DRUG COATED MEDICAL DEVICES

In embodiments, medical devices, such balloon catheters or stents, can deliver a therapeutic agent to body tissue of a patient. The medical device a therapeutic coating comprising a polydopamine coated therapeutic agent disposed on a surface of the expandable medical device. In some instances, the therapeutic agent may comprise everolimus.

FIELD

The present disclosure pertains to medical devices, and methods for manufacturing medical devices. More particularly, the present disclosure pertains to medical devices for therapeutic agent delivery.

BACKGROUND

BRIEF SUMMARY

This disclosure provides design, material, manufacturing method, and use alternatives for medical devices. An example expandable medical device comprises:

a therapeutic coating comprising a polydopamine coated therapeutic agent disposed on a surface of the expandable medical device.

Alternatively or additionally to any of the embodiments above, the therapeutic agent is selected from the group consisting of paclitaxel, everolimus, rapamycin, sirolimus, tacrolimus, heparin, diclofenac, aspirin, and any combination thereof.

Alternatively or additionally to any of the embodiments above, the therapeutic agent has an average particle size in the range of 0.1-20 micrometers.

Alternatively or additionally to any of the embodiments above, the polydopamine has a thickness in the range of 1-40 nanometers.

Alternatively or additionally to any of the embodiments above, the expandable medical device is a balloon catheter

Alternatively or additionally to any of the embodiments above, the balloon catheter comprises:

a catheter shaft comprising an inner tubular member and an outer tubular member, the catheter shaft extending from a proximal end to a distal end; and

an inflatable balloon having a proximal end affixed to the outer tubular member of the catheter shaft and a distal end affixed to the inner tubular member of the catheter shaft proximal to the distal end of the catheter shaft, the inflatable balloon disposed adjacent to the distal end of the catheter shaft.

Alternatively or additionally to any of the embodiments above, the therapeutic coating is disposed over an entire outer surface area of the inflatable balloon.

Alternatively or additionally to any of the embodiments above, the therapeutic coating is disposed over less than an entire outer surface area of the inflatable balloon. Alternatively or additionally to any of the embodiments above, the expandable medical device is a stent.

Alternatively or additionally to any of the embodiments above, the stent comprises:

an elongated tubular member having a first end, a second end and an intermediate region disposed therebetween, the elongated tubular member comprising at least one filament.

Alternatively or additionally to any of the embodiments above, the therapeutic coating is disposed on an outer surface of the stent.

Alternatively or additionally to any of the embodiments above, the therapeutic coating is disposed on an inner surface of the stent.

Alternatively or additionally to any of the embodiments above, the therapeutic coating is disposed over an entire surface area of the stent.

Alternatively or additionally to any of the embodiments above, the therapeutic coating is disposed over less than an entire surface area of the stent

Alternatively or additionally to any of the embodiments above, the therapeutic coating binds with primary amines.

An example expandable medical device comprises:

a therapeutic coating comprising a polydopamine coated therapeutic agent disposed on a surface of the expandable medical device.

Alternatively or additionally to any of the embodiments above, the therapeutic agent is selected from the group consisting of paclitaxel, everolimus, rapamycin, sirolimus, tacrolimus, heparin, diclofenac, aspirin, and any combination thereof.

Alternatively or additionally to any of the embodiments above, the therapeutic agent has an average particle size in the range of 0.1-20 micrometers.

Alternatively or additionally to any of the embodiments above, the polydopamine has a thickness in the range of 1-40 nanometers.

Alternatively or additionally to any of the embodiments above, the therapeutic coating is disposed over an entire outer surface area of the expandable medical device.

Alternatively or additionally to any of the embodiments above, the therapeutic coating is disposed over less than an entire outer surface area of the expandable medical device.

Alternatively or additionally to any of the embodiments above, the expandable medical device is a balloon catheter

Alternatively or additionally to any of the embodiments above, the expandable medical device is a stent.

