HK1242231B - Coating for intraluminal expandable catheter providing contact transfer of drug micro-reservoirs - Google Patents

Description

Coatings for intraluminal expandable catheters providing contact transfer of drug microreservoirs

Incorporation by reference of any priority application

Any and all applications claimed as foreign or domestic priority identified in the Application Data Sheet filed with this application are hereby incorporated by reference pursuant to 37 CFR 1.57.

Technical Field

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

Background Art

Description of Related Technology

Balloon angioplasty is an established method for treating vascular disease by physically dilating areas of reduced lumen diameter or stenosis in atherosclerotic, diseased blood vessels. Typically, angioplasty is performed using a catheter that can be advanced within the circulatory system to the affected area. The catheter has a balloon at its distal end that is inflated to dilate and expand the stenotic area. In many cases, such as in coronary arteries, a stent is also expanded over the balloon's exterior. After the balloon is deflated and removed, the stent remains in place to maintain patency of the expanded lumen.

To achieve physical expansion of the blood vessels, high-pressure balloon inflation exerts significant forces on the vascular tissue. This physical expansion leads to vascular damage, including endothelial cell destruction, rupture of the internal elastic lamina, and dissection of the tunica media. Damage often extends into the adventitia of the outer arteries. Between days 0 and 3, the vascular biological response progresses through a thrombosis phase, including platelet activation and adhesion, and thrombosis. Between days 3 and 8, this thrombosis phase is followed by a cell recruitment phase, involving the infiltration of inflammatory cells, macrophages, and lymphocytes into the site of vascular injury. Between days 8 and 14, growth factors and cytokines released by the inflammatory cells trigger a proliferation phase, in which dormant smooth muscle cells in the tunica media are stimulated to proliferate. Subsequently, the migration of these proliferating smooth muscle cells into the thrombus in the intima and lumen leads to neointimal hyperplasia, a major component of restenosis. Although cell proliferation ceases after 14 days, the continued production of extracellular matrix by the smooth muscle cells continues to increase the extent of neointimal hyperplasia and restenosis. Restenosis effectively reverses dilatation therapy and potentially poses a serious threat to the patient.Human clinical studies have demonstrated that restenosis usually occurs 1 to 3 months after balloon angioplasty, and restenosis typically reaches its peak at about 3 months.

Although balloon angioplasty provides key blood flow increase in diseased blood vessels, restenosis is inherent due to related mechanical damage. One strategy to reduce restenosis reaction is to release drugs into the blood vessel in combination with balloon dilatation therapy to offset inflammatory reaction and healing reaction. Method includes using drug-coated balloons such as paclitaxel and sirolimus (rapamycin), which limit cell proliferation. During the period when the balloon contacts the vascular lumen surface, it is believed that the coating promotes drug transfer to the vascular injury site. These methods attempt to provide a drug concentration that is low enough to minimize the toxicity (which may cause damage or impairment) to the blood vessel while being enough to reduce the restenosis caused by cell proliferation. It is believed that it is desirable to maintain an effective drug concentration for a sufficiently long time to minimize restenosis.

In practice, drug delivery to tissues of the vessel wall via drug-coated balloons described in the art is limited by the short period of time during which 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 antineoplastic drug paclitaxel, which has been shown to inhibit neointimal formation in animals after exposure times of several minutes. 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, 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, 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 a high initial therapeutic concentration, but then the concentration drops rapidly. This is undesirable because most of the active agent on the device is lost as potential embolic particles enter the bloodstream or leave 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 being washed away by blood during balloon manipulation to the treatment site or after the drug coating has been transferred to the vessel surface.

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

Some embodiments provide a catheter comprising an expandable portion on an elongated body and a coating as described herein on the expandable 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 catheter further comprises a protective coating on the coating comprising the microreservoirs.

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 microreservoirs and at least one hydrophobic compound. The plurality of microreservoirs comprises a first active agent and a biodegradable or bioerodible polymer. The fluid disperses or dissolves the at least one hydrophobic compound and suspends the plurality of microreservoirs.

Some embodiments provide a method of coating an expandable portion of a catheter, comprising disposing a coating formulation described herein over a surface of the expanded expandable portion of the catheter, vaporizing the fluid, and collapsing the expandable 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.

BRIEF DESCRIPTION OF THE DRAWINGS

The features, aspects and advantages of the embodiments of the present disclosure are described in detail below with reference to the accompanying drawings of various embodiments, which are intended to illustrate rather than limit the present invention. These drawings depict only several embodiments according to the present disclosure and are not to be considered as limiting the scope thereof.

FIG. 1 depicts one embodiment of a balloon catheter comprising a coating on the expandable portion of the catheter.

FIG. 2 depicts one embodiment of a balloon catheter comprising a release layer between the coating and the expandable portion of the catheter.

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

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

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

DETAILED DESCRIPTION

Detailed Description of the Preferred Embodiments

To overcome the limitations of the prior art, embodiments disclosed herein provide a coating for the expandable portion of a catheter having a time-release drug microreservoir mixed with or dispersed within the coating on the balloon that can be transferred to the luminal surface of the blood vessel within 30 seconds to about 120 seconds of balloon inflation. This method enables extended and controlled release of the drug to the vessel wall over a longer period of time, which can be adjusted to the characteristics of a specific drug or the pathology of the diseased vessel through the design of the microreservoir. In addition to providing sustained release, the coating disclosed herein can also resist blood washout, which both improves drug transfer efficiency and increases patient safety by avoiding excess particles.

coating

Disclosed herein is a coating for an expandable portion of a catheter or catheter system. The catheter is designed for insertion into a living organism for the local delivery of at least one active agent. When the catheter is positioned in a target vessel or body lumen for treatment, or after the coating is delivered to tissue at the treatment site, such as a vessel wall or lumen wall, the coating is formulated and constructed to minimally dissolve and disperse into the bloodstream or body fluids. The coating is configured to transfer to the luminal surface or lumen wall contacted by the coating when the expandable portion is expanded. In some vessels or body lumens, the inner surface of the vessel or lumen may be diseased and may have an irregular topology, such as due to plaque, lesions, or previous interventions. The coating is configured to transfer to the luminal surface including the irregular topology, as described herein by the term lumen wall. In some embodiments, the active agent or drug is delivered to the vessel to prevent or minimize restenosis after balloon angioplasty. In some embodiments, the expandable portion may be the balloon of a balloon catheter.

1 , in some embodiments, a coating 12 for the expandable portion 11 of a catheter 10 comprises two phases, a hydrophobic matrix 14 and a dispersed phase 13. The dispersed phase 13 is dispersed in the hydrophobic matrix 14. The dispersed phase 13 comprises a plurality of microreservoirs, and the plurality of microreservoirs comprises a first active agent and a biodegradable or bioerodible polymer. In some embodiments, the first active agent is mixed with or dispersed in a biodegradable or bioerodible polymer. When the coating 12 is transferred to the lumen wall or lumen surface, the delivered coating will comprise both the hydrophobic matrix 14 and the dispersed phase 13.

In some embodiments, some or a portion of the plurality of microreservoirs may contain a first active agent and a biodegradable or bioerodible polymer, and some may contain a biodegradable or bioerodible polymer without the first active agent.

In some embodiments, the hydrophobic matrix 14 may further comprise a second active agent. The second active agent is present outside the plurality of microreservoirs. The second active agent may be the same as or different from the first active agent.

In some embodiments, the plurality of microreservoirs may further comprise a third active agent. In some embodiments, the plurality of microreservoirs may further comprise a second biodegradable or bioerodible polymer. In some embodiments, the first and second biodegradable or bioerodible polymers may be the same or different. In some embodiments, the plurality of microreservoirs may comprise only one type of microreservoir.

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

The hydrophobic matrix 14 comprises a combination of materials selected for their desired adhesion properties to the luminal surface or luminal wall. Preferred hydrophobic matrices 14 include a combination of hydrophobic compounds that, when applied to the surface of the balloon, resist dissolution into blood or other body fluids, yet provide uniform distribution of the formulation comprising the microreservoirs. In some embodiments, the hydrophobic matrix 14 comprises at least one hydrophobic compound selected from sterols, lipids, phospholipids, fats, fatty acids, surfactants, and their derivatives. Particularly useful formulations are combinations of sterols and fatty acids or phospholipids. The sterol can be one that utilizes the body's natural clearance mechanisms, for example, by forming complexes with serum lipids or aggregates with serum apolipoproteins to provide transport to the liver for metabolic processes. In some embodiments, the sterol can be cholesterol. Due to the natural compatibility of cholesterol and fatty acids or phospholipids, such a combination can provide a uniform mixture for the coating 12 and a uniform coating on the balloon surface. The coating 12 formed from such a combination is uniform without forming micelles or liposomes within the hydrophobic matrix 14.

