JP7842135B2 - Coating for intraluminal expandable catheters that provides contact transfer of drugs in a microreservoir. - Google Patents

Description

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

Balloon angioplasty is an established method for treating vascular disease by physically dilating areas of atherosclerosis, stenosis, or reduced lumen diameter in diseased blood vessels. Angioplasty is typically performed using a catheter that can be advanced through the circulatory system to the affected area. The catheter has a balloon at its distal end, which is inflated to dilate the narrowed area. In many cases, such as in the coronary arteries, a stent is also placed outside the balloon. The balloon is inflated in the area of atherosclerosis, and the stent is placed after the balloon is deflated and removed to maintain patency of the dilated lumen.

During high-pressure balloon inflation, significant force is applied to the vascular wall tissue to achieve physical expansion of the therapeutic area of the blood vessel. This physical expansion leads to vascular damage, including endothelial disruption, fragmentation of the internal elastic lamina, and dissection of the vascular media. Damage often extends to the adventitia as well. The biological response of the blood vessel progresses through a thrombotic phase between days 0 and 3, involving platelet activation and adhesion and thrombus formation. Following this thrombotic phase, a cell recruitment phase progresses between days 3 and 8, including the infiltration of inflammatory cells, macrophages, and lymphocytes into the site of vascular injury. The release of growth factors and cytokines from inflammatory cells triggers a proliferation phase between days 8 and 14, in which dormant smooth muscle cells in the vascular media are stimulated to proliferate. Subsequently, the migration of the proliferating smooth muscle cells to the intima and thrombi originating from the luminal injury lead to neointima-hyperplasia, a major cause of restenosis. Although cell proliferation ceases after 14 days, the continued production of extracellular matrix by smooth muscle cells in the damaged area leads to a continuous increase in the extent of neointimal hyperplasia and restenosis. Restenosis reverses the effects of dilation therapy and poses a potentially significant threat to the patient. Human clinical studies have shown that such restenosis generally occurs 1 to 3 months after balloon angioplasty, typically peaking at around 3 months.

Balloon angioplasty provides a much-needed acute increase in blood flow to diseased vessels, but the associated mechanical damage inherently leads to the problem of restenosis. One strategy to reduce the restenotic response is to release drugs into the vessel in combination with balloon inflation to counteract inflammatory and healing responses. One approach is to coat the balloon with drugs such as paclitaxel or sirolimus (rapamycin), which restrict cell proliferation. The use of excipient coatings is thought to facilitate drug delivery to the site of vascular injury as the balloon contacts the vascular lumen surface. The aim of these methods is to provide a drug concentration in the vessel wall after balloon inflation that is sufficient to reduce restenosis caused by cell proliferation, while simultaneously minimizing toxicity to the vessel that could potentially cause vascular damage or impairment. It is desirable to maintain an effective drug concentration for a sufficient time to minimize the possibility of restenosis.

In practice, drug delivery to vascular wall tissue via drug-coated balloons, as described in the above techniques, is limited to the short time the balloon can be in contact with the vessel. Typically, balloon inflation during angioplasty is performed for approximately 30 to 120 seconds to limit cardiac ischemia and potential patient complications and discomfort. This short balloon inflation and drug delivery time may be sufficient for the antitumor drug paclitaxel, which has demonstrated inhibition of neointima formation in animals after several minutes of exposure. However, to provide maximum therapeutic effect while minimizing potential high-dose toxicity to the vessels, it would be desirable to provide prolonged drug delivery to the vessels, ideally longer than the duration of balloon inflation. Furthermore, drugs such as sirolimus and its analogues, possessing both antiproliferative and anti-inflammatory activity, may provide benefits beyond the acute phase of restenosis if delivered over a prolonged period.

Many drug-coated balloons described in the prior art utilize high initial levels of activators and multiple treatments to produce high initial concentrations, but the concentration subsequently decreases rapidly. This is undesirable because a large portion of the activator on the device is lost into the bloodstream as embolic particles or through diffusion away from the treatment site.

Furthermore, many drug coatings described in the prior art contain hydrophilic polymers and excipients or excipients that are liquid at body temperature. Such hydrophilic coating formulations may provide a hydrophilic matrix for hydrophobic drug particles and be effective in transferring drugs to the vascular wall. However, such coatings do not provide significant resistance to being washed away from the bloodstream, either during balloon manipulation at the treatment site or after drug coating on the vascular surface.

Some embodiments provide a coating for the inflatable portion of a catheter, comprising a hydrophobic matrix and a dispersed phase, wherein the dispersed phase comprises a plurality of microreservoirs dispersed in the hydrophobic matrix, and the plurality of microreservoirs comprises a first activator mixed or dispersed with a first biodegradable or bioerosive polymer. Some embodiments provide a coating in which the dispersed phase comprises a plurality of microreservoirs dispersed in a hydrophobic matrix, and some of the plurality of microreservoirs comprises a first activator and a first biodegradable or bioerosive polymer.

Several embodiments provide a catheter comprising an inflatable portion on a long body and a coating on the inflatable portion. The coating comprises a lipophilic matrix, which comprises at least one lipid and a plurality of microreservoirs dispersed within the lipophilic matrix. The plurality of microreservoirs contain an activator, and the lipophilic matrix is configured to adhere to the lumen surface when the inflatable portion is inflated, and to transfer at least a portion of the plurality of microreservoirs to the lumen surface.

Several embodiments provide catheters comprising an inflatable portion on an elongated body and a coating on the inflatable portion as described herein. In some embodiments, the catheter further includes a release layer between the inflatable portion and the coating, the release layer being configured to release the coating from the inflatable portion. In some embodiments, the catheter further includes a protective coating on the coating.

Several embodiments provide coating formulations for the inflatable 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 activator and a first biodegradable or bio-erosive polymer.

Some embodiments provide a coating formulation for the inflatable portion of a catheter, comprising a plurality of microreservoirs containing an activator and at least one lipid.

Some embodiments provide a method for coating the inflatable portion of a catheter, comprising placing the coating formulation described herein onto the inflated surface of the inflatable portion of the catheter, evaporating the liquid, and then folding the inflatable portion.

Several embodiments provide a method for treating or preventing a pathological condition at a treatment site, comprising advancing a catheter including an inflatable portion to the treatment site. The inflatable portion is coated with a coating described herein, and the method includes inflating the inflatable portion to achieve contact between the coating and the tissue at the treatment site, folding the inflatable portion, and removing the catheter.

The features, aspects, and advantages of the embodiments of this disclosure will be described in detail below with reference to the drawings illustrating various embodiments. While the drawings illustrate the present invention, they are not intended to limit it. The drawings depict only a few embodiments according to the disclosure and should not be considered to limit its scope.

Figure 1 shows one embodiment of a balloon catheter having a coating on the inflatable portion of the catheter. Figure 2 shows one embodiment of a balloon catheter having a release layer between the coating and the inflatable portion of the catheter. Figure 3 shows one embodiment of a balloon catheter having a protective layer on the coating. Figure 4 is a micrograph of the luminal surface of a blood vessel treated with one embodiment of a balloon catheter. Figure 5 is a micrograph of the luminal surface of a blood vessel treated with one embodiment of a balloon catheter. Figure 6 is a micrograph of the surface of a coated balloon at 100x magnification, showing the coating containing crystalline sirolimus microreservoirs. Figure 7 is a micrograph of the arterial surface at 50x magnification, showing the adhesive material. Figure 8 is a micrograph of the arterial surface at 1000x magnification, showing the adhesive material.

To overcome the limitations of the prior art, the embodiments disclosed herein provide coatings for the inflatable portion of a catheter having a time-release microreservoir containing a coating on a balloon mixed or dispersed with a drug delivered to the luminal surface of a blood vessel during a balloon inflation time of 30 to 120 seconds. This approach allows for the appropriate release of the drug over a longer period, which can be adjusted by the properties of the specific drug or the design of the microreservoir for the pathology of the diseased blood vessel. In addition to providing sustained release, the coatings disclosed herein can also resist leakage by blood, thereby increasing drug delivery efficiency and patient safety from excess particles.

(coating)
Disclosed herein are coatings for inflatable sites of catheters or catheter systems. The catheter is designed to be inserted into a body to deliver at least one active agent locally. The coating is formulated and constructed to minimize solubilization and dispersion into the bloodstream while the catheter is positioned in a target vessel for treatment or after the coating has been transferred to the tissue of the vessel 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 inflatable site may be the balloon of a balloon catheter.

Referring to Figure 1, in some embodiments, the coating 12 on the inflatable portion 11 of the catheter 10 comprises two phases: a hydrophobic matrix 14 and a dispersed phase 13. The dispersed phase 13 is dispersed within the hydrophobic matrix 14. The dispersed phase 13 comprises a plurality of microreservoirs, each containing a first activator and a first biodegradable or bioerosive polymer. In some embodiments, the first activator is mixed with or dispersed with the first biodegradable or bioerosive polymer. In some embodiments, several microreservoirs may contain the first activator and the biodegradable or bioerosive polymer. In some embodiments, the plurality of microreservoirs also contain a second activator. In some embodiments, the plurality of microreservoirs may further contain a second biodegradable or bioerosive polymer. In some embodiments, the first and second biodegradable or bioerosive polymers may be the same or different. In some embodiments, the plurality of microreservoirs may contain only one type of microreservoir. In some embodiments, the coating 12 comprises about 10% to about 75% by weight, about 20% to about 65% by weight, or about 30% to about 55% by weight of a plurality of microreservoirs. In some embodiments, the coating 12 has a surface concentration of about 1 μg/mm² to about 10 μg/ ^mm² , about ² μg/ ^mm² to about 9 μg/ ^mm² , or about 3 μg/mm² to about 8 μg/ ^mm² on the inflatable portion of the catheter ¹⁰ .

The hydrophobic matrix 14 comprises a combination of materials selected to obtain desired adhesion properties to the luminal surface. A preferred hydrophobic matrix 14 comprises a combination of hydrophobic compounds that are resistant to dissolution in the blood while providing a uniform distribution of the formulation containing the microreservoir when applied to the balloon surface. In some embodiments, the hydrophobic matrix 14 comprises at least one hydrophobic compound selected from the group consisting of sterols, lipids, phospholipids, fats, fatty acids, surfactants, and their derivatives. Particularly useful formulations are combinations of sterols with fatty acids or phospholipids. The sterol may be one that utilizes the body's natural cleansing action by forming complexes with serum lipids or aggregates with serum apolipoproteins, providing transport to the liver for metabolic processing. In some embodiments, the sterol may be cholesterol. Because cholesterol and fatty acids or phospholipids have a natural compatibility, such combinations provide a homogeneous mixture for the coating 12, resulting in a homogeneous coating on the balloon surface. The coating 12 formed by such combinations is homogeneous without the formation of micelles or liposomes within the hydrophobic matrix 14.

