CN112867514A - Coating of intraluminal expandable catheters providing contact transfer of drug microreservoirs - Google Patents

Abstract

A coating for an expandable portion of a catheter is disclosed that includes a lipophilic matrix and a plurality of micro-reservoirs dispersed in the lipophilic matrix. The plurality of micro-reservoirs comprises an active agent. Coating formulations and methods of forming coatings are also disclosed. A catheter including a coating on an expansible portion and a method for treating a condition are also provided.

Description

Coating of intraluminal expandable catheters providing contact transfer of drug microreservoirs

Technical Field

The present disclosure relates to the field of drug delivery via expandable catheters.

Background

Balloon angioplasty is an established method of treating vascular disease by physically dilating an area of reduced lumen diameter or stenosis in an atherosclerotic, diseased blood vessel. Typically, angioplasty is performed using a catheter that can be advanced within the circulatory system to the diseased area. The catheter has a balloon at the distal end that is inflated to inflate and dilate the stricture. In many cases, such as in coronary arteries, a stent is also mounted over the outside of the balloon. After the balloon is expanded in the atherosclerotic region, deflated and the balloon is removed, the stent remains in place to maintain patency of the inflation lumen.

To achieve physical expansion of the vessel treatment area, a large force is applied to the tissue of the vessel wall during inflation of the high pressure balloon. This physical expansion results in damage to the vessel, including endothelial cell destruction, rupture of the internal elastic lamina, and dissection of the media in the vessel. Lesions also often extend into the adventitia of the external artery. The biological response of the blood vessels progresses through the thrombotic phase during days 0 to 3, including platelet activation and adhesion and thrombosis. During days 3 to 8, the thrombotic phase is followed by a cell recruitment phase involving the infiltration of inflammatory cells, macrophages and lymphocytes to the site of vascular injury. During days 8 to 14, the release of growth factors and cytokines from inflammatory cells results in a proliferative phase in which quiescent smooth muscle cells in the media of blood vessels are stimulated to proliferate. Subsequently, injury-induced thrombus migration of proliferating smooth muscle cells into the intima and lumen results in neointimal hyperplasia, the major component of restenosis. Although cell proliferation ceases after 14 days, the continued production of extracellular matrix by smooth muscle cells at the site of injury continues to increase the degree of neointimal hyperplasia and restenosis. Restenosis effectively reverses dilation therapy and potentially poses a serious threat to the patient. Human clinical studies have demonstrated that restenosis usually occurs within 1 to 3 months after balloon angioplasty, and restenosis typically peaks at about 3 months.

Although balloon angioplasty provides an urgent need for increased blood flow in diseased vessels, restenosis is inherent due to the associated mechanical injury. One strategy to reduce the restenosis response is to release drugs into the vessel in conjunction with balloon dilation therapy to counteract the inflammatory and healing responses. The methods include coating the balloon with a drug such as paclitaxel and sirolimus (rapamycin), which limits cell proliferation. During contact of the balloon with the luminal surface of the vessel, it is believed that the use of the excipient coating promotes drug transfer to the site of vascular injury. These methods attempt to provide a drug concentration in the vessel wall after balloon expansion that is low enough to reduce restenosis due to cell proliferation while minimizing toxicity to the vessel (which may result in damage or damage to the vessel). It is believed that it is desirable to maintain an effective drug concentration long enough to minimize restenosis.

In practice, drug delivery to the tissue of the vessel wall by drug-coated balloons described in the art is limited by the short period of time that the balloon can be placed in contact with the vessel. Typically, balloon inflation during angioplasty is performed for about 30 to about 120 seconds to limit myocardial ischemia and potential patient complications and discomfort. These short balloon inflation and drug delivery times may be sufficient for the anti-tumor drug paclitaxel, which has been shown to inhibit neointimal formation in animals after several minutes of exposure time. However, in order to provide maximum therapeutic effect and minimize potential high dose toxicity to the vessel, it is desirable to provide drug delivery 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 analogs have both antiproliferative and anti-inflammatory activity, and if delivered over an extended period of time, they may provide benefits beyond the acute phase of restenosis.

Many drug coated balloons described in the art use high initial levels of active agent and multiple treatments to produce high initial concentrations, but then the concentration drops rapidly. This is undesirable because most of the active agent on the device is lost as possible embolic particles enter the blood stream or exit the treatment site by diffusion.

Many drug coatings described in the art include hydrophilic polymers and excipients or excipients that are liquid at body temperature. Such hydrophilic coating formulations provide a hydrophilic matrix for hydrophobic drug particles and may be effective in transferring the drug to the vessel wall. However, such coatings do not provide sufficient resistance to washout by blood during manipulation of the balloon to the treatment site or after transfer of the drug coating to the vessel surface.

Disclosure of Invention

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 micro-reservoirs (micro-reservoirs) dispersed in the hydrophobic matrix, wherein the plurality of micro-reservoirs comprises a first active agent mixed with or dispersed in a first biodegradable or bioerodible polymer. Some embodiments provide a coating in which the dispersed phase comprises a plurality of micro-reservoirs dispersed in a hydrophobic matrix, wherein some of the plurality of micro-reservoirs comprise a first active agent and a first biodegradable or bioerodible polymer.

Some embodiments provide a catheter comprising an expansible portion on an elongate body and a coating over the expansible portion. The coating comprises a lipophilic matrix, wherein the lipophilic matrix comprises at least one lipid, a plurality of micro-reservoirs dispersed in the lipophilic matrix, wherein the plurality of micro-reservoirs comprises an active agent, and wherein the lipophilic matrix is configured to adhere to a cavity surface when the expandable portion is expanded and to transfer at least a portion of the plurality of micro-reservoirs to the cavity surface.

Some embodiments provide a catheter comprising an expansible portion on an elongate body and a coating described herein over the expansible portion. In some embodiments, the catheter further comprises a release layer (release layer) between the expandable portion and the coating, wherein the release layer is configured to release the coating from the expandable portion. In some embodiments, the catheter further comprises a protective coating over the coating.

Some embodiments provide a coating formulation for an expandable portion of a catheter comprising a solid portion and a fluid. The solid portion comprises a plurality of micro-reservoirs and at least one hydrophobic compound. The plurality of micro-reservoirs includes a first active agent and a first biodegradable or biodegradable polymer.

Some embodiments provide a coating formulation for an expandable portion of a catheter comprising a plurality of micro-reservoirs comprising an active agent and at least one lipid.

Some embodiments provide a method of coating an expansible portion of a catheter, comprising disposing a coating formulation described herein over a surface of an expanded expansible portion of a catheter, evaporating the fluid and contracting the expansible portion.

Some embodiments provide a method for treating or preventing a condition at a treatment site, comprising advancing a catheter comprising an expandable portion to the treatment site, wherein the expandable portion is coated with a coating described herein, expanding the expandable portion to allow contact between the coating and tissue at the treatment site, collapsing the expandable portion, and removing the catheter.

Drawings

Features and aspects and advantages of embodiments of the present disclosure are described in detail below with reference to the drawings of various embodiments, which are intended to illustrate and not to limit the present disclosure. These drawings depict only several embodiments in accordance with the disclosure and are not to be considered limiting of its scope.

Fig. 1 depicts one embodiment of a balloon catheter comprising a coating on an expansible portion of the catheter.

Fig. 2 depicts one embodiment of a balloon catheter including a release layer between the coating and the expansible portion of the catheter.

Fig. 3 depicts one embodiment of a balloon catheter comprising a protective layer over the coating.

Fig. 4 is a photomicrograph of the luminal surface of a blood vessel treated with one embodiment of the balloon catheter.

Fig. 5 is a photomicrograph of the luminal surface of a blood vessel treated with one embodiment of the balloon catheter.

Fig. 6 is a photomicrograph of the coated balloon surface at 100X magnification showing the coating containing the crystalline sirolimus micro-reservoirs.

FIG. 7 is a photomicrograph of the arterial surface at 50X magnification showing adherent material.

FIG. 8 is a photomicrograph of the arterial surface at 50X magnification showing adherent material.

Detailed Description

To overcome the limitations of the prior art, embodiments disclosed herein provide a coating for an expandable portion of a catheter having time-release drug micro-reservoirs mixed with or dispersed within the coating on the balloon that can be transferred to the luminal surface of a blood vessel within a balloon inflation time of 30 seconds to about 120 seconds. This approach enables prolonged and controlled release of the drug over a longer period of time, which can be tailored to the characteristics of the particular drug or the pathology of the diseased vessel by the design of the micro-reservoirs. In addition to providing sustained release, the coatings disclosed herein can also resist blood wash-off, which both increases drug transfer efficiency and increases patient safety from excessive particles.

Coating layer

Disclosed herein is a coating for an expandable portion of a catheter or catheter system. The catheter is designed for insertion into a living body for local delivery of at least one active agent. The coating is formulated and configured to minimize dissolution and dispersion in the bloodstream when the catheter is placed in the target vessel for treatment, or after transfer of the coating to the tissue of the vessel wall. In some embodiments, an active agent or drug is delivered to the blood vessel for preventing or minimizing restenosis following balloon angioplasty. In some embodiments, the expansible portion may be a balloon of a balloon catheter.

Referring to fig. 1, in some embodiments, a coating 12 for an expandable portion 11 of a catheter 10 includes two phases, a hydrophobic matrix 14 and a dispersed phase 13. The dispersed phase 13 is dispersed in a hydrophobic matrix 14. The dispersed phase 13 includes a plurality of micro-reservoirs, and the plurality of micro-reservoirs includes a first active agent and a first biodegradable or bioerodible polymer. In some embodiments, the first active agent is mixed with or dispersed in a first biodegradable or bioerodible polymer. In some embodiments, some micro-reservoirs may comprise a first active agent and a biodegradable or bioerodible polymer. In some embodiments, the plurality of micro-reservoirs further comprises a second active agent. In some embodiments, the plurality of micro-reservoirs may further include a second biodegradable or bioerodible polymer. In some embodiments, the first and second biodegradable or biodegradable polymers may be the same or different. In some embodiments, the plurality of micro-reservoirs may comprise only one type of micro-reservoir. In some embodiments, the coating 12 includes 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 micro-reservoirs. In some embodiments, the coating 12 has about 1 μ g/mm on the expandable portion of the catheter 10²To about 10. mu.g/mm²About 2. mu.g/mm²To about 9. mu.g/mm²Or about 3. mu.g/mm²To about 8. mu.g/mm²The surface concentration of (a).

The hydrophobic matrix 14 comprises a combination of materials selected for its desired adhesion properties to the luminal surface. The preferred hydrophobic matrix 14 comprises a combination of hydrophobic compounds that resist dissolution into the blood when applied to the surface of the balloon, but provide uniform distribution of the formulation including the micro-reservoirs. In some embodiments, the hydrophobic matrix 14 includes at least one hydrophobic compound selected from sterols, lipids, phospholipids, fats, fatty acids, surfactants, and derivatives thereof. Particularly useful formulations are combinations of sterols and fatty acids or phospholipids. Sterols can be sterols that utilize the body's natural clearance mechanisms, for example by forming complexes with serum lipids or forming aggregates with serum-borne lipoproteins to provide transport to the liver for metabolic processes. In some embodiments, the sterol may be cholesterol. Such a combination may provide a uniform mixture for the coating 12 and a uniform coating produced on the balloon surface due to the natural compatibility of cholesterol and fatty acids or phospholipids. The coating 12 formed by this combination is uniform without the formation of micelles or liposomes in the hydrophobic matrix 14.

