Drug-releasing coating composition

Abstract

To provide coating compositions which safely and reliably increase drug transfer efficiency.SOLUTION: In one aspect, the present disclosure pertains to elutable coating compositions that comprise: an excipient comprising a bio-degradable or bio-stable polymer selected from a poly(lactic-co-glycolic acid) (PLGA) or methyl cellulose (MCC); a binding agent; and a therapeutic agent. In some embodiments, the elutable coating compositions further comprise a solvent, where such compositions may be, for example, applied to a substrate in the form of a layer and subsequently dried, thereby forming an elutable coating on the substrate.SELECTED DRAWING: Figure 1A

Description

Technical Field

[0001] The present invention relates to medical devices and methods for manufacturing medical devices. More particularly, the present invention relates to medical devices for therapeutic drug delivery.

Background Art

[0002] A wide variety of intravascular medical devices have been developed for medical use, such as for use within blood vessels. Some of these devices include guide wires, catheters, and the like. These devices are manufactured by any of a variety of different manufacturing methods and can be used according to any of a variety of methods. Among known medical devices and methods, each has certain advantages and disadvantages. There is a continuing need to provide alternative devices and alternative methods for manufacturing and using medical devices. For example, a medical device coated with a drug may enable the movement of the therapeutic drug to a target area within the body.

Summary of the Invention

Problems to be Solved by the Invention

[0003] It is desirable to provide a coating composition that safely and reliably enhances drug transport efficiency.

Means for Solving the Problems

[0004] The present invention provides designs, materials, manufacturing methods, and alternative uses for medical devices. In a first example, an elutable coating composition can include an excipient comprising a biodegradable or bio-stable polymer selected from poly(lactic-co-glycolic acid) (PLGA) or methylcellulose (MCC), a binder, and a therapeutic agent.

[0005] In another example, alternatively or additionally to any of the above examples, the binder can include ethylcellulose. In another example, alternatively or additionally to any of the above embodiments, the excipient can include PLGA (50:50).

[0006] In another example, alternatively or additionally to any of the above examples, the excipient may include PLGA (85:15). In another example, alternatively or additionally to any of the above examples, the intrinsic viscosity of the excipient may range from about 0.1 deciliter / gram (dL / g) to about 0.8 dL / g.

[0007] In another example, alternatively or additionally to any of the above examples, the excipient may include MCC having a viscosity in the range of about 10 centipoises (cp) to about 500 cp as a 2% aqueous solution.

[0008] In another example, alternatively or additionally to any of the above examples, the excipient may include MCC having a viscosity in the range of about 300 centipoises (cp) to about 4,000 cp as a 2% aqueous solution.

[0009] Alternatively or additionally to any of the above examples, in another example, the therapeutic agent may include from about 60 to about 90 weight percent of the coating composition. Alternatively or additionally to any of the above examples, in another example, the excipient may include from about 5 to about 40 weight percent of the coating composition.

[0010] Alternatively or additionally to any of the above examples, in another example, the binder may include from about 5 to about 15 weight percent of the coating composition. Alternatively or additionally to any of the above examples, in another example, the therapeutic agent is included in the coating composition at about 60 to about 80 weight percent, the excipient is included in the coating composition at about 10 to about 35 weight percent, and the binder may be included in the coating composition at about 5 to about 20 weight percent.

[0011] Alternatively or additionally to any of the above examples, in another example, the therapeutic agent may include everolimus. In another example, the medical product may include a medical article substrate that is at least partially covered by a layer of the lubricious coating composition according to any of the above examples.

[0012] Alternatively or additionally to any of the above examples, in another example, the medical article substrate can be an expandable balloon. Alternatively or additionally to any of the above embodiments, in another embodiment, the medical article substrate can be a stent.

[0013] In another example, the elutable coating composition can include an excipient comprising poly(lactic-co-glycolic acid) (PLGA) having an intrinsic viscosity of from about 0.1 deciliter / gram (dL / g) to about 0.8 dL / g, a binder, and a therapeutic agent.

[0014] Alternatively or additionally to any of the above examples, in another example, the binder can include ethyl cellulose. Alternatively or additionally to any of the above embodiments, in another example, the excipient can include PLGA (50:50).

[0015] Alternatively or additionally to any of the above examples, in another example, the excipient can include PLGA (85:15). Alternatively or additionally to any of the above examples, in another example, the therapeutic agent can include from about 60 to about 90 weight percent of the coating composition.

[0016] Alternatively or additionally to any of the above examples, in another example, the excipient can include from about 5 to about 40 weight percent of the coating composition. Alternatively or additionally to any of the above examples, in another example, the binder can include from about 5 to about 15 weight percent of the coating composition.

[0017] Alternatively or additionally to any of the above examples, in another example, the therapeutic agent can include from about 60 to about 80 weight percent of the coating composition, the excipient can include from about 10 to about 35 weight percent of the coating composition, and the binding agent can include from about 5 to about 20 weight percent of the coating composition.

[0018] Alternatively or additionally to any of the above examples, in another example, the therapeutic agent can include everolimus. In another example, the elutable coating composition may include an excipient, a binder, and a therapeutic agent, including methylcellulose (MCC).

[0019] Alternatively or additionally to any of the above examples, in another example, the binder may include ethylcellulose. Alternatively or additionally to any of the above examples, in another example, MCC, as a 2% aqueous solution, may have a viscosity of about 10 centipoises (cp) to about 500 cp.