In some embodiments, the hydrophobic matrix 14 contains 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, about 1:1.5 to about 2.5:1, or about 1:1 to about 2:1. The cholesterol component of the formulation may include cholesterol, chemically modified cholesterol, or cholesterol conjugates. In some embodiments, the cholesterol is dimethylaminoethane-carbamoyl cholesterol (DC-cholesterol). For physiological compatibility, preferred fatty acids are those commonly found in serum or cell membranes. In some embodiments, the fatty acid is selected from the group consisting of lauric acid, lauroleic acid, tetradecenoic acid, octanoic acid, myristic acid, myristoleic acid, decenoic acid, decanoic acid, hexadecenoic acid, palmitoleic acid, palmitic acid, linolenic acid, linoleic acid, oleic acid, vaccenic acid, stearic acid, eicosapentaenoic acid, arachidonic acid, meadic acid, arachidic acid, docosahexaenoic acid, docosapentaenoic acid, docosatetraenoic acid, docosenoic acid, tetracosanoic acid, hexacosanoic acid, pristanic acid, phytanic acid, and nervonic acid.

In some embodiments, the hydrophobic matrix 14 contains 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 cholesterol component of the formulation may include cholesterol, chemically modified cholesterol, or cholesterol conjugates. In some embodiments, the cholesterol is DC-cholesterol. Preferred phospholipids are phospholipids commonly found in serum or cell membranes. In some embodiments, the phospholipids are selected from the group consisting of phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, or phosphatidylinositol. In some embodiments, the phospholipids have an acyl chain length of about 20 to about 34 carbon atoms. In some embodiments, the hydrophobic matrix 14 further contains a third activator, which may be the same as or different from the first activator in the multiple microreservoirs.

In some embodiments of this 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 this disclosure, the hydrophobic matrix 14 comprises only hydrophobic components such as lipids, sterols, and fatty acids, and no amphiphilic components are present. Preferably, the coating 12 and its components have limited solubility in blood or analogues such as plasma or phosphate-buffered saline. The use of cationic cholesterol or cationic phospholipids in the formulation results in further chemical attraction of the hydrophobic matrix 14 to the vascular surface and possibly the surface of a microreservoir, increasing the resistance of the coating 12 to delivery and subsequent dissolution in the blood. Appropriate cation formation of cholesterol involves modification at the 3-carbon position, bonding a pendant-type tertiary or quaternary amine, and includes DC-cholesterol. Appropriate cation formation of phospholipids involves both naturally occurring phospholipids and synthetic modifications of phospholipids, such as phosphatidylethanolamine, dioleoylphosphatidylethanolamine (DOPE), and amine derivatives of phosphatidylcholine, including ethylphosphatidylcholine.

In some embodiments, the acyl chain length and degree of unsaturation of the phospholipid components of the hydrophobic matrix 14 can be used to modulate 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 vascular surface, while reducing solubility and wash-off due to blood flow exposure. The acyl chain length of fatty acids and the fatty acid portion of phospholipids are described in a short notation of the number of carbon atoms followed by a colon and the number of carbon-carbon double bonds. In the following descriptions of phospholipids, both common and conventional names are used to describe the compound for the first time using stereospecific numbering and short notation. Acyl chain lengths of 20–34 carbon atoms (C20–C34) are suitable for use as coating components, with acyl chain lengths of 20–24 carbon atoms (C20–C24) being particularly preferred. The present invention also works with saturated acyl chains, but one or more unsaturated sites may provide increased chain flexibility. Examples of preferred phospholipids include dieicosenoylphosphatidylcholine (1,2-dieicosenoyl-sn-glycero-3-phosphocholine, C20:1 PC), diarachidonoylphosphatidylcholine (1,2-diarachidoyl-sn-glycero-3-phosphocholine, C20:1 PC), dielcyoylphosphatidylcholine (1,2-dielcyoyl-sn-glycero-3-phosphocholine, C22:1 PC), didocosahexaenoylphosphatidylcholine (1,2-didocosahexaenoyl-sn-glycero-3-phosphocholine, C22:6 PC), and henicocenoylphosphatidylcholine (1,2-henicocenoyl-sn-glycero-3-phosphocholine, C21:1 PC). It contains PC, and dinerbonylphosphatidylcholine (1,2-dinerbonyl-sn-glycero-3-phosphocholine, C24:1 PC). In some embodiments, the phospholipid has a transition temperature above ambient temperature (20°C), and therefore, during storage, the hydrophobic matrix 14 constitutes a solid.

Multiple microreservoirs contain activators and polymers. The activators may be referred to as a first activator or a second activator. The activators work in conjunction with polymers to provide a slow or extended release of the activator from the microreservoirs. In some embodiments, the activators are mixed with or dispersed with a biodegradable or bioerosive polymer. In some embodiments, the activators may be encapsulated by a biodegradable or bioerosive polymer. In some embodiments, multiple microreservoirs may contain a first activator. In some embodiments, multiple microreservoirs may further contain a second activator. Suitable activators may include mTOR inhibitors, inhibitory RNA, inhibitory DNA, steroids, and complement inhibitors such as paclitaxel, sirolimus (rapamycin), and their chemical derivatives or analogues, as well as antiproliferative or anti-inflammatory agents. In some embodiments, the activator is selected from the group consisting of paclitaxel, sirolimus, paclitaxel derivatives, sirolimus derivatives, paclitaxel analogs, sirolimus analogs, inhibitory RNA, inhibitory DNA, steroids, and complement inhibitors. In some embodiments, the activator is present in about 10% to about 50% by weight, about 15% to about 45% by weight, about 20% to about 40% by weight, or about 25% to about 35% by weight of a plurality of microreservoirs. The microreservoirs may contain microparticles or microspheres. In some embodiments, polylactic acid-coglycolic acid (PLGA) microspheres are well suited for the uptake of the activator for sustained release up to about 50% by weight of the activator in the microspheres.

In some embodiments, the hydrophobic matrix 14 may be a lipophilic matrix, and the dispersed phase 13 is dispersed in the lipophilic matrix. In some embodiments, the lipophilic matrix may contain at least one lipid. In some embodiments, the lipid may be a phospholipid, sphingolipid, ceramide, terpene, terpenoid, monoglyceride, diglyceride, triglyceride, phytosterol, prostaglandin, vegetable oil (e.g., amaranth, apricot, argan, almond, avocado, coconut, grape seed, palm, safflower, sesame, soybean, sunflower, and wheat germ oil), vegetable wax (e.g., beeswax, jojoba, and shea butter), paraffin wax, fat-soluble vitamins and provitamins (e.g., carotene and vitamins A, D, E, K), steroids, or squalene. In some embodiments, the phospholipid is a cationic phospholipid. In some embodiments, the lipophilic matrix may further contain sterols such as cholesterol. The lipophilic matrix described is designed to adhere to the lumen surface when the inflatable portion of the catheter expands within a lumen such as a blood vessel. As the inflatable portion of the catheter expands within the lumen, at least a portion of the multiple microreservoirs, along with at least a portion of the lipophilic matrix, is transferred to the lumen surface.

The dispersed phase 13 comprises a plurality of microreservoirs. In some embodiments, the plurality of microreservoirs contain a first activator. In some embodiments, the plurality of microreservoirs contain the first activator and a first biodegradable or bioerosive polymer. In some embodiments, the first activator is mixed with or dispersed with the first biodegradable or bioerosive polymer. In some embodiments, some microreservoirs may contain the first activator alone, and some microreservoirs may contain the first activator mixed with or dispersed with the first biodegradable or bioerosive polymer. In other embodiments, the first activator may be crystalline. In some embodiments, the plurality of microreservoirs may contain only one type of microreservoir.

In some embodiments, the coating 12 comprises about 10% to about 75% by weight, about 20% to about 65% by weight, or about 30% to about 55% by weight of a plurality of microreservoirs. In some embodiments, the coating 12 has a surface concentration of about 1 μg/mm² to about 10 μg/ ^mm² , about ² μg/ ^mm² to about 9 μg/ ^mm² , or about 3 μg/mm² to about 8 μg/ ^mm² on the inflatable portion of the catheter ¹⁰ .

In some embodiments, the microreservoir contains activator microparticles. In some embodiments, the activator, such as sirolimus, may be a powder crystallized by the manufacturer or recrystallized through a controlled process. For example, sirolimus microparticles can be prepared by grinding crystalline powder in Novec 7100 hydrofluoric acid for 2 hours. By selecting the size and hardness of the grinding balls, and the grinding speed and time, crystalline sirolimus can be made finer to particles of micron size or smaller. Grinding can be carried out dry or wet in an anti-solvent of sirolimus, such as water, hexane, or hydrofluorocarbon. The anti-solvent is then removed by drying or reducing the pressure. Alternative methods for size reduction include miniature hammer milling, automated mortar pests, ultrasonic homogenization, electrohydraulic (arc cavitation) homogenization, or any mechanical process that leaves the crystals undissolved in the solvent.

In some embodiments, the ground crystalline sirolimus can be sieved to remove larger particles. For example, an ASTM E-11 sieve no. 100 (mesh size 150 μm) can be used for this sirolimus sample, and the particles that do not pass through are returned to a planetary ball mill for further polishing.

In some embodiments, fine particles within a specific size range can be selected using any particle size sorting technique. For example, particles are passed through progressively smaller sieves into an antisolvent. In some embodiments, any further size reduction may be provided using ultrasonic homogenization probes, electrohydraulic lithography, or other high-shear cavitation techniques known in the art. In some embodiments, a recirculation loop can be constructed to break down particles to less than the size of a red blood cell.

In some embodiments, once the maximum particle size is reduced to less than approximately 10 microns, particle uniformity can be further improved through sorting, such as sieving, to remove finer particles that may cause excessive bursting. In some embodiments, the particles can be circulated in an antisolvent (water, heptane, hydrofluorocarbon), and by controlling the shape and flow rate, particles of a desired size can be collected via precipitation.

In some embodiments, the microreservoirs have average diameters of approximately 0.5 to 10 microns, 1 to 10 microns, 0.5 to 8 microns, 1.8 to 8 microns, 2 to 6 microns, or 3 to 5 microns. In some embodiments, it is desirable that the microreservoirs be large enough to provide sustained release of the activator for non-uniformly sized particles with a diameter or average cross-sectional dimension of approximately 1.5 microns or larger. Smaller microreservoirs typically have a larger surface area-to-volume ratio, reducing the diffusion pathways for the activator that do not provide sufficient sustained release. The maximum size of the microreservoirs is approximately 6 to 8 microns, roughly the size of a red blood cell, to prevent embolus formation in capillaries by any microreservoirs released into the bloodstream during or after treatment. In some embodiments, the microreservoirs do not contain nano-sized particles. In some embodiments, less than 5%, less than 8%, less than 10%, less than 15%, less than 20%, less than 25%, less than 30%, less than 40%, and less than 50% of the microreservoirs have a diameter of 1.5 microns or less. In some embodiments, less than 5%, less than 8%, less than 10%, less than 15%, less than 20%, less than 25%, less than 30%, less than 40%, and less than 50% of the microreservoirs have a diameter of 1 micron or less. In some embodiments, the microreservoirs do not necessarily have affinity or adhesion to the vascular surface.