In some embodiments, the hydrophobic matrix 14 includes cholesterol and a fatty acid. In some embodiments, the weight ratio of cholesterol to fatty acid 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 comprise cholesterol, chemically modified cholesterol or a cholesterol conjugate. In some embodiments, the cholesterol is dimethylaminoethane-carbamoyl cholesterol (DC-cholesterol). For physiological compatibility, the preferred fatty acids are those normally present in serum or cell membranes. In some embodiments, the fatty acid is selected from the group consisting of lauric acid, lauric acid (lauroleic acid), tetradecadienoic acid (tetradienoic acid), caprylic acid, myristic acid, myristoleic acid (myristoleic acid), caproic acid (decenoic acid), capric acid, hexadecenoic acid (hexadienoic acid), palmitoleic acid (palmitoleic acid), palmitic acid, linolenic acid, linoleic acid, oleic acid, vaccenic acid (vaccenic acid), stearic acid, eicosapentaenoic acid, arachidonic acid (arachadonic acid), eicosatrienoic acid (mead acid), arachidic acid, docosahexanoic acid (docosahexanoic acid), docosapentaenoic acid (docosapentaenoic acid), docosatetraenoic acid (docosatenic acid), arachidonic acid (docosatenic acid), docosasenoic acid (docosenoic acid), tetracosenoic acid (tetracosenoic acid), docosahexaenoic acid (hexacosenoic acid), and phytanic acid (phytanic acid).

In some embodiments, the hydrophobic matrix 14 includes cholesterol and a phospholipid. In some embodiments, the weight ratio of cholesterol to phospholipid 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 commonly found in 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 comprises an acyl chain length of about 20 to about 34 carbons. 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 micro-reservoirs.

In some embodiments of the present disclosure, the hydrophobic matrix 14 comprises only hydrophobic components, such as lipids, sterols, and fatty acids. In other words, in some embodiments, the hydrophobic matrix is free of hydrophilic polymers or hydrophilic excipients. In some embodiments of the present disclosure, the hydrophobic matrix 14 comprises 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 the like such as plasma or phosphate buffered saline. The use of cationic cholesterol or cationic phospholipids in the formulation may provide additional chemical attraction of the hydrophobic matrix 14 to the vascular surface and potentially to the micro-reservoir surface to increase the transfer of the coating 12 and resistance to dissolution into the blood following transfer. Suitable cationic forms of cholesterol are modified at the 3 carbon position to attach a side chain tertiary or quaternary amine and comprise DC-cholesterol. Suitable cationic forms of phospholipids include naturally occurring phospholipids and synthetically modified phospholipids, such as phosphatidylethanolamine, Dioleoylphosphatidylethanolamine (DOPE), and amine derivatives of phosphatidylcholine such as ethylphosphocholine.

In some embodiments, the acyl chain length and unsaturation of the phospholipid component of the hydrophobic matrix 14 may be used to adjust the physical and chemical properties of the hydrophobic matrix 14. In some embodiments, long acyl chain lengths are selected to increase the hydrophobicity of phospholipids for adhesion to blood vessel surfaces and to reduce solubility and washout due to blood flow exposure. The acyl chain length of the fatty acid moiety of fatty acids and phospholipids is described by the shorthand notation that the number of carbons: the number of carbon-carbon double bonds. In the following description of phospholipids, generic or trivial names, stereospecific numbering and shorthand notation are used for the first description of the compounds. Acyl chain lengths of 20 to 34 carbons (C20 to C34) are suitable for use as a coating 12 component, with acyl chain lengths of 20 to 24 carbons (C20 to C24) being particularly preferred. Although the present invention is also effective using saturated acyl chains, one or more sites of unsaturation may provide increased chain flexibility. Examples of preferred phospholipids include di (eicosanoyl) (dienoyl) phosphatidylcholine (1, 2-di (eicosanoyl) -sn-glycero-3-phosphocholine, C20:1PC), dianhydrotetraenoyl (dienoyl) phosphatidylcholine (1, 2-di (arachidoyl) -sn-glycero-3-phosphocholine, C20:0PC), dicambaoyl (dienoyl) phosphatidylcholine (1, 2-dicambaoyl-sn-glycero-3-phosphocholine, C22:1PC), di (docosahexenoyl) (didocosahexaenoyl) phosphatidylcholine (1, 2-di (docosahexenoyl) -sn-glycero-3-phosphocholine, C22: 6), heneicosenoyl (PC) phosphatidylcholine (1, 2-heneicosanoyl-sn-glycero-3-phosphocholine, C21:1PC) and dithioyl (dinervonyl) phosphatidylcholine (1, 2-dithioyl-sn-glycero-3-phosphocholine, C24:1 PC). In some embodiments, the phospholipids have a transition temperature equal to or higher than ambient temperature (20 ℃) such that the hydrophobic matrix 14 constitutes a solid during storage.

The plurality of micro-reservoirs includes 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 associated with the polymer in a manner that provides slow or extended release of the active agent from the micro-reservoirs. In some embodiments, the active agent is mixed with or dispersed in the biodegradable or bioerodible polymer. In some embodiments, the active agent may be encapsulated by a biodegradable or bioerodible polymer. In some embodiments, the plurality of micro-reservoirs may comprise a first active agent. In some embodiments, the plurality of micro-reservoirs may further comprise a second active agent. Suitable active agents may include antiproliferative or anti-inflammatory agents, such as paclitaxel, sirolimus (rapamycin) and their chemical derivatives or analogs, 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, paclitaxel derivatives, sirolimus derivatives, paclitaxel analogs, sirolimus analogs, inhibitory RNA, inhibitory DNA, steroids, and complement inhibitors. In some embodiments, the active agent comprises 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 micro-reservoirs. The micro-reservoirs may include microparticles or microspheres. In some embodiments, polylactic-co-glycolic acid (PLGA) microspheres are well suited for the incorporation of active agents for sustained release of up to about 50% by weight of the active agent in the microspheres.

In some embodiments, the hydrophobic matrix 14 may be a lipophilic matrix in which the dispersed phase 13 is dispersed. In some embodiments, the lipophilic matrix may include at least one lipid. In some embodiments, the lipid can be a phospholipid, sphingolipid, ceramide, terpene, monoglyceride, diglyceride, triglyceride, phytosterol, prostaglandin, vegetable oil (e.g., amaranth, apricot kernel, argan nut, almond, avocado, coconut, grape seed, palm, safflower, sesame, soybean, sunflower, and wheat germ oil), vegetable wax (e.g., beeswax, jojoba oil, and shea butter), paraffin, a fat-soluble vitamin and provitamin (e.g., carotene and vitamin A, D, E, K), a steroid, squalene. In some embodiments, the phospholipid is a cationic phospholipid. In some embodiments, the lipophilic matrix may further comprise a sterol, such as cholesterol. The lipophilic matrix is designed to adhere to the surface of the lumen when the expandable portion of the catheter is inflated within the lumen (e.g., a blood vessel). When the expandable portion of the catheter is expanded within the lumen, at least a portion of the plurality of micro-reservoirs is transferred to the surface of the lumen along with at least a portion of the lipophilic matrix.

The dispersed phase 13 includes a plurality of micro-reservoirs. In some embodiments, the plurality of micro-reservoirs includes a first active agent. In some embodiments, the plurality of micro-reservoirs includes a first active agent and a first biodegradable or bioerodible polymer. In some embodiments, the first active agent is mixed with or dispersed in the first biodegradable or bioerodible polymer. In some embodiments, some of the micro-reservoirs may contain only the first active agent, and some of the micro-reservoirs may contain the first active agent mixed with or dispersed within a first biodegradable or bioerodible polymer. In other embodiments, the first active agent may be crystalline. In some embodiments, the plurality of micro-reservoirs may comprise only one type of micro-reservoir.

In some embodiments, the coating 12 includes 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 micro-reservoirs. In some embodiments, the coating 12 has about 1 μ g/mm on the expandable portion of the catheter 10²To about 10. mu.g/mm²About 2. mu.g/mm²To about 9. mu.g/mm²Or about 3. mu.g/mm²To about 8. mu.g/mm²The surface concentration of (a).

In some embodiments, the micro-reservoirs include microparticles of active agent. In some embodiments, the active agent (e.g., sirolimus) may be a crystalline powder from the manufacturer or recrystallized by a controlled process. For example, sirolimus microparticles can be prepared by milling the crystalline powder in Novec 7100 hydrofluorocarbon solvent for 2 hours. By selecting the size and hardness of the milling balls, as well as the milling speed and time, the crystalline sirolimus can be reduced to micron-sized or smaller particles. The milling may be carried out dry or wet in an anti-solvent for sirolimus (such as water, hexane or hydrofluorocarbon) which is then removed by drying or vacuum. Alternative methods of mechanical size reduction include micro-hammer mills, automated mortar and pestles, ultrasonic homogenization, electro-hydraulic (arc cavitation) homogenization, or any mechanical process that leaves the crystals intact without dissolving the crystals in the solvent.

In some embodiments, the milled crystalline sirolimus may then be sieved to remove large particles. For example, ASTM E-11 Screen No. 100(150 μm openings) can be used for the sirolimus sample, with the particles that did not pass back to the planetary ball mill for additional grinding.

In some embodiments, any particle size sorting technique may be used to select microparticles of a particular size range. For example, the particles are passed through a progressively smaller screen in the anti-solvent. In some embodiments, optional further size reduction may be provided by ultrasonic homogenization probes, electro-hydraulic lithotripsy, or other high shear cavitation sources known in the art. In some embodiments, a circulation loop may be constructed to continue breaking down particles into sub-red blood cell sizes.

In some embodiments, once the maximum size of the particles has been reduced to less than about 10 microns, the uniformity of the particles may be further improved by flow sorting, such as winnowing, to remove finer particles that may produce excessive popping effects. In some embodiments, the particles can be circulated in an anti-solvent (water, heptane, hydrofluorocarbons) and by controlling the geometry and flow rate, particles of the desired size can be collected by settling.

In some embodiments, the plurality of micro-reservoirs has an average diameter of about 0.5 microns to about 10 microns, about 1 micron to about 10 microns, about 0.5 microns to about 8 microns, about 1.8 microns to about 8 microns, about 2 microns to about 6 microns, or about 3 microns to about 5 microns. In some embodiments, the micro-reservoirs need to be of a size large enough to provide sustained release of the active agent, with a diameter or average cross-sectional dimension of about 1.5 microns or greater for non-uniformly sized microparticles. Smaller size micro-reservoirs typically have increased surface area to volume ratios and decreased diffusion paths for the active agent, which may not provide sufficient extended release. The micro-reservoirs have a maximum dimension of about the size of red blood cells, about 6 microns to about 8 microns, to prevent embolisation into the capillaries due to any micro-reservoirs released into the blood stream during or after treatment. In some embodiments, the plurality of micro-reservoirs does not comprise 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 of micro-reservoirs have a diameter of 1.5 microns 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 micro-reservoirs have a diameter of 1 micron or less. In some embodiments, the micro-reservoirs do not necessarily have an affinity or adhesion to the surface of the blood vessel.

Biodegradable or bioerodible polymers can provide controlled and extended release of the active agent. The biodegradable or bioerodible polymer can be referred to as a first biodegradable or bioerodible polymer or a second biodegradable or bioerodible polymer. The polymer acts as a barrier to drug diffusion, providing a release profile tailored to the pharmacokinetics of the active agent acting on the treated blood vessel. For example, the active agent may be mixed and distributed in the polymer in a solid solution. The polymer may provide controlled release by reducing diffusion of the active agent or by combining drug release with biodegradation, dissolution or bioerosion of the polymer. In some embodiments, the biodegradable or bioerodible polymer is selected from the group consisting of polylactic acid, polyglycolic acid and copolymers thereof, polydioxanone, polycaprolactone, polyphosphazine, collagen, gelatin, chitosan, glycosaminoglycans (glycoaminoglycans), and combinations thereof. In some embodiments, the micro-reservoirs may also be microspheres or microparticles containing at least one active agent for treating inflammation or a healing response. In some embodiments, the plurality of micro-reservoirs may comprise a first biodegradable or bioerodible polymer. In some embodiments, the plurality of micro-reservoirs may comprise a second biodegradable or bioerodible polymer.

