed for drug release over 8 weeks using previously described methods. Due to the relatively long time intervals between samples compared to previous release experiments, the microreservoirs may not have released drug under complete dissolution conditions at later time points, potentially slowing down the effective release rate. The resulting drug release is shown in Table 4.

Table 4. Extended release drug testing over 56 days

Time [days] Cumulative eluted drug [%] 0 0 7 1.00 14 3.00 31 7.50 56 15.50

[0085] The results confirm the continuous release of drug from the microreservoirs. Microreservoirs can be selected or selected based on the half-life of the drug to provide the drug during the healing period of the dilated vessel.

Example 3: Microreservoir Compositions in a Cholesterol Fatty Acid Coating Formulation with PEG Lipid

[0086] The coating composition was prepared with 107 mg of stearic acid, 105 mg of cholesterol and 50 mg of DPPE-mPEG350 mixed with 14 mg of heptane and heated to 60°C to obtain a clear solution. The solution was then vortexed for 30 seconds and left to cool. 200 mg of sample #6 sirolimus loaded microspheres were then added and the formulation was placed in an ultrasonic bath for 4 minutes to disperse and suspend the microspheres. [Composition 1023E]

[0087] The coating composition was prepared with 58 mg of erucic acid, 43 mg of DC-cholesterol and 6.25 mg of DOPE-mPEG350 mixed with 7 mg of heptane and heated to 60°C to obtain a clear solution. The solution was then vortexed for 30 seconds and left to cool. 100 mg of sample #8 sirolimus loaded microspheres were then added and the formulation was placed in an ultrasonic bath for 5 minutes to disperse and suspend the microspheres. [Composition 0424A]

[0088] The coating composition was prepared with 25 mg of nervonic acid, 75 mg of DC-cholesterol and 6.25 mg of DOPE-mPEG350 mixed with 7 mg of heptane and heated to 60°C to obtain a clear solution. The solution was then vortexed for 30 seconds and left to cool. 97 mg of sample #8 sirolimus loaded microspheres were then added and the formulation was placed in an ultrasonic bath for 5 minutes to disperse and suspend the microspheres. [Composition 0422E]

Example 4: Composition of microreservoirs in a coating composition of cholesterol and fatty acid, PEG lipid and stabilizing additive

[0089] The coating composition was prepared with 77 mg of stearic acid, 40 mg of cholesterol, 50 mg of DPPE-mPEG350, and 58 mg of alpha-tocopherol mixed with 7 mg of heptane and heated to 60°C until a clear solution was obtained. The solution was vortexed for 1 minute and then allowed to cool to room temperature. 100 mg of sample #5 microspheres loaded with sirolimus were then added. The composition was placed in an ultrasonic bath for 5 minutes to disperse and suspend the microspheres. [Composition 1009A]

Example 5: Composition of Microreservoirs in a Cholesterol and Phospholipid Coating Composition

[0090] The coating composition was prepared with 43 mg of cholesterol and 42 mg of L-alpha-phosphatidylcholine mixed with 7 mg of heptane and heated to 60°C. 100 mg of sample #5 microspheres loaded with sirolimus were then added to the flask, which was then placed in an ultrasonic bath for 8 minutes to disperse and suspend the microspheres. [Composition 0311A]

Example 6: Composition of Microreservoirs in a Long Acyl Chain Cholesterol and Phospholipid Coating Formulation with or without Addition of PEG Lipid

[0091] The coating composition was prepared with 51 mg of cholesterol and 51 mg of L-alpha-phosphatidylcholine mixed with 7 mg of heptane and heated to 60°C. 100 mg of sample #7 microspheres loaded with sirolimus were then added to the flask, which was then placed in an ultrasonic bath for 5 minutes to disperse and suspend the microspheres. [Composition 0410A]

[0092] The coating composition was prepared with 20 mg DC-cholesterol, 26 mg cholesterol, 6.25 mg DOPE-mPEG350 and 75 mg dinervonylphosphatidylcholine (DNPC) mixed with 7 mg heptane and heated to 60°C. The formulation had a DNPC to DC-cholesterol weight ratio of 1.6:1. The solution was left to cool to room temperature. 97 mg of sample #7 microspheres loaded with sirolimus were then added to the flask, which was then vortexed for 30 seconds, and then placed in an ultrasonic bath for 5 minutes to disperse and suspend the microspheres. [Composition 0421A]

[0093] The coating composition was prepared with 28 mg of cholesterol and 50 mg of L-alpha-phosphatidylcholine mixed with 7 mg of heptane and heated to 60°C. The solution was vortexed for 30 seconds and then allowed to cool to room temperature. 97 mg of sample #7 microspheres loaded with sirolimus were then added to the flask, which was then placed in an ultrasonic bath for 5 minutes to disperse and suspend the microspheres. [Composition 0421B]

[0094] The coating composition was prepared with 50 mg DC-cholesterol and 50 mg dinervonylphosphatidylcholine (DNPC) mixed with 7 mg heptane and heated to 60°C. The composition had a weight ratio of DNPC to DC-cholesterol of 1:1. The solution was vortexed for 30 seconds and then allowed to cool to room temperature. 100 mg of sample #7 microspheres loaded with sirolimus were then added to the flask, which was then placed in an ultrasonic bath for 4 minutes to disperse and suspend the microspheres. [Composition 1205A]

[0095] The coating composition was prepared with 49 mg DC-cholesterol, 6.25 mg cholesterol, 6.25 mg DOPE-mPEG350 and 50 mg dinervonylphosphatidylcholine (DNPC) mixed with 7 mg heptane and heated to 60°C. The composition had a weight ratio of DNPC to DC-cholesterol of 1:1. The solution was vortexed for 30 seconds and then allowed to cool to room temperature. 100 mg of sample #7 microspheres loaded with sirolimus were then added to the flask, which was then placed in an ultrasonic bath for 2 minutes to disperse and suspend the microspheres. [Composition 1209A]

[0096] The coating composition was prepared with 76 mg DC-cholesterol, 6.25 mg DOPE-mPEG350 and 25 mg dinervonylphosphatidylcholine (DNPC) mixed with 7 mg heptane and heated to 60°C. The composition had a weight ratio of DNPC to DC-cholesterol of 1:3. The solution was left to cool to room temperature. 100.7 mg of sample #8 sirolimus loaded microspheres were then added to the flask, which was then vortexed for 30 seconds, and then placed in an ultrasonic bath for 5 minutes to disperse and suspend the microspheres. [Composition 0513A]

Example 7: Composition of microreservoirs in DC-cholesterol coating composition with variable PEG-lipid content

[0097] The coating composition was prepared with 12.5 mg DOPE-mPEG350, 44 mg DC-cholesterol and 44 mg dinervonoyl phosphatidylcholine (DNPC) mixed with 7 mg heptane heated to 60°C. The clear solution was allowed to cool to room temperature, then 97 mg of sirolimus-loaded microspheres from sample #8 microspheres was added. The formulation was then placed in an ultrasonic bath and sonicated for 5 minutes to disperse and suspend the microspheres. [Composition 0422A]

[0098] The coating composition was prepared with 25 mg DOPE-mPEG350, 37.5 mg DC-cholesterol and 37.5 mg dinervonoyl phosphatidylcholine (DNPC) mixed with 7 mg heptane heated to 60°C. The clear solution was allowed to cool to room temperature, then 97 mg of sirolimus-loaded microspheres from sample #8 microspheres was added. The formulation was then placed in an ultrasonic bath and sonicated for 5 minutes to disperse and suspend the microspheres. [Composition 0422B]

Example 8: Coating with additional drug

[0099] The coating composition was prepared with 72.9 mg DC-cholesterol in 7 mg heptane and heated to 60C until the DC-cholesterol solubilized to obtain a clear solution. 15.5 mg of sirolimus was added to the solution and vortexed for 30 seconds. The solution was heated for 40 minutes, vortexing for 10 seconds every 10 minutes, and sonicated for 5 minutes while cooling to room temperature. 50 mg of DNPC was added to the solution. Once room temperature was reached, the solution was filtered through a 0.2 micrometer PTFE filter to remove large drug particles. The solution was left overnight without observing the macroparticles formed during the night. The solution was analyzed and the content of sirolimus was determined to be 0.96 mg per ml. 98 mg of sirolimus-loaded microspheres from microsphere sample #8 were added to the solution, vortexed for 30 seconds, and sonicated for 8 minutes to disperse and suspend the microspheres. The resulting coating composition contained 0.71% by weight of sirolimus, in which 19.1% of the drug was in a hydrophobic matrix of DC-cholesterol and DNPC and the remainder in microspheres. [Composition 0512A]

[0100] The weight percentages of the coating compositions described in Examples 3, 4, 5, 6, 7 and 8 are presented in Table 5.