Biodegradable or bioerosive polymers can provide controlled and extended release of activators. These polymers may be referred to as first biodegradable or bioerosive polymers, or second biodegradable or bioerosive polymers. The polymers act as barriers to drug diffusion, thereby providing a release profile tailored to the pharmacokinetics of the activator acting on the treated blood vessels. For example, the activator can be mixed or dispersed in a solid solution. The polymers can provide controlled release by reducing the dispersion of the activator, or by coupling drug release with the biodegradation, dissolution, or bioerosion of the polymer. In some embodiments, the biodegradable or bioerosive polymers are selected from the group consisting of polylactic acid, polyglycolic acid and copolymers thereof, polydioxanone, polycaprolactone, polyphosphatidine, collagen, gelatin, chitosan, glycosoaminoglycans, and combinations thereof. In some embodiments, the microreservoir may be a microsphere or microparticle containing at least one activator that treats an inflammatory or healing response. In some embodiments, the microreservoir may contain a first biodegradable or bio-erosive polymer. In some embodiments, the microreservoir may contain a second biodegradable or bio-erosive polymer.

After contact between the coating 12 and the vessel wall, the dynamic characteristics of activator release are controlled by the release of the activator from the microreservoir into the surrounding medium, thereby enabling the sustained elution of the activator into the vessel wall. To provide a significant activator during the initial high-risk period for restenosis after dilation, it is preferable that the activator in the coating 12 is sustainably released with a half-life dynamic characteristic of approximately two weeks to approximately six weeks or more. In some embodiments, multiple microreservoirs have an activator release dynamic characteristic with a half-life of at least 14 days.

The activator release characteristics can be adjusted by the properties of the microreservoir. The therapeutic effect can be adjusted by incorporating two or more microreservoirs with different activators or different release characteristics for the same activator into the coating 12. In some embodiments, some activators may be incorporated into the coating formulation outside the microreservoir to provide rapid initial release of the activator to the vascular wall, thereby allowing the microreservoir to provide sufficient activator to maintain effective tissue concentrations of the activator over a long period. Since healing and recovery of inflammation in dilated areas typically takes 4 to 12 weeks, it is desirable for the microreservoir and coating 12 to release the activator for at least about 4 to 12 weeks post-treatment. In certain applications, such as in vessels with very long and widespread disease, maintaining activator levels for longer than 4 to 12 weeks may be desirable to provide further protection against the less common effects of late restenosis.

The release of activators mixed or dispersed with solids has been shown to follow Higuchi dynamics, where activator release decreases over time. For spherical particles with activators dispersed in polymers, the activator release dynamics also follow the Korsmeyer-Peppas dynamics model, a power law of decreasing release rate, similar to the Higuchi equation. (J. Siepmanna J, Peppas NA, Modeling of active agent release from delivery systems based on hydroxypropyl methylcellulose (HPMC), Advanced Drug Delivery Reviews 48 (2001) 139-157). The dynamic characteristics of activator release from such microreservoirs are well-suited for post-vasodilation therapy. The design and selection of microreservoirs with appropriate release constants provide rapid initial release of activators with sustained activator release and longer-lasting activator retention within the vasoconstrictor compared to conventional devices. The activator release rate can be adjusted by controlling the solubility of the activator in the microreservoir material and the microporosity of the microreservoir. The effective activator delivery length can be adjusted by selecting the size of the microreservoir, the solubility of the activator in the microreservoir material, and the amount of activator loaded into the microreservoir. The total amount of activator delivered is determined by the amount of microreservoir and the degree of activator loading in the coating formulation. In this way, the coating 12 can be formulated to have an activator concentration of about 0.3 to about 3 μg per 1 ^mm² on the surface of the expandable portion 11. The desired dynamic properties of activator release from the coating 12 can be provided by a single type of microreservoir, or alternatively by a mixture of microreservoirs of different sizes or different release properties, to provide the desired release profile to the vascular wall.

In some embodiments, the coating 12 further comprises PEG-lipids to increase blood compatibility. Since the coatings 12 disclosed herein are designed to be delivered to the surface of blood vessels and remain there to release the drug during the vascular healing period, blood compatibility of the coating 12 is desirable. Prior to vascular healing, it is desirable to prevent the dissolution of the coating 12 into the bloodstream, as well as to prevent significant coagulation initiation and the adhesion of fibrin and platelets to the coating surface exposed to blood after delivery. The addition of PEG-lipids to the composition of cholesterol and phospholipids or fatty acids may be used to increase the blood compatibility of the formulation. PEG-grafted polymer surfaces exhibit improved blood contact properties, primarily due to a reduction in interfacial free energy and steric hindrance of the hydrated PEG chains on the surface. While not wanting to be bound by a specific operational theory, it is thought that small amounts of PEG-lipid conjugates added to the composition, particularly relatively low molecular weight PEG-lipids, may migrate to the blood interface surface after delivery. This allows the PEG chains to reduce the interfacial free energy of the blood interface surface. Since the coating material at the blood interface constitutes only a small portion of the total coating, the required amount of PEG-lipid is relatively small.

In some embodiments, the PEG-lipids are 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), and 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine-N-methoxy(polyethylene glycol)-350 (DOPE-mPEG350). 0) Selected from the group consisting of 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-methoxy(polyethylene glycol)-550 (DSPE-mPEG550), 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine-N-methoxy(polyethylene glycol)-550 (DPPE-mPEG550), and 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine-N-methoxy(polyethylene glycol)-500 (DOPE-mPEG550). In some embodiments, the PEG-lipid is about 1% to about 30% by weight of the hydrophobic matrix 14, which consists of a combination of cholesterol, fatty acids, or phospholipids and PEG-lipids. In other embodiments, the PEG-lipid is about 2% to about 25% by weight, about 3% to about 20% by weight, or about 5% to about 10% by weight of the hydrophobic matrix 14. In some embodiments, the amount of PEG-lipid is less than approximately 12%.

In some embodiments, coating 12 further comprises one or more additives. In some embodiments, one or more additives are independently selected from penetration enhancers and stabilizers. For example, coating 12 may further contain additives to enhance performance, such as penetration enhancers. Penetration enhancers can help disperse the activator into the blood vessel wall and maximize the tissue delivery of the activator. Suitable penetration enhancers may include surfactants, cationic excipients, and cationic lipids. In some embodiments, additives may be added to the hydrophobic matrix, microreservoir, or both. In some embodiments, stabilizers may be added before use of the balloon catheter system to protect the drug during sterilization and subsequent storage of the balloon catheter system. Stabilizers may include antioxidants and free radical scavengers. Examples of stabilizers include gallic acid, propyl gallate, tocopherol and tocotrienol (vitamin E), butylated hydroxytoluene, butylated hydroxyanisole, ascorbic acid, thioglycolic acid, ascorbyl palmitate, and EDTA.

In some embodiments, the coating 12 further comprises a third activator, which is located outside the microreservoirs or within the hydrophobic matrix 14. The third activator may be the same as or different from the first or second activators in the microreservoirs. However, since the activator is primarily contained within the microreservoirs and does not directly contact the hydrophobic matrix 14, it is not necessary to solubilize or emulsify the activator within the hydrophobic matrix 14 itself. Furthermore, since the activator is primarily contained within the microreservoirs and does not contact the hydrophobic matrix 14, it is not necessary to include amphiphilic components or components with activator affinity within the hydrophobic matrix 14 itself. Therefore, the hydrophobic matrix 14 can be optimized for appropriate properties for resistance to wash-off by blood and adhesion of the coating 12 to the vascular surface.

(catheter)
Referring to Figure 2, this specification also discloses a catheter 10 comprising an inflatable portion 11 on a long body 17, the coating 12 on the inflatable portion 11, and a release layer 15 between the inflatable portion 11 and the coating 12. In some embodiments, the release layer 15 is configured to release the coating 12 from the inflatable portion 11. The release layer 15, which is immiscible with the coating 12, is preferred to maintain a distinct layered structure. In some embodiments, a PEG-bound lipid is used as the release layer 15, as the degree of hydrophilicity and miscibility with the activator coating 12 can be adjusted by selecting the 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-phosphoethanolamine-N-(methoxy(polyethylene glycol)-550) (DSPE-mPEG550). In some embodiments, the release layer 15 has a surface concentration of about 0.1 μg/ ^mm² to about 5 μg/ ^mm² , 0.25 μg/ ^mm² to about ³ μg/ ^mm² , or 0.5 μg/mm² to about 2 μg/ ^mm² .

Referring to Figure 3, in some embodiments, the catheter 10 further includes a protective layer 16 on top of the coating 12 as a topcoat. In some embodiments, the protective layer 16 includes a hydrophilic polymer, a carbohydrate, or an amphiphilic polymer. In some embodiments, the protective layer 16 is a glycosaminoglycan or 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 crystallinity of these sugars provides a hard surface that protects the underlying microreservoir. 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/ ^mm² to about 5 μg/ ^mm² , about 0.2 μg/ ^mm² to about 4 μg/ ^mm² , or about 0.3 μg/ ^mm² to about 3 μg/ ^mm² .

The inflatable portion 11 of the catheter 10 may be a balloon that acts as the base material for the coating 12. In some embodiments, the balloon may be a low-pressure design using an elastomer material such as polyisoprene, polystyrene copolymer, polysiloxane, or polyurethane. In some embodiments, the balloon may also be a high-pressure design using a high-tensile strength polymer such as polyvinyl chloride, polyethylene, polyethylene terephthalate, or nylon. In some embodiments, the inflatable portion 11 may be made of nylon 12. The coating 12 may adhere well to the inflatable portion 11, but will readily migrate to the tissue of the vascular lining upon contact. In such cases, the release layer may be omitted. In addition, the nylon 12 has sufficient strength (if necessary) so that the balloon can further act as a post-inflated balloon in subsequent procedures after the delivery of the coating 12.

In some embodiments, the target vessel can be dilated using the inflatable portion 11 beneath the coating 12. In some embodiments, the vessel may be pre-dilated with another balloon catheter 10 before treatment with the coated balloon of this embodiment.

(Coating formulation)
This specification also discloses a coating formulation for the inflatable portion 11 of the catheter 10. The formulation comprises a solid portion and a liquid. The solid portion comprises a plurality of microreservoirs and at least one hydrophobic compound. The liquid acts to disperse or solubilize at least one hydrophobic compound. In some embodiments, the liquid can disperse several hydrophobic compounds and solubilize other hydrophobic compounds. The microreservoirs are dispersed and suspended in the resulting fluid mixture to form the coating formulation. The fluid mixture is formulated to form a homogeneous mixture of hydrophobic compounds that do not separate during drying to result in 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 excludes the liquid that evaporates during the drying process of the coating.