The kinetics of active agent release after the coating 12 contacts the vessel wall is controlled by the release of the active agent from the micro-reservoirs into the surrounding medium, thereby allowing for sustained elution penetration of the active agent into the vessel wall. To provide a high amount of active agent during the initial high risk period of restenosis following dilation, it is preferred that the active agent in the coating 12 be released continuously with a half-life release kinetics of about 2 weeks to about 6 weeks or more. In some embodiments, the plurality of micro-reservoirs has a kinetics of active agent release with a half-life of at least 14 days.

The kinetics of active agent release can be modulated by the nature of the micro-reservoirs. Two or more types of micro-reservoirs having different active agents or different release kinetics for the same active agent may be formulated into the coating 12 to tailor the therapeutic effect. In some embodiments, some active agent may be incorporated into the coating formulation outside of the micro-reservoirs to provide rapid initial release of the active agent to the vessel wall, thereby allowing the micro-reservoirs to provide sufficient active agent to maintain an effective tissue concentration of the active agent for an extended period of time. Since healing and resolution of inflammation in the dilated area typically takes 4-12 weeks, it is desirable to have a micro-reservoir and coating 12 to elute the active agent to provide a therapeutic tissue level of at least about 4 weeks to about 12 weeks after treatment. In certain applications, such as very long, widely diseased blood vessels, it may be desirable to maintain active agent levels for longer than 4 to 12 weeks, to provide additional protection from the effects of less common advanced restenosis.

It has been demonstrated that the release of an active agent mixed with or dispersed in a solid follows Higuchi kinetics, with a decrease in active agent release over time. For spherical particles with active agent dispersed in a polymer, the kinetics of active agent release also follows the power law of decreasing release rate, Korsmeyer-Peppas kinetics model, similar to Higuchi's equation (J.Sepmanna J, Peppas NA, Modeling of active agent release from delayed systems based on hydroxypropyl methyl cellulose (HPMC), Advanced Drug Delivery Reviews 48(2001) 139-. The release kinetics of the active agent from such micro-reservoirs is well suited for treatment of the vessel wall after expansion. Design and selection of micro-reservoirs with appropriate release constants compared to prior art devicesFor rapid initial release of the active agent, sustained active agent release over a longer period of time and prolonged residence of the active agent in the vessel wall. The rate of release of the active agent can be modulated by the solubility of the active agent in the micro-reservoir material and by adjusting the microporosity of the micro-reservoirs. The length of effective active agent delivery can be tuned by selecting the micro-reservoir size, the solubility of the active agent in the micro-reservoir material, and the amount of active agent loaded into the micro-reservoir. The total amount of active agent to be delivered is determined by the amount of micro-reservoirs in the coating formulation and their active agent loading. Thus, the coating 12 can be formulated to have a thickness per mm²Is in the range of about 0.3 μ g to about 3 μ g of active agent concentration on the surface of the expansible portion 11. The desired kinetics of active agent release from the coating 12 may be provided by a single type of micro-reservoir or alternatively by a mixture of micro-reservoirs having different sizes or release characteristics to provide a desired release profile to the vessel wall.

In some embodiments, the coating 12 further comprises PEG-lipids for increasing hemocompatibility (hemocompatibility). Since the coating 12 disclosed herein is designed to transfer to the surface of a blood vessel and remain there during healing of the blood vessel to release the drug, the blood compatibility of the coating 12 is required. In addition to preventing the dissolution of the coating 12 into the blood stream prior to vascular healing, it is desirable to prevent the initiation of significant coagulation and the attachment of fibrin and platelets to the surface of the coating exposed to blood after transfer. The addition of PEG-lipids to a combination of cholesterol and phospholipids or fatty acids can be used to improve the blood compatibility of the formulation. PEG graft polymer surfaces exhibit improved blood contact characteristics, primarily by reducing interfacial free energy and steric hindrance of hydrated PEG chains on the surface. While not wishing to be bound by a particular theory of operation, it is believed that small amounts of PEG-lipid conjugates added to the composition can migrate to the blood interface surface after transfer, especially for relatively low molecular weight PEG-lipids. Thus, PEG chains can reduce the interfacial free energy at the blood interface. Since the coating material at the blood interface is a small fraction of the total coating, a relatively small amount of PEG-lipid is required.

In some embodiments, the PEG-lipid is selected from 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-mPEG 550). In some embodiments, the PEG-lipid comprises from about 1% to about 30% by weight of the hydrophobic matrix 14 consisting of cholesterol, fatty acid or phospholipid, and the combination of PEG-lipids. 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 about 12% or less.

In some embodiments, the coating 12 further includes one or more additives. In some embodiments, the one or more additives are independently selected from the group consisting of penetration enhancers and stabilizers. For example, the coating 12 may also include additives to enhance performance, such as penetration enhancers. The permeation enhancer may help the active agent diffuse into the vessel wall and maximize tissue delivery of the active agent. Suitable penetration enhancers may include surfactants, cationic excipients, and cationic lipids. In some embodiments, additives may be added to the hydrophobic matrix, the micro-reservoirs, or both. In some embodiments, a stabilizer 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 hydroxytoluene), butylated hydroxyanisole (butylated hydroxyanisole), ascorbic acid, thioglycolic acid, ascorbyl palmitate and EDTA.

In some embodiments, the coating 12 further comprises a third active agent, wherein the third active agent is external to the micro-reservoirs or within the hydrophobic matrix 14. The third active agent may be the same as or different from the first or second active agent in the plurality of micro-reservoirs. However, since the active agent(s) are primarily contained within the micro-reservoirs and are not in direct contact with the hydrophobic matrix 14, the need to dissolve or emulsify the active agent within the hydrophobic matrix 14 itself is eliminated. Since the active agent(s) are primarily contained within the micro-reservoirs and not in contact with the hydrophobic matrix 14, the need to include amphiphilic components or components with affinity for the active agent within the hydrophobic matrix 14 itself is eliminated. Thus, the hydrophobic matrix 14 may be optimized for suitable properties for resisting blood wash off and adhesion to the vessel surface for coating 12 transfer.

Catheter tube

Referring to fig. 2, also disclosed herein is a catheter 10 comprising an expansible portion 11 on an elongate body 17, a coating 12 as described above over the expansible portion 11, and a release layer 15 between the expansible portion 11 and the coating 12. In some embodiments, the release layer 15 is configured to release the coating 12 from the expansible portion 11. The release layer 15, which is immiscible with the coating 12, is preferably a layer that remains distinct. In some embodiments, a PEG conjugated lipid is used as the release layer 15, as the degree of hydrophilicity and miscibility with the active agent coating 12 can be adjusted by the choice of lipid and PEG chain length. In some embodiments, the 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-mPEG 550). In some embodiments, the release layer 15 has about 0.1 μ g/mm²To about 5. mu.g/mm²、0.25μg/mm²To about 3. mu.g/mm²Or 0.5. mu.g/mm²To about 2. mu.g/mm²The surface concentration of (a).

Referring to fig. 3, in some embodiments, catheter 10 further includes a protective layer 16 as a topcoat layer over coating 12. In some embodiments, the protective layer 16 comprises a hydrophilic polymer, a carbohydrate, or an amphiphilic polymer. In some casesIn embodiments, the protective layer 16 is a glycosaminoglycan or crystalline sugar. Examples of glycosaminoglycans include dextran sulfate, chondroitin sulfate, heparan sulfate, and hyaluronic acid. Examples of crystalline sugars include mannitol, sorbitol, erythritol, and xylitol. The crystalline nature of these sugars provides a hard surface that protects the underlying micro-reservoirs. The thickness of the protective layer 16 may be adjusted so that the protective layer 16 is washed away during the transit time required to advance the catheter 10 to the target site. In some embodiments, protective layer 16 has about 0.1 μ g/mm²To about 5. mu.g/mm²About 0.2. mu.g/mm²To about 4. mu.g/mm²Or about 0.3. mu.g/mm²To about 3. mu.g/mm²The surface concentration of (a).

The expansible portion 11 of the catheter 10 may be a balloon, which serves as a substrate for the coating 12. In some embodiments, the balloon may be a low pressure design using elastomeric materials such as polyisoprene, polystyrene copolymers, silicone, or polyurethane. In some embodiments, the balloon may also be a high pressure design using high tensile strength polymers such as polyvinyl chloride, polyethylene terephthalate, or nylon. In some embodiments, the expansible portion 11 may be made of nylon 12. The coating 12 may be sufficiently adhered to the expansible portion 11, but is easily transferred to the tissue of the vessel lumen upon contact. In this case, the release layer may be omitted. In addition, the nylon 12 has sufficient strength so that after transfer of the coating 12, the balloon can also serve as a post-dilation balloon (if desired) in a subsequent procedure.

In some embodiments, the expandable portion 11 below the coating 12 can be used to expand a target vessel. In some embodiments, the vessel may be pre-dilated with another balloon catheter 10 prior to treatment with the coated balloon of this embodiment.

Coating formulations

Also disclosed herein is a coating formulation for the expansible portion 11 of the catheter 10. The formulation includes a solid portion and a fluid. The solid portion includes a plurality of micro-reservoirs and at least one hydrophobic compound. The fluid is used to disperse or dissolve the at least one hydrophobic compound. In some embodiments, the fluid may disperse some hydrophobic compounds and dissolve other hydrophobic compounds. The micro-reservoirs are dispersed and suspended in the resulting fluid mixture to form a coating formulation. The fluid mixture is formulated to form a homogeneous mixture of hydrophobic compounds that do not separate during drying to produce a uniform conformal coating of the hydrophobic matrix 14. The coating formulation is characterized by the weight of the solid portion, which refers to all non-volatile components of the coating formulation but does not include the fluid that subsequently evaporates during drying of the coating.

The micro-reservoirs 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 bioerodible polymer or a second biodegradable or bioerodible polymer described herein. In some embodiments, the active agent is mixed with or dispersed in the biodegradable or bioerodible polymer described herein. In some embodiments, the formulation may include more than one type of micro-reservoir. For example, the plurality of micro-reservoirs may include a first active agent and a first biodegradable or bioerodible polymer. In some embodiments, the plurality of micro-reservoirs may further include a second active agent. In some embodiments, the plurality of micro-reservoirs may further include a second biodegradable or bioerodible polymer.

The micro-reservoirs may be manufactured by any known method for particle manufacture, including spray drying, agglomeration, micro-molding, and milling. All such methods begin by dissolving the active agent and polymer together in a suitable solvent such as acetonitrile or dichloromethane, and then removing the solvent in a controlled manner to produce uniform particles. The particles may be further shaped by mechanical means. Methods of producing particles having a size distribution with a coefficient of variation of 10% or less are particularly useful for providing more consistent active agent release rates. Methods of producing uniformly sized microspheres are described by forming an emulsion of a microsphere material and extruding the emulsion through a substrate having through-holes of controlled size, as described in US 7,972,543 and US 8,100,348. Alternatively, the microspheres may be produced by spray drying a solution of the polymer, as described in US 6,560,897 and US 20080206349.

The fluid of the coating formulation may include water, organic solvents, perfluorocarbon fluids, or mixtures of such fluids. In some embodiments, the fluid is selected from the group consisting of pentane, hexane, heptane, mixtures of heptane and fluorocarbons, mixtures of alcohols and fluorocarbons, and mixtures of alcohols and water. Fluids that readily dissolve the active agent or polymer of the micro-reservoirs are not preferred because they can extract the active agent from the micro-reservoirs. Such non-preferred fluids include acetic acid, acetonitrile, acetone, dichloromethane, ethyl formate, cyclohexanone, DMSO, and chloroform. Optionally, the fluid/fluid mixture may be selected to saturate at a desired level of extracted active agent. Additional active agent, which is the same as the active agent in the micro-reservoirs, may be added to the fluid in advance to pre-saturate the solution, thereby reducing extraction from the micro-reservoirs during processing of the coating.

In some embodiments, the at least one hydrophobic compound is selected from 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 further include a PEG-lipid as described herein. In some embodiments, the formulation may further include additives such as penetration enhancers and stabilizers.