[0020] Alternatively or additionally to any of the above examples, in another example, MCC, as a 2% aqueous solution, may have a viscosity of about 300 centipoises (cp) to about 4000 cp. Alternatively or additionally to any of the above examples, in another example, the therapeutic agent may include about 60 to about 90 weight percent of the coating composition.

[0021] Alternatively or additionally to any of the above examples, in another example, the excipient may include about 5 to about 40 weight percent of the coating composition. Alternatively or additionally to any of the above examples, in another example, the binder may include about 5 to about 15 weight percent of the coating composition.

[0022] Alternatively or additionally to any of the above examples, in another example, the therapeutic agent may include about 60 to about 80 weight percent of the coating composition, the excipient may include about 10 to about 35 weight percent of the coating composition, and the binding agent may include about 5 to about 20 weight percent of the coating composition.

[0023] Alternatively or additionally to any of the above examples, in another example, the therapeutic agent may include everolimus. In another example, a method for preparing an elutable coating composition comprises forming a mixture by mixing an excipient comprising poly(lactic-co-glycolic acid) (PLGA) or methylcellulose (MCC), a binder comprising ethylcellulose (ECC), and a therapeutic agent; dispersing the mixture in a first solvent to form a first suspension; adding the first suspension to a second solvent to form a second suspension; stirring the second suspension; and incubating the second suspension at room temperature for a certain period of time within the range of 24 to 72 hours.

[0024] Alternatively or additionally to any of the above examples, in another example, the excipient, binder, and therapeutic agent may be mixed in a weight ratio of about 1:1:8. The above summaries of some embodiments are not intended to describe each disclosed embodiment or all implementations of the present invention. The following figures and detailed description illustrate these embodiments more specifically.

[0025] The present invention can be more fully understood in consideration of the following detailed description in connection with the accompanying drawings.

Brief Description of the Drawings

[0026]

Figure 1A

Figure 1B

Figure 2

Figure 3

Modes for Carrying Out the Invention

[0027] Although the present invention is capable of being modified in various ways and alternative forms, specific details thereof are shown by way of example in the drawings and are described in detail. However, it should be understood that the intention is not to limit the present invention to the specific embodiments described. On the contrary, the intention is to cover all modifications, equivalents, and alternatives within the scope of the present invention.

[0028] For the terms defined below, these definitions shall apply unless a different definition is given in the claims or elsewhere in this specification. In this specification, all numerical values are assumed to be modified by the term "about" whether explicitly indicated or not. The term "about" generally refers to a range of numerical values that a person of ordinary skill in the art would consider equivalent to the recited value (i.e., having the same function or result). In many cases, the term "about" may include numerical values rounded to the nearest significant digit.

[0029] The recitation of a numerical range by endpoints includes all numerical values within that range (e.g., 1 to 5 includes 1, 1.5, 2, 2.75, 3, 3.80, 4, 5). As used in this specification and the appended claims, the singular forms "a", "an", and "the" include plural referents unless the content clearly dictates otherwise. As used in this specification and the appended claims, the term "or" is generally used in the sense of "and / or" unless the content clearly dictates otherwise.

[0030] Note that references to "Embodiments", "Some Embodiments", "Other Embodiments", etc. in this specification indicate that the described embodiments may include one or more specific calibrations, structures, and / or characteristics. However, such recitations do not necessarily mean that all embodiments include the specific features, structures, and / or characteristics. Further, when a particular feature, structure, and / or characteristic is described in connection with one embodiment, such feature, structure, and / or characteristic may be used in connection with other embodiments whether or not explicitly recited, unless explicitly stated to the contrary.

[0031] The following detailed description should be read with reference to the drawings in which like elements in different drawings are identically numbered. The drawings, which are not necessarily to scale, illustrate embodiments and are not intended to limit the scope of the invention.

[0032] The body has various passageways such as blood vessels and body lumens. These passageways can be blocked (e.g., by tumors or plaques). To expand blocked blood vessels in the body, for example, a balloon catheter can be used in angioplasty. In some embodiments, the balloon catheter can comprise an inflatable and deflatable balloon carried by a long and narrow catheter body. The balloon can initially be folded around the catheter body to reduce the radial outer profile of the balloon catheter for easy insertion into the body. During use, the folded balloon can be delivered to a target location within the blood vessel, e.g., a portion blocked by plaque, by passing the balloon catheter over a guide wire already disposed within the blood vessel. Next, the balloon is inflated, for example, by introducing a fluid (such as a gas or a liquid) into the interior of the balloon. When the balloon is inflated, the blood vessel expands radially, so the blood vessel can increase the blood flow rate. After use, the balloon is typically deflated and withdrawn from the body. In some cases, it may be desirable to coat, laminate, or otherwise apply a drug or therapeutic agent to the outer surface of the balloon for delivery and / or administration of the drug or therapeutic agent to the lumen wall when the balloon is expanded. During deployment (e.g., expansion of the balloon), the coating containing the drug or therapeutic agent can decompose into particles. Some of the particles may partially deposit on the inner surface of the blood vessel. However, the efficiency of drug or therapeutic agent transport may be low. It may be desirable to provide a coating that can maintain a proper particle profile (e.g., the particle concentration retained within the body where the coating is applied is at a safe level) while maintaining a high viscosity with sufficient particle binding to counteract drug loss when exposed to blood flow. Although the therapeutic coating described herein is described in relation to a balloon and a balloon catheter, the therapeutic coating is considered applicable to and / or combinable with use in other medical devices such as stents, embolization filters, implantable devices, and therapeutic devices.