The microreservoir contains an activator and a polymer. The activator may be referred to as the first activator or the second activator, as described herein. The polymer may be the first biodegradable or bioerosive polymer or the second biodegradable or bioerosive polymer as described herein. In some embodiments, the activator is mixed with or dispersed with the biodegradable or bioerosive polymer as described herein. In some embodiments, the formulation may contain one or more microreservoirs. For example, multiple microreservoirs may contain the first activator and the first biodegradable or bioerosive polymer. In some embodiments, multiple microreservoirs may further contain a second activator. In some embodiments, multiple microreservoirs may also contain a second biodegradable or bioerosive polymer.

Microreservoirs can be manufactured by any known means for particle production, including spray drying, coacervation, micromolding, and milling. All such processes begin by dissolving the activator and polymer together in a suitable solvent such as acetonitrile or dichloromethane, and then removing the solvent in a controlled manner to produce uniform particles. The particles may be further shaped by mechanical means. Processes for producing particles with a size distribution of less than 10% deviation are particularly useful for providing a more consistent activator release rate. Methods for producing uniformly sized microspheres are realized by forming an emulsion of microsphere material and extruding the emulsion through a substrate having sized through-holes, as described in US 7,972,543 and US 8,100,348. Alternatively, microspheres may be manufactured by a spray-dried solution of the polymer, as described in US 6,560,897 and US 20080206349.

The fluid in the coating formulation may include water, organic solvents, perfluorocarbon fluids, or mixtures of these fluids. In some embodiments, the fluid is selected from the group consisting of pentane, hexane, heptane, mixtures of heptane and fluorocarbons, mixtures of alcohol and fluorocarbons, and mixtures of alcohol and water. Fluids that readily solubilize the activator or polymer in the microreservoir are undesirable because they may extract the activator from the microreservoir. Such undesirable fluids include acetic acid, acetonitrile, acetone, dichloromethane, ethyl formate, cyclohexanone, DMSO, and chloroform. Optionally, the fluid/fluid blend may be selected to saturate the solution at a desired level of extracted activator. Additional activators, the same as those in the microreservoir, can be pre-added to the fluid to pre-saturate the solution, thereby reducing extraction from the microreservoir during the coating process.

In some embodiments, at least one hydrophobic compound is selected from the group consisting of sterols, lipids, phospholipids, fats, fatty acids, and surfactants, and their derivatives. In some embodiments, at least one hydrophobic compound comprises cholesterol and fatty acids as described herein. In other embodiments, at least one hydrophobic compound comprises cholesterol and phospholipids as described herein. In some embodiments, the formulation may also contain PEG-lipids as described herein. In some embodiments, the formulation may further contain additives such as penetration enhancers and stabilizers.

In some embodiments, the solid portion further includes a third activator outside the microreservoirs. In other words, the coating formulation can result in a hydrophobic matrix 14 further containing the third activator. The activator outside the microreservoirs may be the same as or different from the activator inside the microreservoirs. In some embodiments, the solid portion may further include PEG-lipids. In some embodiments, the solid portion may further include the additives described herein.

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

(Coating method)
This specification also discloses a method for coating the inflatable portion 11 of the catheter 10. The steps include placing the formulation described herein onto the surface of the inflated inflatable portion 11 of the catheter 10, evaporating the fluid component of the coating formulation, and folding the inflatable portion 11. The step of placing the formulation onto the surface of the inflated inflatable portion 11 includes placing the formulation onto the surface of the inflated inflatable portion 11. In some embodiments, the formulation may be placed on the inflated inflatable portion 11 by spray coating, dip coating, roll 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, a microreservoir is dispersed in the fluid formulation. Once fully mixed, the coating formulation is applied to the surface of an inflatable portion 11, such as a balloon, and allowed to dry to form a coating 12. The application of the coating formulation can be repeated as needed to deposit the desired coating 12, typically about 5 mg to about 9 mg of coating 12 per 1 ^mm² of the balloon surface. The coating 12 is allowed to dry, and the balloon is deflated and folded to allow introduction into the vascular system.

In some embodiments, the method may further include the step of placing a release layer on the surface of the expanded expandable portion 11. Thus, the coating formulation is placed on the release layer, while the release layer is placed on the surface of the expanded expandable portion 11. The release layer is as described above.

(Methods for treating or preventing a disease)
Disclosed herein are methods for treating or preventing a pathological condition at a treatment site. The method includes the steps of advancing a catheter 10 including an inflatable portion 11 to the treatment site; expanding the inflatable portion 11 to allow contact between the coating 12 and the tissue at the treatment site; folding the inflatable portion 11; and removing the catheter 10. The inflatable portion 11 is coated with the coating described herein. In some embodiments, the contact between the tissue and the coating 12 delivers at least a portion of the coating on the inflatable portion 11 to the treatment site during contact for about 30 to about 120 seconds.

A catheter 10 having an inflatable portion 11, such as a coated balloon catheter, is used here to demonstrate the concept of delivering an activator or combination of activators into a blood vessel. The coated balloon catheter is introduced into the blood vessel with the inflatable portion 11 folded to reduce the cross-sectional area and to facilitate percutaneous insertion of the catheter 10, for example by the well-known Seldinger method. After the inflatable portion 11 of the catheter 10 has been advanced to the affected area of the blood vessel for treatment, the balloon is inflated to bring the coating 12 into firm contact with the vascular lumen. The coating is formulated to have affinity with the luminal tissue surface, resulting in adhesion of the coating layer over the vascular lumen. The inflatable portion 11 can be inflated or expanded for 30 seconds to 2 minutes to promote adhesion and provide initial penetration of the activator into the blood vessel. The inflatable portion 11 may be repeatedly expanded and expanded as needed for treatment to manage the time and risk of vascular occlusion or tissue ischemia. The coating is adhering to the vascular lumen through balloon inflation and secure contact of the balloon surface with the vascular lumen surface. This adhesion of the coating to the vascular surface carries and transfers microreservoirs to the vascular surface.

In some embodiments, the pathological condition is selected from the group consisting of atherosclerosis, narrowing or reduction of the lumen diameter in the diseased vessel, restenosis, and in-stent restenosis. In some embodiments, the additional release layer described herein is positioned between the inflatable portion 11 and the coating 12.

While this disclosure is directed toward the treatment of restenosis associated with balloon dilation of blood vessels, the present invention may be used to deliver drugs to various other luminal and hollow structures of the body, such as structures of the suction system, gastrointestinal system, urinary system, reproductive system, and lymphatic system. The coated device may be an inflatable balloon or other inflatable device. Alternatively, the device delivering the coating of the present invention may be a non-inflatable device or any other type of inflatable device used for the treatment of living organisms.

(Example 1)
A drug containing a microreservoir (microsphere) was obtained by coacervation of a polylactic acid-co-glycolic acid copolymer incorporating sirolimus (rapamycin).
Microsphere sample 1: 50% DL-lactide/50% glycolide copolymer, average diameter 3.1 μm, SD 0.44 μm, 39 wt% rapamycin Microsphere sample 2: 75% DL-lactide/25% glycolide copolymer, average diameter 3.2 μm, SD 0.76 μm, 40 wt% rapamycin Microsphere sample 3: 50% DL-lactide/50% glycolide copolymer, average diameter 2.7 μm, SD 0.8 μm, 45 wt% rapamycin Microsphere sample 4: 75% DL-lactide/25% glycolide copolymer, average diameter 3.3 μm, SD 1.2 μm, 46 wt% rapamycin Microsphere sample 5: 75% DL-lactide/25% glycolide copolymer, average diameter 4.1 μm, SD Microsphere sample 6: 75% DL-lactide/25% glycolide copolymer, average diameter 3.78 μm, SD 0.44 μm, 28.8% rapamycin Microsphere sample 7: 75% DL-lactide/25% glycolide copolymer, average diameter 3.8 μm, SD 0.34 μm, 27.7% rapamycin Microsphere sample 8: 75% DL-lactide/25% glycolide copolymer, average diameter 3.79 μm, SD 0.39 μm, 29.4% rapamycin

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

(Example 2: Sustained drug release from a microreservoir under physiological conditions)
The microreservoirs from Example 1 were tested for sustained drug release. To simulate a physiological environment, 2–5 mg of microreservoir sample was placed in a 1.6 ml Eppendorf tube with 1.2 ml of phosphate-buffered saline (PBS). After an initial wash to remove any drugs not incorporated into the microreservoir, the tubes were incubated at 37°C with gentle mixing at 250 rpm. PBS was sampled at time intervals, and the released drugs were quantified by reversed-phase HPLC using a C18 column.

The microreservoir was analyzed for drug elution over a 5-hour period. The obtained drug release was compatible with the Korsmeyer-Peppas dynamics equation for drug release from polymers by dispersed drugs. The results of the Korsmeyer-Peppas model are shown in Table 1.

The short-term delivery results exhibited a drug release constant typical of Korsmeyer-Peppas for drugs dispersed in spherical polymer particles, suggesting that polymer erosion and degradation contributed little to the microsphere samples 1, 2, and 3.

Drug release experiment: To verify drug dissolution over 7 days, microspheres were analyzed using the 5-hour test method described above. The obtained drug release results are listed in Table 2.

The release rate obtained from the 7-day delivery results was in agreement with the Higuchi equation:
Q=A[D(2C-Cs)Cst] ^1/2
Q=K _h (t) ^1/2
Here, Q is the amount of drug released per unit area A per time t, C is the initial drug concentration, Cs is the drug solubility in the polymer medium, and D is the diffusion coefficient of the drug in the microsphere polymer. In the general formula, K _h is the Higuchi constant, which incorporates the area, diffusion coefficient, and drug concentration coefficient.

The Higuchi equation was used to measure the emission half-life of the microreservoir, and the half-life was also estimated as a function of the microsphere size. The obtained emission half-lives are shown in Table 3.

The results showed that the half-life of drug delivery from microreservoirs can be adjusted by the formulation and size of the microreservoirs. It is estimated that a microsphere size of 1.5 microns or larger in diameter is necessary for a delivery half-life of at least 14 days.

Verification of sustained release: Microsphere sample 4 was analyzed using the method described above to obtain drug release over an 8-week period. Compared to the previous release experiment, the relatively long time interval between sampling may mean that the microreservoir was not released under sink conditions at later points in time, potentially slowing the effective release rate. The drug release results are shown in Table 4.

As a result, sustained drug release from the microreservoir was confirmed. Microreservoirs can be adjusted or selected based on their half-life to deliver the drug throughout the healing period of dilated blood vessels.