In some embodiments, the solid portion further comprises a third active agent external to the plurality of micro-reservoirs. In other words, the coating formulation may produce a hydrophobic matrix 14 that also includes a third active agent. The active agent on the exterior of the micro-reservoirs may be the same or different from the active agent(s) in the micro-reservoirs. In some embodiments, the solid portion may further comprise a PEG-lipid. In some embodiments, the solid portion may further comprise an additive described herein.

In some embodiments, the concentration of the solid portion in the coating formulation is from about 1% to about 90% by weight percent. In some embodiments, the solids content of the coating formulation has a concentration of about 2% to about 80% by weight, about 3% to about 70% by weight, or about 4% to about 60% by weight. In some embodiments for spray coating, the solid portion of the coating formulation has a concentration of about 2% to about 7% by weight. The solid portion of the coating formulation 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 micro-reservoirs.

Coating method

Also disclosed herein is a method for coating the expansible portion 11 of the catheter 10. The steps include disposing a formulation as described herein over the surface of the expanded expansible portion 11 of the catheter 10, evaporating the fluid components of the coating formulation, and contracting the expansible portion 11. Disposing the agent over the surface of the expanded expandable portion 11 includes disposing the agent over the surface of the expanded expandable portion 11. In some embodiments, the formulation can be disposed on or over the expanded expandable portion 11 by spraying, dipping, rolling, electrostatic deposition, printing, pipetting, or dispensing.

The coating formulation is prepared by mixing the coating components in a fluid as disclosed herein. In some embodiments, the micro-reservoirs are dispersed into a fluid formulation. Once fully mixed, the coating formulation may be applied to the surface of the expanded expansible portion 11, such as a balloon, and allowed to dry to form the coating 12. The application of the coating formulation can be repeated as necessary to deposit the desired amount of coating 12, typically at each mm²In the range of about 5mg to about 9mg of coating 12 on the balloon surface. The coating 12 is allowed to dry and the balloon is deflated and deflated to allow introduction into the vascular system.

In some embodiments, the method may further comprise disposing a release layer on the surface of the expanded expandable portion 11. Thus, the coating formulation may be disposed on the release layer while the release layer is disposed on the surface of the expanded expandable portion 11. The release layer is as described above.

Methods of treating or preventing a condition

Also disclosed herein are methods of treating or preventing a condition at a treatment site. The method comprises the following steps: advancing the catheter 10 including the expansible portion 11 to the treatment site, expanding the expansible portion 11 to allow contact between the coating 12 and tissue at the treatment site, contracting the expansible portion 11, and removing the catheter 10. The expansible portion 11 is coated with a coating as described herein. In some embodiments, contact between the tissue and the coating 12 causes at least a portion of the coating on the expansible portion 11 to be transferred to the treatment site during a duration of about 30 to about 120 seconds during the contact.

A catheter 10 having an expansible portion 11, such as a coated balloon catheter, is used herein to demonstrate the concept of delivering an active agent or combination of active agents to a blood vessel. The coated balloon catheter is introduced into a blood vessel with the expansible portion 11 collapsed to provide a small cross-sectional profile and to facilitate percutaneous insertion of the catheter 10, such as by the well-known Seldinger technique. After the expansible portion 11 of the catheter 10 is advanced into the diseased area of the blood vessel for treatment, the balloon is inflated and the coating 12 is brought into firm contact with the lumen of the blood vessel. The coating is formulated to have an affinity for the luminal tissue surface, resulting in a layer of the coating adhering to the vessel lumen. The expansible portion 11 may be inflated or expanded for a period of 30 seconds up to 2 minutes to promote adhesion and provide initial penetration of the active agent into the blood vessel. The expansible portion 11 may be repeatedly deflated and inflated as needed for treatment to control the period of time and risk of vessel occlusion or tissue ischemia. When the balloon is inflated and the surface of the balloon is in firm contact with the vessel lumen surface, the coating is transferred adhesively to the vessel lumen. Whereby the adhesion of the coating to the blood vessel surface carries the micro-reservoirs and transfers them to the blood vessel surface.

In some embodiments, the condition is selected from atherosclerosis, reduced lumen diameter or stenosis in a diseased vessel, restenosis, and in-stent restenosis. In some embodiments, an additional release layer as described herein is disposed between the expansible portion 11 and the coating 12.

While the present disclosure relates to the treatment of restenosis associated with balloon dilation of blood vessels, the present invention can be used to deliver drugs to various other lumens and hollow structures of the body of structures such as the respiratory system, gastrointestinal system, urinary system, reproductive system, and lymphatic system. The coating device may be an inflatable balloon or other inflatable device. Alternatively, the device delivering the coating of the present invention may be a non-inflatable device or any other type of expandable device for treating a living body.

Examples

Example 1

Drug-containing micro-reservoirs (microspheres) prepared by coacervation of poly (lactic-co-glycolic acid) conjugated with sirolimus (rapamycin) were obtained.

Microsphere sample 1: 50% DL-lactide/50% glycolide copolymer, mean diameter 3.1 μm, SD 0.44 μm, 39% by weight rapamycin

Microsphere sample 2: 75% DL-lactide/25% glycolide copolymer, mean diameter 3.2 μm, SD 0.76 μm, 40% rapamycin by weight

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

Microsphere sample 4: 75% DL-lactide/25% glycolide copolymer, mean diameter 3.3 μm, SD 1.2 μm, 46% rapamycin by weight

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

Microsphere sample 6: 75% DL-lactide/25% glycolide copolymer, mean diameter 3.78 μm, SD 0.44 μm, 28.8% by weight rapamycin

Microsphere sample 7: 75% DL-lactide/25% glycolide copolymer, mean diameter 3.8 μm, SD 0.34 μm, 27.7% by weight rapamycin

Microsphere sample 8: 75% DL-lactide/25% glycolide copolymer, mean diameter 3.79 μm, SD 0.39 μm, 29.4% by weight rapamycin

The drug content of these micro-reservoirs was verified by HPLC quantification method. Typically, micro-reservoirs (1mg to 5mg) are weighed and dissolved in 1ml acetonitrile, stirred gently at room temperature for several hours or at 37 ℃ for 1 hour, and diluted 50-fold to 200-fold with acetonitrile. The absorbance at 278nm was monitored and the content was determined from a linear calibration curve.

Example 2: sustained drug release from micro-reservoirs under physiological conditions

The micro-reservoirs of example 1 were tested for sustained release of the drug. A sample of 2mg to 5mg weight of micro-reservoirs was placed in a 1.6ml Eppendorf tube with 1.2ml Phosphate Buffered Saline (PBS) to simulate a physiological environment. After an initial wash to remove any drug not bound in the micro-reservoirs, the tubes were incubated at 37 ℃ with gentle mixing at 250 rpm. PBS was sampled at intervals and the released drug was quantified by reverse phase HPLC using a C18 column.

The micro-reservoirs were assayed for drug elution over a 5 hour period. The resulting drug release was fit to the Korsmeyer-Peppas kinetics equation for drug release from polymers with dispersed drug. The results of the Korsmeyer-Peppas model are listed in Table 1.

TABLE 1.5 Korsmeyer-Peppas modeling of drug release at hour

Short-term delivery results demonstrate that the typical Korsmeyer-Peppas drug release constant of drug dispersed in spherical polymer particles, with perhaps little contribution to microsphere samples 1,2, and 3, comes from polymer erosion or degradation.

Prolonged drug release study: drug elution of the microspheres over 7 days was determined using the method described for the test over 5 hours. The resulting drug release is listed in table 2.

TABLE 2.7 days drug Release test

The release rate from the 7 day delivery results was fitted to 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 unit area A over time t, C is the initial concentration of the drug, 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, Kh is the Higuchi constant for the binding area, diffusion coefficient and drug concentration coefficient.

The Higuchi equation is used to determine the release half-life of the micro-reservoirs and is also used to estimate the half-life as a function of the microsphere size. The resulting release half-life is shown in table 3.

TABLE 3 drug release half-lives from Higuchi modeling

The results indicate that the half-life of drug delivery from the micro-reservoirs can be modulated by the formulation and size of the micro-reservoirs. For a delivery half-life of at least 14 days, it is estimated that a microsphere size of 1.5 microns in diameter or greater is required.

Verification of extended release: drug release from microsphere sample 4 was determined over 8 weeks using the method described previously. Due to the relatively long time interval between sampling compared to previous release experiments, the micro-reservoirs may not be released into sink conditions at a later point in time, potentially slowing the effective release rate. The resulting drug release is listed in table 4.

TABLE 4 extended drug Release test over 56 days

The results demonstrate sustained release of drug from the micro-reservoirs. The micro-reservoirs may be tuned or selected to have a half-life that provides the drug throughout the healing period of the dilated blood vessel.

Example 3: formulating micro-reservoirs in coating formulations of cholesterol and fatty acids with PEG-lipids

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

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

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

Example 4: formulation of micro-reservoirs in coating formulations of cholesterol, fatty acids, PEG-lipids and stabilizing additives

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

Example 5: formulation of micro-reservoirs in coating formulations of cholesterol and phospholipids

A coating formulation was prepared using 43mg of cholesterol and 42mg of L- α -phosphatidylcholine mixed with 7mL of heptane and heated to 60 ℃. The solution was vortex mixed for 30 seconds and then allowed to cool to room temperature. Next, 100mg of sirolimus-loaded microspheres from sample #5 were added to the vial, which was then placed in an ultrasonic bath for 8 minutes to disperse and suspend the microspheres. [ preparation 0311A ]

Example 6: formulation in coating formulations of cholesterol and long acyl chain phospholipids with and without PEG-lipids Micro storage

A coating formulation was prepared with 51mg of DC-cholesterol, 6.25mg of DOPE-mPEG350 and 51mg of dicapryl phosphatidyl choline (DEPC) mixed with 7mL of heptane and heated to 60 ℃. The solution was vortex mixed for 30 seconds and then allowed to cool to room temperature. Next, 100mg of sirolimus-loaded microspheres from sample #7 were added to the vial, which was then placed in an ultrasonic bath for 5 minutes to disperse and suspend the microspheres. [ preparation 0410A ]

A coating formulation was prepared with 20mg of DC-cholesterol, 26mg of cholesterol, 6.25mg of DOPE-mPEG350 and 75mg of Didecylphosphatidylcholine (DNPC) mixed with 7mL of heptane and heated to 60 ℃. The formulation had a weight ratio of DNPC to DC-cholesterol of 1.6: 1. The solution was cooled to room temperature. Next, 97mg of sirolimus-loaded microspheres from sample #7 were added to the vial, which was then vortex mixed for 30 seconds and then placed in an ultrasonic bath for 5 minutes to disperse and suspend the microspheres.