Table 5. Weight Percentages of Coating Compositions

Coating composition Fatty acid or phospholipid Cholesterol PEG lipid Microspheres Other Heptane Sirolimus ° [%] [%] [%] [%] [%] [%] [%] 1023E Stearic acid Cholesterol DPPE-mPEG350 1.07% 1.05% 0.50% 2.01% 95.37% 0.58% 0424A Erucic acid DC Cholesterol DOPE-mPEG350 1.17% 0.87% 0.13% 2.01% 95.82% 0.59% 0422E Nervonic acid DC Cholesterol DOPE-mPEG350 0.50% 1.51% 0.13% 1.96% 95.90% 0.57% 1009A Stearic acid Cholesterol DPPE-mPEG350 alpha tocopherol 1.52% 0.79% 0.98% 1.97% 1.14% 93.60% 0.45% 0311A L-alpha phosphatidylcholine Cholesterol 0.85% 0.87% 2.02% 96.26% 0.47% 0410A DEPC DC Cholesterol DOPE-mPEG350 1.03% 1.03% 0.13% 2.01% 95.81% 0.56% 0421A DNPC Cholesterol/DC Cholesterol DOPE-mPEG350 1.51% 0.52%/0.40% 0.13% 1.95% 95.50% 0.54% 0421B DNPC Cholesterol/DC Cholesterol DOPE-mPEG350 1.01% 0.52%/0.56% 0.13% 1.95% 95.82% 0.54% 1205A DNPC DC Cholesterol 1.01% 1.01% 2.02% 95.96% 0.56% 1209A DNPC DC Cholesterol DOPE-mPEG350 1.01% 0.99% 0.13% 2.02% 95.86% 0.56% 0513A DNPC DC Cholesterol DOPE-mPEG350 0.50% 1.53% 0.13% 2.03% 95.81% 0.60% 0422A DNPC DC Cholesterol DOPE-mPEG350 0.89% 0.89% 0.25% 1.96% 96.01% 0.58% 0422B DNPC DC Cholesterol DOPE-mPEG350 0.76% 0.76% 0.50% 1.96% 96.02% 0.58% 0512A DNPC DC Cholesterol Sirolimus in a hydrophobic matrix 1.00% 1.46% 1.97% 0.13% 95.43% 0.71%

Example 9: Coating a Balloon Catheter

[0101] The stearic acid coating composition of Example 3 (formulation 1023E) was sprayed onto the surface of a nylon angioplasty balloon with a diameter of 5.0 mm and a length of 20 mm. Seven ml of the coating composition was loaded into a 25 ml gas-tight syringe with a built-in magnetic stirrer. The formulation was continuously stirred during spraying to maintain a good suspension of the drug microreservoirs. A syringe pump delivered the coating formulation at a rate of 0.11 mL/min through a 120 kHz ultrasonic nozzle activated by 5.5 W [Sonotek DES1000]. To verify the parameters of the method, a cylinder made of cylinder material with a diameter of 5.0 mm × 20 mm long was cut out, weighed and placed on a cylinder of a similar size. This shell of balloon material was then coated and approximately 2.2 mg of total coating was weighed for verification, corresponding to a coating density of 7 μg/mm ² . Of the 7 μg/mm ² formulation from Example 3, stearic acid was approximately 1.6 μg/mm ² , cholesterol was 1.6 μg/mm ² , DPPE-mPEG350 was 0.8 μg/mm ² and sirolimus loaded microspheres from microsphere sample #5 was 3 μg/mm ² , providing a drug density of 0.87 μg/mm ² . Once the target shell weight was confirmed to be achieved, the balloons were completely coated. A 5.0 mm diameter x 20 mm long balloon was inflated, positioned under the nebulizer, and then continuously rotated, moving back and forth 5 times. The balloon was then removed and left to dry. The method was repeated until 6 balloons were coated. The same method was repeated to spray the coating composition from Example 6 (composition 0513A) onto 3.0 mm diameter x 20 mm length canisters. The target coating weight of a 3.0 mm diameter x 20 mm long balloon shell with the composition of Example 6 (Formulation 0513A) was 1.4 mg to achieve a coating density of 7.6 μg/mm ² . Of this 7.6 μg/mm ^{2 ,} dinervonoyl phosphatidylcholine was 0.9 μg/mm ² , DC-cholesterol was 2.7 μg/mm ² , DOPE-mPEG350 was 0.23 μg/mm ² , and sirolimus-loaded microspheres from sample #5 were 3.7 μg/mm ² , providing a drug density of 1.08 μg/mm ² .

[0102] The coating compositions of Examples 4, 5, 6, 7 and 8 were also sprayed onto the surface of the 20 mm long canisters using the composition spray method as previously described for Example 3. The resulting coating masses and coating densities are presented in Table 6.

Table 6. Balloon Catheter Coatings

Example Compound Cylinder diameter % coating solids (w/w) Coating weight Coating Density Cholesterol Density Fatty acid or phospholipid density PEG lipid density Microsphere density Drug density [mm] [%] [mg] [µg/mm ² ] [µg/mm ² ] [µg/mm ² ] [µg/mm ² ] [µg/mm ² ] [µg/mm ² ] 3 1023E 5 4.86% 2.19 6.97 1.58 1.61 0.75 3.02 0.87 3 424A 5 4.36% 2.05 6.53 1.35 1.83 0.20 3.15 0.93 3 0422E 5 4.27% 1.82 5.79 2.14 0.71 0.18 2.76 0.81 4 109A/
1010D 5 6.83% 2.54 8.09 1.00 1.92 1.24 2.49 0.57 5 0311A 5 3.89% 1.7 5.41 1.26 1.23 0.00 2.93 0.67 6 410A 5 4.38% 2.31 7.35 1.80 1.80 0.22 3.53 0.98 6 0421A 5 4.71% 1.88 5.98 1.23 2.00 0.17 2.59 0.72 6 0421B 5 4.36% 1.83 5.83 1.52 1.41 0.18 2.73 0.76 6 1205A 5 4.20% 1.78 5.67 1.42 1.42 0.00 2.83 0.78 6 1209A 5 4.32% 2.24 7.13 1.70 1.74 0.22 3.47 0.96 6 513A 3 4.37% 1.43 7.59 2.77 0.91 0.23 3.67 1.08 7 0422A 5 4.15% 1.8 5.73 1.28 1.28 0.36 2.81 0.83 7 0422B 5 4.14% 1.83 5.83 1.11 1.11 0.74 2.87 0.84 8 512A 3 4.79% 1.51 8.01 2.57 1.76 0.00 3.45 1.25

[0103] For canisters coated with the composition of Example 4, an additional topcoat composition (1010D) consisting of 1 mg of cholesterol and PEG600-cholesterol was sprayed onto each canister to coat the microreservoir layer. To prepare this topcoat, 23 mg of cholesterol-PEG600 and 224 mg of cholesterol were dissolved in 7 ml of isopropanol. A target coating mass of 1 mg on a 5.0 mm diameter x 20 mm long canister corresponds to 3.2 μg/mm ² total topcoat consisting of 0.3 μg/mm ² cholesterol-PEG600 and 2.9 μg/mm ² cholesterol.

Example 10: Adhesion of coatings to the surface of the lumen of a vessel

[0104] Ex-vivo porcine arteries were flushed with 37°C lactated Ringer's solution at a pulsatile flow of 50 ml/min (approximately 72 beats/min) for 5 minutes. Balloons coated with the composition of Example 3 were inflated into the lumen of ex-vivo porcine arteries. vivo to an approximate stretch of 1:1.2 to transfer the drug-containing coating into the lumen of the vessel. The solution passed through the arteries before and after inflation (before and after flushing), the balloon applied to the arteries, and the portion of the artery in contact with the inflated balloon were subsequently analyzed for drug content 5 minutes after inflation. Vessels treated with formulations 1205A and 1209A were washed for 60 minutes to evaluate the increased stability of the transferred coating. The amount of drug measured in all analysis sources was summed and compared with the estimated drug content of the cylinder based on the weight of the coating. The proportion of drug transferred into the artery, based on the estimated drug content of the balloon taking into account the coating mass, was used as an indicator of transfer efficiency.