[0033] In some cases, a drug-coated balloon (DCB) involves a coating of a blend of drug and excipient. When the balloon is deployed, the coating may peel off like a small waterfall of particles. Some of the coating may be lost while following a path, some may be lost during deployment, and only a tiny portion may actually deposit on the artery (or other target location). Solid particles on the arterial wall may have one of several different potential outcomes. For example, some may be washed from the arterial wall into the bloodstream. The portion remaining in contact with the arterial wall may slowly dissolve, with some fraction dissolving into the bloodstream and some fraction being taken up by the blood vessel (such as a therapeutic dose). The coating compositions described herein may enable high drug transfer efficiency, a safe particle profile, and sustained drug release.

[0034] FIG. 1A is a cross-sectional side view of a distal end region of an exemplary medical device 10, which in this example takes the form of a catheter disposed within a body lumen 40. In at least some embodiments, catheter 10 can be a balloon catheter. Catheter 10 can include an elongate catheter shaft 12 having a proximal end (not shown) and a distal end region 14. The catheter shaft 12 can extend proximally from the distal end region 14 to a proximal end configured to remain outside the patient's body. Although not shown, the proximal end of the catheter shaft 12 can include a hub attached to provide a port for connecting other treatment devices or facilitating other treatments. It is contemplated that the stiffness and size of the catheter shaft 12 can be varied to form catheter 10 for use at various locations within the body. Catheter 10 can be configured to advance through a guide sheath, delivery sheath, or other guiding means.

[0035] The catheter 10 may further include an inflatable balloon 16 attached adjacent to the distal end region 14 of the catheter shaft 12. The size of the balloon 16 can vary based on where it is used in the body (e.g., along the coronary arteries and / or peripheral vasculature, within the pulmonary vasculature, along the airway, along another body lumen, etc.). The balloon 16 can 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 balloon 16 can have a length in the range of 5 mm to 300 mm, or about 5 to 100 mm, or about 10 to 50 mm. The balloon 16 can 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.

[0036] The catheter shaft 12 can include an outer tubular member 18 and an inner tubular member 20. The proximal waist 22 of the balloon 16 can be fixed to the distal end region 26 of the outer tubular member 18. The distal waist 24 of the balloon 16 can be fixed to the distal end region 28 of the inner tubular member 20. The inner tubular member 20 can extend distally beyond the distal waist 24 of the balloon 16, although this is not essential. Optionally, an annular inflation lumen 30 can be disposed between the outer tubular member 18 and the inner tubular member 20. The inflation lumen 30 can enable inflation fluid to pass from an inflation fluid source configured to remain outside the body to the interior region 32 of the balloon 16. The inner tubular member 20 can further define a lumen 34 through which a guide wire (not explicitly shown) can be passed to advance the catheter 10 to a predetermined position, although this is not essential.

[0037] In some embodiments, the outer surface 38 of the balloon 16 can be coated with or otherwise include an elutable drug or coating 36. Coating 36 may include one or more polymers (e.g., excipients), binders, and therapeutic agents or drugs. The terms "therapeutic agent", "drug", "bioactive agent", "pharmaceutical", "pharmaceutically active agent", and other related terms may be used interchangeably herein and include genetic therapeutic agents, non-genetic therapeutic agents, and cells. Therapeutic agents can be used alone or in combination. The filling of therapeutic agents can be used in combination with the devices of the present invention in various ways, and the pharmaceutically effective amount can be readily determined by those skilled in the art, but ultimately depends on, for example, the condition being treated, the nature of the therapeutic agent itself, the tissue into which the dosage form is introduced, etc.

[0038] Some specific beneficial agents include antithrombotic agents, antiproliferative agents, anti-inflammatory agents, anti-migratory agents, agents that affect the production and organization of the extracellular matrix, anti-neoplastic agents, anti-mitotic agents, anesthetics, anticoagulants, vascular cell growth promoters, vascular cell growth inhibitors, cholesterol-lowering agents, vasodilators, and agents that interfere with endogenous vascular action mechanisms.

[0039] More specific drugs or therapeutic agents include paclitaxel, rapamycin, sirolimus, everolimus, tacrolimus, heparin, diclofenac, aspirin, epo D, dexamethasone, estradiol, halofuginone, cilostazol, geldanamycin, ABT-578 (Abbott Laboratories), trapidil, liprostin, Actinomicin, Resten-NG, Ap-17, abciximab, clopidogrel, Ridogrel, beta-blockers, bARKct inhibitors, phospholamban inhibitors, Serca 2 gene / protein, resiquimod, imiquimod (including other imidazoquinoline immune response substances), human apolipoproteins (e.g., AI, AII, AIII, AIV, AV, etc.), vascular endothelial growth factor (e.g., VEGF-2), and derivatives of the above.

[0040] A number of additional therapeutic agents useful in the practice of the present invention can be selected from those described in co-assigned U.S. Patent No. 8,211,455, the entire disclosure of which is incorporated herein by reference.