[ preparation 0421A ]

A coating formulation was prepared with 28mg of DC-cholesterol, 26mg of cholesterol, 6.25mg of DOPE-mPEG350 and 50mg of Didecylphosphatidylcholine (DNPC) mixed with 7mL of heptane and heated to 60 ℃. The solution was vortex mixed for 30 seconds and then allowed to cool to room temperature. Next, 97mg of sirolimus-loaded microspheres from sample #7 were added to the vial, which was then placed in an ultrasonic bath for 5 minutes to disperse and suspend the microspheres. [ preparation 0421B ]

The coating formulation was prepared with 50mg of DC-cholesterol and 50mg of digluconate phosphatidylcholine (DNPC) mixed with 7mL of heptane and heated to 60 ℃. The formulation had a weight ratio of DNPC to DC-cholesterol of 1:1. The solution was vortex mixed for 30 seconds and then allowed to cool to room temperature. Next, 100mg of sirolimus-loaded microspheres from sample #7 were added to the vial, which was then placed in an ultrasonic bath for 4 minutes to disperse and suspend the microspheres. [ preparation 1205A ]

A coating formulation was prepared with 49mg of DC-cholesterol, 6.25mg of DOPE-mPEG350 and 50mg of Dithiolphosphatidylcholine (DNPC) mixed with 7mL of heptane and heated to 60 ℃. The formulation had a weight ratio of DNPC to DC-cholesterol of 1:1. The solution was vortex mixed for 30 seconds and then allowed to cool to room temperature. Next, 100mg of sirolimus-loaded microspheres from sample #7 were added to the vial, which was then placed in an ultrasonic bath for 2 minutes to disperse and suspend the microspheres. [ preparation 1209A ]

A coating formulation was prepared with 76mg of DC-cholesterol, 6.25mg of DOPE-mPEG350 and 25mg of Dithiolphosphatidylcholine (DNPC) mixed with 7mL of heptane and heated to 60 ℃. The formulation had a weight ratio of DNPC to DC-cholesterol of 1: 3. The solution was cooled to room temperature. Next, 100.7mg of sirolimus-loaded microspheres from sample #8 were added to the vial, vortex mixed for 30 seconds, and then placed in an ultrasonic bath for 5 minutes to disperse and suspend the microspheres. [ preparation 0513A ]

Example 7: formulation of micro-reservoirs in coating formulations of DC-cholesterol with different PEG-lipid content

A coating formulation was prepared with 12.5mg DOPE-mPEG350, 44mg DC-cholesterol and 44mg of diglucoylphosphatidyl choline (DNPC) mixed with 7mL heptane heated to 60 ℃. The clear solution was cooled to room temperature and then 97mg of sirolimus-loaded microspheres from sample #8 microspheres were added. The formulation was then placed in an ultrasonic bath and sonicated for 5 minutes to disperse and suspend the microspheres. [ formulation 0422A ]

A coating formulation was prepared with 25mg DOPE-mPEG350, 37.5mg DC-cholesterol and 37.5mg of Dithiolphosphatidylcholine (DNPC) mixed with 7mL heptane heated to 60 ℃. The clear solution was cooled to room temperature and then 97mg of sirolimus-loaded microspheres from microsphere sample #8 were added. The formulation was then placed in an ultrasonic bath and sonicated for 5 minutes to disperse and suspend the microspheres. [ preparation 0422B ]

Example 8: coatings with additional drugs

The coating formulation was prepared with 72.9mg of DC-cholesterol in 7mL of heptane and heated to 60 ℃ until the DC-cholesterol dissolved to yield a clear solution. To the solution was added 15.5mg of sirolimus and vortex mixed for 30 seconds. The solution was heated for 40 minutes, vortexed for 10 seconds every 10 minutes, and sonicated for 5 minutes while cooling to room temperature. To the solution was added 50mg of DNPC. When at room temperature, the solution was filtered through a 0.2 micron PTFE filter to remove large drug particles. The solution was left overnight with no formation of particles observed overnight. The solution was assayed and found to have a sirolimus content of 0.96 mg/ml. To the solution was added 98mg of sirolimus loaded microspheres from microsphere sample #8, vortex mixed for 30 seconds, and sonicated for 8 minutes to disperse and suspend the microspheres. The resulting coating formulation contained 0.71% by weight sirolimus with 19.1% of the drug in the DC-cholesterol and DNPC hydrophobic matrix and the remainder in the microspheres. [ preparation 0512A ]

The weight percent compositions of the coating formulations described in examples 3, 4, 5, 6, 7, and 8 are shown in table 5.

TABLE 5 composition of coating formulations in weight percent

Example 9: applying a coating formulation to a balloon catheter

The stearic acid coating formulation of example 3 (formulation 1023E) was sprayed onto the balloon surface of a 5.0mm diameter x 20mm length nylon angioplasty balloon. 7mL of the coating formulation was loaded into a 25mL airtight syringe with an integrated magnetic stir bar system. The formulation was continuously stirred during spraying to keep the drug micro-reservoirs well suspended. The syringe pump was operated at a rate of 0.11mL/min with a power of 5.5 watts [ Sonotek DES1000]The coating formulation was delivered by an activated 120kHz ultrasonic nozzle. To verify the process parameters, a cylinder of balloon material of 5.0mm diameter x 20mm length was cut, weighed and placed on a balloon of the same dimensions. The sleeve of balloon material was then coated and weighed to verify that about 2.2mg of total coating was applied, corresponding to 7 μ g/mm²The coating density of (2). At the 7. mu.g/mm from example 3²In the formulation of (1), the stearic acid comprises about 1.6 μ g/mm²Cholesterol contained 1.6. mu.g/mm²、DPPE-mPEG350 0.8μg/mm²And sirolimus-loaded microspheres from microsphere sample #5 of 3 μ g/mm²Yield 0.87. mu.g/mm²The drug density of (a). Once the sleeve weight confirmed that the target weight had been reached, the entire balloon was coated. A balloon of 5.0mm diameter x 20mm length was inflated, placed under the nebulizer, and then rotated continuously while moving back and forth 5 times. The balloon is then removed and allowed to dry. This process was repeated until 6 balloons were coated. The same procedure was repeated to spray the coating formulation of example 6 (formulation 0513A) on a balloon of 3.0mm diameter by 20mm length. The sleeve coating target weight for the 3.0mm diameter x 20mm length balloon with formulation of example 6 (formulation 0513A) was 1.4mg to achieve 7.6 μ g/mm²The coating density of (2). At 7.6. mu.g/mm²In (b), the diacylphosphatidylcholine contained 0.9. mu.g/mm²2.7. mu.g/mm of DC-cholesterol²、DOPE-mPEG350 0.23μg/mm²And sirolimus-loaded microsphere package of sample #5Containing 3.7. mu.g/mm²Yield 1.08. mu.g/mm²The drug density of (a).

The coating formulations of examples 4, 5, 6, 7 and 8 were also sprayed on the surface of a 20mm length balloon in a manner that the formulation of example 3 was previously sprayed. The resulting coating weights and coating densities are shown in table 6.

TABLE 6 coating of balloon catheters

For the balloons coated with the formulation of example 4, each balloon was sprayed with an additional topcoat formulation (1010D) consisting of 1mg of cholesterol and a cholesterol-PEG 600 coating to cover the micro-reservoir layer. To prepare the topcoat, 23mg of cholesterol-PEG 600 and 224mg of cholesterol were dissolved in 7mL of isopropanol. A target coating weight of 1mg on a 5.0mm diameter by 20mm length balloon corresponds to 3.2 μ g/mm²Of 0.3. mu.g/mm²cholesterol-PEG 600 and 2.9. mu.g/mm²Of cholesterol.

Example 10: adhesion coating to vessel luminal surface

Isolated porcine arteries were flushed with 37 ℃ lactated ringer's solution at 50mL/min pulsed flow (about 72BPM) for 5 minutes. The balloon coated with the formulation of example 3 was inflated in the lumen of a excised porcine artery to an over-expansion of about 1:1.2 to transfer the drug-containing coating to the vascular lumen. The solutions passed through the artery before and after inflation (before and after flushing), the balloon for the artery and the portion of the artery that contacted the inflated balloon were then measured 5 minutes after flushing after inflation. The vessels treated with formulations 1205A and 1209A were rinsed for a total of 60 minutes to evaluate the extended stability of the transferred coating. The amount of drug measured from all sources in the assay is summed and compared to the estimated drug content of the balloon based on the coating weight. The proportion of drug transferred to the artery based on the estimated drug content of the balloon by weight of the coating was used as a measure of transfer efficiency.

TABLE 7 stearic acid-cholesterol formulation [ formulation 1023E ]

TABLE 8 erucic acid-DC-cholesterol formulation [ formulation 0424A ]

TABLE 9 nervonic acid-DC-Cholesterol formulations [ formulation 0422E ]

The balloon coated with the formulation of example 4 was also tested in isolated porcine arteries.

TABLE 10 stearic acid-cholesterol-alpha tocopherol formulation [ formulation 1009A/1010D ]

The balloon coated with the formulation of example 5 was also tested in isolated porcine arteries.

TABLE 11L- α -Phosphatidylcholine-cholesterol formulation [ formulation 0311A ]

The balloon coated with the formulation of example 6 was also tested in isolated porcine arteries.

TABLE 12 DEPC-DC-Cholesterol [ formulation 0410A ]

TABLE 13 DNPC-DC-Cholesterol formulations [ formulation 0421A ]

TABLE 14 DNPC-DC-Cholesterol formulation [ formulation 0421B ]

TABLE 15 DNPC-DC-Cholesterol (without PEG-lipids) formulations [ formulation 1205A ]

TABLE 16 DNPC-DC-Cholesterol (PEG-lipid-free) formulations [ formulation 1209A ]

TABLE 17 DNPC-DC-Cholesterol (PEG-lipid) formulations [ formulation 0513A ]

After inflation of the balloon coated with formulation 1209A and one hour of fluid flushing after inflation, the luminal surface of the artery was observed under a dark field microscope. Fig. 4 is a photomicrograph of the luminal surface at 200X magnification showing the adhered material. Fig. 5 is a photomicrograph of a surface at 1000X magnification showing that the adhered material is a layer of spherical micro-reservoirs surrounded by coating material.

Example 11: adhesion of coating formulations with varying PEG-lipid content to vessel luminal surfaces

The samples from example 7 were tested for coating transfer and rinse resistance using the method of example 10. The results are tabulated for comparison with coatings having equal weight ratios of DNPC and DC-cholesterol and varying amounts of DOPE-mPEG 350. [ preparations 1205A, 1209A, 0422B ]

TABLE 18 coating transfer and rinse resistance of the respective coating formulations

The results confirmed the mass transfer of the drug coating to the vessel lumen. For the coating formulation with 25% PEG-lipid, the loss of drug coating during pre-rinse increases.

Example 12: adhesion of coatings with additional rapamycin to vessel luminal surfaces

The formulation of example 8 was tested for coating transfer and rinse resistance using the method of example 10.

TABLE 19 DNPC-DC-Cholesterol formulation with additional drugs [ formulation 0512A ]

The results demonstrate mass transfer of the drug from the coating with the additional drug added to the phospholipid and cholesterol components of the coating formulation to the vessel lumen.

Example 13: in vivo release of drug into treated blood vessels

To prepare a balloon catheter coated with a formulation containing drug micro-reservoirs, 100mg of DNPC, 103mg of DC-cholesterol, and 12.5mg of DOPE-mPEG350 were mixed into 14mL of heptane. The mixture was heated to 60 ℃ to dissolve the solid components and cooled to room temperature. Next, 195mg of microsphere sample #6 was added and stirred to suspend the microspheres. A balloon catheter with a balloon 3.0mm diameter x 20mm length was coated with the formulation using the method described in example 9. The coated balloon catheter was allowed to dry. An average of 1.28mg ± 0.12mg of dry coating was applied to the balloon, yielding 6.80 μ g/mm²And a coating density of 1.06. mu.g/mm²The drug density of (a). The balloon is deflated and deflated to a pre-disposed (deployment) configuration having a smaller cross-section and packaged in a sleeve to maintain the deflated configuration. The balloon catheters were packaged and sterilized by ionizing radiation at a minimum dose of 25 kgy.

The iliac-femoral artery of the rabbit was used to assess the in vivo transfer of the drug coating to the arterial vessel. First, the iliac-femoral segment for treatment was endothelialized to reproduce the tissue damage after angioplasty. The common carotid artery was dissected and a balloon wedge catheter of size 5F was inserted into the artery and directed under fluoroscopy guide to the treatment site of the iliac-femoral artery. Contrast was injected through the catheter and an angiogram of the iliac-femoral artery was recorded. The balloon wedge catheter was replaced with a standard angioplasty balloon catheter of 3.0mm diameter x 8mm length under fluoroscopic guidance, inflated and in its inflated state proximally withdrawn to a level near the iliac bifurcation to uncover the cross section of the artery. The angioplasty balloon catheter was replaced with a drug-coated balloon catheter. The catheter was advanced to the bare vessel section and inflated for 120 seconds. The balloon is deflated and removed. The right and left iliac arteries of each animal were treated.