In some embodiments, hydrophobic matrix 14 includes cholesterol and fatty acid. In some embodiments, the weight ratio of cholesterol to fatty acid is 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 amount and ratio of cholesterol and fatty acid are enough to allow coating to transfer to the lumen wall from the expandable portion of catheter. The cholesterol component of preparation can include cholesterol, chemically modified cholesterol or cholesterol conjugate. In some embodiments, cholesterol is dimethylaminoethane-carbamyl cholesterol (DC-cholesterol). For physiological compatibility, preferred fatty acids are fatty acids that are commonly present in serum or cell membranes. In some embodiments, the fatty acid is selected from the group consisting of lauric acid, lauroleic acid, tetradeadienoic 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, arachadonic acid, mead acid, arachidic acid, docosahexaenoic acid, docosapentaenoic acid, docosatetraenoic acid, docosenoic acid, tetracosanoic acid, hexacosenoic acid, pristanic acid, phytanic acid, and nervonic acid.

In some embodiments, the hydrophobic matrix 14 comprises cholesterol and phospholipids. In some embodiments, the weight ratio of cholesterol to phospholipids 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 amount and ratio of cholesterol and phospholipids are sufficient to allow the coating to transfer from the expandable portion of the catheter to the lumen wall. The cholesterol component of the preparation can include cholesterol, chemically modified cholesterol, or cholesterol conjugates. In some embodiments, cholesterol is DC-cholesterol. Preferred phospholipids are those commonly found in serum or cell membranes. In some embodiments, the phospholipids are selected from phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, or phosphatidylinositol. In some embodiments, the phospholipids comprise an acyl chain length of about 20 to about 34 carbons.

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 does not contain 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 does not contain amphiphilic components. Preferably, the coating 12 and its components have limited solubility in blood or analogs such as plasma or phosphate-buffered saline. The use of cationic cholesterol or cationic phospholipids in the formulation can provide the hydrophobic matrix 14 with additional chemical attraction to the lumen wall and potentially to the microreservoir surface to increase the transfer of the coating 12 and its resistance to dissolution into the blood after transfer. Suitable cationic forms of cholesterol are modified at the 3-carbon position to attach a side chain tertiary amine or quaternary amine and include 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 ethylphosphatidylcholine.

In some embodiments, the acyl chain length and degree of unsaturation of the phospholipid component of the hydrophobic matrix 14 can 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 the phospholipids for adhesion to the lumen wall and to reduce solubility and washout due to bloodstream exposure. Fatty acids and the acyl chain length of the fatty acid portion of phospholipids are described using a shorthand notation: number of carbons: number of carbon-carbon double bonds. In the following description of phospholipids, the common or common name, stereospecific number, and shorthand notation are used for the initial description of the compound. Acyl chain lengths of 20 to 34 carbons (C20 to C34) are suitable for use as coating 12 components, 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 can provide increased chain flexibility. Examples of preferred phospholipids include diicosenoylphosphatidylcholine (1,2-diicosenoyl-sn-glycero-3-phosphocholine, C20:1PC), diarachidonoylphosphatidylcholine (1,2-diarachidoyl-sn-glycero-3-phosphocholine, C20:0PC), dierucoylphosphatidylcholine (1,2-dierucoyl-sn-glycero-3-phosphocholine, C22: : 1PC), didocosahexaenoyl phosphatidylcholine (1,2-didocosahexaenoyl-sn-glycero-3-phosphocholine, C22: 6PC), heneicosenoyl phosphatidylcholine (1,2-heneicosenoyl-sn-glycero-3-phosphocholine, C21: 1PC) and dinervonyl phosphatidylcholine (1,2-dinervonyl-sn-glycero-3-phosphocholine, C24: 1PC). In some embodiments, the phospholipids have a transition temperature equal to or higher than ambient temperature (20° C.), such that the hydrophobic matrix 14 forms a solid during storage.

The multiple micro-reservoirs include an active agent and a polymer. The active agent can be referred to as the first active agent or the third active agent. The active agent is associated with the polymer in a manner that provides a slow or extended release of the active agent from the micro-reservoirs. In some embodiments, the active agent is mixed with a biodegradable or bioerodible polymer or is dispersed in a biodegradable or bioerodible polymer. In some embodiments, the active agent can be encapsulated by a biodegradable or bioerodible polymer. In some embodiments, multiple micro-reservoirs can include a first active agent. In some embodiments, multiple micro-reservoirs can also include a third active agent. In some embodiments, a second active agent can be present outside of multiple micro-reservoirs. The second active agent can be included in the hydrophobic matrix portion. Suitable active agents such as the first, second or third active agent can include antiproliferative agents 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 paclitaxel, sirolimus, paclitaxel derivatives, sirolimus derivatives, paclitaxel analogs, sirolimus analogs, inhibitory RNA, inhibitory DNA, steroids and complement inhibitors. In some embodiments, the active agent accounts for about 10% to about 50%, about 15% to about 45%, about 20% to about 40% or about 25% to about 35% by weight of a plurality of microreservoirs. The microreservoirs may include microparticles or microspheres. In some embodiments, poly(lactic-co-glycolic acid) (PLGA) microspheres are very suitable 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, a plurality of microreservoirs have an average diameter of about 0.5 micron to about 8 microns, about 2 microns to about 6 microns or about 3 microns to about 5 microns. In some embodiments, it is desirable that the microreservoirs have a sufficiently large size to provide sustained release of the active agent, and for microparticles of non-uniform size, the diameter or average cross-sectional dimension is about 1.5 microns or larger. Smaller-sized microreservoirs typically have an increased surface area to volume ratio and have a reduced diffusion pathway for not providing an active agent that fully prolongs release. The maximum size of the microreservoirs is close to the size of a red blood cell of about 6 microns to about 8 microns to prevent embolism of the capillaries due to any microreservoirs released into the bloodstream during or after treatment. In some embodiments, the microreservoirs do not necessarily have affinity or adhesion to the lumen wall.

Biodegradable or bioerodible polymers can provide controlled and extended release of active agents. Biodegradable or bioerodible polymers can be referred to as first biodegradable or bioerodible polymers or second biodegradable or bioerodible polymers. The polymer acts as a barrier to drug diffusion, thereby providing a release profile that adjusts the pharmacokinetics of the active agent acting on the treated blood vessel. For example, the active agent can be mixed and distributed in a polymer in a solid solution. The polymer can provide controlled release by reducing active agent diffusion or by combining drug release with biodegradation, dissolution or bioerodibility of the polymer. In some embodiments, the biodegradable or bioerodible polymer is selected from polylactic acid, polyglycolic acid and their copolymers, polydioxanone, polycaprolactone, polyphosphazene, collagen, gelatin, chitosan, glycosaminoglycans and combinations thereof. In some embodiments, the microreservoir can also be a microsphere or microparticle containing at least one active agent for treating inflammation or healing response. In some embodiments, a plurality of microreservoirs can comprise a first biodegradable or bioerodible polymer. In some embodiments, the plurality of microreservoirs may comprise a second biodegradable or bioerodible polymer.

After coating 12 contacts the lumen wall in vivo, the kinetics of active agent release are controlled by the release of the active agent from the microreservoirs into the surrounding medium, thereby achieving sustained elution and penetration of the active agent into the vessel wall. To provide a large amount of active agent during the initial high-risk period of restenosis after dilation, it is preferred that the active agent from coating 12 be continuously released with a half-life release kinetics of about 2 weeks to about 6 weeks or longer. In some embodiments, the plurality of microreservoirs have an active agent release kinetics with a half-life of at least 14 days.

The active agent release kinetics can be adjusted by the properties of the microreservoirs. Two or more types of microreservoirs with different active agents or different release kinetics for the same active agent can be formulated into the coating 12 to adjust the therapeutic effect. In some embodiments, some active agents can be incorporated into the coating formulation outside the microreservoirs to provide a rapid initial release of the active agent to the vessel wall, thereby allowing the microreservoirs to provide enough active agent to maintain the effective tissue concentration of the active agent for a prolonged period of time. Since the healing and resolution of inflammation in the dilated area typically requires 4-12 weeks, it is desirable to have microreservoirs and coatings 12 to elute the active agent to provide therapeutic tissue levels for at least about 4 weeks to about 12 weeks after treatment. In certain applications, such as very long, extensively diseased blood vessels, it may be desirable to maintain active agent levels for longer than 4 to 12 weeks to provide additional protection against the effects of less common late restenosis.