(Example 3: Formulation of microreservoirs in cholesterol and fatty acid coating formulations using PEG-lipids)
The coating formulation was mixed with 107 mg of stearic acid, 105 mg of cholesterol, and 50 mg of DPPE-mPEG350 in 14 mL of heptane, and heated to 60°C until a clear solution was obtained. The solution was then stirred for 30 seconds and allowed to cool. Subsequently, 200 mg of sirolimus-filled microspheres of sample #6 were added, and the mixture was placed in an ultrasonic bath for 4 minutes to disperse and suspend the microspheres. [Formulation 1023E]

A coating formulation was prepared by mixing 58 mg of erucic acid, 43 mg of DC-cholesterol, and 6.25 mg of DOPE-mPEG350 with 7 mL of heptane and heating to 60°C until a clear solution was obtained. Next, the solution was stirred for 30 seconds and allowed to cool. Subsequently, 100 mg of sirolimus-filled microspheres (sample #8) were added, and the mixture was placed in an ultrasonic bath for 5 minutes to disperse and suspend the microspheres. [Formulation 0424A]

A coating formulation was prepared by mixing 25 mg of nervonic acid, 75 mg of DC-cholesterol, and 6.25 mg of DOPE-mPEG350 with 7 mL of heptane and heating to 60°C until a clear solution was obtained. Next, the solution was stirred for 30 seconds and allowed to cool. Subsequently, 97 mg of sirolimus-filled microspheres (sample #8) were added, and the mixture was placed in an ultrasonic bath for 5 minutes to disperse and suspend the microspheres. [Formulation 0422E]

(Example 4: Formulation of microreservoirs in coated formulations of cholesterol, fatty acids, PEG-lipids, and stabilizing additives)
A coating formulation was prepared by mixing 77 mg of stearic acid, 40 mg of cholesterol, 50 mg of DPPE-mPEG 350, and 58 mg of α-tocopherol with 7 mL of heptane and heating to 60°C until a clear solution was obtained. The solution was stirred for 1 minute and cooled to room temperature. Subsequently, 100 mg of sirolimus-filled microspheres of 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 cholesterol and phospholipid coated formulations)
A coating formulation was prepared by mixing 43 mg of cholesterol and 42 mg of L-α-phosphatidylcholine with 7 mL of heptane and heating to 60°C. The solution was stirred for 30 seconds and then cooled to room temperature. Subsequently, 10 mg of sirolimus-filled microspheres of sample #5 were added to the vial, and the vial was placed in an ultrasonic bath for 8 minutes to disperse and suspend the microspheres. [Formulation 0311A]

(Example 6: Microreservoir formulation in cholesterol and long acyl chain phospholipid coated formulations with or without PEG-lipids)
A coating formulation was prepared by mixing 51 mg of DC-cholesterol, 6.25 mg of DOPE-mPEG350, and 51 mg of die-coil phosphatidylcholine (DEPC) with 7 mL of heptane and heating to 60°C. The solution was stirred for 30 seconds and then cooled to room temperature. Subsequently, 100 mg of sirolimus-filled microspheres of sample #7 were added to the vial and placed in an ultrasonic bath for 5 minutes to disperse and suspend the microspheres. [Formulation 0410A]

A coated formulation was prepared by mixing 20 mg of DC-cholesterol, 26 mg of cholesterol, 6.25 mg of DOPE-mPEG 350, and 75 mg of dinerbonylphosphatidylcholine (DNPC) with 7 mL of heptane and heating to 60°C. The weight ratio of DNPC to DC-cholesterol in this formulation was 1.6:1. The solution was cooled to room temperature. Subsequently, 97 mg of sirolimus-filled microspheres (sample #7) were added to the vial, stirred 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 by mixing 28 mg of DC-cholesterol, 26 mg of cholesterol, 6.25 mg of DOPE-mPEG 350, and 50 mg of dinerbonylphosphatidylcholine (DNPC) with 7 mL of heptane and heating to 60°C. The solution was stirred for 30 seconds and then cooled to room temperature. Subsequently, 97 mg of sirolimus-filled microspheres (sample #7) were added to the vial, and the vial was placed in an ultrasonic bath for 5 minutes to disperse and suspend the microspheres. [Formulation 0421B]

A coated formulation was prepared by mixing 50 mg of DC-cholesterol and 50 mg of dinerbonylphosphatidylcholine (DNPC) with 7 mL of heptane and heating to 60°C. The weight ratio of DNPC to DC-cholesterol in this formulation was 1:1. The solution was stirred for 30 seconds and then cooled to room temperature. Subsequently, 100 mg of sirolimus-filled microspheres (sample #7) were added to a vial, and the vial was placed in an ultrasonic bath for 4 minutes to disperse and suspend the microspheres. [Formulation 1205A]

A coated formulation was prepared by mixing 49 mg of DC-cholesterol, 6.25 mg of DOPE-mPEG 350, and 50 mg of dinerbonylphosphatidylcholine (DNPC) with 7 mL of heptane and heating to 60°C. The weight ratio of DNPC to DC-cholesterol in this formulation was 1:1. The solution was stirred for 30 seconds and then cooled to room temperature. Subsequently, 100 mg of sirolimus-filled microspheres (sample #7) were added to the vial, and the vial was placed in an ultrasonic bath for 2 minutes to disperse and suspend the microspheres. [Formulation 1209A]

A coated formulation was prepared by mixing 76 mg of DC-cholesterol, 6.25 mg of DOPE-mPEG 350, and 25 mg of dinerbonylphosphatidylcholine (DNPC) with 7 mL of heptane and heating to 60°C. The weight ratio of DNPC to DC-cholesterol in this formulation was 1:3. The solution was cooled to room temperature. Subsequently, 100.7 mg of sirolimus-filled microspheres (sample #8) were added to the vial, stirred 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 coated formulations of DC-cholesterol having various PEG-lipid contents)
A coating formulation was prepared by mixing 12.5 mg of DOPE-mPEG 350, 44 mg of DC-cholesterol, and 44 mg of dinerbonylphosphatidylcholine (DNPC) with 7 mL of heptane heated to 60°C. The clear solution was cooled to room temperature, and then 97 mg of sirolimus-filled microspheres of microsphere sample #8 were added. Subsequently, this formulation was placed in an ultrasonic bath and sonicated for 5 minutes to disperse and suspend the microspheres. [Formulation 0422A]

A coating formulation was prepared by mixing 25 mg of DOPE-mPEG 350, 37.5 mg of DC-cholesterol, and 37.5 mg of dinerbonylphosphatidylcholine (DNPC) with 7 mL of heptane heated to 60°C. The clear solution was cooled to room temperature, and then 97 mg of sirolimus-filled microspheres (microsphere sample #8) were added. Subsequently, this formulation was placed in an ultrasonic bath and sonicated for 5 minutes to disperse and suspend the microspheres. [Formulation 0422B]

(Example 8: Coating with additional chemicals)
72.9 mg of DC-cholesterol was dissolved in 7 mL of heptane, and the solution was heated to 60°C until the DC-cholesterol was solubilized and a clear solution was obtained, thereby preparing a coated formulation. 15.5 mg of sirolimus was added to this solution and stirred for 30 seconds. The solution was heated for 40 minutes, stirred for 10 seconds every 10 minutes, and sonicated for 5 minutes while cooling to room temperature. 50 mg of DNPC was also added to the solution. At room temperature, the solution was filtered through a 0.2 micron PTFE filter to remove large drug particles. The solution was left overnight, and no fine particles formed overnight were observed. Analysis of the solution revealed a sirolimus content of 0.96 mg/ml. 98 mg of sirolimus-filled microspheres (microsphere sample #8) was added to this solution, stirred for 30 seconds, and sonicated for 8 minutes to disperse and suspend the microspheres. The resulting coated formulation contained 0.71% by weight of sirolimus, of which 19.1% was located in the DC-cholesterol and DNPC hydrophobic matrix, and the remainder was in the microspheres. [Formulation 0512A]

Table 5 shows the weight percentage composition of the coating formulations described in Examples 3, 4, 5, 6, 7, and 8.

(Example 9: Application of coating formulation to balloon catheter)
The stearic acid coating formulation of Example 3 (Formulation 1023E) was sprayed onto the balloon surface of a nylon angioplasty balloon measuring 5.0 mm in diameter and 20 mm in length. 7 ml of the coating formulation was loaded into a 25 mL gas-tight syringe equipped with an integrated magnetic stirring bar system. The drug was continuously stirred during spraying to maintain a well-suspended state in the drug microreservoir. The coating formulation was delivered at a rate of 0.11 mL/min using a syringe pump via a 120 kHz ultrasonic nozzle [Sonotek DES1000] operated at 5.5 watts. To verify the process parameters, a cylinder of balloon material measuring 5.0 mm in diameter and 20 mm in length was cut, weighed, and placed on a balloon of the same size. The sleeve of this balloon material was coated with approximately 2.2 mg of coating (corresponding to a coating concentration of 7 μg/ ^mm² ). The formulation of Example 3, at 7 μg/ ^mm² , contained approximately 1.6 μg/ ^mm² of stearic acid, approximately 1.6 μg/ ^mm² of cholesterol, 0.8 μg/ ^mm² of DPPE-mPEG350, and 3 μg/mm² of sirolimus-filled microspheres from microsphere sample # ⁵ , resulting in a drug concentration of 0.87 μg/ ^mm² . After confirming that the sleeve weight reached the target weight, the full balloons were coated. A balloon with a diameter of 5.0 mm and a length of 20 mm was inflated, placed under the spray, and rotated five times while moving it back and forth. The balloon was then removed and dried. This process was repeated until six balloons were coated. The same process was repeated to spray the coating formulation of Example 6 (Formulation 0513A) onto balloons with a diameter of 3.0 mm and a length of 20 mm. For Example 6 (Formulation 0513A), the target weight for sleeve coating a balloon with a diameter of 3.0 mm x 20 mm was 1.4 mg, achieving a coating density of 7.6 μg/ ^mm² . Of this 7.6 μg/ ^mm² , 0.9 μg/ ^mm² of dinerbonylphosphatidylcholine, 2.7 μg/ ^mm² of DC-cholesterol, 0.23 μg/ ^mm² of DOPE-mPEG350, and 3.7 μg/ ^mm² of the sirolim-filled microspheres of sample #5 were included, resulting in a drug density of 1.08 μg/ ^mm² .

The coating formulations of Examples 4, 5, 6, 7, and 8 were also sprayed onto the surface of a 20 mm long balloon using the same spraying method as the formulation of Example 3 described above. The obtained coating weights and coating densities are shown in Table 6.

For balloons coated with the formulation of Example 4, an additional topcoat agent (1010D) consisting of 1 mg of cholesterol and a cholesterol-PEG600 coating was sprayed onto each balloon 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. For a balloon with a diameter of 5.0 mm and a length of 20 mm, the target coating weight of 1 mg corresponds to a total topcoat of 3.2 μg/ ^mm² consisting of 0.3 μg/ ^mm² of cholesterol-PEG600 and 2.9 μg/ ^mm² of cholesterol.