Table 7. Composition stearic acid - cholesterol [Composition 1023E]

Cylinder sample Extracted sirolimus [mcg] Total sirolimus extracted [µg] % of total ballooned sirolimus transferred into the artery 1 min before rinsing 1 minute after rinsing 2 minutes after rinsing Remaining on the cylinder Artery 53 12 110 10 9 66 207 16 54 27 120 10 19 90 266 22 55 thirty 87 7 26 136 286 33 56 23 177 10 6 53 269 13 57 37 186 9 6 99 337 24 58 16 148 10 0 38 212 9 Average 24.2 138.0 9.3 11.0 80.3 262.8 19.5 SD 9.2 39.17 1.2 9.6 35.5 48.6 9

Table 8. Composition erucic acid - DC-cholesterol [Composition 0424A]

Cylinder sample Extracted sirolimus [mcg] Total sirolimus extracted [µg] % of total ballooned sirolimus transferred into the artery 1 min before rinsing 1 minute after rinsing 2 minutes after rinsing Remaining on the cylinder Artery 0424A-1 1 4 1 160 8 185 3 0424A-2 2 5 2 214 12 247 5 0424A-3 2 9 1 253 7 290 3 Average 1.8 5.9 1.5 209.2 8.8 240.8 3.9 SD 0.4 2.7 0.8 46.7 2.9 53.0 1.3

Table 9. Composition nervonic acid - DC-cholesterol [Composition 0422E]

Cylinder sample Extracted sirolimus [mcg] Total sirolimus extracted [µg] % of total ballooned sirolimus transferred into the artery 1 min before rinsing 1 minute after rinsing 2 minutes after rinsing Remaining on the cylinder Artery 0422E-1 5 28 6 128 62 229 22 0422E-2 3 39 4 90 35 171 12 0422E-3 16 8 4 76 84 187 29 Average 8 25 4 98 61 196 21.2 SD 7 16 1 27 25 thirty 8.6

[0105] Balloons coated with the composition of Example 4 were also tested on porcine arteries ex-vivo.

Table 10. Composition stearic acid - cholesterol-alpha tocopherol [Composition 1009A/1010D]

Cylinder sample Extracted sirolimus [mcg] Total sirolimus extracted [µg] % of total ballooned sirolimus transferred into the artery 1 min before rinsing 1 minute after rinsing 2 minutes after rinsing Remaining on the cylinder Artery 40 N/A 78 3 354 28 463 6 41 12 120 4 301 31 468 6

[0106] Balloons coated with the composition of Example 5 were also tested on porcine arteries ex-vivo.

Table 11. Composition of L-alpha-phosphatidylcholine - cholesterol [Composition 0311A]

Cylinder sample Extracted sirolimus [mcg] Total sirolimus extracted [µg] % of total ballooned sirolimus transferred into the artery 1 min before rinsing 1 min after 2 minutes after Remaining on the cylinder Artery 0311A-1 51 60 4 12 26 153 9 0311A-2 100 74 4 25 7 210 2 0311A-3 44 92 5 26 45 212 15 Average 65.0 75.3 4.3 21.0 26.0 191.7 8.7 SD 30.5 16.0 0.6 7.8 19.0 33.5 6.5

[0107] Balloons coated with the composition of Example 6 were also tested on porcine arteries ex-vivo.

Table 12. DEPC - DC-cholesterol [Composition 0410A]

Cylinder sample Extracted sirolimus [mcg] Total sirolimus extracted [µg] % of total ballooned sirolimus transferred into the artery 1 min before rinsing 1 min after 2 minutes after Remaining on the cylinder Artery 0410A-1 17 21 3 12 196 249 52 0410A-2 34 12 2 15 228 290 60 0410A-3 17 thirty 1 14 137 199 53 Average 65 75 4 21 26 192 55 SD 31 16 1 8 19 34 6.3

Table 13. Composition of DNPC - DC-Cholesterol [Composition 0421A]

Cylinder sample Extracted sirolimus [mcg] Total sirolimus extracted [µg] % of total ballooned sirolimus transferred into the artery 1 min before rinsing 1 min after 2 minutes after Remaining on the cylinder Artery 0421A-1 16 6 1 32 127 259 40% 0421A-2 18 13 3 29 114 240 35% 0421A-3 21 9 7 24 138 264 43% Average 18.4 9.4 3.6 28.4 126.4 254.4 39.4% SD 2.7 3.6 2.7 4.2 12.2 12.5 3.8%

Table 14. Composition of DNPC - DC-Cholesterol - Cholesterol [Composition 0421B]

Cylinder sample Extracted sirolimus [mcg] Total sirolimus extracted [µg] % of total ballooned sirolimus transferred into the artery 1 min before rinsing 1 min after 2 minutes after Remaining on the cylinder Artery 0421B-1 8 16 1 120 131 276 45 0421B-2 5 21 2 196 108 331 37 0421B-3 4 22 5 137 83 250 28 Average 5.3 19.7 2.7 151.2 107.1 286.0 36.7 SD 2.1 2.9 2.0 39.9 23.9 41.3 8.2

Table 15. Composition of DNPC - DC-Cholesterol (No PEG Lipid) [Composition 1205A]

Cylinder sample Extracted sirolimus [mcg] Total sirolimus extracted [µg] % of total ballooned sirolimus transferred into the artery 1 min before rinsing 1 min after 2 minutes after Remaining on the cylinder Artery 106 14 47 3 94 168 326 47 105 10 84 5 142 165 406 46 107 8 68 4 100 147 327 41 108 9 43 4 121 144 321 41 109 4 66 9 62 158 299 45 110 3 52 1 128 126 310 35 Average 8.0 60.0 4.3 107.8 151.3 331.5 42.5 SD 4.0 15.5 2.7 28.6 15.6 38.0 4.5

Table 16. [ Composition DNPC - DC-Cholesterol (PEG-lipid) [Composition 1209A]

Cylinder sample Extracted sirolimus [mcg] Total sirolimus extracted [µg] % of total ballooned sirolimus transferred into the artery 1 min before rinsing 1 min after 2 minutes after Remaining on the cylinder Artery 124 5 64 1 thirty 148 248 38 125 5 79 4 88 158 334 41 126 4 45 9 144 152 354 39 127 8 73 5 135 124 345 32 128 2 49 5 98 190 344 49 129 4 89 5 90 149 337 38 Average 4.7 66.5 4.8 97.5 153.5 327.0 39.5 SD 2.0 17.2 2.6 40.7 21.3 39.3 5.5

Table 17. Composition of DNPC - DC-Cholesterol (PEG-lipid) [Composition 0513A]

Cylinder sample Extracted sirolimus [mcg] Total sirolimus extracted [µg] % of total ballooned sirolimus transferred into the artery 1 min before rinsing 1 min after 2 minutes after Remaining on the cylinder Artery 0513A-1 6 4 1 134 67 212 thirty% 0513A-2 5 12 2 150 85 254 38% 0513A-3 5 2 1 152 88 248 39% Average 5.3 6.0 1.3 145.3 80.0 238.0 35.4% SD 0.6 5.3 0.6 9.9 11.4 22.7 5.0%

[0108] The lumen surface of the artery after expansion of the 1209A-coated balloon and one hour after flushing with the postexpansion fluid was examined by dark field microscopy. Figure 4 is a micrograph of the lumen surface at 200x magnification showing adherent material. Figure 5 is a micrograph of the surface at 1000x magnification, showing that the adherent material is a layer of spherical microreservoirs surrounded by coating material.

Example 11: Adhesion of coatings to the intraluminal surface of a vessel for formulations with variable PEG-lipid content

[0109] Samples from Example 7 were tested for coating transfer and wash resistance using the methods of Example 10. The results are tabulated to compare coatings with DNPC and DC-Cholesterol in equal proportions with varying amounts of DOPE-mPEG350. [Compositions 1205A, 1209A, 0422A, 0422B]

Table 18. Coating Transfer and Wash Resistance of Various Coating Formulations

Compound Extracted sirolimus [mcg] Total sirolimus extracted [µg] % of total ballooned sirolimus transferred into the artery 1 min before rinsing 1 min after 2 minutes after Remaining on the cylinder Artery No PEG lipid 8.0
±4.0 60.0
±15.5 4.3
±2.7 107.8
±28.6 151.3
±15.6 331.5
±38.0 42.5
±4.5 5.9% mPEG 350 4.7
±2.0 66.5
±17.2 4.8
±2.6 97.5
±40.7 153.5
±21.3 327.0
±39.3 39.5
±5.5 12.4% mPEG 350 6.5
±3.2 38.9
±21.0 4.5
±0.6 107.4
±35.5 90.4
±29.2 247.6
±55.1 30.0
±9.7% 25% mPEG 350 25.0
±26.1 68.3
±36.7 6.2
±3.2 17.9
±12.0 106.7
±19.8 224.1
±27.8 36.0
±6.7%

[0110] The results demonstrate significant transfer of the drug-containing coating into the lumen of the vessel. Loss of drug coating during prewash increased for the 25% PEG-lipid coating formulation.

Example 12: Adhesion of a coating containing additional rapamycin to the intraluminal surface of a vessel

[0111] The composition of Example 8 was tested for coating transfer and wash-off resistance using the methods of Example 10.