It has been shown that the release of active agents mixed with solids or dispersed in solids follows Higuchi kinetics, with active agent release decreasing over time. For spherical particles with active agents dispersed in polymers, active agent release kinetics also follows a power law that reduces the release rate, the Korsmeyer-Peppas kinetic model, which is similar to the Higuchi equation (J.Sepmanna J, Peppas NA, Modeling of active agent release from delivery systems based on hydroxypropyl methylcellulose (HPMC), Advanced Drug Delivery Reviews 48 (2001) 139-157). The release kinetics of active agents from such microreservoirs are very suitable for the treatment of dilated vascular walls. Compared to the devices of the prior art, the design and selection of microreservoirs with appropriate release constants provide rapid initial release of active agents, sustained active agent release over a longer period of time, and prolonged residence of active agents in the vascular wall. The active agent release rate can be adjusted by the solubility of the active agent in the microreservoir material and by adjusting the microporosity of the microreservoir. The length of effective active agent delivery can be regulated by selecting microreservoir size, the solubility of active agent in microreservoir material and the amount of active agent loaded in the microreservoir. The total amount of active agent to be delivered is determined by the amount of microreservoirs in the coating formulation and their active agent loading. Therefore, coating 12 can be formulated to have an active agent concentration in the range of about 0.3 μg to about 3 μg on the surface of expandable portion 11 per mm ^2. The desired kinetics of active agent release from coating 12 can be provided by a single type of microreservoir or alternatively by a mixture of microreservoirs with different sizes or release characteristics to provide a desired release curve to the vessel wall.

In some embodiments, the coating 12 also includes PEG-lipids for increasing blood compatibility. In some embodiments, the coating 12 disclosed herein is designed to be transferred to the luminal surface or luminal wall of a blood vessel and remain there to release the drug during the healing period, so the blood compatibility of the coating 12 is required. In addition to preventing the coating 12 from dissolving into the bloodstream before the blood vessel heals, it is desirable to prevent the initiation of significant coagulation and the adhesion of fibrin and platelets on the coating surface exposed to blood after transfer. Adding PEG-lipids to a composition of cholesterol and phospholipids or fatty acids can be used to improve the blood compatibility of the formulation. PEG-grafted polymer surfaces show improved blood contact properties, primarily by reducing interfacial free energy and steric hindrance of hydrated PEG chains on the surface. Although not wishing to be bound by a particular theory of operation, it is believed that a small amount of PEG-lipid conjugate added to the composition can migrate to the blood interface surface after transfer, especially for relatively low molecular weight PEG-lipids. Therefore, the PEG chains can reduce the interfacial free energy at the blood interface. Since the coating material at the blood or fluid 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), In some embodiments, the PEG-lipid comprises about 1% to about 30% of the weight of the hydrophobic matrix 14 composed of a combination of cholesterol, fatty acids or phospholipids and PEG-lipids. In other embodiments, the PEG-lipid comprises about 2% to about 25%, about 3% to about 20%, or about 5% to about 10% of the weight of the hydrophobic matrix 14. In some embodiments, the amount of PEG-lipid is about 12% or less.

In some embodiments, coating 12 also includes one or more additives. In some embodiments, one or more additives are independently selected from penetration enhancers and stabilizers. For example, coating 12 may also include additives to enhance performance, such as penetration enhancers. Penetration enhancers can help active agents diffuse into the vascular wall and maximize the tissue delivery of active agents. Suitable penetration enhancers may include surfactants, cationic excipients, and cationic lipids. In some embodiments, additives may be added to hydrophobic matrix, microreservoirs, or both. In some embodiments, stabilizers may be added to protect the drug during the sterilization of the balloon catheter system and its subsequent storage period before use. Stabilizers may include antioxidants and free radical scavengers. Examples of stabilizers include gallic acid, propyl gallate, tocopherol and tocotrienols (vitamin E), butylated hydroxytoluene, 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 outside the microreservoir or in the hydrophobic matrix 14. The third active agent may be the same or different from the first or second active agent in the plurality of microreservoirs. However, since the (multiple) active agents are primarily contained in the microreservoirs and are not in direct contact with the hydrophobic matrix 14, the need for dissolving or emulsifying the active agent in the hydrophobic matrix 14 itself is eliminated. Since in some embodiments, the (multiple) active agents are primarily contained in the microreservoirs and are not in direct contact with the hydrophobic matrix 14, the need for including amphiphilic components or components with active agent affinity in the hydrophobic matrix 14 itself is eliminated. Therefore, the hydrophobic matrix 14 can be optimized for suitable properties for resisting blood or body fluid washout and adhering to the lumen surface or lumen wall for transfer of the coating 12.

catheter

Referring to FIG. 2 , a catheter 10 is also disclosed herein, comprising an expandable portion 11 on an elongated body 17 , a coating 12 as described above on the expandable portion 11 , and a release layer 15 between the expandable portion 11 and the coating 12 . In some embodiments, the release layer 15 is configured to release the coating 12 from the expandable portion 11 . The release layer 15, which is immiscible with the coating 12 , preferably remains a distinct layer. In some embodiments, a PEG-conjugated lipid is used as the release layer 15 , as the hydrophilicity and degree of 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-mPEG550). In some embodiments, release layer 15 has a surface concentration of about 0.1 μg/mm ² to about 5 μg/mm ² , about 0.25 μg/mm ² to about 3 μg/mm ² , or about 0.5 μg/mm ² to about 2 μg/mm ² .

3 , in some embodiments, the catheter 10 further comprises a protective layer 16 as a topcoat on the coating 12. In some embodiments, the protective layer 16 comprises a hydrophilic polymer, a carbohydrate, or an amphiphilic polymer. In some embodiments, the protective layer 16 is a glycosaminoglycan or a 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 microreservoirs. The thickness of the protective layer 16 can 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, the protective layer 16 has a surface concentration of about 0.1 μg/mm ² to about 5 μg/mm ² , about 0.2 μg/mm ² to about 4 μg/mm ² , or about 0.3 μg/mm ² to about 3 μg/mm ² .

The expandable portion 11 of catheter 10 can be a balloon, which serves as the substrate of coating 12. In some embodiments, the balloon can be a low-pressure design using an elastomeric material such as polyisoprene, polystyrene copolymer, polysiloxane or polyurethane. In some embodiments, the balloon can also be a high-pressure design using a high-tensile strength polymer such as polyvinyl chloride, polyethylene, polyethylene terephthalate or nylon. In some embodiments, expandable portion 11 can be made of nylon 12. Coating 12 can be fully adhered to expandable portion 11, but is easily transferred to the tissue of the vascular cavity when in contact. In this case, the release layer can be omitted. In addition, nylon 12 has enough strength so that after the transfer of coating 12, the balloon can also further serve as a post-expansion balloon (if needed) in subsequent procedures.

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

Coating formulations

Also disclosed herein is a coating formulation for the expandable portion 11 of the catheter 10. The formulation includes a solid portion and a fluid. The solid portion includes a plurality of microreservoirs 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 can disperse some hydrophobic compounds and dissolve other hydrophobic compounds. The microreservoirs are dispersed and suspended in the resulting fluid mixture to form a coating formulation. The fluid mixture is formulated to form a uniform mixture of hydrophobic compounds that does 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 fluid that subsequently evaporates during the drying of the coating.

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

The microreservoirs can be manufactured by any known method for particle manufacturing, including spray drying, coacervation, micromolding and grinding. All of these 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 can be further shaped by mechanical methods. Methods for producing particles with a size distribution having a coefficient of variation of 10% or less are particularly useful for providing a more consistent active agent release rate. Methods for producing uniformly sized microspheres are described by forming an emulsion of microsphere material and extruding the emulsion through a substrate with through-holes of controlled size, as described in US 7,972,543 and US 8,100,348. Alternatively, microspheres can be produced by spray drying a solution of the polymer, as described in US 6,560,897 and US 20080206349.

The fluid of coating formulation can comprise the mixture of water, organic solvent, perfluorocarbon fluid or this fluid.In some embodiments, fluid is selected from the mixture of pentane, hexane, heptane, heptane and fluorocarbon, the mixture of alcohol and fluorocarbon and the mixture of alcohol and water.It is not preferred that the fluid of the activating agent of dissolving microreservoir easily or polymer is because they can extract activating agent from microreservoir.This non-preferred fluid comprises acetic acid, acetonitrile, acetone, ethyl formate, pimelinketone, DMSO and chloroform.Optionally, can select fluid/fluid mixture to be saturated under the required level of the activating agent extracted.Can in advance other activating agent identical with the activating agent in the microreservoir be added in the fluid with presaturated solution, thereby reduce the extraction from microreservoir during the processing of coating.

In some embodiments, the at least one hydrophobic compound is selected from sterols, lipids, phospholipids, fats, fatty acids, and surfactants and their derivatives. In some embodiments, the at least one hydrophobic compound comprises cholesterol and fatty acids as described herein. In other embodiments, the at least one hydrophobic compound comprises cholesterol and phospholipids as described herein. In some embodiments, the formulation may further include PEG-lipids 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 outside the plurality of microreservoirs. In other words, the coating formulation can produce a hydrophobic matrix 14 that also comprises a third active agent. The active agent outside the microreservoirs can be the same or different from the active agent(s) in the microreservoirs. In some embodiments, the solid portion can further comprise a PEG-lipid. In some embodiments, the solid portion can further comprise an additive as described herein.