An example balloon catheter comprises:

a catheter shaft comprising an inner tubular member and an outer tubular member, the catheter shaft extending from a proximal end to a distal end;

an inflatable balloon having a proximal end affixed to the outer tubular member of the catheter shaft and a distal end affixed to the inner tubular member of the catheter shaft proximal to the distal end of the catheter shaft, the inflatable balloon disposed adjacent to the distal end of the catheter shaft; and

a therapeutic coating comprising a polydopamine coated therapeutic agent disposed on an outer surface of the inflatable balloon.

Alternatively or additionally to any of the embodiments above, the therapeutic agent is everolimus.

Alternatively or additionally to any of the embodiments above, the therapeutic agent has an average particle size in the range of 0.1-20 micrometers.

Alternatively or additionally to any of the embodiments above, the polydopamine has a thickness in the range of 1-40 nanometers.

Alternatively or additionally to any of the embodiments above, the therapeutic coating is disposed over an entire outer surface area of the inflatable balloon.

Alternatively or additionally to any of the embodiments above, the therapeutic coating is disposed over less than an entire outer surface area of the inflatable balloon.

An example stent comprises:

an elongated tubular member having a first end, a second end and an intermediate region disposed therebetween, the elongated tubular member comprising at least one filament; and

a therapeutic coating comprising a polydopamine coated therapeutic agent disposed on a surface of the elongated tubular member.

Alternatively or additionally to any of the embodiments above, the therapeutic agent is everolimus.

Alternatively or additionally to any of the embodiments above, the therapeutic agent has an average particle size in the range of 0.1-20 micrometers.

Alternatively or additionally to any of the embodiments above, the polydopamine has a thickness in the range of 1-40 nanometers.

Alternatively or additionally to any of the embodiments above, the therapeutic coating is disposed over an entire outer surface area of the stent.

Alternatively or additionally to any of the embodiments above, the therapeutic coating is disposed over less than an entire outer surface area of the stent.

DETAILED DESCRIPTION

The body includes various passageways such as blood vessels and body lumens. These passageways sometimes become occluded (for example, by a tumor or plaque). To widen an occluded body vessel, balloon catheters can be used, for example, in angioplasty.

In some embodiments, a balloon catheter can include an inflatable and deflatable balloon carried by a long and narrow catheter body. The balloon can be initially folded around the catheter body to reduce the radial profile of the balloon catheter for easy insertion into the body. During use, the folded balloon can be delivered to a target location in the vessel, for example, a portion occluded by plaque, by threading the balloon catheter over a guide wire previously located in the vessel. The balloon is then inflated, for example, by introducing a fluid (such as a gas or a liquid) into the interior of the balloon. Inflating the balloon can radially expand the vessel so that the vessel can permit an increased rate of blood flow. After use, the balloon is typically deflated and withdrawn from the body. In some instances, it may be desirable to coat, layer, or otherwise apply a drug or therapeutic agent to an outer surface of the balloon to deliver and/or administer the drug or therapeutic agent to a lumen wall when the balloon is expanded. However, it may be difficult to deposit certain therapeutic agents on the surface of certain balloons. While the therapeutic coating described herein is discussed relative to balloons and balloon catheters, it is contemplated that the therapeutic coating can be applied to and/or used in conjunction with other medical devices, such as, but not limited to, stents, embolic filters, implantable devices, treatment devices, etc.

FIG. 1Ais a cross-sectional side view of a distal end region of an example medical device10that, in this example, takes the form of a catheter, disposed in a body lumen40. In at least some embodiments, the catheter10may be a balloon catheter. The catheter10may include an elongate catheter shaft12having a proximal end (not shown) and a distal end region14. The catheter shaft12may extend proximally from the distal end region14to the proximal end which is configured to remain outside of a patient's body. Although not shown, the proximal end of the catheter shaft12may include a hub attached thereto for connecting other treatment devices or providing a port for facilitating other treatments. It is contemplated that the stiffness and size of the catheter shaft12may be modified to form a catheter10for use in various locations within the body. The catheter10may be configured to be advanced through a guide sheath, delivery sheath, or other guide means.