A total of 11 animals were treated. One animal (2 iliac arteries treated) was euthanized 1 hour after treatment and the vessel segments were recovered for microscopic examination. Another animal (2 iliac arteries treated) was euthanized 24 hours post-treatment and the vessel segments were recovered for microscopic examination. Three animals (6 iliac arteries) were recovered at each time point of 1 hour, 7 days and 28 days. Blood samples were taken from these animals at 0.5 hours, 1 hour, 4 hours post-treatment and at sacrifice and prior to surgery. The vessel sections were recovered and the drug content was quantified by HPLC/MS.

Analysis of the blood samples showed a rapid drop in the circulating blood of the drug at a concentration of 4.75ng/ml at 30 minutes, 2.63ng/ml at 1 hour and 0.82ng/ml at 4 hours. Blood concentrations of drug collected at the time of death at the 7 day and 28 day time points were below the detection limit for the quantitative analysis. Blood levels were fitted to an exponential decay curve with a half-life of 0.77 hours, indicating rapid dilution and clearance of the drug in the bloodstream.

Scanning electron microscopy and light microscopy of tissue samples taken at 1 hour and 24 hours post-treatment revealed a layer of material on the luminal surface of the vessel and spherical drug micro-reservoirs were observed within the layer. A patch-like area of fibrin was observed on the luminal surface, but no large fibrin deposits were observed associated with the coating indicating blood incompatibility.

Analysis of the treated vessel sections showed that the tissue drug levels were 261 μ g/g 116.5 μ g/g 1 hour post-treatment, 43.8 μ g/g 34.2 μ g/g 7 days post-treatment, and 21.5 μ g/g 17.3 μ g/g 28 days post-treatment. The results indicate that the drug-containing micro-reservoir coating adheres to the luminal surface of the artery with the continued presence of drug bound to the tissue of the treated vessel over the entire 28 days. The tissue binding level of the drug showed a rapid initial decline, which slowed down between day 7 and day 28. Tissue bound drug levels from day 7 and day 28 were fitted to an exponential decay, indicating a half-life of about 20.4 days.

Example 14: adhesion of coating to vessel luminal surface of coating formulation comprising sirolimus microparticles

The crystalline sirolimus powder was ground, 100mg selected and added to about 75mg of a phospholipid excipient formulation (about 15% DOPE-mPEG350, 35% DNPC, 50% DC-Chol). The milled sirolimus microparticles were dispersed and suspended in the formulation by magnetic stirring and then sprayed onto a 4x30mm balloon catheter using a Sonotek PSI ultrasonic spray system. The flow rate of the ultrasonic spray formulation was set to 0.210ml/min and used 4 times to achieve a target coating weight of 2 milligrams, equivalent to per mm²The balloon surface area was about 3 μ g sirolimus. Fig. 6 is a photomicrograph of the surface of the coated balloon at 100X magnification showing that the coating contains crystalline sirolimus micro-reservoirs.

Several porcine carotid arteries 4mm in diameter were connected at a rate of approximately 100ml/min to a 72BPM pulsating flow system of ringer's lactate solution. A coated balloon catheter was inserted into the artery and deflated while pumping liquid through the artery for 1 minute and collecting the liquid to simulate washout during tracking of the lesion. The balloon was then inflated for one minute, deflated, removed, and the artery flushed, and one minute of fluid collected. The wash-off was collected for the second minute and then flowed for an additional 3 minutes for a total of 5 minutes. After 5 minutes, the length of the artery was cut, visually inspected, and then sirolimus was measured. Three coated catheters of the same formulation were tested in the artery. A white residual coating was visible on the dried artery indicating that significant metastasis had occurred. FIG. 7 is a photomicrograph of the arterial surface at 50X magnification showing adherent material. Fig. 8 is a photomicrograph of the arterial surface at 1000X magnification showing adherent material.

After visual inspection, 3 treated arteries were dissolved in acetonitrile and tested for sirolimus. Sirolimus residual analysis was performed on the balloon catheter. 1 minute before, 1 minute after and 2 minutes after washing, the sample was filtered with a 0.2um PTFE filter and dissolved with acetonitrile. The amount of sirolimus recovered from each group is shown in table 20. Of the total drug mass tracked, an average of 42% adhered to the porcine artery after 5 minutes of flushing. This indicates that this milled microcrystalline sirolimus coating is able to transfer to the artery.

TABLE 20 transfer and washability of the coating

Additional embodiments

Although the present invention has been disclosed in the context of certain preferred embodiments and examples, it will be understood by those skilled in the art that the present invention extends beyond the specifically disclosed embodiments to other alternative embodiments and/or uses of the invention and obvious modifications and equivalents thereof. Furthermore, it is contemplated that the various aspects and features of the invention described may be practiced separately, combined together or substituted for one another, and that various combinations and sub-combinations of the various features and aspects may be made and still fall within the scope of the invention. Moreover, any particular feature, aspect, method, property, characteristic, quality, attribute, element, etc. disclosed herein in connection with an embodiment may be used in all other embodiments set forth herein. Therefore, it is intended that the scope of the invention herein disclosed should not be limited by the particular disclosed embodiments described above, but should be determined only by a fair reading of the claims.

Conditional language such as "can", "might", "migt" or "might" is generally intended to convey that certain embodiments include but other embodiments do not include certain features or elements unless expressly specified otherwise or understood otherwise in the context of use. Thus, such conditional language is not generally intended to imply that a feature or element is in any way essential to one or more embodiments.

Detailed description of the preferred embodimentsSummary of (1)

A coating for an expandable portion of a catheter, comprising a hydrophobic matrix and a dispersed phase comprising a plurality of micro-reservoirs dispersed in the hydrophobic matrix, wherein the plurality of micro-reservoirs comprises a first active agent and a first biodegradable or bioerodible polymer.

In embodiments of the above coating, the first active agent is mixed with or dispersed in the first biodegradable or bioerodible polymer.

In an embodiment of the above coating, the plurality of micro-reservoirs further comprises a second active agent. The second active agent is selected from the group consisting of: paclitaxel, sirolimus, paclitaxel derivatives, sirolimus derivatives, paclitaxel analogs, sirolimus analogs, inhibitory RNA, inhibitory DNA, steroids, and complement inhibitors.

In an embodiment of the above coating, the plurality of micro-reservoirs further comprises a second biodegradable or bioerodible polymer. The second biodegradable or bioerodible polymer is selected from the group consisting of: polylactic acid, polyglycolic acid and copolymers thereof, polydioxanone, polycaprolactone, polyphosphazine, collagen, gelatin, chitosan, glycosaminoglycan and combinations thereof.

In an embodiment of the above coating, the hydrophobic matrix comprises at least one hydrophobic compound selected from the group consisting of sterols, lipids, phospholipids, fats, fatty acids, surfactants, and derivatives thereof.

In some embodiments of the above coating, wherein the hydrophobic matrix comprises cholesterol and a fatty acid. In some embodiments, the weight ratio of cholesterol to fatty acid is in the range of about 1:2 to about 3: 1.

In an embodiment of the above coating, the fatty acid is selected from the group consisting of lauric acid, tetradecenoic acid, caprylic acid, myristic acid, myristoleic acid, decenoic acid, capric acid, hexadecenoic acid, palmitoleic acid, palmitic acid, linolenic acid, linoleic acid, oleic acid, vaccenic acid, stearic acid, eicosapentaenoic acid, arachidonic acid, eicosatrienoic acid, arachidic acid, docosahexaenoic acid, docosapentaenoic acid, docosatetraenoic acid, docosenoic acid, tetracosenoic acid, hexacosenoic acid, pristanic acid, phytanic acid, and nervonic acid.

In still other embodiments of the above coating, wherein the hydrophobic matrix comprises cholesterol and a phospholipid. In some embodiments, the weight ratio of cholesterol to phospholipid is in the range of about 1:2 to about 3: 1.

In some embodiments, the phospholipid is selected from the group consisting of phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, and phosphatidylinositol.

In some embodiments, the phospholipid is a cationic phospholipid. In some embodiments, the cationic phospholipid is phosphatidylethanolamine, Dioleoylphosphatidylethanolamine (DOPE), or an amine derivative of phosphatidylcholine.

In some embodiments, the phospholipid comprises an acyl chain length of about 20 to about 34 carbons. In some embodiments, the phospholipid is selected from the group consisting of di (eicosanoyl) phosphatidylcholine (1, 2-di (eicosanoyl) -sn-glycero-3-phosphocholine, C20:1PC), dianhydrotetraallylphosphatidylcholine (1, 2-di-arachidoyl-sn-glycero-3-phosphocholine, C20:0PC), dicambaoylphosphatidylcholine (1, 2-di-erucyl-sn-glycero-3-phosphocholine, C22:1PC), di (docosahexaenoyl) phosphatidylcholine (1, 2-di (docosahexaenoyl) -sn-glycero-3-phosphocholine, C22:6PC), heneicosenoylphosphatidylcholine (1, 2-heneicosanoyl-sn-glycero-3-phosphocholine, c21:1PC) and digeracylphosphatidylcholine (1, 2-digeracylsn-sn-glycero-3-phosphocholine, C24:1 PC).

In an embodiment of the above coating, the cholesterol is DC-cholesterol.

In an embodiment of the above coating, the plurality of micro-reservoirs comprises about 10% to about 75% by weight of the coating.

In an embodiment of the above coating, the plurality of micro-reservoirs has an average diameter of about 1.5 microns to about 8 microns. In some embodiments, the plurality of micro-reservoirs has an average diameter of about 2 microns to about 6 microns. In some embodiments, the plurality of micro-reservoirs has an average diameter of about 3 microns to about 5 microns.

In an embodiment of the above coating, the plurality of micro-reservoirs has an active ingredient release kinetics with a half-life of at least 14 days.

In embodiments of the above coating, the first biodegradable or bioerodible polymer is selected from the group consisting of polylactic acid, polyglycolic acid and copolymers thereof, polydioxanone, polycaprolactone, polyphosphazine, collagen, gelatin, chitosan, glycosaminoglycan, and combinations thereof.

In an embodiment of the above coating, the first active agent is selected from the group consisting of paclitaxel, sirolimus, paclitaxel derivatives, sirolimus derivatives, paclitaxel analogs, sirolimus analogs, inhibitory RNA, inhibitory DNA, steroids, and complement inhibitors.

In an embodiment of the above coating, the first active agent comprises from about 10% to about 50% by weight of the plurality of micro-reservoirs.

In an embodiment of the above coating, the coating further comprises a third active agent outside the plurality of micro-reservoirs. In some embodiments, the third active agent is selected from the group consisting of paclitaxel, sirolimus, paclitaxel derivatives, sirolimus derivatives, 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.

In an embodiment of the above coating, the hydrophobic matrix further comprises a PEG-lipid. In some embodiments, the PEG-lipid is selected from 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-mPEG 550). In some embodiments, 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.

In an embodiment of the above coating, the coating further comprises one or more additives independently selected from the group consisting of penetration enhancers and stabilizers.

In an embodiment of the above coating, wherein the coating has about 1 μ g/mm²To about 10. mu.g/mm²The surface concentration of (a).

A catheter comprising an expansible portion on an elongate body and any embodiment of the above-described coating over the expansible portion. In some embodiments, the catheter further comprises a release layer between the expandable portion and the coating, wherein the release layer is configured to release the coating from the expandable portion. In some embodiments, the release layer comprises DSPE-mPEG350 or DSPE-mPEG 500. In some embodiments, the release layer has about 0.1 μ g/mm²To about 5. mu.g/mm²The surface concentration of (a).

In embodiments of the above catheter, the catheter further comprises a protective coating over the 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 a crystalline sugar. In some embodiments, the protective coating has about 0.1 μ g/mm²To about 5. mu.g/mm²The surface concentration of (a).