[0041] In one example, the drug coating 36 can include one or more excipients, one or more binders, and one or more therapeutic agents such as, but not limited to, everolimus. Although the drug coating 36 described herein is described with respect to everolimus, it is contemplated that other drugs or therapeutic agents can be used as needed. Some exemplary excipients can include, but are not limited to, poly(lactic-co-glycolic acid) (PLGA) or methylcellulose (MCC). It is contemplated that other biodegradable or bio-stable polymers can be used as needed. An exemplary, but non-limiting, binder can include ethylcellulose. In some cases, the coating can include a mixture of poly(lactic-co-glycolic acid) (PLGA), ethylcellulose (ECC), and everolimus. In another example, the coating can include a mixture of methylcellulose (MCC), ECC, and everolimus. The weight percentage (wt%) of the therapeutic agent in the elutable drug coating 36 can be about 50 to about 99 wt%, about 60 to about 95 wt%, or about 70 to about 90 wt%, or about 80 wt%. The weight percentage of the excipient in the elutable drug coating 36 can be about 1 to about 45 wt%, about 5 to about 30 wt%, or about 10 wt%. The weight percentage of the binder in the elutable drug coating 36 can be about 1 to about 20 wt%, about 5 to about 15 wt%, or about 10 wt%.

[0042] The properties of PLGA can be manipulated by changing the ratio of lactide and glycolide used during the polymerization process. Different forms can be identified by the molar ratio of the monomers used. For example, PLGA 50:50 indicates a copolymer with a composition of 50% lactic acid and 50% glycolic acid, and PLGA 75:25 indicates a copolymer with a composition of 75% lactic acid and 25% glycolic acid. PLGA can also be synthesized as a random copolymer or a block copolymer and can be additionally used to control the properties of PLGA. In some cases, increasing the glycolide content may shorten the degradation time of PLGA. An exception to this is PLGA 50:50, which can have the fastest degradation time. It is contemplated that the release of drugs from a coating containing a drug, a binder (e.g., ethyl cellulose), and PLGA can be regulated by manipulating the lactic acid to glycolic acid ratio in PLGA. For example, increasing the ratio of lactic acid in PLGA makes the coating more hydrophobic (e.g., less water-soluble), slows down the PLGA degradation time, and allows the release of therapeutic agents to be regulated. Further, it is contemplated that increasing the molecular weight of PLGA increases the viscosity of the coating in situ, increases the time it takes for PLGA to dissolve, and may help the therapeutic agent stay in the blood vessel wall for a longer period. The increase in viscosity and dissolution time can increase the contact time of the coating with the blood vessel or target area and thus may enable more drug to be absorbed into the body at the target area. Examples of PLGA materials useful in the present invention include PLGA(50:50) DL 2A, PLGA(85:15) DL 4A, and PLGA(85:15) DL high IV, all of which are available from Evonik Industries AG (Essen, Germany). Suitable PLGA materials can have an intrinsic viscosity in the range of about 0.1 deciliter / gram (dL / g) to about 0.8 dL / g. Further, it is contemplated that PLGA materials with an intrinsic viscosity less than 0.1 dL / g or greater than 0.8 dL / g can also be used.

[0043] The properties of the coating 36 can also be manipulated when methylcellulose is used as an excipient. In some cases, the properties of methylcellulose can vary depending on the number of hydroxyl groups that are replaced by methoxide during synthesis and / or the average length of the polymer backbone. For example, the viscosity of an aqueous solution of methylcellulose can be proportional to the molecular weight or chain length of a particular formulation. As noted above, increasing the viscosity and dissolution time increases the contact time between the coating and the blood vessel or target area, and thus allows more drug to be absorbed into the body at the target area. Examples of MCC materials useful in the present invention include Methocel® A15 LV, Methocel® A4C Premium, and Methocel® A4M (HV), all of which are available from The Dow Chemical Company, Midland, Michigan. Suitable MCC materials can have viscosities (for a 2% MCC aqueous solution) in the range of 10 centipoises (cp) to about 4,000 (cp), or about 10 cp to about 500 cp, or about 300 cp to about 4,000 cp. Further, it is contemplated that MCC materials having viscosities less than 10 cp or greater than 4,000 cp can also be used.

[0044] Binders can be used to hold drug particles together (e.g., through increased cohesive forces). By binding drug particles, the drug can remain at the target area for a longer period of time (e.g., reducing the number of blood particles washed away from the target area by flowing body fluids such as blood). In some cases, ethylcellulose (ECC) can be used as a binder, although other binders such as, but not limited to, starch, xanthan gum, guar gum, povidone, etc. can be used.

[0045] When preparing a liquid coating composition for application to balloon 16, a drug (such as, but not limited to, everolimus) can first be converted from an amorphous form to a crystalline form. Briefly, a slurry of the amorphous drug and a solvent is formed and can be allowed to change over time. An exemplary method for converting an amorphous macrolide drug to crystalline everolimus is described in U.S. Patent No. 8,669,360, which is commonly assigned and the entire disclosure of which is incorporated herein by reference. However, in some cases, everolimus can be converted from an amorphous form to a crystalline form while the liquid coating suspension is being prepared. The use of a liquid suspension can promote crystal growth with a narrower size distribution.

[0046] Next, the drug, excipient, and binder can be added to a first solvent such as, but not limited to, ethyl acetate to form a first solution or suspension. Next, the first suspension (e.g., the drug, excipient, binder, and first solvent) can be dispersed in a second solvent such as, but not limited to, heptane to form a second suspension containing the solvent and the coating composition. In some cases, the first suspension can be added dropwise (e.g., from a pipette or spatula) to the second solvent. It is contemplated that the first and second solvents can be used in various amounts. For example, the ratio of the first solvent to the second solvent in the second suspension can range from about 1:10 to about 10:1.