The catheter10may further include an inflatable balloon16affixed adjacent to the distal end region14of the catheter shaft12. The size of the balloon16may vary based on where in the body it is used (e.g., along the coronary and/or peripheral vasculature, in a pulmonary vessel, along an airway, along another body lumen, or the like). The balloon16may have an outer diameter (in the inflated state) in the range of 1 millimeter (mm) to 26 mm, or about 2 to 10 mm, or about 2.5 to 8 mm. The balloon16may have a length in the range of 5 mm to 300 mm, or about 5 to 100 mm, or about 10-50 mm. The balloon16may have a wall thickness in the range of 10 micrometers (μm) to 100 μm, or about 10 to 75 μm, or about 10 to 50 μm. The catheter shaft12may include an outer tubular member18and an inner tubular member20. A proximal waist22of the balloon16may be secured to a distal end region26of the outer tubular member18. A distal waist24of the balloon16may be secured to a distal end region28of the inner tubular member20. The inner tubular member20may extend distally beyond the distal waist24of the balloon16, although this is not required. In some instances, an annular inflation lumen30may be disposed between the outer tubular member18and the inner tubular member20. The inflation lumen30may allow inflation fluid to pass from an inflation fluid source configured to remain outside the body to the interior region32of the balloon16. The inner tubular member20may further define a lumen34through which a guidewire (not explicitly shown) may be passed in order to advance the catheter10to a predetermined position, although this is not required.

In some embodiments, an outer surface38of the balloon16may be coated with or otherwise include an elutable drug or coating36. The coating36can be substantially (e.g., about 60% or more, about 95% or more, about 98% or more, about 99% or more, about 100%) formed of one or more therapeutic agents. The coating can be substantially (e.g., about 60% or more, about 95% or more, about 98% or more, about 99% or more, about 100%) free of a polymer or low molecular weight organic matrix (e.g., a polymeric or low molecular weight matrix in which the therapeutic agent may be incorporated), although this is not required. As used herein, “about” or “approximately” can refer to a margin of error of ±2% of a given numerical value or ratio. A coating without a polymer or low molecular weight matrix can decrease the likelihood of adverse bodily reactions to the polymer or low molecular weight matrix and/or or its degradation products. With the presence of a polymer or low molecular weight organic matrix, the drug coating can release a greater amount of drug in a shorter amount of time.

The terms “therapeutic agents,” “drugs,” “bioactive agents,” “pharmaceuticals,” “pharmaceutically active agents”, and other related terms may be used interchangeably herein and include genetic therapeutic agents, non-genetic therapeutic agents, and cells. Therapeutic agents may be used singly or in combination. A wide range of therapeutic agent loadings can be used in conjunction with the devices of the present invention, with the pharmaceutically effective amount being readily determined by those of ordinary skill in the art and ultimately depending, for example, upon the condition to be treated, the nature of the therapeutic agent itself, the tissue into which the dosage form is introduced, and so forth.

Numerous additional therapeutic agents useful for the practice of the present invention may be selected from those described in paragraphs [0040] to [0046] of commonly assigned U.S. Patent Application Pub. No. 2003/0236514, the entire disclosure of which is hereby incorporated by reference.

In some instances, drug coated balloons (DCB) have involved coating everolimus on the balloon from an organic solvent. The resulting amorphous coating was vapor annealed in ethanol vapor to convert the amorphous everolimus to the less soluble crystalline form.

A preclinical animal study showed significant tissue levels of everolimus at 28 days for DCB using the vapor annealing process (greater drug levels than observed with other eluting balloons). However, the vapor annealing process may have some drawbacks. For example, the vapor annealing process may damage some balloons. It may be desirable to deposit crystalline everolimus directly on the balloon, thereby eliminating the vapor annealing step. In some instances, microcrystalline everolimus particles may be dispersed in water. However, it may not be possible to coat this dispersion using the traditional commercial syringe coating processes. For example, the everolimus particles in the dispersion may flocculate (aggregate), resulting in settling of the dispersion in the lines of the coater and plugging of the lines. A number of surfactants were evaluated in an attempt to stabilize the dispersion, however none were effective at stabilizing the everolimus drug particles.