(Example 10: Adhesion of coating to the vascular lumen surface)
The exvivovota artery was flushed with 37°C Ringer's lactate solution at a pulsatile flow rate of 50 mL/min (approximately 72 BPM) for 5 minutes. A balloon coated with the formulation from Example 3 was inflated in the lumen of the exvivovota artery to an approximate hyperextension of 1:1.2 to deliver the drug, including the coating, into the vascular lumen. Subsequently, the solution that passed through the artery before and after inflation (pre- and post-flush), the balloon used in the artery, and the cross-section of the artery that came into contact with the inflated balloon were analyzed for the drug 5 minutes after the post-inflation flush. The blood vessels treated with formulations 1205A and 1209A were flushed for a total of 60 minutes to evaluate the sustained release of the delivered coating. The amount of drug measured from all sources in the analysis was totaled and compared with the estimated drug content of the balloon based on the coating weight. The proportion of drug delivery to the artery based on the estimated drug content of the balloon based on the coating weight was used as a measure of delivery efficiency.

Balloons coated with the formulation of Example 4 were also tested in the exvivota artery.

Balloons coated with the formulation of Example 5 were also tested in the exvivota artery.

Balloons coated with the formulation of Example 6 were also tested in the exvivota artery.

The lumen surface of an artery was observed using a dark-field microscope after inflating a balloon coated with formulation 1209A and rinsing it for one hour. Figure 4 is a micrograph of the lumen surface at 200x magnification, showing the adhesive material. Figure 5 is a micrograph of the lumen surface at 1000x magnification, showing the adhesive material forming the layer of the spherical microreservoir surrounded by the coating material.

(Example 11: Adhesion of PEG-lipid formulations with different coatings to the vascular lumen surface)
The samples from Example 7 were tested for coating delivery and resistance to wash-off using the method of Example 10. The results were compiled, and coatings with DNPC and DC-cholesterol were compared in equiweight ratios with varying amounts of DOPE-mPEG350. [Formulations 1205A, 1209A, 0422A, 0422B]

The results demonstrate superior drug delivery to the vascular lining. Drug coating loss during pre-flush increased with formulations coated with 25% PEG-lipid.

(Example 12: Adhesion of additional rapamycin coating to the vascular lumen surface)
The formulation of Example 8 was tested for coating delivery and resistance to wash-off using the method of Example 10.

The results demonstrate significant drug delivery from the coating of the phospholipid and cholesterol components of the coated formulation to the vascular lumen.

(Example 13: Drug release into blood vessels after in vivo treatment)
To prepare a balloon catheter coated with a drug microreservoir-containing formulation, 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 then cooled to room temperature. Next, 195 mg of microsphere sample #6 was added and stirred to suspend the microspheres. A balloon catheter with a balloon measuring 3.0 mm in diameter and 20 mm in length was coated with the formulation using the method described in Example 9. The coated balloon catheter was then dried. An average dry coating of 1.28 mg ± 0.12 mg was applied to the balloon, resulting in a coating density of 6.80 μg/ ^mm² and a drug density of 1.06 μg/ ^mm² . To obtain a pre-deployment configuration with a smaller cross-section, the balloon was deflated and folded, and then packaged in a sleeve to maintain the folded configuration. Furthermore, the balloon catheters were packaged and sterilized with ionizing radiation at a minimum dose of 25 kGray.

The in vivo delivery of drug-coated iliofemoral vascular tissue to the iliofemoral artery of rabbits was evaluated. The iliofemoral artery segment to be treated was initially prepared to expose the endothelium to replicate tissue damage after angioplasty. The common carotid artery was dissected, and a size 5F balloon wedge catheter was inserted into the artery, guiding the treatment site of the iliofemoral artery under fluoroscopic guidance. Contrast medium was injected through the catheter, and angiography of the iliofemoral artery was recorded. Under fluoroscopic guidance, the balloon wedge catheter was replaced with a standard 3.0 mm diameter x 8 mm length angioplasty balloon catheter, inflated, and then proximal withdrawn to the level of the iliac bifurcation to expose the arterial cross-section. The angioplasty balloon catheter was replaced with the drug-coated balloon catheter. The catheter was advanced to the exposed vascular portion and inflated for 120 seconds. The balloon was deflated and withdrawn. Both the left and right iliac arteries were treated in each animal.

A total of 11 animals were treated. One animal (two iliac arteries treated) was euthanized one hour after treatment, and the vascular segments were collected for microscopic examination. Another animal (two iliac arteries treated) was euthanized 24 hours after treatment, and the vascular segments were collected for microscopic examination. Additionally, three animals (six iliac arteries) were collected at 1 hour, 7 days, and 28 days. Blood samples were taken from these animals before surgery, 0.5 hours, 1 hour, 4 hours after treatment, and at euthanasia. The vascular segments were collected, and drug content was analyzed by HPLC/MS quantification.

Analysis of blood samples showed a rapid decrease in blood drug concentration: 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 slaughter, at 7 and 28 days, were below the detection limit of the quantitative method. Blood levels matched 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 one and twenty-four hours after treatment revealed a layer of material on the vascular lumen surface, within which spherical drug microreservoirs were observed. While mottled fibrin areas were observed on the lumen surface, large fibrin deposits indicating blood incompatibility were not associated with the coating.

Analysis of the treated vascular segments revealed tissue drug levels of 261 μg/g ± 116.5 μg/g at 1 hour post-treatment, 43.8 μg/g ± 34.2 μg/g at 7 days post-treatment, and 21.5 μg/g ± 17.3 μg/g at 28 days post-treatment. These results indicate that the drug, including the microreservoir coating, adhered to the luminal surface of the arteries, and that the drug remained present in the treated vascular tissue for 28 days. The levels of the drug in the tissue decreased rapidly initially, then slowed down between days 7 and 28. The levels of the drug in the tissue at days 7 and 28 decayed exponentially, with a half-life of approximately 20.4 days.

(Example 14: Adhesion of a coating formulation containing sirolimus microparticles to the luminal surface of a blood vessel)
Crystalline sirolimus powder was pulverized, and 100 mg was selected and added to approximately 75 mg of a phospholipid excipient formulation (consisting of approximately 15% DOPE-mPEG350, 35% DNPC, and 50% DC-Chol). The ground sirolimus microparticles were dispersed and suspended in the formulation by magnetic stirring, and then sprayed onto a 4 x 30 mm balloon catheter using a Sonotek PSI ultrasonic spray system. The ultrasonic spray formulation flow rate was set to 0.210 ml/min, and the mixture was layered using four passes until a target coating weight of 2 milligrams was achieved, resulting in approximately 3 μg of sirolimus per 1 ^mm² of balloon surface area. Figure 6 is a micrograph of the coated balloon surface at 100x magnification, showing the coating containing the crystalline sirolimus microreservoir.

Multiple 4 mm diameter porcine carotid arteries were connected to a 72 BPM pulsatile flow system of approximately 100 ml/min of lactated Ringer's solution. To simulate washoff during tracking to the lesion, a coated balloon catheter was inserted into the artery and, while deflated, the fluid was delivered through the artery for 1 minute. The balloon was then inflated, deflated, and removed for 1 minute, the artery was flushed, and fluid was collected for another 1 minute. A second 1-minute washoff collection was performed separately before a further 3-minute flow, totaling 5 minutes. After 5 minutes, the arteries were transected, visually examined, and analyzed for sirolimus. Three catheters coated with the same formulation were tested in the arteries. A white residue coating was visible on the dried arteries, indicating significant delivery was achieved. Figure 7 is a micrograph of the arterial surface at 50x magnification showing the adhesive material, and Figure 8 is a micrograph of the arterial surface at 1000x magnification showing the adhesive material.

After visual inspection, the three treated arteries were dissolved in acetonitrile and analyzed for sirolimus. Balloon catheters were analyzed for residual sirolimus, and samples taken after 1 minute pre-wash-off, 1 minute post-wash-off, and 2 minutes post-wash-off were filtered through a 0.2 μm PTFE filter and dissolved in acetonitrile. The amount of sirolimus recovered from each group is shown in Table 20. Of the total amount of drug tracked, an average of 42% was found to be adhering to the pig arteries after 5 minutes of washing. This indicates that such a pulverized microcrystalline sirolimus coating can be delivered to the arteries.

(Additional Embodiments)
While the present invention is disclosed in the form of certain preferred embodiments and examples, it will be understood by those skilled in the art that the invention extends beyond the specifically disclosed embodiments to other alternative embodiments and/or uses of the invention, as well as obvious modifications and equivalents thereof. Furthermore, it is intended that the various features and aspects of the invention described herein may be implemented separately, in combination, together, or in place of each other, and that various combinations and subcombinations of features and aspects may be made, all of which remain within the scope of the invention. Moreover, any particular features, aspects, methods, properties, characteristics, qualities, attributes, elements, etc., disclosed herein relating to an embodiment may be used in all other embodiments shown herein. Accordingly, it is intended that the scope of the invention disclosed herein should not be limited by the specific disclosed embodiments described above, but should be determined solely by a fair interpretation of the claims.

Unless otherwise specified, conditional language such as “can,” “may,” or “may,” or other similar terms used herein, are generally intended to indicate that certain features or elements are included in certain embodiments but not in other embodiments. Therefore, such conditional language is generally not intended to imply that a certain feature or element is essential in any way to one or more embodiments.

(Summary of the embodiment)
A coating for an inflatable portion of a catheter, comprising a hydrophobic matrix and a dispersed phase comprising a plurality of microreservoirs dispersed in the hydrophobic matrix, wherein the plurality of microreservoirs comprise a first activator and a first biodegradable or bio-erosive polymer.

In the coating embodiment described above, the first activator is either mixed with the first biodegradable or bio-erosive polymer, or dispersed within the first biodegradable or bio-erosive polymer.

In the above-described coating embodiment, the multiple microreservoirs further contain a second activator. The second activator 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-described embodiment of the coating, the multiple microreservoirs further comprise a second biodegradable or bio-erosive polymer. The second biodegradable or bio-erosive polymer is selected from the group consisting of polylactic acid, polyglycolic acid and copolymers thereof, polydioxanone, polycaprolactone, polyphosphatidine, collagen, gelatin, chitosan, glycosoaminoglycan, and combinations thereof.

In the above-described 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 coating described above, the hydrophobic matrix contains 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 the above-described coating embodiment, the fatty acid is selected from the group consisting of lauric acid, lauroleic acid, tetradecenoic acid, octanoic acid, myristic acid, myristoleic acid, 10-hydroxy-2-decenoic acid, decanoic acid, hexadecenoic acid, palmitoleic acid, palmitic acid, linolenic acid, linoleic acid, oleic acid, vaccenic acid, stearic acid, eicosapentaenoic acid, arachidonic acid, meadic acid, arachidic acid, docosahexaenoic acid, docosapentaenoic acid, docosatetraenoic acid, docosenoic acid, tetracosanoic acid, hexacosanoic acid, pristanic acid, phytanic acid, and nervonic acid.

In other embodiments of the coating described above, 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 the group consisting of phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, and phosphatidylinositol.