[0047] Next, the second suspension can be stirred (e.g., shaken or agitated) and incubated. In some examples, the second suspension can be incubated at 29° C. for about 72 hours. The latency period can allow the amorphous drug to crystallize. The second suspension can be applied to a medical device (e.g., balloon 16) by any method known in the art, including but not limited to spraying, dipping, rolling, pipetting, painting (e.g., brush painting, sponge painting, etc.). Next, the second suspension can be dried by evaporating the solvent to form a drug coating 36. In some cases, balloon 16 can be dried overnight under ambient conditions. However, in some cases, balloon 16 can be dried at an elevated temperature (e.g., above room temperature). In the dried form, the coating 36 can include from about 50 weight percent (wt%) to about 90 wt% of a therapeutic agent, from about 5 wt% to about 30 wt% of an excipient, and from about 5 wt% to about 15 wt% of a binder. The therapeutic agent, excipient, and binder can have the same or similar weight ratios to each other in the suspension form as in the dried coating form. In some cases, some biodegradable or biostable polymers may form microspheres. The dried coating can be analyzed (e.g., using differential scanning calorimetry or X-ray diffraction) to determine the percentage of crystallinity. In some cases, the dried coating can have a dried coating range in crystalline form of about 60-90%.

[0048] In some embodiments, the dried coating 36 on the balloon 16 can have a thickness in the range of 0.1 micrometer or less to 20 micrometers or more (e.g., up to 0.1-0.2 micrometers, up to 0.5 micrometers, up to 1 micrometer, up to 2 micrometers, up to 5 micrometers, up to 10 micrometers, up to 20 micrometers), or from about 0.1 to about 5 micrometers. The thickness of the coating can be affected by, among other factors, the solids percentage in the second suspension and the coating technique. Multiple coatings can be applied to achieve the desired coating thickness.

[0049] In some embodiments, the elutable drug coating 36 may cover the entire surface area 38 of the balloon 16. In other embodiments, the elutable drug coating 36 may cover a portion of the surface area of the balloon 16. For example, the elutable drug coating 36 may 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 outer surface 38 of the balloon.

[0050] In some embodiments, the catheter 10 can advance through the lumen 40 having the lumen wall 42, with or without a guide wire or other guiding means. When the balloon 16 is positioned adjacent to the desired treatment area, the balloon 16 can be expanded to bring the elutable drug coating 36 into contact with the lumen wall 42. The drug coating 36 can elute a therapeutic agent such as, but not limited to, everolimus microparticles, onto the lumen wall 42. The balloon 16 can remain inflated for a desired time sufficient to transfer the coating 36 from the balloon 16 to the wall 42.

[0051] As described herein, the excipient in the coating 36 can be water-soluble. When the coating 36 migrates to the wall 42, the coating 36 can begin to dissolve in the blood stream or can be washed away by the blood stream. Excipients having a higher viscosity as they hydrate can potentially increase the contact time with the vessel wall 42 (e.g., be less likely to be washed away), and thus allow an increase in the amount of drug transferred from the coating 36 to the lumen wall 42. In other words, as the intrinsic viscosity of the excipient increases, the ability of the coating 36 to remain in contact with the vessel wall 42 can also increase. As used herein, the intrinsic viscosity of an excipient refers to a measure of the contribution of the solute (e.g., the excipient) to the viscosity of the solution.

[0052] Figure 1B is a side view of an exemplary intraluminal implant 50, such as, but not limited to, a stent. In some cases, the stent 50 can be formed from an elongate tubular member 52. Although the stent 50 is generally described as being tubular, it is contemplated that the stent 50 can take on any desired cross-sectional shape. The stent 50 can have a first, or proximal, end 54 and a second, or distal, end 56. The stent 50 can include a lumen 60 that extends from a first opening adjacent the first end 54 to a second opening adjacent the second end 56 to allow passage of food, fluid, etc. In some embodiments, the outer surface 62 of the stent 50 can be coated with, or otherwise include, an elutable drug or coating 66. The coating 66 can be similar in form and function to the elutable drug coating 36 described herein. Alternatively, or additionally, the coating 66 can be coated on the inner surface of the stent 50.

[0053] In some embodiments, the elutable drug coating 66 can cover the entire surface area of the stent 50. In other embodiments, the elutable drug coating 66 can cover a portion of the surface area of the stent 50. For example, the elutable drug coating 66 can 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 stent 50.

[0054] The stent 50 can be expandable from a first folded configuration (not explicitly shown) to a second expanded configuration. The stent 50 can be configured to extend across a stenosis and apply a radially outward pressure to the stenosis within the lumen to open the lumen and allow passage of food, fluid, air, etc.