In some embodiments, the coating formulation has a solid content of about 1% to about 90% by weight. In some embodiments, the coating formulation has a solid content 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 spraying, the solid content of the coating formulation has a concentration of about 2% to about 7% by weight. The solid content of the coating formulation comprises a plurality of microreservoirs of about 10% to about 75%, about 20% to about 65%, or about 30% to about 55% by weight.

The coating composition can be prepared by forming a mixture of at least two hydrophobic compounds and a plurality of microreservoirs as described herein. The plurality of microreservoirs comprises a first active agent and a biodegradable or bioerodible polymer. The at least two hydrophobic compounds comprise cholesterol and a phospholipid or cholesterol and a fatty acid, wherein the at least two hydrophobic compounds are present in an amount and ratio sufficient to transfer the coating from the expandable portion of the catheter to the luminal wall, such as the wall of a blood vessel. In some embodiments, the mixture further comprises a PEG-lipid as described above.

Coating method

Also disclosed herein is a method for coating the expandable portion 11 of the catheter 10. The steps include disposing a formulation described herein on the surface of the expanded expandable portion 11 of the catheter 10, evaporating the fluid component of the coating formulation, and shrinking the expandable portion 11. Disposing the formulation on the surface of the expanded expandable portion 11 includes disposing the formulation on 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, roller coating, 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 microreservoirs are dispersed into the fluid formulation. Once fully mixed, the coating formulation can be applied to the surface of the expandable portion 11 of the expansion, such as a balloon, and allowed to dry to form a coating 12. The coating of the coating formulation can be repeated as needed to deposit the desired amount of coating 12, typically within the range of about 5 mg to about 9 mg of coating 12 on the balloon surface per mm ^2. The coating 12 is dried, and the balloon is deflated and folded to allow introduction into the vascular system. In some embodiments, a release layer has been provided on the surface of the expandable portion 11 of the expansion, and the coating formulation can be applied to the existing release layer and dried to form a coating 12. Therefore, the release layer is between the surface of the expandable portion 11 of the expansion and the coating 12.

In some embodiments, the method may further include 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 for treating or preventing conditions

Also disclosed herein is a method for treating or preventing a condition at a treatment site. The method comprises the steps of advancing a catheter 10 comprising an expandable portion 11 to the treatment site, expanding the expandable portion 11 to allow contact between the coating and tissue at the treatment site, defusing the expandable portion 11, and removing the catheter 10. The expandable portion 11 is coated with the coating described herein. In some embodiments, contact between the tissue and the coating causes at least a portion of the coating on the expandable portion 11 to transfer to the expandable portion 11 and the coating at the treatment site for a period of about 30 to about 120 seconds.

A catheter 10, such as a coated balloon catheter, having an expandable portion 11 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 expandable portion 11 folded to provide a small cross-sectional profile and facilitate percutaneous insertion of the catheter 10, for example, using the well-known Seldinger technique. After the expandable portion 11 of the catheter 10 is advanced to the lesioned area of the blood vessel for treatment, the balloon is inflated, bringing the coating into firm contact with the vessel lumen. The coating is formulated to have an affinity for the luminal tissue surface, resulting in a layer of coating adhering to the vessel lumen. The expandable portion 11 can be inflated or expanded for periods of 30 seconds to 2 minutes to promote adhesion and provide initial penetration of the active agent into the vessel wall. Depending on the treatment needs, the expandable portion 11 can be repeatedly deflated and inflated to control the duration and risk of vessel occlusion or tissue ischemia. When the balloon is inflated and the balloon surface is in firm contact with the vessel lumen, the coating adhesively transfers to the vessel lumen. This adhesion of the coating to the vessel surface thus carries the microreservoirs and transfers them to the vessel surface.

In some embodiments, the condition is selected from atherosclerosis, lumen diameter reduction 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 expandable portion 11 and the coating.

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, such as structures of the respiratory, gastrointestinal, urinary, reproductive, and lymphatic systems. The coating device can be an inflatable balloon or other inflatable device. Alternatively, the device for delivering the coating of the present invention can be a non-inflatable device or any other type of inflatable device used to treat a living organism.

Example

Example 1

Drug-containing microreservoirs (microspheres) prepared by coacervation of poly(lactic-co-glycolic acid) bound to sirolimus (rapamycin) were obtained.

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

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, mean 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, mean 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% rapamycin by weight

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

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

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

Example 2: Sustained drug release from microreservoirs under physiological conditions

The sustained release of the drug from the microreservoir of Example 1 was tested. Samples of the microreservoir, ranging in weight from 2 mg to 5 mg, were placed in 1.6 ml Eppendorf tubes with 1.2 ml of phosphate-buffered saline (PBS) to simulate a physiological environment. After an initial wash to remove any drug not bound to the microreservoir, the tubes were incubated at 37° C. with gentle mixing at 250 rpm. PBS was sampled at regular intervals and the released drug was quantified by reverse-phase HPLC using a C18 column.

The drug elution from the microreservoirs was measured over a 5-hour period. The resulting drug release was fitted to the Korsmeyer-Peppas kinetic equation for drug release from the polymer with dispersed drug. The results of the Korsmeyer-Peppas model are listed in Table 1.

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

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

The short-term delivery results demonstrated typical Korsmeyer-Peppas drug release constants for the drug dispersed in the spherical polymer particles, with likely minor contributions from polymer erosion or degradation for microsphere samples 1, 2, and 3.

Extended drug release studies: Drug elution from the microspheres was determined over 7 days using the method described for testing over 5 hours. The resulting drug release is listed in Table 2.

Table 2. 7-day drug release test

The release rates from the 7-day delivery results were 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 in time t, C is the initial drug concentration, Cs is the solubility of the drug in the polymer medium, and D is the diffusion coefficient of the drug in the microsphere polymer. In the generalized equation, _Kh is the Higuchi constant for the binding area, diffusion coefficient, and drug concentration coefficient.

The Higuchi equation was used to determine the release half-life of the microreservoirs and was also used to estimate the half-life as a function of microsphere size. The resulting release half-lives are shown in Table 3.

Table 3. Drug release half-lives from Higuchi modeling

The results indicate that the delivery half-life of drugs from microreservoirs can be tuned by the formulation and size of the microreservoirs. For a delivery half-life of at least 14 days, it is estimated that a microsphere size of 1.5 micrometers in diameter or greater is required.

Verification of extended release: Drug release from microsphere sample 4 was determined over 8 weeks using the aforementioned method. Due to the relatively long time interval between sampling compared to previous release experiments, the microreservoirs may not release into sink conditions at later time points, potentially slowing down the effective release rate. The resulting drug release is listed in Table 4.

Table 4. Extended drug release testing over 56 days

The results demonstrate sustained release of the drug from the microreservoir. The microreservoir can be adjusted or selected to have a half-life that provides the drug throughout the healing period of the dilated vessel.

Example 3: Formulation of Microreservoirs in Coating Formulations of Cholesterol and Fatty Acids with PEG-Lipids

A coating formulation was prepared with 107 mg of stearic acid, 105 mg of cholesterol, and 50 mg of DPPE-mPEG350 mixed with 14 mL of heptane and heated to 60°C to obtain a clear solution. The solution was then vortexed for 30 seconds and allowed to cool. Next, 200 mg of sirolimus-loaded microspheres from 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 58 mg of erucic acid, 43 mg of DC-cholesterol, and 6.25 mg of DOPE-mPEG350 mixed with 7 mL of heptane and heated to 60°C to obtain a clear solution. The solution was then vortexed for 30 seconds and allowed to cool. Next, 100 mg of sirolimus-loaded microspheres from 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 25 mg of nervonic acid, 75 mg of DC-cholesterol, and 6.25 mg of DOPE-mPEG350 mixed with 7 mL of heptane and heated to 60°C to obtain a clear solution. The solution was then vortexed for 30 seconds and allowed to cool. Next, 97 mg of sirolimus-loaded microspheres from Sample #8 were added, and the formulation was placed in an ultrasonic bath for 5 minutes to disperse and suspend the microspheres. [Formulation 0422E]

Example 4: Formulation of Microreservoirs in Coating Formulations of Cholesterol, Fatty Acids, PEG-Lipids, and Stabilizing Additives

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

Example 5: Formulation of Microreservoirs in a Coating Formulation of Cholesterol and Phospholipids

A coating formulation was prepared using 43 mg of cholesterol and 42 mg of L-α-phosphatidylcholine mixed with 7 mL of heptane and heated to 60°C. The solution was vortexed for 30 seconds and then allowed to cool to room temperature. Next, 100 mg 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. [Formulation 0311A]