Table 19. Composition of DNPC - DC-Cholesterol with additional drug [Composition 0512A]

Cylinder sample Extracted sirolimus [mcg] Total sirolimus extracted [µg] % of total ballooned sirolimus transferred into the artery 1 min before rinsing 1 min after 2 minutes after Remaining on the cylinder Artery 0512A-1 3 43 2 155 76 279 29% 0512A-2 5 9 10 51 39 114 15% 0512A-3 6 8 2 135 47 198 18% Average 4.7 20.0 4.7 113.7 54.0 197.0 20.9% SD 1.5 19.9 4.6 55.2 19.5 82.5 7.5%

[0112] The results demonstrate significant drug transfer into the lumen of the vessel from the coating with the addition of additional drug to the phospholipid and cholesterol components of the coating composition.

Example 13: Release of drug into the vessel to be treated in-vivo

[0113] To prepare balloon catheters coated with a drug-containing microreservoir formulation, 100 mg of DNPC, 103 mg of DC-cholesterol, and 12.5 mg of DOPE-mPEG350 were mixed with 14 mg of heptane. The mixture was heated to 60°C to dissolve the solid components and cooled to room temperature. 195 mg of sample #6 microspheres were then added and mixed to suspend the microspheres. Balloon catheters with 3.0 mm diameter x 20 mm length balloons were coated using the methods described in Example 9. The coated balloon catheters were dried. An average of 1.28 mg ± 0.12 mg of dry coating was applied to the canisters, resulting in a coating density of 6.80 μg/mm ² and a drug density of 1.06 μg/mm ² . The cylinders were deflated and folded for later use into a configuration with a smaller cross-section and packaged in a casing to maintain the folded configuration. Balloon catheters were packaged and sterilized with ionizing radiation at a minimum dose of 25 kiloGy.

[0114] Rabbit ileofemoral artery was used to evaluate in vivo transport of drug coating into the arterial vessel. The treatment segment of the ileofermoral artery was first freed from the endothelium to reproduce tissue damage after angioplasty. An incision was made in the common carotid artery, and a balloon-sized wedge-shaped catheter was inserted into the artery and guided under fluoroscopic guidance to the treatment site of the ideofemoral artery. Contrast agent was administered through the catheter and angiograms of the ideofemoral arteries were recorded. The balloon wedge catheter was replaced with a standard angioplasty balloon catheter of 3.0 mm in diameter and 8 mm in length under fluoroscopic guidance, inflated and retracted proximally in its extended state to approximately the level of the iliac bifurcation to expose part of the artery. The angioplasty balloon catheter was replaced with a drug-eluting balloon catheter. The catheter was advanced to the exposed vessel site and inflated for 120 seconds. The balloon was deflated and removed. Both the right and left iliac arteries of each animal were treated.

[0115] A total of 11 animals were treated. One animal (2 treated iliac arteries) was euthanized 1 hour after treatment, and vascular sections were removed for microscopic examination. Another animal (2 treated iliac arteries) was euthanized 24 hours after treatment, and vascular sections were removed for microscopic examination. Three animals (6 iliac arteries) were removed at each time point of 1 hour, 7 days, and 28 days. Blood samples from these animals were collected before surgery, 0.5, 1, 4 hours after treatment and at sacrifice. Vessel segments were removed and analyzed for drug content by HPLC/MS quantification.

[0116] Analysis of blood samples showed a rapid decrease in the amount of drug in the circulating blood with a concentration of 4.75 ng/ml after 30 minutes, 2.63 ng/ml after 1 hour and 0.82 ng/ml after 4 hours. Drug concentrations in blood collected at sacrifice on days 7 and 28 were below the detection limit for quantitative analysis. Blood levels followed an exponential decay curve with a half-life of 0.77 hours, indicating rapid dilution and clearance of the drug through the bloodstream.

[0117] Scanning electron microscopy and light microscopy of tissue samples collected 1 hour and 24 hours after treatment showed a layer of material on the intraluminal surface of the vessel with spherical drug microreservoirs within the layer. Irregular areas of fibrin were observed on the intraluminal surface, but large fibrin deposits indicative of blood incompatibility associated with the coating were not observed.

[0118] Analysis of treated vascular segments showed tissue drug levels of 261 μg/g ± 116.5 μg/g 1 hour after treatment, 43.8 μg/g ± 34.2 μg/g 7 days after treatment and 21.5 µg/g ± 17.3 µg/g 28 days after treatment. The results indicate adhesion of the coating containing drug microreservoirs to the intraluminal surface of the artery with the continuous presence of drug bound to the tissue of the treated vessel after 28 days. Tissue-bound drug levels showed a rapid initial decline that slowed between 7 and 28 days. Tissue bound drug levels from days 7 to 28 followed an exponential decay, indicating a half-life of approximately 20.4 days.

Example 14: Adhesion of coatings to the intraluminal surface of a vessel for a coating composition containing sirolimus microparticles

[0119] Sirolimus crystalline powder was crushed, 100 mg was taken and added to approximately 75 mg of a phospholipid excipient composition (approximately 15% DOPE-mPEG350, 35% DNPC, 50% DC-Cholesterol). Milled sirolimus microparticles were dispersed and suspended in the formulation using a magnetic stirrer and then nebulized onto 4x30 mm balloon catheters using a Sonotek PSI ultrasonic nebulization system. The flow rate of the ultrasonic nebulization formulation was set at 0.210 ml/min and 4 passes were used to achieve a target coating mass of 2 milligrams, corresponding to approximately 3 μg of sirolimus per mm ² canister surface area. Fig. 6 is a micrograph of the surface of a coated balloon at 100x magnification showing the coating containing microreservoirs containing crystalline sirolimus.

[0120] Several 4 mm diameter porcine carotid arteries were connected to a pulsatile flow system of lactated Ringer's solution at 72 bpm at a rate of approximately 100 ml/min. Covered balloon catheters were inserted into the artery and left deflated while fluid was pumped through the artery for 1 minute and collected to simulate flushing while moving to the lesion. The balloon was then inflated for one minute, deflated, removed, the artery irrigated, and fluid collected for an additional minute. During the second minute, the rinsing fluid was collected separately, after which the fluid was allowed to flow for another 3 minutes, for a total of 5 minutes. After 5 minutes, the artery was cut lengthwise, visually inspected, and then analyzed for sirolimus content. Three coated catheters with the same composition were tested on arteries. Dried arteries show a coating of white sediment, indicating significant transfer. Fig. 7 is a micrograph of the surface of an artery at 50x magnification showing adherent material, and FIG. 8 is a micrograph of the surface of an artery at 1000x magnification showing adherent material.

[0121] After visual inspection, the 3 treated arteries were dissolved in acetonitrile and analyzed for sirolimus content. Balloon catheters were analyzed for residual sirolimus. Samples 1 minute before, 1 minute and 2 minutes after washing were filtered through 0.2 μm PTFE filters and dissolved in acetonitrile. The amount of sirolimus isolated from each group is presented in Table 20. Of the total drug mass monitored, an average of 42% was found to adhere to the porcine artery after 5 minutes of washout. This demonstrates that this crushed microcrystalline coating of sirolimus is capable of transport into arteries.

Table 20. Coating Transfer and Wash Resistance

ID Extracted sirolimus [mcg] Total sirolimus extracted [µg] 1 min before rinsing 1 min after 2 minutes after Remaining on the cylinder Artery FR 4-1 24,537 71,876 3.5756 120.77 167.28 388.04 FR 4-2 1.3316 65.114 3.1056 140.61 212.24 422.40 FR 4-3 4.2115 68,768 5.7644 191.6 130.43 400.77 Average 10.03 68.59 4.15 150.99 169.98 403.74 Percent 2.5% 17.0% 1.0% 37.4% 42.1% 100.0%

Additional implementation options

[0122] While the present invention has been disclosed in the context of certain preferred embodiments and examples, those skilled in the art will appreciate that the present invention extends beyond the specific embodiments disclosed to include other alternative embodiments and/or uses of the invention and obvious modifications and equivalents thereof. . It is further contemplated that the various aspects and features of the described invention may be practiced separately, combined together, or substituted for each other, and that many combinations and subcombinations of the features and aspects may be implemented and still be within the scope of the present invention. In addition, the disclosure herein of any specific feature, aspect, method, property, characteristic, quality, attribute, element, or the like in connection with an embodiment may be used in all other embodiments set forth herein. Thus, it is intended that the scope of the present invention described herein should not be limited to the specific disclosed embodiments described above, but should only be determined by a clear reading of the claims.