Relatively recent research on understanding the underlying mechanism of the excellent wet adhesion observed with Mussels on various substrates has shown that the adhesive protein secreted by Mussels is high in the catechol DOPA (3,4-dihydroxyphenyl-L-alanine) (Mussel-Inspired Adhesives and Coatings.Annual Review of Materials Research.2011. 41:90-132). The catechol group is able to strongly interact with the substrate through very strong non-covalent and covalent bonding under wet conditions. Subsequent work focused on the preparation of synthetic biomimetic mussel like adhesives has involved the synthesis of polymers containing the catechols DOPA (or dopamine).FIG. 2shows the structure of dopamine. It has been observed that aqueous solutions of dopamine at a basic pH (in the range of 8-9 or approximately 8.5) will oxidize and spontaneous polymerize at room temperature (Mussel-Inspired Surface Chemistry for Multifunctional Coatings.SCIENCE2007. 318:426-430). Polydopamine may deposit on any solid surface present in the solution during polymerization. The resulting coating thickness may be self-limiting at about 40 nanometers (nm) and the coating is tightly adhered to the substrate. This may be due to strong non-covalent and covalent bonding through the catechol groups. The resulting polydopamine coating can be functionalized with molecules containing primary amine groups. For example, polydopamine coatings may covalently bind with proteins containing primary amines under physiological conditions. While the structure of polydopamine is not precisely known, it is believed to be the same as, or similar to, eumelanin—the pigment contained in human skin.FIG. 3illustrates the spontaneous polymerization of dopamine to polydopamine. Research has shown polydopamine to be biocompatible (Polydopamine Coating Enhance Biointegration of a Model Polymeric Implant. Soft Matter 2011. 7:8305-8312).

It is contemplated that a microcrystalline drug particle, such as, but not limited to, everolimus, can be coated with polydopamine. The polydopamine coating may impart several properties to the everolimus particles. For example, the polydopamine coating may improve the bonding of the drug particle to a target tissue site. In addition, polydopamine coating may impart several unexpected properties to the everolimus particles. For example, the polydopamine coating may desirably reduce or eliminate foaming of the aqueous drug dispersion. The polydopamine coating may also desirably reduce or eliminate agglomeration of the everolimus microparticles in a dispersion. The observed ability of polydopamine to reduce foaming and agglomeration of the everolimus particles was unexpected. These properties may make it possible to coat the dispersion onto a balloon, such as balloon16shown inFIG. 1A, or other medical device, without settling of the particles and/or clogging of the tubing used in the coating process. It is further contemplated that the polydopamine coating may also cause a reduction in large particulates after balloon inflation and impart the ability of the particles to covalently bind to the artery thereby increasing drug transfer efficiency.

In some instances, the elutable drug coating36may include polydopamine coated everolimus microparticles. However, it is contemplated that the drug coating36may comprise other polydopamine coated drugs, such as, but not limited to those disclosed herein. It is contemplated that the polydopamine may surround or encapsulate the everolimus microparticles. The everolimus microparticles may have an average particle size in the range of 0.1-20 micrometers (μm), 1-20 μm, or 5-15 μm. The polydopamine coating may have a thickness in the range of 1-40 nanometers (nm), 10-30 nm, or 10-20 nm. It is contemplated that the thickness of the polydopamine coating may be determined and controlled by the incubation time and/or the concentration of dopamine solution (for example, the amount of time dopamine is allowed to polymerize onto a substrate). The elutable drug36may be coated onto the balloon16in any thickness desired to achieve the desired drug concentration. For example, the elutable drug coating36may have a thickness in the range of 1-20 μm, 5-15 μm, or 7-13 μm. These are just examples.

In some embodiments, the elutable drug coating36may cover the entire surface area38of the balloon16. In other embodiments, the elutable drug coating36may cover a portion of the surface area of the balloon16. For example, the elutable drug coating36may cover 90% or less (e.g., about 80% or less, about 70% or less, about 60% or less, about 50% or less, about 40% or less, about 30% or less, about 20% or less, or about 10% or less) and/or about 10% or more (e.g., about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, 80% or more, or 90% or more) of the balloon's outer surface38.