Example 6: Formulation of Cholesterol and Long Acyl Chain Phospholipids in Coating Formulations with and without PEG-Lipids microreservoirs

The coating formulation was prepared with 51 mg of DC-cholesterol, 6.25 mg of DOPE-mPEG350, and 51 mg of dieucylphosphatidylcholine (DEPC) mixed with 7 mL of heptane and heated to 60°C. The solution was vortexed for 30 seconds and then allowed to cool to room temperature. Next, 100 mg 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. [Formulation 0410A]

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

A coating formulation was prepared with 28 mg of DC-cholesterol, 26 mg of cholesterol, 6.25 mg of DOPE-mPEG350, and 50 mg of dineuraminic acid phosphatidylcholine (DNPC) mixed with 7 mL of heptane and heated to 60°C. The solution was vortexed for 30 seconds and then allowed to cool to room temperature. Next, 97 mg 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. [Formulation 0421B]

A coating formulation was prepared with 50 mg of DC-cholesterol and 50 mg of dineuraminic acid phosphatidylcholine (DNPC) mixed with 7 mL of heptane and heated to 60°C. The formulation had a 1:1 weight ratio of DNPC to DC-cholesterol. The solution was vortexed for 30 seconds and then allowed to cool to room temperature. Next, 100 mg 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. [Formulation 1205A]

A coating formulation was prepared with 49 mg of DC-cholesterol, 6.25 mg of DOPE-mPEG350, and 50 mg of dineuraminic acid phosphatidylcholine (DNPC) mixed with 7 mL of heptane and heated to 60°C. The formulation had a 1:1 weight ratio of DNPC to DC-cholesterol. The solution was vortexed for 30 seconds and then allowed to cool to room temperature. Next, 100 mg 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. [Formulation 1209A]

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

Example 7: Formulation of microreservoirs in DC-cholesterol coating formulations with varying PEG-lipid content

A coating formulation was prepared using 12.5 mg of DOPE-mPEG350, 44 mg of DC-cholesterol, and 44 mg of dineuraminic acid phosphatidylcholine (DNPC) mixed with 7 mL of heptane heated to 60°C. The clear solution was cooled to room temperature before adding 97 mg of sirolimus-loaded microspheres from sample #8. 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 using 25 mg of DOPE-mPEG350, 37.5 mg of DC-cholesterol, and 37.5 mg of dineuraminic acid phosphatidylcholine (DNPC) mixed with 7 mL of heptane heated to 60°C. The clear solution was cooled to room temperature before adding 97 mg of sirolimus-loaded microspheres from microsphere sample #8. The formulation was then placed in an ultrasonic bath and sonicated for 5 minutes to disperse and suspend the microspheres. [Formulation 0422B]

Example 8: Coating with additional drugs

A coating formulation was prepared using 72.9 mg of DC-cholesterol in 7 mL of heptane and heated to 60°C until the DC-cholesterol dissolved to produce a clear solution. 15.5 mg of sirolimus was added to the solution and vortexed for 30 seconds. The solution was heated for 40 minutes, vortexed for 10 seconds every 10 minutes, and sonicated for 5 minutes while cooling to room temperature. 50 mg of DNPC was added to the solution. Once at room temperature, the solution was filtered through a 0.2-micron PTFE filter to remove large drug particles. The solution was allowed to stand overnight; no particle formation was observed. The solution was assayed and found to contain 0.96 mg/mL of sirolimus. 98 mg of sirolimus-loaded microspheres from microsphere sample #8 were added to the solution, vortexed for 30 seconds, and sonicated for 8 minutes to disperse and suspend the microspheres. The resulting coating formulation contained 0.71% sirolimus by weight, with 19.1% of the drug contained in the hydrophobic matrix of DC-cholesterol and DNPC, and the remainder contained within 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. Weight percent composition of coating formulations

Example 9: Applying the coating formulation to a balloon catheter

The stearic acid coating formulation of Example 3 (Formulation 1023E) was sprayed onto the balloon surface of a 5.0 mm diameter x 20 mm length nylon angioplasty balloon. 7 ml of the coating formulation was loaded into a 25 mL gastight syringe with an integrated magnetic stir bar system. The formulation was continuously stirred during spraying to keep the drug microreservoir fully suspended. A syringe pump delivered the coating formulation at a rate of 0.11 mL/min through a 120 kHz ultrasonic nozzle activated by 5.5 watts of power [Sonotek DES1000]. To verify the process parameters, a 5.0 mm diameter x 20 mm length cylinder of balloon material was cut, weighed, and placed on a balloon of the same size. The sleeve of the balloon material was then coated and weighed to verify that approximately 2.2 mg of the total coating had been applied, corresponding to a coating density of 7 μg/mm ² . In this 7 μg/mm ² formulation from Example 3, stearic acid comprises approximately 1.6 μg/mm ² , cholesterol comprises 1.6 μg/mm ² , DPPE-mPEG350 comprises 0.8 μg/mm ² , and sirolimus-loaded microspheres from microsphere sample #5 comprise 3 μg/mm ² , resulting in a drug density of 0.87 μg/mm ^2. Once the sleeve weight confirms that the target weight has been reached, the entire balloon is coated. A 5.0 mm diameter x 20 mm length balloon is inflated, placed under the sprayer, and then continuously rotated while moving back and forth 5 times. The balloon is then removed and allowed to dry. This process is repeated until 6 balloons have been coated. This same process is repeated to spray the coating formulation of Example 6 (Formulation 0513A) onto a 3.0 mm diameter x 20 mm length balloon. The target sleeve coating weight for a 3.0 mm diameter x 20 mm length balloon having the formulation of Example 6 (Formulation 0513A) was 1.4 mg to achieve a coating density of 7.6 μg/mm ^2. Of the 7.6 μg/mm ² , dimeranoylphosphatidylcholine comprised 0.9 μg/mm ² , DC-cholesterol 2.7 μg/mm ² , DOPE-mPEG350 0.23 μg/mm ² , and sirolimus-loaded microspheres of Sample #5 comprised 3.7 μg/mm ² , resulting in a drug density of 1.08 μg/mm ² .

The coating formulations of Examples 4, 5, 6, 7 and 8 were also sprayed on the surface of a 20 mm long balloon in the same manner as the formulation of Example 3. The resulting coating weights and coating densities are shown in Table 6.

Table 6. Balloon Catheter Coatings

For the balloons coated with the formulation of Example 4, each balloon was sprayed with an additional topcoat formulation (1010D) consisting of 1 mg of cholesterol and a cholesterol-PEG600 coating to cover the microreservoir layer. To prepare this topcoat, 23 mg of cholesterol-PEG600 and 224 mg of cholesterol were dissolved in 7 mL of isopropanol. A target coating weight of 1 mg on a 5.0 mm diameter x 20 mm length balloon corresponded to a total topcoat of 3.2 μg/mm ² consisting of 0.3 μg/mm ² of cholesterol-PEG 600 and 2.9 μg/mm ² of cholesterol.

Example 10: Adhesion of the coating to the vascular lumen surface

The isolated porcine artery was flushed with 37°C lactated Ringer's solution at 50 mL/min pulsatile flow (about 72 BPM) for 5 minutes. The balloon coated with the formulation of Example 3 was inflated to an overexpansion of about 1:1.2 in the lumen of the isolated porcine artery to transfer the coating containing the drug to the vessel lumen. Subsequently, after 5 minutes of flushing after inflation, the solution (before and after flushing) passing through the artery before and after inflation was measured, for the balloon of the artery and the drug in the arterial portion contacting the inflated balloon. The blood vessels treated with formulations 1205A and 1209A were flushed 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 was totaled and compared with the estimated drug content of the balloon based on the coating weight. The ratio of the drug transferred to the artery based on the estimated drug content of the balloon based on the coating weight 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. Neuroacid-DC-Cholesterol Formulations [Formulation 0422E]

Balloons coated with the formulation of Example 4 were also tested in ex vivo porcine arteries.

Table 10. Stearic acid-cholesterol-α-tocopherol formulation [Formulation 1009A/1010D]

Balloons coated with the formulation of Example 5 were also tested in ex vivo porcine arteries.

Table 11. L-α-Phosphatidylcholine-Cholesterol Formulation [Formulation 0311A]

Balloons coated with the formulation of Example 6 were also tested in ex vivo porcine arteries.

Table 12. DEPC-DC-Cholesterol [Formulation 0410A]

Table 13. DNPC-DC-Cholesterol Formulation [Formulation 0421A]

Table 14. DNPC-DC-Cholesterol-Cholesterol Formulation [Formulation 0421B]

Table 15. DNPC-DC-Cholesterol (no PEG-lipid) formulation [Formulation 1205A]

Table 16. [DNPC–DC-Cholesterol (PEG-Lipid) Formulations [Formulation 1209A]

Table 17. DNPC-DC-Cholesterol (PEG-Lipid) Formulation [Formulation 0513A]

The luminal surface of the artery was observed under dark field microscopy after inflation of a balloon coated with Formulation 1209A and after a one-hour post-inflation fluid flush. Figure 4 is a photomicrograph of the luminal surface at 200X magnification showing adhered material. Figure 5 is a photomicrograph of the surface at 1000X magnification showing that the adhered material is a layer of spherical microreservoirs surrounded by the coating material.