[0123] Conventional language, such as, but not limited to, “could,” “perhaps,” or “could,” unless specifically stated otherwise or otherwise clear from the context, is generally intended to express that certain embodiments include certain features or elements that other embodiments do not include. Thus, such conventional language as a whole is not intended to imply that features or elements are in any way necessary for one or more embodiments.

Summary of implementation options

[0124] A coating for an expandable catheter portion comprising a hydrophobic matrix and a dispersed phase comprising a plurality of microreservoirs in the hydrophobic matrix, the plurality of microreservoirs comprising a first active agent and a first biodegradable or biodegradable polymer.

[0125] In coating embodiments as described above, the first active agent is mixed with or dispersed in the first biodegradable or biodegradable polymer.

[0126] In coating embodiments as described above, the plurality of microreservoirs further comprise a second active agent. The second active agent is selected from the group consisting of paclitaxel, sirolimus, a paclitaxel derivative, a sirolimus derivative, paclitaxel analogues, sirolimus analogues, inhibitory RNA, inhibitory DNA , steroids and complement inhibitors.

[0127] In coating embodiments as described above, the plurality of microreservoirs further comprise a second biodegradable or biodegradable polymer. The second biodegradable or biodegradable polymer is selected from the group consisting of polylactic acid, polyglycolic acid and copolymers thereof, polydioxanone, polycaprolactone, polyphosphazine, collagen, gelatin, chitosan, glycosaminoglycans, and combinations thereof.

[0128] In embodiments of the coating as described above, the hydrophobic matrix includes at least one hydrophobic compound selected from the group consisting of sterols, lipids, phospholipids, fats, fatty acids, surfactants, and derivatives thereof.

[0129] In some embodiments of the coating described above, the hydrophobic matrix includes cholesterol and a fatty acid. In some embodiments, the cholesterol to fatty acid weight ratio ranges from about 1:2 to about 3:1.

[0130] In coating embodiments as described above, the fatty acid is selected from the group consisting of lauric acid, lauroleic acid, tetradecadienoic acid, octanoic acid, myristic acid, myristoleic acid, decenoic acid, decanoic acid, hexadecadienoic acid, palmitoleic acid, palmitic acid, linolenic acid, linoleic acid, oleic acid, vaccenic acid, stearic acid, eicosapentaenoic acid, arachidonic acid, midic acid, arachidic acid, docosahexaenoic acid, docosapentaenoic acid, docosatetraenoic acid, docosenoic acid, tetracosanoic acid, hexacosenoic acid, pristanic acid , phytanic acid and nervonic acid.

[0131] In some embodiments of the coating described above, the hydrophobic matrix includes cholesterol and a phospholipid. In some embodiments, the cholesterol to phospholipid weight ratio is in the range of from about 1:2 to about 3:1.

[0132] In some embodiments, the phospholipid is selected from the group consisting of phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, or phosphatidylinositol.

[0133] In some embodiments, the phospholipid is a cationic phospholipid. In some embodiments, the cationic phospholipid is phosphatidylethanolamine, dioleoylphosphatidylethanolamine (DOPE), or an amino derivative of phosphatidylcholine.

[0134] In some embodiments, the phospholipid contains an acyl chain of about 20 to about 34 carbon atoms in length. In some embodiments, the phospholipid is selected from the group consisting of dieicosenoylphosphatidylcholine (1,2-dieicosenoyl-sn-glycero-3-phosphocholine, C20:1 PC), diarachidonoylphosphatidylcholine (1,2-diarachidoyl-sn-glycero-3-phosphocholine, C20 :0 PC), dierucoylphosphatidylcholine (1,2-dierucoyl-sn-glycero-3-phosphocholine, C22:1 PC), didocosahexaenoylphosphatidylcholine (1,2-didocosahexaenoyl-sn-glycero-3-phosphocholine, C22:6 PC), heneicosenoylphosphatidylcholine (1,2-geneicosenoyl-sn-glycero-3-phosphocholine, C21:1 PC) and dinervonoyl-phosphatidylcholine (1,2-dinervonoyl-sn-glycero-3-phosphocholine, C24:1 PC).

[0135] In embodiments of the coating as described above, the cholesterol is DC-Cholesterol.

[0136] In coating embodiments as described above, the plurality of micro-reservoirs comprise from about 10% to about 75% by weight of the coating.

[0137] In coating embodiments as described above, the plurality of microreservoirs have an average diameter of from about 1.5 micrometers to about 8 micrometers. In some embodiments, the plurality of microreservoirs have an average diameter of from about 2 micrometers to about 6 micrometers. In some embodiments, the plurality of microreservoirs have an average diameter of from about 3 micrometers to about 5 micrometers.

[0138] In embodiments of the coating as described above, the plurality of microreservoirs have active agent release kinetics with a half-life of at least 14 days.

[0139] In coating embodiments as described above, the first biodegradable or biodegradable polymer is selected from the group consisting of polylactic acid, polyglycolic acid and copolymers thereof, polydioxanone, polycaprolactone, polyphosphazine, collagen, gelatin, chitosan, glycosaminoglycans, and combinations thereof.

[0140] In coating embodiments as described above, the first active agent is selected from the group consisting of paclitaxel, sirolimus, a paclitaxel derivative, a sirolimus derivative, paclitaxel analogs, sirolimus analogs, inhibitory RNA, inhibitory DNA, steroids, and complement inhibitors.

[0141] In coating embodiments as described above, the first active agent constitutes from about 10% to about 50% by weight of the plurality of microreservoirs.

[0142] In embodiments of the coating as described above, the coating further comprises a third active agent outside the plurality of microreservoirs. In some embodiments, the third active agent is selected from the group consisting of paclitaxel, sirolimus, a paclitaxel derivative, a sirolimus derivative, paclitaxel analogs, sirolimus analogs, inhibitory RNA, inhibitory DNA, steroids, and complement inhibitors. In some embodiments, the third active agent is the same as the first active agent.

[0143] In coating embodiments as described above, the hydrophobic matrix further includes a PEG lipid. In some embodiments, the PEG lipid is selected from the group consisting of 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-methoxy(polyethylene glycol)-350 (DSPE-mPEG350), 1,2-dipalmitoyl-sn-glycero -3-phosphoethanolamine-methoxy(polyethylene glycol)-350 (DPPE-mPEG350), 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine-N-methoxy(polyethylene glycol)-350 (DOPE-mPEG350), 1,2-distearoyl -sn-glycero-3-phosphoethanolamine-N-methoxy(polyethylene glycol)-550 (DSPE-mPEG550), 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine-N-methoxy(polyethylene glycol)-550 (DPPE-mPEG550) and 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine-N-methoxy(polyethylene glycol)-500 (DOPE-mPEG550). In some embodiments, the PEG lipid comprises from about 1% to about 30% by weight of the hydrophobic matrix. In some embodiments, the PEG lipid comprises about 12% or less by weight of the hydrophobic matrix.

[0144] In coating embodiments as described above, the coating further comprises one or more additives independently selected from penetration enhancers and stabilizers.

[0145] In embodiments of the coating as described above, the coating has a surface concentration of from about 1 μg/mm ² to about 10 μg/mm ² .

[0146] A catheter comprising an expandable portion on an elongate body, and any coating embodiment described above on the expandable portion. In some embodiments, the catheter further includes a separating layer between the expandable portion and the cover, wherein the separating layer is designed to separate the cover from the expandable portion. In some embodiments, the separation layer comprises DSPE-mPEG350 or DSPE-mPEG500. In some embodiments, the release layer has a surface concentration of from about 0.1 μg/mm ² to about 5 μg/mm ² .

[0147] In catheter embodiments as described above, the catheter further comprises a protective coating on the cover. In some embodiments, the protective coating comprises a hydrophilic polymer, a carbohydrate, or an amphiphilic polymer. In some embodiments, the protective coating is a glycosaminoglycan or crystallized sugar. In some embodiments, the protective coating has a surface concentration of from about 0.1 μg/mm ² to about 5 μg/mm ² .

[0148] A coating composition for an expandable portion of a catheter, comprising a solid portion and a liquid. The solid portion contains a plurality of microreservoirs and at least one hydrophobic compound, the plurality of microreservoirs containing a first active agent and a first biodegradable or biodegradable polymer. In some embodiments, the first active agent is mixed with or dispersed in the first biodegradable or biodegradable polymer.

[0149] In some embodiments, the plurality of microreservoirs also include a second active agent. In some embodiments, the second active agent is selected from the group consisting of paclitaxel, sirolimus, a paclitaxel derivative, a sirolimus derivative, paclitaxel analogs, sirolimus analogs, inhibitory RNA, inhibitory DNA, steroids and complement inhibitors. In some embodiments, the plurality of microreservoirs further includes a second biodegradable or biodegradable polymer. In some embodiments, the second biodegradable or biodegradable polymer is selected from the group consisting of polylactic acid, polyglycolic acid and copolymers thereof, polydioxanone, polycaprolactone, polyphosphazine, collagen, gelatin, chitosan, glycosaminoglycans, and combinations thereof.