In some embodiments, the drug elutable coating36may optionally include a polymer or low molecular weight organic compound. The polymer or compound can be biodegradable. The polymer or organic compound can, for example, provide structural support for a therapeutic agent coating36that may be fragile, and/or can slow or speed up the release of a therapeutic agent within the coating. The coating36can include about 90% or less (e.g., about 75% or less, about 50% or less, about 25% or less, about 10% or less, about 5% or less or 1% or less) and/or about 5% or more (e.g., about 10% or more, about 25% or more, about 50% or more, or about 75% or more) by weight of a polymer or organic compound. The polymer or organic compound can form a homogeneous mixture with one or more therapeutic agents within the coating, or can be a separate layer over or under the one or more therapeutic agents. In some embodiments, the polymer or organic compound can form a porous network that intertwines with a layer of one or more therapeutic agents.

In some embodiments, the catheter10may be advanced through a lumen40having a lumen wall42, with or without a guidewire, or other guide means. When the balloon16is positioned adjacent to the desired treatment region, the balloon16may be expanded to bring the elutable drug coating36into contact with the lumen wall42. The drug coating36may elute a therapeutic agent, such as, but not limited to, polydopamine coated everolimus microparticles to the body lumen wall42. The balloon16may remain inflated for a desired amount of time sufficient to transfer the coating36from the balloon16to the wall42.

Polydopamine coatings can bind proteins that contain primary amine functional amino acids (Improving the Blood Compatibility of Material Surfaces Via Biomolecule-Immobilized Mussel-Inspired Coatings. Journal of Biomedical Materials Research A. 2011. Vol. 96. Issue 1: 38-45). Everolimus-polydopamine particles from a deployed drug coated balloon may also bind with proteins on the surface of the artery such as, for example, collagen (in the case of in-stent restenosis). This may result in anchoring of the particle to the vessel wall to reduce particle wash-out and hence increase transfer efficiency. This is shown schematically inFIG. 11. The everolimus microparticle400may have a thin polydopamine coating402. The polydopamine coating402may bind with the proteins404in the vessel wall406.

FIG. 1Billustrates a side view of an illustrative endoluminal implant50, such as, but not limited to, a stent. In some instances, the stent50may be formed from an elongated tubular member52. While the stent50is described as generally tubular, it is contemplated that the stent50may take any cross-sectional shape desired. The stent50may have a first, or proximal, end54and a second, or distal, end56. The stent50may include a lumen60extending from a first opening adjacent the first end54to a second opening adjacent to the second end56to allow for the passage of food, fluids, etc. In some embodiments, an outer surface62of the stent50may be coated with or otherwise include an elutable drug or coating66. The coating66may be similar in form and function to the elutable drug coating36described herein. Alternatively, or additionally, the coating66may be coated onto an inner surface of the stent50.

In some embodiments, the elutable drug coating66may cover the entire surface area of the stent50. In other embodiments, the elutable drug coating66may cover a portion of the surface area of the stent50. For example, the elutable drug coating66may cover 90% or less (e.g., about 80% or less, about 70% or less, about 60% or less, about 50% or less, about 40% or less, about 30% or less, about 20% or less, or about 10% or less) and/or about 10% or more (e.g., about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, 80% or more, or 90% or more) of the stent50.

The stent50may be expandable from a first collapsed configuration (not explicitly shown) to a second expanded configuration. The stent50may be structured to extend across a stricture and to apply a radially outward pressure to the stricture in a lumen to open the lumen and allow for the passage of foods, fluids, air, etc.