Example 11: Adhesion of coating formulations with different PEG-lipid contents to the vascular luminal surface

The samples from Example 7 were tested for coating transfer and washout resistance using the methods 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-mPEG350. [Formulations 1205A, 1209A, 0422A, 0422B]

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

The results demonstrated substantial transfer of the drug coating to the vessel lumen. For the coating formulation with 25% PEG-lipid, drug coating loss during the pre-washout period was increased.

Example 12: Adhesion of coatings with additional rapamycin to vascular luminal surfaces

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

Table 19. DNPC-DC-Cholesterol Formulations with Additional Drugs [Formulation 0512A]

The results demonstrated substantial drug transfer to the vascular lumen from the coating with additional drug added to the phospholipid and cholesterol components of the coating formulation.

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

To prepare a balloon catheter coated with a formulation containing drug microreservoirs, 100 mg of DNPC, 103 mg of DC-cholesterol, and 12.5 mg of DOPE-mPEG350 were mixed in 14 mL of heptane. The mixture was heated to 60°C to dissolve the solid components and cooled to room temperature. Next, 195 mg of microsphere sample #6 was added and stirred to suspend the microspheres. A balloon catheter having a 3.0 mm diameter x 20 mm length balloon was coated with the formulation using the method described in Example 9. The coated balloon catheter was allowed to dry. An average of 1.28 mg ± 0.12 mg of the dried coating was applied to the balloon, resulting in a coating density of 6.80 μg/ ^mm2 and a drug density of 1.06 μg/ ^mm2 . The balloon was deflated and folded into a pre-deployment configuration with a smaller cross-section and packaged in a sleeve to maintain the folded configuration. The balloon catheter was packaged and sterilized by ionizing radiation at a minimum dose of 25 kGy.

The iliofemoral arteries of rabbits were used to evaluate the in vivo transfer of drug coatings into arterial vessels. First, the iliofemoral artery segment to be treated was stripped of endothelial tissue to replicate the tissue damage after angioplasty. The common carotid artery was dissected, and a 5 French balloon wedge catheter was inserted into the artery and directed to the treatment site of the iliofemoral artery under fluoroscopic guidance. Contrast agent was injected through the catheter, and angiograms of the iliofemoral arteries were recorded. Under fluoroscopic guidance, the balloon wedge catheter was replaced with a standard angioplasty balloon catheter 3.0 mm diameter x 8 mm long, inflated, and proximally withdrawn in its inflated state to near the level of the iliac bifurcation to expose the arterial cross-section. The angioplasty balloon catheter was replaced with a drug-coated balloon catheter. The catheter was advanced into the exposed vessel segment and inflated for 120 seconds. The balloon was deflated and removed. The right and left iliac arteries of each animal were treated.

11 animals were processed in total. One animal (processing 2 iliac arteries) was euthanized 1 hour after treatment, and the vessel segments were recovered for microscopic examination. Another animal (processing 2 iliac arteries) was euthanized 24 hours after 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 collected from these animals at 0.5 hour, 1 hour, 4 hours after treatment, and at the time of execution and before surgery. The vessel segments were recovered and the drug content was quantitatively determined by HPLC/MS.

Analysis of blood samples showed a rapid decline in circulating drug, with concentrations of 4.75 ng/ml at 30 minutes, 2.63 ng/ml at 1 hour, and 0.82 ng/ml at 4 hours. Blood concentrations of the drug collected at the time of sacrifice at 7 and 28 days were below the detection limit of 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 from the bloodstream.

Scanning electron microscopy and light microscopy of tissue samples taken 1 and 24 hours after treatment revealed a layer of material on the luminal surface of the vessels, with spherical drug microdepots observed within the layer. Patchy areas of fibrin were observed on the luminal surface, but no large fibrin deposits, indicative of blood incompatibility, were observed associated with the coating.

Analysis of treated vessel segments showed tissue drug levels of 261 μg/g ± 116.5 μg/g at 1 hour post-treatment, 43.8 μg/g ± 34.2 μg/g 7 days post-treatment, and 21.5 μg/g ± 17.3 μg/g 28 days post-treatment. The results indicate adhesion of the drug-containing microreservoir coating to the luminal surface of the artery, accompanied by the persistence of the drug bound to the tissue of the treated vessels throughout the 28 days. Tissue-bound drug levels exhibited a rapid initial decline that slowed between days 7 and 28. Tissue-bound drug levels from days 7 and 28 were fitted to an exponential decay, indicating a half-life of approximately 20.4 days.

Additional Implementation Plans

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. In addition, it is contemplated that the various aspects and features of the invention described may be implemented individually, 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. In addition, any particular feature, aspect, method, property, characteristic, quality, attribute, element, etc. disclosed herein in conjunction with the embodiments may be used in all other embodiments set forth herein. Therefore, it is intended that the scope of the invention disclosed herein should not be limited by the specifically disclosed embodiments described above, but should be determined solely by a fair reading of the claims.

Unless expressly stated otherwise or understood otherwise in the context of use, conditional language such as "could," "might," or "may" is generally intended to convey that some embodiments include and other embodiments do not include certain features or elements. Thus, such conditional language is generally not intended to imply that a feature or element is in any way essential to one or more embodiments.

Summary of the implementation plan

A coating for an expandable portion of a catheter comprises a hydrophobic matrix and a dispersed phase comprising a plurality of microreservoirs dispersed in the hydrophobic matrix, wherein the plurality of microreservoirs contain a first active agent and a biodegradable or bioerodible polymer. The coating is configured to transfer to the lumen wall when the expandable portion is expanded.

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

In the above coating embodiment, the biodegradable or bioerodible polymer is selected from polylactic acid, polyglycolic acid and copolymers thereof, polydioxanone, polycaprolactone, polyphosphazene, collagen, gelatin, chitosan, glycosaminoglycans and combinations thereof.

In the above embodiment of the 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 fatty acids. In some embodiments, the weight ratio of cholesterol to fatty acids 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 lauric acid, lauroleic acid, tetradecadienoic 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, tetracosanoic acid, hexacosenoic acid, prismatic acid, phytanic acid and nervonic acid.

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

In some embodiments, the phospholipid is selected from 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 di(eicosenoyl)phosphatidylcholine (1,2-di(eicosenoyl)-sn-glycero-3-phosphocholine, C20:1PC), diarachidonoylphosphatidylcholine (1,2-diacadonoyl-sn-glycero-3-phosphocholine, C20:0PC), dieucoylphosphatidylcholine (1,2-dieucoyl-sn-glycero-3-phosphocholine, C22:1PC), C), di(docosahexaenoyl)phosphatidylcholine (1,2-di(docosahexaenoyl)-sn-glycero-3-phosphocholine, C22:6PC), heneicosenoylphosphatidylcholine (1,2-heneicosenoyl-sn-glycero-3-phosphocholine, C21:1PC), and dimeruinoylphosphatidylcholine (1,2-dineuroyl-sn-glycero-3-phosphocholine, C24:1PC).

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

In the above coating embodiments, the plurality of microreservoirs comprises from about 10% to about 75% by weight of the coating.

In embodiments of the above coatings, the plurality of microreservoirs have an average diameter of about 1.5 microns to about 8 microns. In some embodiments, the plurality of microreservoirs have an average diameter of about 2 microns to about 6 microns. In some embodiments, the plurality of microreservoirs have an average diameter of about 3 microns to about 5 microns.

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

In the above coating embodiment, the first biodegradable or bioerodible polymer is selected from polylactic acid, polyglycolic acid and copolymers thereof, polydioxanone, polycaprolactone, polyphosphazene, collagen, gelatin, chitosan, glycosaminoglycans and combinations thereof.

In embodiments of the above coatings, 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 the above coating embodiments, the first active agent comprises from about 10% to about 50% by weight of the plurality of microreservoirs.

In embodiments of the above coating, the coating further comprises a second active agent external to the plurality of microreservoirs. In some embodiments, the second active agent is selected from paclitaxel, sirolimus, paclitaxel derivatives, sirolimus derivatives, paclitaxel analogs, sirolimus analogs, inhibitory RNA, inhibitory DNA, steroids, and complement inhibitors. In some embodiments, the second active agent is the same as the first active agent.

In the 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- In some embodiments, the PEG-lipid comprises 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 embodiments of the above coatings, the coating further comprises one or more additives independently selected from penetration enhancers and stabilizers.