[0150] In some embodiments of the coating composition described above, the liquid is selected from the group consisting of pentane, hexane, heptane, heptane and fluorocarbon mixture, alcohol and fluorocarbon mixture, and alcohol and water mixture.

[0151] In some embodiments of the coating composition described above, the solid portion further contains a third active agent outside the plurality of microreservoirs. In some embodiments, the third active agent is selected from the group consisting of paclitaxel, sirolimus, a paclitaxel derivative, a sirolimus derivative, paclitaxel analogs, sirolimus analogs, inhibitory RNA, inhibitory DNA, steroids, and complement inhibitors.

[0152] In some embodiments of the coating composition as described above, the first active agent is selected from the group consisting of paclitaxel, sirolimus, a paclitaxel derivative, a sirolimus derivative, paclitaxel analogs, sirolimus analogs, inhibitory RNA, inhibitory DNA, steroids, and complement inhibitors.

[0153] In some embodiments of the coating composition described above, the at least one hydrophobic compound is selected from the group consisting of sterols, lipids, phospholipids, fats, fatty acids, surfactants, and derivatives thereof.

[0154] In some embodiments of the coating composition described above, at least one hydrophobic compound comprises cholesterol and a fatty acid. In some embodiments, the cholesterol to fatty acid weight ratio ranges from about 1:2 to about 3:1. In some embodiments, the fatty acid is selected from the group consisting of lauric acid, lauroleic acid, tetradecadienoic acid, octanoic acid, myristic acid, myristoleic acid, decenoic acid, decanoic acid, hexadecenoic acid, palmitoleic acid, palmitic acid, linolenic acid, linoleic acid , oleic acid, vaccenic acid, stearic acid, eicosapentaenoic acid, arachidonic acid, midic acid, arachidic acid, docosahexaenoic acid, docosapentaenoic acid, docosatetraenoic acid, docosenoic acid, tetracosanoic acid, hexacosenoic acid, pristanic acid, phytanic acid and nervonic acid.

[0155] In some embodiments of the coating composition described above, at least one hydrophobic compound comprises cholesterol and a phospholipid. In some embodiments, the cholesterol to phospholipid weight ratio is in the range of from about 1:2 to about 3:1. In some embodiments, the phospholipid is selected from the group consisting of phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, and phosphatidylinositol.

[0156] In some embodiments, the phospholipid is a cationic phospholipid. In some embodiments, the cationic phospholipid is phosphatidylethanolamine, dioleoylphosphatidylethanolamine (DOPE), or an amino derivative of phosphatidylcholine.

[0157] In some embodiments, the phospholipid contains an acyl chain of about 20 to about 34 carbon atoms in length. In some embodiments, the phospholipid is selected from the group consisting of dieicosenoylphosphatidylcholine (1,2-dieicosenoyl-sn-glycero-3-phosphocholine, C20:1 PC), diarachidonoylphosphatidylcholine (1,2-diarachidoyl-sn-glycero-3-phosphocholine, C20 :0 PC), dierucoylphosphatidylcholine (1,2-dierucoyl-sn-glycero-3-phosphocholine, C22:1 PC), didocosahexaenoylphosphatidylcholine (1,2-didocosahexaenoyl-sn-glycero-3-phosphocholine, C22:6 PC), heneicosenoylphosphatidylcholine (1,2-geneicosenoyl-sn-glycero-3-phosphocholine, C21:1 PC) and dinervonoyl-phosphatidylcholine (1,2-dinervonoyl-sn-glycero-3-phosphocholine, C24:1 PC).

[0158] In some embodiments of the coating composition described above, the cholesterol is DC-Cholesterol.

[0159] In some embodiments of the coating composition described above, the solid portion further comprises a PEG lipid and/or additive. In some embodiments, the PEG lipid is selected from the group consisting of 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-methoxy(polyethylene glycol)-350 (DSPE-mPEG350), 1,2-dipalmitoyl-sn-glycero -3-phosphoethanolamine-methoxy(polyethylene glycol)-350 (DPPE-mPEG350), 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine-N-methoxy(polyethylene glycol)-350 (DOPE-mPEG350), 1,2-distearoyl -sn-glycero-3-phosphoethanolamine-N-methoxy(polyethylene glycol)-550 (DSPE-mPEG550), 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine-N-methoxy(polyethylene glycol)-550 (DPPE-mPEG550) and 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine-N-methoxy(polyethylene glycol)-500 (DOPE-mPEG550).

[0160] In some embodiments of the coating composition described above, the plurality of microreservoirs comprise from about 10% to about 75% by weight of the solid portion.

[0161] In some embodiments of the coating composition described above, the solids portion comprises from about 2 to about 7% by weight of the coating composition.

[0162] A method of coating an expandable portion of a catheter, comprising applying a coating composition according to any of the embodiments described above to the surface of an inflated expandable portion of a catheter, evaporating the liquid, and deflating the expandable portion. In some embodiments, application of the coating composition includes spraying, dip coating, roll coating, electrostatic deposition, printing, pipetting, or dispensing.

[0163] In some embodiments of the method described above, the method further includes applying a release layer to the expandable portion. In some embodiments, the separation layer comprises DSPE-mPEG350 or DSPE-mPEG500.

[0164] A method of treating or preventing a condition at a treatment site, comprising introducing a catheter comprising an expandable portion to the treatment site, wherein the expandable portion is coated with a coating according to any embodiment described above, inflating the expandable portion to provide contact between the coating and tissue at treatment site, descent of the expandable part, and removal of the catheter.

[0165] In embodiments of the method described above, contact between the tissue and the coating causes at least a portion of the coating on the expandable portion to be transferred to the treatment site. In some embodiments, the method further includes maintaining contact between the coating and the fabric for a period of from about 30 to about 120 seconds.

[0166] In embodiments of any of the methods described above, the condition is selected from the group consisting of atherosclerosis, stenosis or reduction in lumen diameter in the affected blood vessel, restenosis and in-stent restenosis, and combinations thereof.

[0167] In embodiments of any of the methods described above, an additional release layer is applied between the expandable portion and the coating.

[0168] In some embodiments, the catheter includes an expandable portion on an elongated body; and a coating on the outer surface of the expandable portion, wherein the coating includes a lipophilic matrix, wherein the lipophilic matrix includes at least one lipid; a plurality of microreservoirs are dispersed in a lipophilic matrix, the plurality of microreservoirs containing an active agent; and wherein the lipophilic matrix is configured to adhere to the intraluminal surface upon expansion of the expandable portion and transfer at least a portion of the plurality of microreservoirs to the intraluminal surface.

[0169] In some embodiments of the catheter described above, the active agent is crystalline.

[0170] In some embodiments of the catheter described above, the plurality of microreservoirs further includes a biodegradable or biodegradable polymer. In some embodiments, the biodegradable or biodegradable polymer is selected from the group consisting of polylactic acid, polyglycolic acid and copolymers thereof, polydioxanone, polycaprolactone, polyphosphazine, collagen, gelatin, chitosan, and glycosaminoglycans. In some embodiments, the active agent makes up from about 10% to about 50% by weight of the microreservoirs.

[0171] In some embodiments of the catheter described above, at least one lipid comprises a phospholipid. In some embodiments, the phospholipid has an acyl chain length of from about 20 to about 34 carbon atoms. In some embodiments, the phospholipid is selected from the group consisting of phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, and phosphatidylinositol. In some embodiments, the phospholipid is selected from the group consisting of dieicosenoylphosphatidylcholine (1,2-dieicosenoyl-sn-glycero-3-phosphocholine, C20:1 PC), diarachidonoylphosphatidylcholine (1,2-diarachidoyl-sn-glycero-3-phosphocholine, C20 :0 PC), dierucoylphosphatidylcholine (1,2-dierucoyl-sn-glycero-3-phosphocholine, C22:1 PC), didocosahexaenoylphosphatidylcholine (1,2-didocosahexaenoyl-sn-glycero-3-phosphocholine, C22:6 PC), heneicosenoylphosphatidylcholine (1,2-geneicosenoyl-sn-glycero-3-phosphocholine, C21:1 PC) and dinervonoyl-phosphatidylcholine (1,2-dinervonoyl-sn-glycero-3-phosphocholine, C24:1 PC).