The stent50may have a woven structure, fabricated from a number of filaments or struts64. In some embodiments, the stent50may be braided with one filament. In other embodiments, the stent50may be braided with several filaments, as is found, for example, in the WallFlex®, WALLSTENT®, and Polyflex® stents, made and distributed by Boston Scientific, Corporation. In another embodiment, the stent50may be knitted, such as the Ultraflex™ stents made by Boston Scientific, Corporation. In yet another embodiment, the stent50may be of a knotted type, such the Precision Colonic™ stents made by Boston Scientific, Corporation. In still another embodiment, the stent50may be a laser cut tubular member, such as the EPIC™ stents made by Boston Scientific, Corporation. A laser cut tubular member may have an open and/or closed cell geometry including one or more interconnected filaments. In some instances, an inner and/or outer surface of the stent50may be entirely, substantially or partially, covered with a polymeric covering or coating. For example, a covering or coating which may help reduce food impaction and/or tumor or tissue ingrowth.

The disclosure may be further clarified by reference to the following Examples, which serve to exemplify some of the embodiments, and not to limit the disclosure.

To prepare a microcrystalline everolimus dispersion, amorphous everolimus was dissolved in isopropyl alcohol at 40 weight percent with gentle warming at 40 degrees Celsius (° C.). The solution was allowed to sit at room temperature overnight resulting in crystallization of the everolimus. The large crystals were dried under vacuum at room temperature. 0.1 grams (g) of crystalline everolimus, 0.16 g of water and 1.85 g of 100 micrometer (μm) zirconia (Zr) beads were added to a stainless steel ampule. The ampule was sealed and placed on a high speed amalgamator shaker for 20 min. Water (2 milliliters (mL)) was added to the resulting paste and the mixture was swirled to disperse the milled everolimus particles.

The water/everolimus dispersion was decanted off from the Zr beads and filtered through a 30 μm nylon mesh filter. The Zr bead slurry was then washed an additional three times using about 2 mL water each time and each time the water/everolimus dispersion was filtered through 30 μm nylon mesh filter. The combined (from each wash) filtered dispersion was then centrifuged at 4,000 rpm for 10 minutes. The supernatant was decanted off until there was about 1-2 mL of liquid remaining in the centrifuge tube along with the everolimus particles resulting in a microcrystalline everolimus dispersion in water.

To prepare the polydopamine coated everolimus particles, the microcrystalline everolimus dispersion in water from above was washed/centrifuged two to three times with a solution of dopamine dissolved in tris(hydroxymethyl) aminomethane (THAM) buffer at pH 8.5 with a concentration of 2 milligrams (mg) of dopamine per milliliter of buffer. After the final wash, about 10 mL of the dopamine solution was left in the centrifuge tube and the tube placed on a shaker at 150 rpm for 1 hour at room temperature. Additional 10 mL samples of the dopamine solution were left in the centrifuge tube and the tube placed on a shaker at 150 rpm for 2, 4, and 24 hours at room temperature. The incubation times allow the dopamine to polymerize on the everolimus particles, forming a polydopamine coated everolimus particle. The resulting dispersions were washed two to four times with deionized water and centrifuged to remove the excess dopamine solution. The resulting dispersion was 2-5% (weight) solids. The dispersion is bronze in color due to the polydopamine coating.FIG. 4is a photograph100of the dispersions of varying polymerization (incubation) times of polydopamine coated everolimus. A control everolimus dispersion102is shown on the far left. As can be seen, the dispersion is substantially colorless. An everolimus/polydopamine dispersion that was placed on the shaker for one hour is shown at104. An everolimus/polydopamine dispersion that was placed on the shaker for four hours is shown at106. An everolimus/polydopamine dispersion that was placed on the shaker for 24 hours is shown at108. The polydopamine coating thickness increases with incubation time which can be observed with the increase in color of the dispersion with time, as shown inFIG. 4.

The amount of polydopamine in the dispersion (everolimus/polydopamine ratio) was determined by high performance liquid chromatography (HPLC). The dispersion was dried to remove the water (forming everolimus/polydopamine particles). The particles were dissolved in tetrahydofuran (THF) and injected into the HPLC. The results are shown inFIG. 5, which is a graph120of the percent of everolimus weight/weight (% wt/wt) in the everolimus/polydopamine particles as a function of incubation times. As can be seen the graph120, for everolimus incubated in a dopamine solution for less than 4 hours the dopamine content was approximately less than 1% (wt/wt). At a 24 hour incubation the polydopamine content was about 7%.