In an embodiment of the above coating, wherein the coating has a surface concentration of about 1 μg/mm ² to about 10 μg/mm ² .

A catheter comprising an expandable portion on an elongated body and any embodiment of the above-described coating on the expandable 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-mPEG500. In some embodiments, the release layer has a surface concentration of about 0.1 μg/ ^mm2 to about 5 μg/ ^mm2 .

In an embodiment of the above-described 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 a surface concentration of about 0.1 μg/mm ² to about 5 μg/mm ² .

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

In some embodiments, the first active agent is selected from paclitaxel, sirolimus, paclitaxel derivatives, sirolimus derivatives, paclitaxel analogs, sirolimus analogs, inhibitory RNA, inhibitory DNA, steroids, and complement inhibitors. In some embodiments, the biodegradable or bioerodible polymer is selected from polylactic acid, polyglycolic acid, and copolymers thereof, polydioxanones, polycaprolactones, polyphosphazenes, collagen, gelatin, chitosan, glycosaminoglycans, and combinations thereof.

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

In some embodiments of the above coating formulations, the solid portion further comprises a second active agent outside the plurality of microreservoirs. In some embodiments, the second active agent is selected from 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, the at least one hydrophobic compound is selected from the group consisting of sterols, lipids, phospholipids, fats, fatty acids, surfactants, and derivatives thereof.

In some embodiments of the above-mentioned coating formulations, wherein the at least one hydrophobic compound comprises cholesterol and a fatty acid. In some embodiments, the weight ratio of the cholesterol to the 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, laureic acid, tetradecadienoic 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, tetracosanoic acid, hexacosenoic acid, pristanic acid, phytanic acid and nervonic acid.

In some embodiments of the above coating formulations, 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 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 di(eicosenoyl)phosphatidylcholine (1,2-di(eicosenoyl)-sn-glycero-3-phosphocholine, C20:1PC), diarachidonoylphosphatidylcholine (1,2-diacadonoyl-sn-glycero-3-phosphocholine, C20:0PC), dieucoylphosphatidylcholine (1,2-dieucoyl-sn-glycero-3-phosphocholine, C22:1PC), C), di(docosahexaenoyl)phosphatidylcholine (1,2-di(docosahexaenoyl)-sn-glycero-3-phosphocholine, C22:6PC), heneicosenoylphosphatidylcholine (1,2-heneicosenoyl-sn-glycero-3-phosphocholine, C21:1PC), and dimeruinoylphosphatidylcholine (1,2-dineuroyl-sn-glycero-3-phosphocholine, C24:1PC).

In some embodiments of the above coating formulations, 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), mPEG350), 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-methoxy(polyethylene glycol)-550 (DSPE-mPEG550), 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine-N-methoxy(polyethylene glycol)-550 (DPPE-mPEG550), and 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine-N-methoxy(polyethylene glycol)-500 (DOPE-mPEG550).

In some embodiments of the aforementioned coating formulations, the plurality of microreservoirs comprises from 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 applying a coating formulation of any of the above embodiments onto a surface of the expanded expandable portion of the catheter, evaporating the fluid, and contracting the expandable portion. In some embodiments, applying the coating formulation comprises spraying, dipping, roller coating, 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-mPEG500.

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 above embodiments, expanding the expandable portion to allow contact between the coating and tissue at the treatment site, collapsing the expandable portion; and removing the catheter.

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

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

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

Claims (57)