[0172] In some embodiments, the phospholipid comprises a cationic phospholipid. In some embodiments, the cationic phospholipid is phosphatidylethanolamine, dioleoylphosphatidylethanolamine, or an amino derivative of phosphatidylcholine. In some embodiments, the lipophilic matrix further comprises a sterol. In some embodiments, the sterol is selected from the group consisting of cholesterol, stigmasterol, lanosterol, sitosterol, DHEA, N4-cholesterol-spermine, guanidium-cholesterol/BGTC, and DC-cholesterol.

[0173] In some catheter embodiments, the coating has a melting point between room temperature and body temperature. In some embodiments of the catheter, the coating comprises from about 10% to about 75% by weight of the plurality of microreservoirs.

[0174] In some embodiments of the catheter, the plurality of microreservoirs have an average diameter of from about 1.5 micrometers to about 8 micrometers. In some embodiments, the plurality of microreservoirs have an average diameter of from about 2.0 micrometers to about 6 micrometers.

[0175] In some catheter embodiments, the active agent is selected from the group consisting of paclitaxel, sirolimus, a paclitaxel derivative, a sirolimus derivative, paclitaxel analogs, sirolimus analogs, inhibitory RNA, inhibitory DNA, steroids, and complement inhibitors.

[0176] In some embodiments of the catheter, the coating further comprises a polyethylene glycol-containing lipid (PEG-lipid). In some embodiments, the PEG lipid is selected from the group consisting of 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-methoxy(polyethylene glycol)-350 (DSPE-mPEG350), 1,2-dipalmitoyl-sn-glycero -3-phosphoethanolamine-methoxy(polyethylene glycol)-350 (DPPE-mPEG350), 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine-N-methoxy(polyethylene glycol)-350 (DOPE-mPEG350), 1,2-distearoyl -sn-glycero-3-phosphoethanolamine-N-methoxy(polyethylene glycol)-550 (DSPE-mPEG550), 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine-N-methoxy(polyethylene glycol)-550 (DPPE-mPEG550) and 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine-N-methoxy(polyethylene glycol)-500 (DOPE-mPEG550). In some embodiments, the PEG lipid comprises from about 1% to about 10% by weight of the hydrophobic matrix.

[0177] In some embodiments of the catheter, the coating further comprises one or more additives independently selected from permeation enhancers and stabilizers.

[0178] In some embodiments of the catheter, the coating has a surface concentration of from about 1 μg/mm ² to about 10 μg/mm ² .

[0179] In some embodiments, the catheter includes an expandable portion on an elongated body; a coating on an outer surface of the expandable portion, wherein the coating includes a lipophilic matrix, wherein the lipophilic matrix includes at least one lipid; a plurality of microreservoirs are dispersed in a lipophilic matrix, the plurality of microreservoirs containing an active agent; and wherein the lipophilic matrix is configured to adhere to the intraluminal surface upon expansion of the expandable portion and transfer at least a portion of the plurality of microreservoirs to the intraluminal surface; and a separating layer between the expandable portion and the cover, wherein the separating layer is configured to release the cover from the expandable portion.

[0180] In some embodiments, the separation layer comprises DSPE-mPEG350 or DSPE-mPEG500. In some embodiments, the release layer has a surface concentration of from about 0.1 μg/mm ² to about 5 μg/mm ² .

[0181] In some embodiments, the catheter further includes a protective coating over the first coating. In some embodiments, the protective coating comprises a hydrophilic polymer, a carbohydrate, or an amphiphilic polymer. In some embodiments, the protective coating is a glycosaminoglycan or crystallized sugar. In some embodiments, the protective coating has a surface concentration of from about 0.1 μg/mm ² to about 5 μg/mm ² .

[0182] In some embodiments, a method of coating an expandable portion of a catheter is provided, comprising: applying a coating composition to the surface of an inflated expandable portion of a catheter, wherein the coating composition includes: a plurality of microreservoirs containing an active agent; at least one lipid; and a liquid, wherein the liquid is selected from the group consisting of a mixture of pentane, hexane, heptane, heptane and fluorocarbon, a mixture of alcohol and fluorocarbon, and a mixture of alcohol and water; evaporation of liquid; and lowering the expandable part. In some embodiments, the coating composition comprises a solid including a plurality of microreservoirs and at least one lipid, and the plurality of microreservoirs comprises from about 10% to about 75% by weight of the solid.

[0183] In some embodiments of the method, the plurality of microreservoirs further includes a biodegradable or biodegradable polymer. In some embodiments, the active agent is selected from the group consisting of paclitaxel, sirolimus, a paclitaxel derivative, a sirolimus derivative, paclitaxel analogs, sirolimus analogs, inhibitory RNA, inhibitory DNA, steroids, and complement inhibitors.

[0184] In some embodiments of the method, the active agent is crystalline.

[0185] In some embodiments of the method, the at least one lipid comprises a phospholipid. In some embodiments, the phospholipid is selected from the group consisting of phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, and phosphatidylinositol.

[0186] In some embodiments, the phospholipid includes a phospholipid with an acyl chain of about 20 to about 34 carbon atoms in length. In some embodiments, the phospholipid is selected from the group consisting of dieicosenoylphosphatidylcholine (1,2-dieicosenoyl-sn-glycero-3-phosphocholine, C20:1 PC), diarachidonoylphosphatidylcholine (1,2-diarachidoyl-sn-glycero-3-phosphocholine, C20 :0 PC), dierucoylphosphatidylcholine (1,2-dierucoyl-sn-glycero-3-phosphocholine, C22:1 PC), didocosahexaenoylphosphatidylcholine (1,2-didocosahexaenoyl-sn-glycero-3-phosphocholine, C22:6 PC), heneicosenoylphosphatidylcholine (1,2-geneicosenoyl-sn-glycero-3-phosphocholine, C21:1 PC) and dinervonoyl-phosphatidylcholine (1,2-dinervonoyl-sn-glycero-3-phosphocholine, C24:1 PC).

[0187] In some embodiments of the method described above, the phospholipid includes a cationic phospholipid. In some embodiments, the cationic phospholipid is phosphatidylethanolamine, dioleoylphosphatidylethanolamine, or an amino derivative of phosphatidylcholine.

[0188] In some embodiments of the method described above, the coating composition further comprises a sterol. In some embodiments, the sterol is selected from the group consisting of cholesterol, stigmasterol, lanosterol, sitosterol, DHEA, N4-cholesterol-spermine, guanidium-cholesterol/BGTC, and DC-cholesterol.

[0189] In some embodiments of the method described above, the coating composition has a solids content of from about 2% to about 7% by weight, wherein the solids include a plurality of microreservoirs and at least one lipid.

[0190] In some embodiments of the method described above, the coating composition further comprises a polyethylene glycol-containing lipid (PEG-lipid).

[0191] In some embodiments of the method described above, application of the coating composition includes spraying, dip coating, roll coating, electrostatic deposition, printing, pipetting, or dispensing.

[0192] In some embodiments, the method described above further includes applying a release layer to the surface of the inflated expandable portion prior to applying the coating composition.

[0193] In some embodiments, a method of treating or preventing a condition at a treatment site is described, comprising introducing the catheter of claim 1 to the treatment site; inflating the expandable portion to ensure contact between the coating and the tissue at the treatment site; descent of the expandable part; and catheter removal.

[0194] In some embodiments of the method described above, contact between the tissue and the coating causes at least a portion of the coating on the expandable portion to be transferred to the treatment site.

[0195] In some embodiments, the method described above further includes maintaining contact between the expandable portion and the cover for a period of about 30 to about 120 seconds.

[0196] In some embodiments of the method described above, the condition is selected from the group consisting of atherosclerosis, stenosis or reduction in lumen diameter in the affected blood vessel, restenosis, and in-stent restenosis.