A coating formulation for an expandable portion of a catheter comprising a solid portion and a fluid. The solid portion comprises a plurality of micro-reservoirs and at least one hydrophobic compound, wherein the plurality of micro-reservoirs comprises a first active agent and a first biodegradable or bioerodible polymer. In some embodiments, the first active agent is mixed with or dispersed in the first biodegradable or bioerodible polymer.

In some embodiments, the plurality of micro-reservoirs further comprises a second active agent. In some embodiments, the second active agent is selected from the group consisting of: paclitaxel, sirolimus, paclitaxel derivatives, sirolimus derivatives, paclitaxel analogs, sirolimus analogs, inhibitory RNA, inhibitory DNA, steroids, and complement inhibitors. In some embodiments, the plurality of micro-reservoirs further comprises a second biodegradable or bioerodible polymer. In some embodiments, the second biodegradable or bioerodible polymer is selected from the group consisting of: polylactic acid, polyglycolic acid and copolymers thereof, polydioxanone, polycaprolactone, polyphosphazine, collagen, gelatin, chitosan, glycosylaminoglycans, and combinations thereof.

In some embodiments of the above coating formulation, the fluid is selected from the group consisting of pentane, hexane, heptane, a mixture of heptane and fluorocarbon, a mixture of alcohol and fluorocarbon, and a mixture of alcohol and water.

In some embodiments of the above coating formulation, wherein the solid portion further comprises a third active agent external to the plurality of micro-reservoirs. In some embodiments, the third active agent is selected from the group consisting of paclitaxel, sirolimus, paclitaxel derivatives, sirolimus derivatives, paclitaxel analogs, sirolimus analogs, inhibitory RNA, inhibitory DNA, steroids, and complement inhibitors.

In some embodiments of the above coating formulations, wherein the first active agent is selected from the group consisting of paclitaxel, sirolimus, paclitaxel derivatives, sirolimus derivatives, paclitaxel analogs, sirolimus analogs, inhibitory RNA, inhibitory DNA, steroids, and complement inhibitors.

In some embodiments of the above coating formulations, wherein the at least one hydrophobic compound is selected from sterols, lipids, phospholipids, fats, fatty acids, surfactants, and derivatives thereof.

In some embodiments of the above coating formulation, wherein the at least one hydrophobic compound comprises cholesterol and a fatty acid. In some embodiments, the weight ratio of cholesterol to fatty acid is in the range of about 1:2 to about 3: 1. In some embodiments, the fatty acid is selected from lauric acid, tetradecenoic acid, caprylic acid, myristic acid, myristoleic acid, decenoic acid, capric acid, hexadecenoic acid, palmitoleic acid, palmitic acid, linolenic acid, linoleic acid, oleic acid, vaccenic acid, stearic acid, eicosapentaenoic acid, arachidonic acid, eicosatrienoic acid, arachidic acid, docosahexaenoic acid, docosapentaenoic acid, docosatetraenoic acid, docosenoic acid, tetracosenoic acid, hexacosenoic acid, pristanic acid, phytanic acid, and nervonic acid.

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

In some embodiments, the phospholipid is a cationic phospholipid. In some embodiments, the cationic phospholipid is phosphatidylethanolamine, Dioleoylphosphatidylethanolamine (DOPE), or an amine derivative of phosphatidylcholine.

In some embodiments, the phospholipid comprises an acyl chain length of about 20 to about 34 carbons. In some embodiments, the phospholipid is selected from the group consisting of di (eicosanoyl) phosphatidylcholine (1, 2-di (eicosanoyl) -sn-glycero-3-phosphocholine, C20:1PC), dianhydrotetraallylphosphatidylcholine (1, 2-di-arachidoyl-sn-glycero-3-phosphocholine, C20:0PC), dicambaoylphosphatidylcholine (1, 2-di-erucyl-sn-glycero-3-phosphocholine, C22:1PC), di (docosahexaenoyl) phosphatidylcholine (1, 2-di (docosahexaenoyl) -sn-glycero-3-phosphocholine, C22:6PC), heneicosenoylphosphatidylcholine (1, 2-heneicosanoyl-sn-glycero-3-phosphocholine, c21:1PC) and digeracylphosphatidylcholine (1, 2-digeracylsn-sn-glycero-3-phosphocholine, C24:1 PC).

In some embodiments of the above coating formulation, the cholesterol is DC-cholesterol.

In some embodiments of the above coating formulations, the solid portion further comprises a PEG-lipid and/or an additive. In some embodiments, the PEG-lipid is selected from 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-mPEG 550).

In some embodiments of the above coating formulations, the plurality of micro-reservoirs comprises about 10% to about 75% by weight of the solid portion.

In some embodiments of the above coating formulations, the solid portion comprises from about 2 to about 7% by weight of the coating formulation.

A method for coating an expandable portion of a catheter comprising disposing the coating formulation of any of the embodiments above over a surface of an expanded expandable portion of the catheter, evaporating the fluid and contracting the expandable portion. In some embodiments, disposing the coating formulation comprises spraying, dipping, rolling, electrostatic deposition, printing, pipetting, or dispensing.

In some embodiments of the above method, the method further comprises disposing a release layer on the expandable portion. In some embodiments, the release layer comprises DSPE-mPEG350 or DSPE-mPEG 500.

A method for treating or preventing a condition at a treatment site comprising advancing a catheter comprising an expandable portion into the treatment site, wherein the expandable portion is coated with a coating as described in any of the embodiments above, expanding the expandable portion to allow contact between the coating and tissue at the treatment site, contracting the expandable portion; and removing the catheter.

In embodiments of the above method, contact between the tissue and the coating causes at least a portion of the coating on the expansible portion to transfer to the treatment site. In some embodiments, the method further comprises maintaining contact between the coating and the tissue for a time period of about 30 to about 120 seconds.

In an embodiment of any of the above methods, the condition is selected from atherosclerosis, reduced lumen diameter or stenosis in a diseased vessel, restenosis, in-stent restenosis, and combinations thereof.

In an embodiment of any of the above methods, wherein an additional release layer is disposed between the expandable portion and the coating.

In some embodiments, a catheter includes an expandable portion on an elongate body; and a coating over an outer surface of the expandable portion, wherein the coating comprises a lipophilic matrix, wherein the lipophilic matrix comprises at least one lipid; a plurality of micro-reservoirs dispersed in the lipophilic matrix, wherein the plurality of micro-reservoirs comprises an active agent; and wherein the lipophilic matrix is configured to adhere to a cavity surface when the expandable portion is expanded and to transfer at least a portion of the plurality of micro-reservoirs to the cavity surface.

In some embodiments of the above catheter, wherein the active agent is crystalline.

In some embodiments of the catheter described above, wherein the plurality of micro-reservoirs further comprises a biodegradable or bioerodible polymer. In some embodiments, the biodegradable or bioerodible polymer is selected from the group consisting of: polylactic acid, polyglycolic acid and copolymers thereof, polydioxanone, polycaprolactone, polyphosphazine, collagen, gelatin, chitosan, and glycosylaminoglycans. In some embodiments, the active agent is about 10% to about 50% by weight of the micro-reservoirs.

In some embodiments of the above catheter, wherein the at least one lipid comprises a phospholipid. In some embodiments, the phospholipid comprises an acyl chain length of about 20 to about 34 carbons. 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: bis (eicosanoyl) phosphatidylcholine (1, 2-bis (eicosanoyl) -sn-glycero-3-phosphocholine, C20:1PC), dianhydrotetraacrylphosphatidylcholine (1, 2-dianhydroacyl-sn-glycero-3-phosphocholine, C20:0PC), dicambal phosphatidylcholine (1, 2-dicambal-sn-glycero-3-phosphocholine, C22:1PC), bis (docosahexaenoyl) phosphatidylcholine (1, 2-bis (docosahexaenoyl) -sn-glycero-3-phosphocholine, C22:6PC), heneicosenoylphosphatidylcholine (1, 2-heneicosenoyl-sn-glycero-3-phosphocholine, c21:1PC) and digeracylphosphatidylcholine (1, 2-digeracylsn-sn-glycero-3-phosphocholine, C24:1 PC).

In some embodiments, the phospholipid comprises a cationic phospholipid. In some embodiments, the cationic phospholipid is an amine derivative of phosphatidylethanolamine, dioleoylphosphatidylethanolamine, or phosphatidylcholine. In some embodiments, the lipophilic matrix further comprises a sterol. In some embodiments, wherein the sterol is selected from the group consisting of: cholesterol, stigmasterol, lanosterol, sitosterol, DHEA, N4-cholesteryl-spermine, guanidino-cholesterol/BGTC, and DC-cholesterol.

In some embodiments of the catheter, wherein 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 micro-reservoirs.

In some embodiments of the catheter, the plurality of micro-reservoirs has an average diameter of about 1.5 microns to about 8 microns. In some embodiments, the plurality of micro-reservoirs has an average diameter of about 2.0 microns to about 6 microns.

In some embodiments of the catheter, wherein the active agent is selected from the group consisting of paclitaxel, sirolimus, paclitaxel derivatives, sirolimus derivatives, paclitaxel analogs, sirolimus analogs, inhibitory RNA, inhibitory DNA, steroids, and complement inhibitors.

In some embodiments of the catheter, wherein the coating further comprises a polyethylene glycol-lipid (PEG-lipid). In some embodiments, the PEG-lipid is selected from 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-mPEG 550). In some embodiments, PEG-lipid comprises from about 1% to about 10% by weight of the hydrophobic matrix.

In some embodiments of the catheter, the coating further comprises one or more additives independently selected from the group consisting of penetration enhancers and stabilizers.

In some embodiments of the catheter, the coating has about 1 μ g/mm²To about 10. mu.g/mm²The surface concentration of (a).

In some embodiments, a catheter includes an expandable portion on an elongate body; a coating on an outer surface of the expandable portion, wherein the coating comprises a lipophilic matrix, wherein the lipophilic matrix comprises at least one lipid; a plurality of micro-reservoirs dispersed in the lipophilic matrix, wherein the plurality of micro-reservoirs comprises an active agent; and wherein the lipophilic matrix is configured to adhere to a cavity surface when the expandable portion is expanded and to transfer at least a portion of the plurality of micro-reservoirs to the cavity surface; and a release layer between the expandable portion and the coating, wherein the release layer is configured to release the coating from the expandable portion.

In some embodiments, the release layer comprises DSPE-mPEG350 or DSPE-mPEG 500. In some embodiments, the release layer has about 0.1 μ g/mm²To about 5. mu.g/mm²The surface concentration of (a).

In some embodiments, the catheter further comprises 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 a crystalline sugar. In some embodiments, the protective coating has about 0.1 μ g/mm²To about 5. mu.g/mm²The surface concentration of (a).

In some embodiments, a method for coating an expandable portion of a catheter comprises: placing a coating formulation on a surface of an expandable portion of a catheter, wherein the coating formulation comprises: a plurality of micro-reservoirs comprising an active agent; at least one lipid; and a fluid, wherein the fluid is selected from the group consisting of: pentane, hexane, heptane and fluorocarbon mixtures, alcohol and fluorocarbon mixtures, and alcohol and water mixtures; evaporating the fluid; and contracting the expansible portion. In some embodiments, the coating formulation has a solids content comprising a plurality of micro-reservoirs and at least one lipid, and the plurality of micro-reservoirs is about 10% to about 75% by weight of the solids content.

In some embodiments of the method, the plurality of micro-reservoirs further comprises a biodegradable or bioerodible polymer. In some embodiments, the active agent is selected from the group consisting of: paclitaxel, sirolimus, paclitaxel derivatives, sirolimus derivatives, paclitaxel analogs, sirolimus analogs, inhibitory RNA, inhibitory DNA, steroids, and complement inhibitors.

In some embodiments of the above method, the active agent is crystalline.

In some embodiments of the above 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.