[0055] The stent 50 can have a woven structure manufactured from several filaments or struts 64. In some embodiments, the stent 50 can be woven from a single filament. In other embodiments, the stent 50 can be woven from several filaments, as seen in, for example, the WallFlex®, WALLSTENT®, and Polyflex® stents manufactured and sold by Boston Scientific Corporation. In another embodiment, the stent 50 can be woven, such as with the Ultraflex™ stent manufactured by Boston Scientific. In yet another embodiment, the stent 50 can be of a knot type, such as the Precision Colonic™ stent manufactured by Boston Scientific. In yet another embodiment, the stent 50 can be a laser-cut tubular member, such as the EPIC™ stent manufactured by Boston Scientific. The laser-cut tubular member can have the shape of open cells and / or closed cells, including one or more interconnected filaments. Optionally, the inner surface and / or outer surface of the stent 50 can be fully, substantially, or partially covered with a polymer coating or covering. For example, the coating or covering may help reduce food entrapment and / or ingrowth of tumors or tissue. The present invention can be further clarified by reference to the examples, which can serve to illustrate some embodiments but do not limit the present invention. In some embodiments, the stent 50 can be woven from several filaments, as seen in, for example, the WallFlex®, WALLSTENT®, and Polyflex® stents manufactured and sold by Boston Scientific Corporation. In another embodiment, the stent 50 can be woven, such as with the Ultraflex™ stent manufactured by Boston Scientific. In yet another embodiment, the stent 50 can be of a knot type, such as the Precision Colonic™ stent manufactured by Boston Scientific. In yet another embodiment, the stent 50 can be a laser-cut tubular member, such as the EPIC™ stent manufactured by Boston Scientific. The laser-cut tubular member can have the shape of open cells and / or closed cells, including one or more interconnected filaments. Optionally, the inner surface and / or outer surface of the stent 50 can be fully, substantially, or partially covered with a polymer coating or covering. For example, the coating or covering may help reduce food entrapment and / or ingrowth of tumors or tissue. The present invention can be further clarified by reference to the examples, which can serve to illustrate some embodiments but do not limit the present invention.

[0056] (Example 1) Three coating compositions were prepared using poly(lactic-co-glycolic acid) (PLGA), a biodegradable polymer. Each coating composition used a different grade of PLGA with a different viscosity. The first coating composition was prepared with PLGA (50:50) having an intrinsic viscosity (IV) of 0.16 deciliters / gram (dL / g). The second coating composition was prepared with PLGA (85:15) having an intrinsic viscosity of 0.41 dL / g. The third coating composition was prepared with PLGA (85:15) having an intrinsic viscosity of 0.75 dL / g. For each coating composition, first, crystalline everolimus, ethylcellulose (ECC), and PLGA were individually prepared by mixing them in a weight ratio of 8:1:1 (everolimus:ECC:PLGA) to form a first mixture. Next, each composition was individually dissolved in ethyl acetate in a weight ratio of 8:1:1:90 (everolimus:ECC:PLGA:ethyl acetate) to produce a first suspension. Next, the first suspension was dropped and dispersed in heptane with a weight ratio of ethyl acetate to heptane of 1:5 to produce a second suspension. Next, the second suspension was stirred (shaken or stirred, etc.) and incubated at 29 °C for about 72 hours. Next, each liquid coating composition was coated on two different balloons, resulting in six balloons being coated with the PLGA-containing composition. The balloons were dried overnight under ambient conditions. Two more balloons were coated with a coating composition having only crystalline everolimus. The dried coating compositions are described in Table 1 below.

[0057] Table 1. Coating Compositions

[0058]

Table 1

[0059] The coated balloons were individually advanced through plastic tubes with water flowing through them to simulate blood flow. At the target position within the plastic tubes, the balloons were inflated to simulate the delivery of therapeutic agents in the body. Next, the balloons were deflated and removed from the tubes. The water used to flush the plastic tubes was collected and analyzed to determine the amount of therapeutic agent (such as everolimus) lost in the simulated blood flow. After removing the balloons, the plastic tubes were also analyzed to determine how much of the therapeutic agent had transferred to the tubes. Similarly, the balloons were analyzed to determine the amount of therapeutic agent remaining on the balloons. Next, the following equation was used to determine the transfer efficiency of the drug to the tube wall (e.g., of the drug):

[0060] [Number]

[0061] Here, the total amount of drug is the sum of the drug in the water used for flushing, the drug on the tube, and the drug remaining on the balloon. The results are shown in Figure 2. This figure shows a graph of the drug transfer efficiency using biodegradable polymers. As can be seen, the addition of PLGA and ECC improved the transfer efficiency compared to the coating of everolimus alone. As the intrinsic viscosity of PLGA increased, the drug transfer efficiency also increased.

[0062] The water used to flush the tubes (e.g., that simulates blood) was also analyzed to determine the particle loading of the coating composition. The amount of particles was determined for three particle sizes (10 microns, 25 microns, and 50 microns) using light obscuration and normalized by the balloon size. The microparticles for each coating and each size range are summarized in the following table.

[0063] Table 2. Comparison of Particles

[0064] [Table 2]

[0065] The addition of PLGA and ECC increased the particle loading in the 10-micron size range, but decreased the particle loading in the 25-micron and 50-micron ranges. However, the particle loading in the 10-micron size range of the composition containing PLGA and ECC is still within the acceptable range. It should be noted that it is highly desirable to have fewer larger particles achieved with the composition containing PLGA and ECC.

[0066] (Example 2) Three coating compositions were prepared using the biostable polymer methylcellulose (MCC). Different grades of MCC with different viscosities were used in each coating composition. The first coating composition was prepared with MCC having a viscosity of 15 centipoise (cp). The second coating composition was prepared with MCC having a viscosity of 400 cp. The third coating composition was prepared with MCC having a viscosity of 3893 cp. The viscosities of the different grades of MCC are based on a 2% aqueous solution of MCC. Each coating composition was individually prepared by first mixing crystalline everolimus, ethylcellulose (ECC), and MCC in a weight ratio of 8:1:1 (everolimus: ECC: MCC) to form a first mixture. Next, each composition was individually dissolved in ethyl acetate in a weight ratio of 8:1:1:90 (everolimus: ECC: PLGA: ethyl acetate) to produce a first suspension. Next, the first suspension was dropped into and dispersed in heptane with a weight ratio of ethyl acetate to heptane of 1:5 to produce a second suspension. Next, the second suspension was stirred (shaken or stirred, etc.) and incubated at 29 °C for about 24 to 72 hours. Next, each liquid coating composition was coated on two different balloons, resulting in six balloons being coated with the MCC-containing composition. The balloons were dried overnight under ambient conditions. Two more balloons were coated with a coating composition having only crystalline everolimus. The dried coating compositions are described in Table 3 below.