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

In some embodiments, the phospholipid has an acyl chain length of about 20 to about 34 carbon atoms. In some embodiments, the phospholipid is dieicosenoylphosphatidylcholine (1,2-dieicosenoyl-sn-glycero-3-phosphocholine, C20:1 PC), diarachidonoylphosphatidylcholine (1,2-diarachidoyl-sn-glycero-3-phosphocholine, C20:1 PC), dielcyoylphosphatidylcholine (1,2-dielcyoyl-sn-glycero-3-phosphocholine, C22:1 PC), didocosahexaenoylphosphatidylcholine (1,2-didocosahexaenoyl-sn-glycero-3-phosphocholine, C22:6 PC), henicocenoylphosphatidylcholine (1,2-henicosenoyl-sn-glycero-3-phosphocholine, C21:1 PC) The group is selected from the following: PC, and dinerbonylphosphatidylcholine (1,2-dinerbonyl-sn-glycero-3-phosphocholine, C24:1 PC).

In the above-described coating embodiment, the cholesterol is DC-cholesterol.

In the above-described coating embodiment, the number of microreservoirs is approximately 10% to approximately 75% by weight of the coating.

In the coating embodiments described above, the microreservoirs have an average diameter of approximately 1.5 to 8 microns. In some embodiments, the microreservoirs have an average diameter of approximately 2 to 6 microns. In some embodiments, the microreservoirs have an average diameter of approximately 3 to 5 microns.

In the coating embodiment described above, the multiple microreservoirs have active ingredient release characteristics with a half-life of at least 14 days.

In the above-described embodiment of the coating, the first biodegradable or bio-erosive polymer is selected from the group consisting of polylactic acid, polyglycolic acid and their copolymers, polydioxanone, polycaprolactone, polyphosphatidine, collagen, gelatin, chitosan, glycosoaminoglycan, and combinations thereof.

In the above-described coating embodiment, the first activator 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-described coating embodiment, the first activator is present in an amount of approximately 10% to approximately 50% by weight of the multiple microreservoirs.

In the above-described coating embodiments, the coating further includes a third activator on the outside of the multiple microreservoirs. In some embodiments, the third activator is selected from the group consisting of paclitaxel, sirolimus, paclitaxel derivatives, sirolimus derivatives, paclitaxel analogs, sirolimus analogs, inhibitory RNA, inhibitory DNA, steroids, and complement inhibitors. In some embodiments, the third activator is the same as the first activator.

In the above-described coating embodiments, the hydrophobic matrix further comprises PEG-lipids. In some embodiments, the PEG-lipids are 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), and 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine-N-methoxy(polyethylene glycol)-350 (DOPE-mPEG350). The PEG-lipid is selected from the group consisting of 0), 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-methoxy(polyethylene glycol)-550 (DSPE-mPEG550), 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine-N-methoxy(polyethylene glycol)-550 (DPPE-mPEG550), and 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine-N-methoxy(polyethylene glycol)-500 (DOPE-mPEG550). In some embodiments, the PEG-lipid is about 1% to about 30% by weight of the hydrophobic matrix. In some embodiments, the PEG-lipid is about 12% or less by weight of the hydrophobic matrix.

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

In the above-described embodiment of the coating, the coating has a surface concentration of approximately 1 μg/ ^mm² to approximately 10 μg/ ^mm² .

A catheter having an inflatable portion on a long body and comprising any embodiment relating to the coating on the inflatable portion. In some embodiments, the catheter further includes a release layer between the inflatable portion and the coating, the release layer being configured to release the coating from the inflatable portion. In some embodiments, the release layer comprises DSPE-mPEG 350 or DSPE-mPEG 500. In some embodiments, the release layer has a surface concentration of about 0.1 μg/ ^mm² to about 5 μg/ ^mm² .

In the catheter embodiments described above, the catheter further includes a protective coating on 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 crystallized sugar. In some embodiments, the protective coating has a surface concentration of about 0.1 μg/mm² to about 5 μg/mm².

A coating formulation for the inflatable portion of a catheter, comprising a solid portion and a liquid portion. The solid portion comprises a plurality of microreservoirs and at least one hydrophobic compound, the plurality of microreservoirs comprising a first activator and a first biodegradable or bioerosive polymer. In some embodiments, the first activator is mixed with or dispersed with the first biodegradable or bioerosive polymer.

In some embodiments, the microreservoirs further comprise a second activator. In some embodiments, the second activator is selected from the group consisting of paclitaxel, sirolimus, paclitaxel derivatives, sirolimus derivatives, paclitaxel analogs, sirolimus analogs, inhibitory RNA, inhibitory DNA, steroids, and complement inhibitors. In some embodiments, the microreservoirs further comprise a second biodegradable or biocorrosive polymer. In some embodiments, the second biodegradable or biocorrosive polymer is selected from the group consisting of polylactic acid, polyglycolic acid and their copolymers, polydioxanone, polycaprolactone, polyphosphatidine, collagen, gelatin, chitosan, glycosoaminoglycans, and combinations thereof.

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

In some embodiments of the coating formulation described above, the solid portion further comprises a third activator outside a plurality of microreservoirs. In some embodiments, the third activator is selected from the group consisting of paclitaxel, sirolimus, paclitaxel derivatives, sirolimus derivatives, paclitaxel analogs, sirolimus analogs, inhibitory RNA, inhibitory DNA, steroids, and complement inhibitors.

In some embodiments of the coating formulation described above, the first activator is selected from the group consisting of paclitaxel, sirolimus, paclitaxel derivatives, sirolimus derivatives, paclitaxel analogs, sirolimus analogs, inhibitory RNA, inhibitory DNA, steroids, and complement inhibitors.

In some embodiments of the coating formulations described above, 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 coating formulations described above, at least one hydrophobic compound comprises cholesterol and a fatty acid. In some embodiments, the weight ratio of cholesterol to fatty acid is in the range of about 1:2 to about 3:1. In some embodiments, the fatty acid is selected from the group consisting of lauric acid, lauroleic acid, tetradecenoic acid, octanoic acid, myristic acid, myristoleic acid, 10-hydroxy-2-decenoic acid, decanoic acid, hexadecenoic acid, palmitoleic acid, palmitic acid, linolenic acid, linoleic acid, oleic acid, vaccenic acid, stearic acid, eicosapentaenoic acid, arachidonic acid, meadic acid, arachidic acid, docosahexaenoic acid, docosapentaenoic acid, docosatetraenoic acid, docosenic acid, tetracosanoic acid, hexacosanoic acid, pristanic acid, phytanic acid, and nervonic acid.

In some embodiments of the coating formulations described above, at least one hydrophobic compound 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 phospholipids are selected from the group consisting of phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, and phosphatidylinositol.

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

In some embodiments, the phospholipid has an acyl chain length of about 20 to about 34 carbon atoms. In some embodiments, the phospholipid is dieicosenoylphosphatidylcholine (1,2-dieicosenoyl-sn-glycero-3-phosphocholine, C20:1 PC), diarachidonoylphosphatidylcholine (1,2-diarachidoyl-sn-glycero-3-phosphocholine, C20:1 PC), dielcyoylphosphatidylcholine (1,2-dielcyoyl-sn-glycero-3-phosphocholine, C22:1 PC), didocosahexaenoylphosphatidylcholine (1,2-didocosahexaenoyl-sn-glycero-3-phosphocholine, C22:6 PC), henicocenoylphosphatidylcholine (1,2-henicosenoyl-sn-glycero-3-phosphocholine, C21:1 PC) The group is selected from the following: PC, and dinerbonylphosphatidylcholine (1,2-dinerbonyl-sn-glycero-3-phosphocholine, C24:1 PC).

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

In some embodiments of the coating formulations described above, the solid portion further comprises a PEG-lipid and/or additives. In some embodiments, the PEG-lipid is 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), or 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine-N-methoxy(polyethylene glycol)-350 (DOPE-mPEG350). Selected from the group consisting of (0) 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 coating formulation described above, the number of microreservoirs is approximately 10% to 75% by weight of the solid portion.

In some embodiments of the coating formulations described above, the solid portion constitutes approximately 2% to 7% by weight of the coating formulation.

A method for coating the inflatable portion of a catheter, comprising the steps of: placing one of the coating formulations according to the above embodiment onto the surface of the inflated inflatable portion of the catheter; evaporating a fluid; and folding the inflatable portion. In some embodiments, the step of placing the coating formulation includes spray coating, dip coating, roll coating, electrostatic deposition, printing, pipetting, or dispensing.

In some embodiments of the method described above, the method further includes placing a release layer on the expandable portion. In some embodiments, the release layer includes DSPE-mPEG 350 or DSPE-mPEG 500.

A method for treating or preventing a pathological condition at a treatment site includes the steps of: advancing a catheter including an inflatable portion to the treatment site; inflating the inflatable portion to allow contact between the coating and the tissue at the treatment site; folding the inflatable portion; and removing the catheter, wherein the inflatable portion is coated with one of the coatings according to the above embodiment.

In embodiments of the method described above, contact between the tissue and the coating results in the delivery of at least a portion of the coating to the treatment site on the expandable area. In some embodiments, the method further includes maintaining contact between the coating and the tissue for about 30 to about 120 seconds.

In any embodiment of the method described above, the pathological condition is selected from the group consisting of atherosclerosis, narrowing or reduction of the lumen diameter in the diseased vessel, restenosis, in-stent restenosis, and combinations thereof.

In any embodiment of the method described above, a further release layer is placed between the expandable portion and the coating.

In some embodiments, a catheter comprises an inflatable portion on a long body and a coating on the outer surface of the inflatable portion, wherein the coating comprises a lipophilic matrix and a plurality of microreservoirs dispersed in the lipophilic matrix. The lipophilic matrix contains at least one lipid, and the plurality of microreservoirs contain an activator. Furthermore, the lipophilic matrix is configured to adhere to the lumen surface when the inflatable portion expands, and to deliver at least a portion of the plurality of microreservoirs to the lumen surface.

In some embodiments of the catheter described above, the activator is crystalline.

In some embodiments of the catheter described above, the microreservoirs further comprise a biodegradable or bioerosive polymer. In some embodiments, the biodegradable or bioerosive polymer is selected from the group consisting of polylactic acid, polyglycolic acid and copolymers thereof, polydioxanone, polycarbonate, polyphosphatidine, collagen, gelatin, chitosan, and glycosaminoglycans. In some embodiments, the activator is present in an amount of about 10% to about 50% by weight of the microreservoirs.

In some embodiments of the catheter described above, at least one lipid is a phospholipid. In some embodiments, the phospholipid has an acyl chain length of about 20 to about 34 carbon atoms. In some embodiments, the phospholipid is dieicosenoylphosphatidylcholine (1,2-dieicosenoyl-sn-glycero-3-phosphocholine, C20:1 PC), diarachidonoylphosphatidylcholine (1,2-diarachidoyl-sn-glycero-3-phosphocholine, C20:1 PC), dielcyoylphosphatidylcholine (1,2-dielcyoyl-sn-glycero-3-phosphocholine, C22:1 PC), didocosahexaenoylphosphatidylcholine (1,2-didocosahexaenoyl-sn-glycero-3-phosphocholine, C22:6 PC), henicocenoylphosphatidylcholine (1,2-henicocenoyl-sn-glycero-3-phosphocholine, C21:1 PC) The group is selected from the following: PC, and dinerbonylphosphatidylcholine (1,2-dinerbonyl-sn-glycero-3-phosphocholine, C24:1 PC).