In some embodiments, the phospholipid comprises a phospholipid having an acyl chain length of about 20 to about 34 carbons. In some embodiments, the phospholipid is selected from the group consisting of di (eicosanoyl) phosphatidylcholine (1, 2-di (eicosanoyl) -sn-glycero-3-phosphocholine, C20:1PC), dianhydrotetraallylphosphatidylcholine (1, 2-di-arachidoyl-sn-glycero-3-phosphocholine, C20:0PC), dicambaoylphosphatidylcholine (1, 2-di-erucyl-sn-glycero-3-phosphocholine, C22:1PC), di (docosahexaenoyl) phosphatidylcholine (1, 2-di (docosahexaenoyl) -sn-glycero-3-phosphocholine, C22:6PC), heneicosenoylphosphatidylcholine (1, 2-heneicosanoyl-sn-glycero-3-phosphocholine, c21:1PC) and digeracylphosphatidylcholine (1, 2-digeracylsn-sn-glycero-3-phosphocholine, C24:1 PC).

In some embodiments of the above method, the phospholipid comprises a cationic phospholipid. In some embodiments, the cationic phospholipid is an amine derivative of phosphatidylethanolamine, dioleoylphosphatidylethanolamine, or phosphatidylcholine.

In some embodiments of the above method, the coating formulation further comprises a sterol. In some embodiments, the sterol is selected from the group consisting of: cholesterol, stigmasterol, lanosterol, sitosterol, DHEA, N4-cholesteryl-spermine, guanidino-cholesterol/BGTC, and DC-cholesterol.

In some embodiments of the above method, the coating formulation has a solids content of about 2 wt% to about 7 wt%, wherein the solids content comprises the plurality of micro-reservoirs and the at least one lipid.

In some embodiments of the above method, the coating formulation further comprises a polyethylene glycol-lipid (PEG-lipid).

In some embodiments of the above method, disposing the coating formulation comprises spraying, dipping, rolling, electrostatic deposition, printing, pipetting, or dispensing.

In some embodiments of the above method, further comprising placing a release layer on a surface of the expanded expandable portion prior to placing the coating formulation.

In some embodiments, a method for treating or preventing a condition at a treatment site is described, the method comprising advancing the catheter of claim 1 to the treatment site; expanding the expandable portion to allow contact between the coating and tissue at the treatment site; contracting the expansible portion; and removing the catheter.

In some embodiments of the above method, contact between the tissue and the coating causes at least a portion of the coating on the expandable portion to transfer to the treatment site.

In some embodiments of the above method, further comprising maintaining contact between the expandable portion and the coating for about 30 to about 120 seconds.

In some embodiments of the above methods, the condition is selected from the group consisting of: atherosclerosis, stenosis or reduction in lumen diameter of diseased vessels, restenosis, and in-stent restenosis.

Claims (51)

1. A catheter, comprising:

an expansible portion on the elongate body; and

a coating on an outer surface of the expandable portion, wherein the coating comprises:

a lipophilic matrix, wherein the lipophilic matrix comprises at least one lipid;

a plurality of micro-reservoirs dispersed in the lipophilic matrix, wherein the plurality of micro-reservoirs comprises an active agent; and

wherein the lipophilic matrix is configured to adhere to a luminal surface upon expansion of the expandable portion and to transfer at least a portion of the plurality of micro-reservoirs to the luminal surface.

2. The catheter of claim 1, wherein the active agent is crystalline.

3. The catheter of claim 1, wherein the plurality of micro-reservoirs further comprises a biodegradable or bioerodible polymer.

4. The catheter of claim 3, wherein the biodegradable or bioerodible polymer is selected from the group consisting of: polylactic acid, polyglycolic acid and copolymers thereof, polydioxanone, polycaprolactone, polyphosphazine, collagen, gelatin, chitosan, and glycosaminoglycans.

5. The catheter of claim 3, wherein the active agent is about 10% to about 50% by weight of the micro-reservoirs.

6. The catheter of claim 1, wherein the at least one lipid comprises a phospholipid.

7. The catheter of claim 6, wherein the phospholipid comprises an acyl chain length of about 20 to about 34 carbons.

8. The catheter of claim 6, wherein the phospholipid is selected from the group consisting of: phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, and phosphatidylinositol.

9. The catheter of claim 6, wherein the phospholipid is selected from the group consisting of: bis (eicosanoyl) phosphatidylcholine (1, 2-bis (eicosanoyl) -sn-glycero-3-phosphocholine, C20:1PC), dianhydrotetraacrylphosphatidylcholine (1, 2-dianhydroacyl-sn-glycero-3-phosphocholine, C20:0PC), dicambal phosphatidylcholine (1, 2-dicambal-sn-glycero-3-phosphocholine, C22:1PC), bis (docosahexaenoyl) phosphatidylcholine (1, 2-bis (docosahexaenoyl) -sn-glycero-3-phosphocholine, C22:6PC), heneicosenoylphosphatidylcholine (1, 2-heneicosenoyl-sn-glycero-3-phosphocholine, c21:1PC) and digeracylphosphatidylcholine (1, 2-digeracylsn-sn-glycero-3-phosphocholine, C24:1 PC).

10. The catheter of claim 6, wherein the phospholipid comprises a cationic phospholipid.

11. The catheter of claim 10, wherein the cationic phospholipid is phosphatidylethanolamine, dioleoylphosphatidylethanolamine, or an amine derivative of phosphatidylcholine.

12. The catheter of claim 10, wherein the lipophilic matrix further comprises a sterol.

13. The catheter of claim 12, wherein the sterol is selected from the group consisting of: cholesterol, stigmasterol, lanosterol, sitosterol, DHEA, N4-cholesterol-spermine, coronary-cholesterol/BGTC, and DC-cholesterol.

14. The catheter of claim 1, wherein the coating has a melting point between room temperature and body temperature.

15. The catheter of claim 1, wherein the coating comprises from about 10% to about 75% by weight of the plurality of micro-reservoirs.

16. The catheter of claim 1, wherein the plurality of micro-reservoirs has an average diameter of about 1.5 microns to about 8 microns.

17. The catheter of claim 1, wherein the plurality of micro-reservoirs has an average diameter of about 2.0 microns to about 6 microns.

18. The catheter of claim 1, wherein the active agent is selected from the group consisting of: paclitaxel, sirolimus, paclitaxel derivatives, sirolimus derivatives, paclitaxel analogs, sirolimus analogs, inhibitory RNA, inhibitory DNA, steroids, and complement inhibitors.

19. The catheter of claim 1, wherein the coating further comprises a polyethylene glycol lipid (PEG-lipid).

20. The catheter of claim 19, wherein 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-mPEG 550).

21. The catheter of claim 19, wherein the PEG-lipid comprises about 1% to about 10% by weight of the hydrophobic matrix.

22. The catheter of claim 1, wherein the coating further comprises one or more additives independently selected from the group consisting of penetration enhancers and stabilizers.

23. The coating of claim 1, wherein the coating has about 1 μ g/mm²To about 10. mu.g/mm²The surface concentration of (a).

24. A catheter, comprising:

an expansible portion on the elongate body;

the coating of claim 1 on the expandable portion; and

a release layer between the expandable portion and the coating, wherein the release layer is configured to release the coating from the expandable portion.

25. The catheter of claim 24, wherein the release layer comprises DSPE-mPEG350 or DSPE-mPEG 500.

26. The catheter of claim 24, wherein the release layer has about 0.1 μ g/mm²To about 5. mu.g/mm²The surface concentration of (a).

27. The catheter of claim 24, further comprising a protective coating over the first coating.

28. The catheter of claim 27, wherein the protective coating comprises a hydrophilic polymer, a carbohydrate, or an amphiphilic polymer.

29. The catheter of claim 27, wherein the protective coating is a glycosaminoglycan or a crystalline sugar.

30. The catheter of claim 27, wherein the protective coating has about 0.1 μ g/mm²To about 5. mu.g/mm²The surface concentration of (a).

31. A method of coating an expandable portion of a catheter, comprising:

placing a coating formulation on a surface of the expanded expandable portion of the catheter, wherein the coating formulation comprises:

a plurality of micro-reservoirs comprising an active agent; and

at least one lipid; and

a fluid, wherein the fluid is selected from the group consisting of: pentane, hexane, heptane and fluorocarbon mixtures, alcohol and fluorocarbon mixtures, and alcohol and water mixtures; and

evaporating the fluid; and

the expansible portion is contracted.

32. The method of claim 31, wherein the coating formulation has a solids content comprising the plurality of micro-reservoirs and at least one lipid, and the plurality of micro-reservoirs is about 10% to about 75% by weight of the solids content.

33. The method of claim 31, wherein the plurality of micro-reservoirs further comprises a biodegradable or bioerodible polymer.

34. The method of claim 31, wherein the active agent is selected from the group consisting of: paclitaxel, sirolimus, paclitaxel derivatives, sirolimus derivatives, paclitaxel analogs, sirolimus analogs, inhibitory RNA, inhibitory DNA, steroids, and complement inhibitors.

35. The method of claim 31, wherein the active agent is crystalline.

36. The method of claim 31, wherein the at least one lipid comprises a phospholipid.

37. The method of claim 36, wherein the phospholipid is selected from the group consisting of: phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, and phosphatidylinositol.

38. The method of claim 36, wherein the phospholipid comprises a phospholipid having an acyl chain length of about 20 to about 34 carbons.

39. The method of claim 36, wherein the phospholipid is selected from the group consisting of: bis (eicosanoyl) phosphatidylcholine (1, 2-bis (eicosanoyl) -sn-glycero-3-phosphocholine, C20:1PC), dianhydrotetraacrylphosphatidylcholine (1, 2-dianhydroacyl-sn-glycero-3-phosphocholine, C20:0PC), dicambal phosphatidylcholine (1, 2-dicambal-sn-glycero-3-phosphocholine, C22:1PC), bis (docosahexaenoyl) phosphatidylcholine (1, 2-bis (docosahexaenoyl) -sn-glycero-3-phosphocholine, C22:6PC), heneicosenoylphosphatidylcholine (1, 2-heneicosenoyl-sn-glycero-3-phosphocholine, c21:1PC) and digeracylphosphatidylcholine (1, 2-digeracylsn-sn-glycero-3-phosphocholine, C24:1 PC).

40. The method of claim 36, wherein the phospholipid comprises a cationic phospholipid.

41. The method of claim 40, wherein the cationic phospholipid is phosphatidylethanolamine, dioleoylphosphatidylethanolamine, or an amine derivative of phosphatidylcholine.

42. The method of claim 40, wherein the coating formulation further comprises a sterol.

43. The method of claim 42, wherein the sterol is selected from the group consisting of: cholesterol, stigmasterol, lanosterol, sitosterol, DHEA, N4-cholesterol-spermine, coronary-cholesterol/BGTC, and DC-cholesterol.

44. The method of claim 31, wherein the coating formulation has a solids content of about 2% to about 7% by weight, wherein the solids content comprises a plurality of micro-reservoirs and at least one lipid.

45. The method of claim 31, wherein the coating formulation further comprises a polyethylene glycol lipid (PEG-lipid).

46. The method of claim 31, wherein disposing the coating formulation comprises spraying, dipping, rolling, electrostatic deposition, printing, pipetting, or dispensing.

47. The method of claim 31, further comprising placing a release layer on the surface of the expanded expandable portion prior to placing the coating formulation.

48. A method for treating or preventing a condition at a treatment site, comprising:

advancing the catheter of claim 1 to the treatment site;

expanding the expandable portion to allow contact between the coating and tissue at the treatment site;

contracting the expansible portion; and

removing the catheter.

49. The method of claim 48, wherein the contact between the tissue and the coating causes at least a portion of the coating on the expandable portion to transfer to the treatment site.

50. The method of claim 48, further comprising maintaining contact between the expandable portion and the coating for a time of about 30 to about 120 seconds.

51. The method of claim 48, wherein the disorder is selected from the group consisting of: atherosclerosis, stenosis or reduction in lumen diameter in diseased vessels, restenosis, and in-stent restenosis.

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