[0067] Table 3. Coating Compositions

[0068]

Table 3

[0069] The coated balloons were individually advanced through a plastic tube through which water was flowing to simulate blood flow. At the target position within the plastic tube, the balloons were inflated to simulate the delivery of therapeutic agents in the body. Next, the balloons were deflated and removed from the tube. The water used to flush the plastic tube was collected and analyzed to determine the amount of therapeutic agent (such as everolimus) lost in the simulated blood flow. After removing the balloons, the plastic tube was also analyzed to determine how much of the therapeutic agent had been transferred to the tube. Similarly, the balloons were analyzed to determine the amount of therapeutic agent remaining on the balloons. Next, the following equation was used to determine the transfer efficiency of the drug to the tube wall (for example, of the drug):

[0070]

Equation

[0071] Here, the total amount of drug is the sum of the drug in the water used for flushing, the drug on the tube, and the drug remaining on the balloons. The results are shown in Figure 3. This figure shows a graph of the drug transfer efficiency using a bio-stable polymer. As can be seen, the addition of MCC and ECC improved the transfer efficiency compared to the coating with everolimus alone. As the viscosity of MCC increased, the drug transfer efficiency also increased. The variation between samples also decreased as the viscosity increased.

[0072] The water used to flush the tube (e.g., that simulates blood) was also analyzed to determine the particle loading of the coating composition. The amount of particles was determined using light obscuration for three particle sizes (10 microns, 25 microns, and 50 microns) and normalized by the balloon size. The particulates for each coating and each size range are summarized in the table below.

[0073] Table 4. Comparison of Particles

[0074] [Table 4]

[0075] The addition of MCC and ECC increased the particle loading in the 10-micron size range, but decreased the particle loading in the 25-micron and 50-micron ranges. However, the particle loading in the 10-micron size range of the composition containing MCC and ECC is still within the acceptable range. Note that it is highly desirable to have fewer large particles. This is achieved with the composition containing MCC and ECC.

[0076] The various components of the catheter 10 (and / or other instruments disclosed herein) and the materials that can be used for the various tubular members disclosed herein can include those commonly associated with medical devices. For simplicity, the following description refers to the catheter 10. However, this is not intended to limit the instruments and methods described herein, as the description of the invention can be applied to other similar medical devices and / or components of medical devices disclosed herein.

[0077] Catheter 10 can be made of metal, metal alloy, polymer (some examples of which are disclosed below), metal-polymer composite, ceramic, combinations thereof, etc., or other suitable materials. Some examples of suitable metals and metal alloys include stainless steels such as 304V, 304L, and 316LV stainless steel; mild steel; nickel-titanium alloys such as linear elastic and / or superelastic nitinol, nickel-chromium-molybdenum alloys (e.g., UNS:N06625 such as Inconel® 625, UNS:N06022 such as Hastelloy® C-22, UNS:N10276 such as Hastelloy C276®, other Hastelloy® alloys, etc.), nickel-copper alloys (e.g., UNS:N04400 such as Monel® 400, NickelVAC® 400, Micorros® 400), nickel-cobalt-chromium-molybdenum alloys (e.g., UNS:R30035 such as MP35-N®), nickel-molybdenum alloys (e.g., UNS:N10665 such as Hastelloy® ALLOY B2®), other nickel-chromium alloys, other nickel-molybdenum alloys, other nickel-cobalt alloys, other nickel-iron alloys, other nickel-copper alloys, other nickel-tungsten or tungsten alloys, etc., other nickel alloys; cobalt-chromium alloys; cobalt-chromium-molybdenum alloys (e.g., UNS:R30003 such as Elgiloy®, Phynox®); platinum-reinforced stainless steel; titanium; combinations thereof, etc., or other suitable materials are included.

[0078] As understood herein, the group of commercially available nickel-titanium or nitinol alloys includes a category called "linear elastic" or "non-superelastic", which may be chemically similar to conventional shape memory and superelastic varieties, but may exhibit distinct and useful mechanical properties. Linear elastic and / or non-superelastic nitinol can be distinguished from superelastic nitinol in that the linear elastic and / or non-superelastic nitinol does not exhibit a substantial "superelastic plateau" or "flag region" like superelastic nitinol in its stress-strain curve at its stress. Instead, in linear elastic and / or non-superelastic nitinol, as the recoverable strain increases, the stress continues to increase in a substantially linear, or somewhat linear, relationship until plastic deformation begins, or at least until a relationship that is more linear than the superelastic plateau and / or flag region that might be seen in superelastic nitinol. Thus, for the purposes of the present invention, linear elastic and / or non-superelastic nitinol may also be referred to as "substantially" linear elastic and / or non-superelastic nitinol.

[0079] In some cases, linear elastic and / or non-superelastic nitinol can also be distinguished from superelastic nitinol in that the linear elastic and / or non-superelastic nitinol can accept up to about 2-5% strain while substantially maintaining elasticity (e.g., before plastic deformation), whereas superelastic nitinol can accept up to about 8% strain before plastic deformation. Both of these materials can be distinguished from other linear elastic materials, such as stainless steel, which can only accept up to about 0.2-0.44 percent strain before plastic deformation (which can also be distinguished based on its composition).