Claims (62)

1. Catheter containing: an expandable portion on the elongated body; And a coating on the outer surface of the expandable portion, wherein said coating comprises: a lipophilic matrix, wherein the lipophilic matrix contains at least one lipid, more than one microreservoir comprising only the crystalline active agent dispersed in a lipophilic matrix; And wherein the lipophilic matrix is configured to provide adhesion to the intraluminal surface when the expandable portion is inflated, and transfer at least a portion from more than one microreservoir to the intraluminal surface; And wherein more than one microreservoir is uniform in size and has a maximum particle size of 10 microns, and less than 5% of the more than one microreservoir has a diameter of 1 micron or less. 2. Catheter according to claim 1, characterized in that at least one lipid contains a phospholipid. 3. The catheter of claim 2, wherein the phospholipid contains an acyl chain of about 20 to about 34 carbon atoms in length. 4. The catheter according to claim 2, characterized in that the phospholipid is selected from the group consisting of phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, dioleoylphosphatidylethanolamine and an amino derivative of phosphatidylcholine. 5. The catheter according to claim 2, characterized in that the phospholipid is selected from the group consisting of dieicosenoylphosphatidylcholine (1,2-dieicosenoyl-sn-glycero-3-phosphocholine, C20:1 PC), diarachidonoylphosphatidylcholine (1,2-diarachidoyl-sn -glycero-3-phosphocholine, C20:0 PC), dierucoylphosphatidylcholine (1,2-dierucoyl-sn-glycero-3-phosphocholine, C22:1 PC), didocosahexaenoylphosphatidylcholine (1,2-didocosahexaenoyl-sn-glycero-3-phosphocholine , C22:6 PC), heneicosenoylphosphatidylcholine (1,2-heneicosenoyl-sn-glycero-3-phosphocholine, C21:1 PC) and dinervonoylphosphatidylcholine (1,2-dinervonoyl-sn-glycero-3-phosphocholine, C24:1 PC) . 6. Catheter according to claim 2, characterized in that the phospholipid contains a cationic phospholipid. 7. Catheter according to claim 6, characterized in that the cationic phospholipid is phosphatidylethanolamine, dioleoylphosphatidylethanolamine or an amino derivative of phosphatidylcholine. 8. Catheter according to claim 6, characterized in that the lipophilic matrix additionally contains sterol. 9. The catheter according to claim 8, characterized in that the sterol is selected from the group consisting of cholesterol, stigmasterol, lanosterol, sitosterol, DHEA, N4-cholesterol-spermine, guanidium-cholesterol/BGTC and DC-cholesterol. 10. Catheter according to any one of paragraphs. 1-9, characterized in that the coating has a melting point from room temperature to body temperature. 11. Catheter according to any one of paragraphs. 1-9, characterized in that the coating contains from 10 to 75% by weight of more than one microreservoir. 12. Catheter according to any one of paragraphs. 1-9, characterized in that more than one microreservoir has an average diameter from 1.5 to 8 microns. 13. Catheter according to any one of paragraphs. 1-9, characterized in that more than one microreservoir has an average diameter from 2.0 to 6 microns. 14. Catheter according to any one of paragraphs. 1-9, characterized in that the active agent is selected from the group consisting of paclitaxel, sirolimus, a paclitaxel derivative, a sirolimus derivative, paclitaxel analogues, sirolimus analogues, inhibitory RNA, inhibitory DNA, steroids and complement inhibitors. 15. Catheter according to any one of paragraphs. 1-9, characterized in that the coating additionally contains a polyethylene glycol-containing lipid (PEG-lipid). 16. Catheter according to claim 15, characterized in that the PEG lipid is selected from the group consisting of 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-methoxy(polyethylene glycol)-350 (DSPE-mPEG350), 1 ,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine-methoxy(polyethylene glycol)-350 (DPPE-mPEG350), 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine-N-methoxy(polyethylene glycol)-350 (DOPE- mPEG350), 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-methoxy(polyethylene glycol)-550 (DSPE-mPEG550), 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine-N-methoxy(polyethylene glycol )-550 (DPPE-mPEG550) and 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine-N-methoxy(polyethylene glycol)-500 (DOPE-mPEG550). 17. Catheter according to claim 15, characterized in that the PEG lipid constitutes from 1 to 10% by weight of the hydrophobic matrix. 18. Catheter according to any one of paragraphs. 1-9, characterized in that the coating additionally contains one or more additives independently selected from permeability enhancers and stabilizers. 19. Catheter according to any one of paragraphs. 1-9, characterized in that the coating has a surface concentration from 1 to 10 μg/mm ² . 20. Catheter according to any one of paragraphs. 1-9, further comprising a separating layer between the expandable portion and the cover, wherein the separating layer is configured to release the coating from the expandable portion. 21. Catheter according to claim 20, characterized in that the separation layer contains DSPE-mPEG350 or DSPE-mPEG500. 22. Catheter according to claim 20 or 21, characterized in that the separation layer has a surface concentration of 0.1 to 5 μg/mm ² . 23. Catheter according to any one of paragraphs. 20-22, further comprising a protective coating on the first coating. 24. Catheter according to claim 23, characterized in that the protective coating contains a hydrophilic polymer, carbohydrate or amphiphilic polymer. 25. Catheter according to claim 23, characterized in that the protective coating is glycosaminoglycan or crystallized sugar. 26. Catheter according to any one of paragraphs. 23-25, characterized in that the protective coating has a surface concentration from 0.1 to 5 μg/mm ² . 27. A method of coating an expandable portion of a catheter, comprising applying a coating composition to the surface of the inflated expandable part of the catheter, wherein the coating composition contains: more than one microreservoir containing only crystalline active agent, wherein more than one microreservoir is uniform in size and has a maximum particle size of 10 μm, and less than 5% of the more than one microreservoir has a diameter of 1 μm or less; And at least one lipid; And a liquid, wherein the liquid is selected from the group consisting of pentane, hexane, heptane, a mixture of heptane and a fluorocarbon, a mixture of an alcohol and a fluorocarbon, and a mixture of an alcohol and water; And evaporation of liquid; And descent of the expandable part. 28. The method of claim 27, wherein the coating composition comprises a solid comprising more than one microreservoir, and at least one lipid and the more than one microreservoir constitute from 10 to 75% by weight of the solid. 29. The method according to claim 27 or 28, characterized in that the active agent is selected from the group consisting of paclitaxel, sirolimus, a paclitaxel derivative, a sirolimus derivative, paclitaxel analogues, sirolimus analogues, inhibitory RNA, inhibitory DNA, steroids and complement inhibitors. 30. Method according to any one of paragraphs. 27-29, characterized in that at least one lipid contains a phospholipid. 31. The method according to claim 30, characterized in that the phospholipid is selected from the group consisting of phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, dioleoylphosphatidylethanolamine and an amino derivative of phosphatidylcholine. 32. The method according to claim 30, characterized in that the phospholipid includes a phospholipid with an acyl chain of 20 to 34 carbon atoms in length. 33. The method according to claim 30, characterized in that the phospholipid is selected from the group consisting of dieicosenoylphosphatidylcholine (1,2-dieicosenoyl-sn-glycero-3-phosphocholine, C20:1 PC), diarachidonoylphosphatidylcholine (1,2-diarachidoyl-sn -glycero-3-phosphocholine, C20:0 PC), dierucoylphosphatidylcholine (1,2-dierucoyl-sn-glycero-3-phosphocholine, C22:1 PC), didocosahexaenoylphosphatidylcholine (1,2-didocosahexaenoyl-sn-glycero-3-phosphocholine , C22:6 PC), heneicosenoylphosphatidylcholine (1,2-heneicosenoyl-sn-glycero-3-phosphocholine, C21:1 PC) and dinervonoylphosphatidylcholine (1,2-dinervonoyl-sn-glycero-3-phosphocholine, C24:1 PC) . 34. The method according to claim 30, characterized in that the phospholipid contains a cationic phospholipid. 35. The method according to claim 34, characterized in that the cationic phospholipid is phosphatidylethanolamine, dioleoylphosphatidylethanolamine or an amino derivative of phosphatidylcholine. 36. The method according to claim 34, characterized in that the coating composition additionally contains sterol. 37. The method according to claim 36, characterized in that the sterol is selected from the group consisting of cholesterol, stigmasterol, lanosterol, sitosterol, DHEA, N4-cholesterol-spermine, guanidium-cholesterol/BGTC and DC-cholesterol. 38. The method of claim 27, wherein the coating composition has a solids content of from 2 to 7% by weight, wherein the solids include more than one microreservoir and at least one lipid. 39. Method according to any one of paragraphs. 27-38, characterized in that the coating composition additionally contains a polyethylene glycol-containing lipid (PEG-lipid). 40. Method according to any one of paragraphs. 27-39, characterized in that the application of the coating composition includes spraying, dip coating, roll coating, electrostatic deposition, printing, pipetting or dispensing. 41. Method according to any one of paragraphs. 27-40, further comprising applying a release layer to the surface of the inflated expandable portion prior to applying the coating composition. 42. A method of treating a condition at the point of treatment, comprising: introduction of a catheter according to paragraphs. 1-26 to the place of treatment; inflating the expandable portion to ensure contact between the coating and the tissue of the treatment site; descent of the expandable part; And removal of the catheter. 43. The method of claim 42, wherein the contact between the tissue and the coating transfers at least a portion of the coating of the expandable portion to the treatment site. 44. The method of claim 42 or 43, further comprising maintaining contact between the expandable portion and the coating for a period of 30 to 120 seconds. 45. Method according to any one of paragraphs. 42-44, characterized in that the condition is selected from the group consisting of atherosclerosis, stenosis or reduction in the diameter of the lumen in the affected blood vessel, restenosis and in-stent restenosis.