FIG. 6Ais an optical micrograph130of an everolimus dispersion. As can be seen, the everolimus control particles135, which appear darker than the background, are agglomerated into large clusters.FIG. 6Bis an optical micrograph140of an everolimus/polydopamine dispersion that was prepared according to the procedure above and allowed to incubate for one hour. As can be seen, the everolimus/polydopamine particles145, which appear darker than the background, shows no agglomeration of the particles145. Thus, polydopamine is effective at stabilizing the everolimus microparticles from agglomeration. Attempts to coat medical device balloons, such as the balloon16described above, using a commercial syringe coater was not possible with the everolimus control dispersion. Agglomeration of the dispersion in the line resulted in settling/separation of the drug particles and clogging of the line at tube connector junctions. However, coating of balloons using the commercial syringe coater was possible using the everolimus-polydopamine dispersion due to stabilization of the dispersion by the polydopamine coating.

FIG. 7Ais a scanning electron microscope (SEM) image150of the dried everolimus particles.FIG. 7Bis an SEM image160of a dried everolimus/polydopamine dispersion that was prepared according to the procedure above and allowed to incubate for one hour. As can be seen, the SEM image150of the dried everolimus particles and the SEM image160of the dried everolimus/polydopamine particles look about the same. Based on the polydopamine content of the everolimus/polydopamine particles at an incubation time of one hour (approximately 0.5-1%, as shown inFIG. 5), the thickness of the polydopamine coating is estimated to be approximately 16 nanometers (nm), assuming an average particle size of approximately 5 μm.

Polydopamine coatings have been shown to be permeable to organic solvents and water (Deposition Mechanism and Properties of Thin Polydopamine Films for High Added Value Applications in Surface Science at the Nanoscale. BioNanoSci. 2012. 2:16-34). The impact of the polydopamine coating on the rate of dissolution of the drug in water was determined. An amorphous everolimus dispersion was treated with 2 mg/mL dopamine in THAM buffer at room temperature for 1 hour. Super saturated dispersions of dopamine treated and non-dopamine treated particles were each incubated in water at 37° C. for 30 minutes, 1 hour, 2 hours, 3 hours, and 4 hours. After the incubation periods, the dispersions were centrifuged. 1 mL of the supernatant was removed and filtered through a 0.2 μm filter and the everolimus content was determined by HPLC.FIG. 8shows a plot170of the dissolution profiles for both uncoated everolimus particles180and the polydopamine coated everolimus particles190. For example,FIG. 8shows the concentration of everolimus in micrograms per milliliter (μg/mL) as a function of incubation time. Both the uncoated180and polydopamine coated everolimus particles190display similar drug dissolution profiles, as shown inFIG. 8. Thus, the nanometer thin polydopamine coating does not inhibit the dissolution of the drug particle.

To quantify the impact of polydopamine coating on the adhesion of particles to tissue, polymethylmethacrylate (PMMA) beads (10-20 um) containing a fluorescent dye were used as a model for drug microparticles. PMMA beads were prepared by oil/water emulsion. The beads were then treated with 2 mg/mL dopamine in tris buffer (pH 8.5) for 1 hour at room temperature. Control beads were also prepared that did not have the polydopamine coating. An approximately 0.25 by 0.25 inch (0.634 centimeter by 0.64 centimeter) square sample of pig aorta was rinsed with deionized water and 1-2 drops of the bead dispersion in water was placed on the artery for 60 sec. The artery was imaged under a microscope with UV black light illumination.FIG. 12Ais a microscope image500of the control beads505after being placed on the pig artery.FIG. 12Cis a microscope image520of the polydopamine coated beads525after being placed on the pig artery. During this time the beads settled to the surface of the artery. The artery was then rinsed in a beaker of deionized water stirred with a magnetic stir bar at 300 rpm for 30 sec. The artery was then imaged again.FIG. 12Bis a microscope image510of the control beads515on the pig after the deionized water rinse.FIG. 12Dis a microscope image530of the polydopamine coated beads535on the pig after the deionized water rinse. Image analysis was used to count the beads before and after rinsing to determine the percentage of beads retained on the artery. The results are summarized in Table 1 below:

TABLE 1Percentage of beads remaining after rinsingCoating% Beads retained after rinsingPMMA control0.5%PMMA coated with polydopamine72%
As can be seen, in the absence of the polydopamine coating essentially all the microspheres washed off the artery. In contrast, microspheres coated with polydopamine showed an approximately 70% retention of the beads to the artery post rinsing. Thus, the polydopamine coating is able to impart a strong adhesive interaction of the microsphere to the artery within seconds.