[0080] In some embodiments, the linear elastic and / or non-superelastic nickel-titanium alloy is an alloy that does not exhibit a martensite / austenite phase change detectable by differential scanning calorimetry (DSC) and dynamic mechanical thermal analysis (DMTA) over a wide temperature range. For example, in some embodiments, the linear elastic and / or non-superelastic nickel-titanium alloy may not have a martensite / austenite phase change detectable by DSC and DMTA analysis in the range of about -60 degrees Celsius (°C) to about 120 °C. Thus, the mechanical bending properties of such materials can generally be inert to the effects of temperature over this very wide temperature range. In some embodiments, the mechanical bending properties of the linear elastic and / or non-superelastic nickel-titanium alloy at ambient or room temperature are substantially the same as the mechanical properties at body temperature, for example, in that no superelastic plateau and / or flag region is shown. In other words, over a wide temperature range, the linear elastic and / or non-superelastic nickel-titanium alloy maintains its linear elastic and / or non-superelastic properties and / or characteristics.

[0081] In some embodiments, in the linear elastic and / or non-superelastic nickel-titanium alloy, about 50 to about 60 weight percent can be nickel and the remainder is generally titanium. In some embodiments, the composition has nickel in the range of about 54 to about 57 weight percent. An example of a suitable nickel-titanium alloy is the FHP-NT alloy commercially available from Furukawa Techno-Material Co., Ltd. in Kanagawa Prefecture, Japan. Some examples of nickel-titanium alloys are disclosed in U.S. Patent Nos. 5,238,004 and 6,508,803, which are incorporated herein by reference. Other suitable materials include ULTANIUM (trademark, available from Neo-Metrics) and GUMMETAL (trademark, available from Toyota). In some other embodiments, superelastic alloys, such as superelastic Nitinol, can be used to achieve the desired properties.

[0082] In at least some embodiments, some or all of the catheter 10 may also be doped with a radiopaque material, formed from a radiopaque material, or otherwise include a radiopaque material. The radiopaque material is understood to be a material that can generate a relatively bright image on a fluoroscopy screen or another imaging technique during a medical procedure. This relatively bright image helps the user of the catheter 10 to determine its position. Some examples of radiopaque materials can include, but are not limited to, gold, platinum, palladium, tantalum, tungsten alloys, polymeric materials filled with radiopaque fillers, etc. Additionally, other radiopaque marker bands and / or coils can also be incorporated into the design of the catheter 10 to achieve the same result.

[0083] In some embodiments, a degree of magnetic resonance imaging (MRI) compatibility is provided to the catheter 10. For example, the catheter 10 or a portion thereof can be formed from a material that does not substantially distort the image and does not generate substantial artifacts (i.e., gaps in the image). For example, certain ferromagnetic materials may not be suitable as they can potentially create artifacts in the MRI image. The catheter 10 or a portion thereof can also be made from materials that can be imaged by an MRI device. Some materials exhibiting these properties include, for example, tungsten, cobalt-chromium-molybdenum alloys (e.g., UNS:R30003 such as ELGILOY®, PHYNOX®), nickel-cobalt-chromium-molybdenum alloys (e.g., UNS:R30035 such as MP35-N®), nitinol, and others.

[0084] It should be understood that this disclosure is illustrative in many respects. Without departing from the scope of the disclosure, particularly with regard to the shape, size, and arrangement of steps, details can be changed. This can include the use of any of the features of the exemplary embodiments in other embodiments within an appropriate scope. Needless to say, the scope of the present invention is defined by the language in which the appended claims are expressed.

Claims

1. A method for preparing a dissolvable coating composition, comprising: forming a mixture by mixing an excipient comprising poly(lactic-co-glycolic acid) (PLGA) or methylcellulose (MCC), a binder comprising ethylcellulose (ECC), and a therapeutic agent; dispersing the mixture in a first solvent to form a first suspension; adding the first suspension to a second solvent to form a second suspension; stirring the second suspension; incubating the second suspension at room temperature for a certain period of time within the range of 24 to 72 hours, wherein the therapeutic agent comprises crystalline everolimus.

2. The method according to claim 1, wherein the excipient, the binder, and the therapeutic agent are mixed in a weight ratio of about 1:1:

8.

3. The method according to claim 1 or 2, wherein the first suspension comprises ethyl acetate.

4. The method according to any one of claims 1 to 3, wherein the second suspension comprises heptane.

5. The method according to any one of claims 1 to 4, wherein the first suspension is added dropwise to the second solvent.

6. The method according to any one of claims 1 to 5, wherein the excipient comprises PLGA (50:50).

7. The method according to any one of claims 1 to 5, wherein the excipient comprises PLGA (85:15).

8. The method according to claim 6 or 7, wherein the intrinsic viscosity of the excipient is in the range of about 0.1 deciliter / gram (dL / g) to about 0.8 dL / g.

9. The method according to any one of claims 1 to 5, wherein the excipient comprises MCC having a viscosity in the range of about 10 centipoises (cp) to about 500 cp as a 2% aqueous solution.

10. The method according to any one of claims 1 to 5, wherein the excipient comprises MCC having a viscosity in the range of about 300 centipoises (cp) to about 4,000 cp as a 2% aqueous solution.

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