1. A coating for an expandable portion of a catheter, comprising: A hydrophobic matrix, wherein the hydrophobic matrix comprises cholesterol and fatty acids, wherein the weight ratio of cholesterol to fatty acids is in the range of 1:2 to 3:1, or the hydrophobic matrix comprises cholesterol and phospholipids, wherein the weight ratio of cholesterol to phospholipids is in the range of 1:2 to 3:1, wherein the phospholipids comprise an acyl chain length of 20 to 34 carbons; and A dispersed phase comprising multiple micro-reservoirs dispersed in the hydrophobic matrix, wherein the multiple micro-reservoirs comprise a first activator and a biodegradable or biosoluble polymer. 2. The coating of claim 1, wherein the first activator is mixed or dispersed in the biodegradable or biosoluble polymer. 3. The coating of claim 1 or 2, wherein the biodegradable or biosolvable polymer is selected from polylactic acid, polyglycolic acid and copolymers thereof, polydioxanone, polycaprolactone, polyphosphazene, collagen, gelatin, chitosan, glycosaminoglycans and combinations thereof. 4. The coating according to claim 1 or 2, wherein the fatty acid is selected from lauric acid, myrcenoic acid, tetradecadienoic acid, octanoic acid, myristic acid, myristone acid, decenoic acid, decanoic acid, hexadecenoic acid, palmitoleic acid, palmitic acid, linolenic acid, oleic acid, isoleic acid, stearic acid, eicosapentaenoic acid, arachidonic acid, eicosatrienoic acid, arachidic acid, docosahexaenoic acid, docosapentaenoic acid, docosatraenoic acid, docosahexaenoic acid, docosapentaenoic acid, docosahexaenoic acid, docosacosanoic acid, docosahexaenoic acid, docosahexaenoic acid, norphytic acid, phytic acid, and nervonic acid. 5. The coating of claim 1 or 2, wherein the phospholipid is selected from phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, and phosphatidylinositol. 6. The coating of claim 1 or 2, wherein the phospholipid is a cationic phospholipid. 7. The coating of claim 6, wherein the cationic phospholipid is phosphatidylethanolamine, dioleoylphosphatidylethanolamine (DOPE), or an amine derivative of phosphatidylcholine. 8. The coating of claim 1, wherein the phospholipid is selected from bis(eicosenoyl)phosphatidylcholine (1,2-bis(eicosenoyl)-sn-glycero-3-phosphocholine, C20:1PC), bisarachidonicylphosphatidylcholine (1,2-bisarachidonic-sn-glycero-3-phosphocholine, C20:0PC), and disorhoylphosphatidylcholine (1,2-disorhoyl-sn-glycero-3-phosphocholine, C20:0PC). 2:1PC), bis(docosahexaenoyl)phosphatidylcholine (1,2-bis(docosahexaenoyl)-sn-glycero-3-phosphocholine, C22:6PC), docosaenoyl phosphatidylcholine (1,2-docosaenoyl-sn-glycero-3-phosphocholine, C21:1PC), and bisnervonic phosphatidylcholine (1,2-bisnervonic-sn-glycero-3-choline phosphate, C24:1PC). 9. The coating of claim 1 or 2, wherein the cholesterol is DC cholesterol. 10. The coating of claim 1 or 2, wherein the coating comprises 10% to 75% by weight of the plurality of micro reservoirs. 11. The coating of claim 1 or 2, wherein the plurality of micro reservoirs have an average diameter of 1.5 micrometers to 8 micrometers. 12. The coating of claim 11, wherein the plurality of micro reservoirs have an average diameter of 2 micrometers to 6 micrometers. 13. The coating of claim 11, wherein the plurality of micro reservoirs have an average diameter of 3 to 5 micrometers. 14. The coating of claim 1 or 2, wherein the plurality of micro reservoirs have active ingredient release kinetics with a half-life of at least 14 days. 15. The coating of claim 1 or 2, wherein the first active agent is selected from paclitaxel, sirolimus, paclitaxel derivatives, sirolimus derivatives, paclitaxel analogs, sirolimus analogs, repressive RNA, repressive DNA, steroids, and complement inhibitors. 16. The coating of claim 1 or 2, wherein the first activator comprises 10% to 50% by weight of the plurality of micro-reservoirs. 17. The coating of claim 1 or 2, wherein the coating further comprises a second activator outside the plurality of micro reservoirs. 18. The coating of claim 17, wherein the second activator is selected from paclitaxel, sirolimus, paclitaxel derivatives, sirolimus derivatives, paclitaxel analogs, sirolimus analogs, repressive RNA, repressive DNA, steroids, and complement inhibitors. 19. The coating of claim 17, wherein the second activator is the same as the first activator. 20. The coating of claim 1 or 2, wherein the hydrophobic matrix further comprises PEG-lipid. 21. The coating of claim 20, wherein the PEG-lipid is selected from 1,2-distearyl-sn-glycero-3-phosphate ethanolamine-N-methoxy(polyethylene glycol)-350 (DSPE-mPEG350), 1,2-dipalmitoyl-sn-glycero-3-phosphate ethanolamine-methoxy(polyethylene glycol)-350 (DPPE-mPEG350), 1,2-dioleoyl-sn-glycero-3-phosphate ethanolamine-N-methoxy(polyethylene glycol)-350 (DPPE-mPEG350), and 1,2-dioleoyl-sn-glycero-3-phosphate ethanolamine-N-methoxy(polyethylene glycol)-350 (DPPE-mPEG350). The following are listed: OPE-mPEG350, 1,2-distearyl-sn-glycero-3-phosphoethanolamine-N-methoxy(polyethylene glycol)-550 (DSPE-mPEG550), 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine-N-methoxy(polyethylene glycol)-550 (DPPE-mPEG550), and 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine-N-methoxy(polyethylene glycol)-500 (DOPE-mPEG550). 22. The coating of claim 20, wherein the PEG-lipid accounts for 1% to 30% by weight of the hydrophobic matrix. 23. The coating of claim 20, wherein the PEG-lipid comprises 12% or less by weight of the hydrophobic matrix. 24. The coating as claimed in claim 1 or 2 further comprises one or more additives independently selected from penetration enhancers and stabilizers. 25. The coating of claim 1 or 2, wherein the coating has a surface concentration of 1 μg/ ^mm² to 10 μg/ ^mm² . 26. A catheter comprising: The expandable portion on the slender body; and The coating of any one of claims 1 to 25 on the expandable portion. 27. The catheter of claim 26, further comprising a release layer between the expandable portion and the coating, wherein the release layer is configured to release the coating from the expandable portion. 28. The catheter of claim 27, wherein the release layer comprises 1,2-distearyl-sn-glycero-3-phosphate ethanolamine-N-methoxy(polyethylene glycol)-350 or 1,2-distearyl-sn-glycero-3-phosphate ethanolamine-N-methoxy(polyethylene glycol)-550. 29. The catheter of claim 27 or 28, wherein the release layer has a surface concentration of 0.1 μg/ ^mm² to 5 μg/ ^mm² . 30. The conduit as claimed in any one of claims 26 to 28, further comprising a protective coating over the coating. 31. The catheter of claim 30, wherein the protective coating comprises a hydrophilic polymer, a carbohydrate, or an amphiphilic polymer. 32. The conduit of claim 30, wherein the protective coating is a glycosaminoglycan or a crystalline sugar. 33. The conduit of claim 30, wherein the protective coating has a surface concentration of 0.1 μg/ ^mm² to 5 μg/ ^mm² . 34. The catheter according to any one of claims 26 to 27, used as a device for treating or preventing a condition at a treatment site, wherein the condition is selected from atherosclerosis, reduced or narrowed lumen diameter in a diseased vessel, restenosis, in-stent restenosis, and combinations thereof. 35. A coating formulation for an expandable portion of a catheter, comprising: The solid portion comprises: Multiple micro reservoirs, wherein the multiple micro reservoirs contain a first activator and a biodegradable or biosoluble polymer; At least one hydrophobic compound, wherein the at least one hydrophobic compound comprises cholesterol and a fatty acid, wherein the weight ratio of cholesterol to fatty acid is in the range of 1:2 to 3:1, or wherein the at least one hydrophobic compound comprises cholesterol and a phospholipid, wherein the weight ratio of cholesterol to phospholipid is in the range of 1:2 to 3:1, wherein the phospholipid comprises an acyl chain length of 20 to 34 carbons; and fluid. 36. The coating formulation of claim 35, wherein the first activator is mixed or dispersed in the biodegradable or biosoluble polymer. 37. The coating formulation of claim 35 or 36, wherein the biodegradable or biosolvable polymer is selected from polylactic acid, polyglycolic acid and copolymers thereof, polydioxanone, polycaprolactone, polyphosphazene, collagen, gelatin, chitosan, glycosaminoglycans and combinations thereof. 38. The coating formulation of claim 35 or 36, wherein the fluid is selected from pentane, hexane, heptane, a mixture of heptane and fluorocarbons, a mixture of alcohols and fluorocarbons, and a mixture of alcohols and water. 39. The coating formulation of claim 35 or 36, wherein the solid portion further comprises a second activator outside the plurality of microreservoirs. 40. The coating formulation of claim 39, wherein the second activator is selected from paclitaxel, sirolimus, paclitaxel derivatives, sirolimus derivatives, paclitaxel analogs, sirolimus analogs, repressive RNA, repressive DNA, steroids, and complement inhibitors. 41. The coating formulation of claim 35 or 36, wherein the first active agent is selected from paclitaxel, sirolimus, paclitaxel derivatives, sirolimus derivatives, paclitaxel analogs, sirolimus analogs, repressive RNA, repressive DNA, steroids, and complement inhibitors. 42. The coating formulation of claim 35, wherein the fatty acid is selected from lauric acid, myrcenoic acid, tetradecadienoic acid, octanoic acid, myristic acid, myristone acid, decenoic acid, decanoic acid, hexadecenoic acid, palmitoleic acid, palmitic acid, linolenic acid, oleic acid, isoleic acid, stearic acid, eicosapentaenoic acid, arachidonic acid, eicosatrienoic acid, arachidic acid, docosahexaenoic acid, docosapentaenoic acid, docosatraenoic acid, docosahexaenoic acid, docosapentaenoic acid, docosahexaenoic acid, docosacosanoic acid, docosahexaenoic acid, docosahexaenoic acid, norphytic acid, phytic acid, and nervonic acid. 43. The coating formulation of claim 35, wherein the phospholipid is selected from phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, and phosphatidylinositol. 44. The coating formulation of claim 35, wherein the phospholipid is a cationic phospholipid. 45. The coating formulation of claim 44, wherein the cationic phospholipid is phosphatidylethanolamine, dioleoylphosphatidylethanolamine (DOPE), or an amine derivative of phosphatidylcholine. 46. The coating formulation of claim 35, wherein the phospholipid is selected from bis(eicosenoyl)phosphatidylcholine (1,2-bis(eicosenoyl)-sn-glycero-3-phosphocholine, C20: 1PC), arachidonicylphosphatidylcholine (1,2-disarachidonic-sn-glycero-3-phosphocholine, C20: 0PC), disorhoylphosphatidylcholine (1,2-disorhoyl-sn-glycero-3-phosphocholine, C20: 0PC), and disorhoylphosphatidylcholine (1,2-disorhoyl-sn-glycero-3-phosphocholine, C20: 0PC). C22:1PC), bis(docosahexaenoyl)phosphatidylcholine (1,2-bis(docosahexaenoyl)-sn-glycero-3-phosphocholine, C22:6PC), docosaenoyl phosphatidylcholine (1,2-docosaenoyl-sn-glycero-3-phosphocholine, C21:1PC), and bisnervonic phosphatidylcholine (1,2-bisnervonic-sn-glycero-3-choline phosphate, C24:1PC). 47. The coating formulation of claim 35, wherein the cholesterol is DC cholesterol. 48. The coating formulation of claim 35, wherein the solid portion further comprises PEG-lipids and/or additives. 49. The coating formulation of claim 48, wherein the PEG-lipid is selected from 1,2-distearyl-sn-glycero-3-phosphate ethanolamine-N-methoxy(polyethylene glycol)-350 (DSPE-mPEG350), 1,2-dipalmitoyl-sn-glycero-3-phosphate ethanolamine-methoxy(polyethylene glycol)-350 (DPPE-mPEG350), 1,2-dioleoyl-sn-glycero-3-phosphate ethanolamine-N-methoxy(polyethylene glycol)-350 (DSPE ... DOPE-mPEG350), 1,2-distearyl-sn-glycero-3-phosphoethanolamine-N-methoxy(polyethylene glycol)-550 (DSPE-mPEG550), 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine-N-methoxy(polyethylene glycol)-550 (DPPE-mPEG550) and 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine-N-methoxy(polyethylene glycol)-500 (DOPE-mPEG550). 50. The coating formulation of claim 35, wherein the plurality of microreservoirs account for 10% to 75% by weight of the solid portion. 51. The coating formulation of claim 35, wherein the solid portion comprises 2 to 7% by weight of the coating formulation. 52. A method for coating an expandable portion of a catheter, comprising: The coating formulation according to any one of claims 35 to 51 is disposed on the surface of the expanded expandable portion of the catheter; Evaporate the fluid; and The expandable portion is then contracted. 53. The method of claim 52, wherein setting the coating formulation includes spraying, dipping, rolling, electrostatic deposition, printing, pipetting, or dispensing. 54. The method of claim 52 or 53, further comprising providing a release layer on the surface of the expandable portion. 55. The method of claim 54, wherein the coating formulation is disposed on the release layer. 56. The method of claim 54, wherein the release layer comprises 1,2-distearyl-sn-glycero-3-phosphate ethanolamine-N-methoxy(polyethylene glycol)-350 or 1,2-distearyl-sn-glycero-3-phosphate ethanolamine-N-methoxy(polyethylene glycol)-550. 57. A catheter comprising an expandable portion coated with any one of claims 1-25, serving as a means for treating or preventing a condition at a treatment site, wherein the coating is applied to the expandable portion of the catheter, and the condition is selected from atherosclerosis, reduced or narrowed lumen diameter in a diseased vessel, restenosis, in-stent restenosis, and combinations thereof.