Crystalline everolimus microparticles were coated with polydopamine as described in Example 1. A control sample of 2% solids everolimus dispersion in deonized water and a sample of polydopamine coated crystalline everolimus were coated on individual glass slides using a microsyringe to a drug density of about 3 ug/mm2and dried for 10 min at 45° C. A flat section of pig aorta was placed on the coated slide and a 45 gram weight was placed on artery for 1 minute to approximate the deployment of a drug coated balloon within an artery. The aorta was then rinsed in a beaker of deionized water stirred with a magnetic stir bar at 300 rpm for 30 sec. The drug content of the artery and glass slide were determined by HPLC The results are summarized in Table 2 below:

TABLE 2Percentage of drug transfer and retention% Drug transferred% Drug retainedfrom glass slide to arteryon arteryFormulation(pre-rinse)(post-rinse)Everolimus control70%22%Everolimus/polydopamine76%41%
Comparing the uncoated drug control (everolimus) and polydopamine coated drug particles, about the same amount of drug is initially transferred to the artery before rinsing. After rinsing, approximately double the amount of drug is retained on the artery in the case of drug particles coated with polydopamine.

Coating of Balloons

Several 4.0 millimeter (mm) (diameter) by 16 mm (length) Liberté™ component balloons (manufactured by Boston Scientific Corporation, Marlborough, Mass.) were syringe coated by hand with either an everolimus dispersion or an everolimus-polydopamine dispersion. One set of balloons was coated with the dispersions (everolimus or everolimus/polydopamine) to a dose of 3 μg drug/mm2. In another set the balloons were 1st coated with acetyltributylcitrate (ATBC) to a dose of 0.75 μg/mm2. As one of ordinary skill in the art may be aware, ATBC may help release the drug from the balloon. The balloons were then overcoated with the everolimus or everolimus-polydopamine dispersions to a dose of 3 μg/mm2. The coated balloons were immersed in water for one minute and the coating was scraped off of the balloon with the edge of a spatula into the water. A control balloon, from the Agent™ Paclitaxel-coated PTCA balloon catheter (manufactured by Boston Scientific Corporation, Marlborough, Mass.) was also immersed in water for one minute. The coating was then scraped off of the balloon with the edge of a spatula into the water. The vials with the coatings were imaged to qualitatively show the resulting particulates.

FIG. 9shows the coating particulates in water for the Agent™ Paclitaxel-coated PTCA balloon200, the everolimus over ATBC control balloon210, and the everolimus-polydopamine over ATBC balloon220. As can be seen, both the everolimus over ATBC control balloon210and the everolimus-polydopamine over ATBC balloon220show significantly smaller particulates than the Agent™ Paclitaxel-coated PTCA balloon200,FIG. 10shows the coating particulates in water for the everolimus control balloon300and the everolimus-polydopamine balloon310. It appears that the particles of everolimus-polydopamine220,310are smaller than the everolimus controls210,300(which show larger particle agglomerates). This is likely due to the polydopamine coating preventing the everolimus particles from agglomerating in the dried coating and upon subsequent rehydration. It may be desirable for the drug particulates to be small in size as large particulates may create embolisms.

The materials that can be used for the various components of catheter10(and/or other devices disclosed herein) and the various tubular members disclosed herein may include those commonly associated with medical devices. For simplicity purposes, the following discussion makes reference to catheter10. However, this is not intended to limit the devices and methods described herein, as the discussion may be applied to other similar medical devices and/or components of medical devices disclosed herein.