In some embodiments, the phospholipids include cationic phospholipids. In some embodiments, the cationic phospholipids are phosphatidylethanolamine, dioleoylphosphatidylethanolamine, or amine derivatives of phosphatidylcholine. In some embodiments, the lipophilic matrix further includes sterols. In some embodiments, the sterols are selected from the group consisting of cholesterol, stigmasterol, lanosterol, sitosterol, DHEA, N4-cholesterol-spermine, guanidium-cholesterol/BGTC, and DC-cholesterol.

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

In some embodiments of the catheter, the multiple microreservoirs have an average diameter of approximately 1.5 microns to approximately 8 microns. In some embodiments, the multiple microreservoirs have an average diameter of approximately 2.0 microns to approximately 6 microns.

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

In some embodiments of the catheter, the coating further comprises polyethylene glycol-lipid (PEG-lipid). In some embodiments, the PEG-lipid is 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), or 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine-N-methoxy(polyethylene glycol)-350 (DOPE-mPEG350). 0) Selected from the group consisting of 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-methoxy(polyethylene glycol)-550 (DSPE-mPEG550), 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine-N-methoxy(polyethylene glycol)-550 (DPPE-mPEG550), and 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine-N-methoxy(polyethylene glycol)-500 (DOPE-mPEG550). In some embodiments, the PEG-lipid is about 1% to about 10% by weight of the hydrophobic matrix.

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

In some embodiments of the catheter, the coating has a surface concentration of about 1 μg/ ^mm² to about 10 μg/ ^mm² .

In some embodiments, a catheter comprises an inflatable portion on a long body, a coating on the outer surface of the inflatable portion, and a release layer between the inflatable portion and the coating, wherein the coating comprises a lipophilic matrix containing at least one lipid and a plurality of microreservoirs dispersed in the lipophilic matrix. The plurality of microreservoirs contain an activator, and the lipophilic matrix is configured to adhere to the lumen surface when the inflatable portion expands, delivering at least a portion of the plurality of microreservoirs to the lumen surface. The release layer is configured to peel the coating away from the inflatable portion.

In some embodiments, the release layer comprises DSPE-mPEG 350 or DSPE-mPEG 500. In some embodiments, the release layer has a surface concentration of about 0.1 μg/ ^mm² to about 5 μg/ ^mm² .

In some embodiments, the catheter further comprises a protective coating on the first coating. In some embodiments, the protective coating comprises a hydrophilic polymer, a carbohydrate, or an amphiphilic polymer. In some embodiments, the protective coating is a glycosaminoglycan or a crystallized sugar. In some embodiments, the protective coating has a surface concentration of about 0.1 μg/ ^mm² to about 5 μg/ ^mm² .

In some embodiments, a method for coating an inflatable portion of a catheter comprises the steps of: placing one of the coating formulations on the surface of the inflated inflatable portion of the catheter; evaporating a fluid; and folding the inflatable portion. The coating formulation comprises a plurality of microreservoirs containing an activator, at least one lipid, and the fluid. The fluid is selected from the group consisting of pentane, hexane, heptane, a mixture of heptane and a fluorocarbon, a mixture of alcohol and a fluorocarbon, and a mixture of alcohol and water. In some embodiments, the coating formulation has a solid component comprising the plurality of microreservoirs and at least one lipid, with the plurality of microreservoirs accounting for about 10% to about 75% by weight of the solid component.

In some embodiments of this method, the microreservoirs further comprise biodegradable or bioerosive polymers. In some embodiments, the activator is selected from the group consisting of paclitaxel, sirolimus, paclitaxel derivatives, sirolimus derivatives, paclitaxel analogs, sirolimus analogs, inhibitory RNA, inhibitory DNA, steroids, and complement inhibitors.

In some embodiments of the methods described above, the activator is crystalline.

In some embodiments of the methods described above, at least one lipid is a phospholipid. In some embodiments, the phospholipid is selected from the group consisting of phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, and phosphatidylinositol.

In some embodiments, the phospholipids include phospholipids having an acyl chain length of about 20 to about 34 carbon atoms. In some embodiments, the phospholipids include dieicosenoylphosphatidylcholine (1,2-dieicosenoyl-sn-glycero-3-phosphocholine, C20:1 PC), diarachidonoylphosphatidylcholine (1,2-diarachidoyl-sn-glycero-3-phosphocholine, C20:1 PC), dielcoiphosphatidylcholine (1,2-dielcoiphosenoyl-sn-glycero-3-phosphocholine, C22:1 PC), didocosahexaenoylphosphatidylcholine (1,2-didocosahexaenoyl-sn-glycero-3-phosphocholine, C22:6 PC), and henicocenoylphosphatidylcholine (1,2-henicosenoyl-sn-glycero-3-phosphocholine, C21:1 PC). The group is selected from the following: PC, and dinerbonylphosphatidylcholine (1,2-dinerbonyl-sn-glycero-3-phosphocholine, C24:1 PC).

In some embodiments of the methods described above, the phospholipid includes a cationic phospholipid. In some embodiments, the cationic phospholipid is phosphatidylethanolamine, dioleoylphosphatidylethanolamine, or an amine derivative of phosphatidylcholine.

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

In some embodiments of the methods described above, the coating formulation has a solid content of about 2% to about 7% by weight, and the solid content comprises a plurality of microreservoirs and at least one lipid.

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

In some embodiments of the methods described above, the step of applying the coating formulation includes spray coating, dip coating, roll coating, electrostatic deposition, printing, pipetting, or dispensing.

In some embodiments of the above-described method, the step of placing a release layer on the surface of the expanded, expandable portion is further included before placing the coating formulation.

In some embodiments, a method for treating or preventing a pathological condition at a treatment site is described, comprising the steps of: advancing a catheter according to claim 1 to a treatment site; inflating an inflatable portion to allow contact between the coating and the tissue at the treatment site; folding the inflatable portion; and removing the catheter.

In some embodiments of the methods described above, contact between the tissue and the coating results in the delivery of at least a portion of the coating to the treatment site on the expandable area.

In some embodiments of the methods described above, the step of maintaining contact between the expandable portion and the coating for about 30 seconds to about 120 seconds is further included.

In some embodiments of the method described above, the pathological condition is selected from the group consisting of atherosclerosis, narrowing or reduction of the lumen diameter in the diseased vessel, restenosis, and in-stent restenosis.

Claims (25)

A coating for the inflatable portion of a catheter,
The aforementioned coating is
A lipophilic matrix containing at least one lipid and sterol ,
The system comprises a plurality of microreservoirs containing only crystalline activators dispersed in the aforementioned lipophilic matrix,
The lipophilic matrix adheres to the lumen surface when the expandable portion expands, and delivers at least a portion of the plurality of microreservoirs to the lumen surface.
A coating in which each of the plurality of microreservoirs has a uniform size, with a maximum particle size of 10 microns, and less than 5% of the plurality of microreservoirs have a diameter of 1 micron or less. The coating according to claim 1, wherein the at least one lipid comprises a phospholipid. The coating according to claim 2, wherein the phospholipid comprises an acyl chain length of 20 to 34 carbon atoms. The coating according to claim 2, wherein the phospholipid is selected from the group consisting of phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, dioleoylphosphatidylethanolamine, and amine derivatives of phosphatidylcholine. The phospholipids are diecosenoylphosphatidylcholine (1,2-diecosenoyl-sn-glycero-3-phosphocholine, C20:1 PC), diarachidonoylphosphatidylcholine (1,2-diarachidoyl-sn-glycero-3-phosphocholine, C20:1 PC), diecoylphosphatidylcholine (1,2-diecoyl-sn-glycero-3-phosphocholine, C22:1 PC), didocosahexaenoylphosphatidylcholine (1,2-didocosahexaenoyl-sn-glycero-3-phosphocholine, C22:6 PC), henicocenoylphosphatidylcholine (1,2-henicocenoyl-sn-glycero-3-phosphocholine, C21:1 PC) The coating according to claim 2, selected from the group consisting of PC and dinerbonylphosphatidylcholine (1,2-dinerbonyl-sn-glycero-3-phosphocholine, C24:1 PC). The coating according to claim 2, wherein the phospholipid includes a cationic phospholipid. The coating according to claim 6, wherein the cationic phospholipid is phosphatidylethanolamine, dioleoylphosphatidylethanolamine, or an amine derivative of phosphatidylcholine. The coating according to claim 1 , wherein the sterol is selected from the group consisting of cholesterol, stigmasterol, lanosterol, sitosterol, DHEA, N4-cholesterol-spermine, guanidium-cholesterol/BGTC, and DC-cholesterol. The coating according to any one of claims 1 to 8 , wherein the coating has a melting point between room temperature and body temperature. The coating according to any one of claims 1 to 8 , wherein the coating comprises 10% to 75% by weight of the plurality of microreservoirs . The coating according to any one of claims 1 to 8 , wherein the plurality of microreservoirs have an average diameter of 1.5 microns to 8 microns. The coating according to any one of claims 1 to 8 , wherein the plurality of microreservoirs have an average diameter of 2.0 microns to 6 microns. The coating according to any one of claims 1 to 8, wherein the plurality of microreservoirs are selected from the group consisting of paclitaxel, sirolimus, paclitaxel derivatives, sirolimus derivatives, paclitaxel analogs, sirolimus analogs, inhibitory RNA, inhibitory DNA, steroids , and complement inhibitors. The coating according to any one of claims 1 to 8 , further comprising polyethylene glycol-lipid (PEG-lipid). The aforementioned PEG-lipids are 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), and 1,2-distearoyl The coating according to claim 14, selected from the group consisting of -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). The coating according to claim 14 , wherein the PEG-lipid is 1% to 10% by weight of the lipophilic matrix. The coating according to any one of claims 1 to 8 , further comprising one or more additives independently selected from penetration enhancers and stabilizers. The coating according to any one of claims 1 to ⁸ , wherein the coating has a surface concentration of 1 μg/ ^mm² to 10 μg/mm². The coating according to any one of claims 1 to 8 , further comprising a release layer between the expandable portion and the coating, wherein the release layer is configured to peel the coating from the expandable portion. The coating according to claim 19 , wherein the release layer comprises DSPE-mPEG 350 or DSPE-mPEG 500. The coating according to claim 19 , wherein the surface concentration of the release layer is 0.1 μg/ ^mm² to 5 μg/ ^mm² . The coating according to claim 19 , further comprising a protective coating on the first coating. The coating according to claim 22 , wherein the protective coating comprises a hydrophilic polymer, a carbohydrate, or an amphiphilic polymer. The coating according to claim 22 , wherein the protective coating is a glycosaminoglycan or a crystallized sugar. The protective coating according to claim 22 , wherein the protective coating has a surface concentration of 0.1 μg/ ^mm² to 5 μg/ ^mm² .