Medical devices comprising therapeutic coatings formed from bioresorbable and reversible thermal gelling excipients

Abstract

A medical device may be coated with a therapeutic composition comprising everolimus. The everolimus crystals may be coated with a mixture of excipients to form encapsulated everolimus crystals suspended in the coating composition. An exemplary coating composition may include a mixture of excipients including a bioabsorbable or thermal gelling polymer and a plasticizer, and a therapeutic agent. The bioabsorbable or thermal gelling polymer may be selected from the group consisting of polycaprolactone (PCL) or poloxamer.

Description

Cross-references to related applications

[0001] This application claims the benefit of priority to U.S. Provisional Patent Application No. 63 / 458,727, filed April 12, 2023, the entire disclosure of which is incorporated herein by reference. Technical Field

[0002] This disclosure relates to medical devices, and more specifically to medical devices comprising a therapeutic coating formed of a bioabsorbable and reversible thermogelling excipient. Background Technology

[0003] A wide variety of medical devices have been developed for medical applications, such as intravascular applications. Some of these devices include guidewires, catheters, balloons, stents, etc. These devices are manufactured using any of a variety of different methods and can be used according to any of these methods. Some of these medical devices may include therapeutic agents. Each of the known medical devices and methods has certain advantages and disadvantages. There has always been a need for alternative medical devices and alternative methods for manufacturing and using these devices. This could include forming therapeutic agents with a reduced drug dissolution rate to provide a prolonged therapeutic effect. Summary of the Invention

[0004] This disclosure relates to medical devices, and more specifically to medical devices comprising a therapeutic coating formed by a bioabsorbable and reversible thermogelling excipient.

[0005] In the first example, the washable coating composition may comprise a mixture of excipients and a therapeutic agent, the mixture of excipients comprising a bioabsorbable polymer or a thermogelatinizing polymer and a plasticizer, the bioabsorbable polymer or thermogelatinizing polymer being selected from polycaprolactone (PCL) or poloxamer.

[0006] As an alternative to or supplement to any of the above examples, in another example, the plasticizer may contain acetylated tributyl citrate (ATBC) or acetylated trihexyl citrate (ATHC).

[0007] As an alternative to or supplement to any of the above examples, in another example, the mixture of excipients may contain polycaprolactone.

[0008] As an alternative to or supplement to any of the above examples, in another example, polycaprolactone may have a molecular weight of about 10,000 g / mol or less.

[0009] As an alternative to or supplement to any of the above examples, in another example, the mixture of excipients may contain approximately equal parts of polycaprolactone and acetylated tributyl citrate (ATBC).

[0010] As an alternative to or supplement to any of the above examples, in another example, the mixture of excipients may contain poloxamer.

[0011] As an alternative to or supplement to any of the above examples, in another example, poloxamer may include poloxamer 181 or poloxamer 188.

[0012] As an alternative to or supplement to any of the above examples, in another example, the mixture of excipients may contain approximately equal parts of poloxamer and acetyl tributyl citrate (ATBC).

[0013] As an alternative to or supplement to any of the above examples, in another example, the mixture of excipients may comprise about 10% to about 40% by weight of the washable coating composition.

[0014] As an alternative to or supplement to any of the above examples, in another example, the therapeutic agent may comprise about 60% to about 90% by weight of the washable coating composition.

[0015] As an alternative or supplement to any of the above examples, in another example, the therapeutic agent may comprise about 60% to about 90% by weight of the washable coating composition, the bioabsorbable polymer or thermogelling polymer may comprise about 5% to about 20% by weight of the washable coating composition, and the plasticizer may comprise about 5% to about 20% by weight of the washable coating composition.

[0016] As an alternative to or supplement to any of the above examples, in another example, the therapeutic agent may contain everolimus.

[0017] As an alternative to or supplement to any of the above examples, in another example, the washable coating composition may also contain an antioxidant.

[0018] In another example, the medical device may include medical device components that are at least partially covered by a layer of the washable coating composition described in any of the examples herein.

[0019] As an alternative to or supplement to any of the above examples, in another example, the medical device component may be an expandable balloon or an expandable stent.

[0020] In another example, the washable coating composition may comprise an excipient comprising acetyl trihexy citrate (ATHC) and a therapeutic agent comprising multiple everolimus crystals. The ATHC may encapsulate each of the multiple everolimus crystals.

[0021] As an alternative to or supplement to any of the above examples, in another example, the therapeutic agent may comprise about 80% to about 95% by weight of the elutable coating composition, and the excipient may comprise about 5% to about 20% by weight of the elutable coating composition.

[0022] As an alternative to or supplement to any of the above examples, in another example, the washable coating composition may also contain an antioxidant.

[0023] In another example, a method of coating a medical device with encapsulated everolimus crystals may include: forming a coating suspension (coating suspension, coating suspension) by suspending everolimus crystals in a first premix comprising acetyltritol tributyl citrate (ATBC); adding a second premix comprising a bioabsorbable polymer or a thermogelatinizing polymer to the first premix, the bioabsorbable polymer or thermogelatinizing polymer being mixed with ATBC and encapsulating the everolimus crystals to form a coating suspension comprising encapsulated everolimus crystals; and coating the coating suspension onto the medical device.

[0024] As an alternative to or supplement to any of the above examples, in another example, once the second premix is ​​added to the first premix, the bioabsorbable polymer or thermogelatinizing polymer and ATBC may be present in approximately equal parts.

[0025] As an alternative to or supplement to any of the above examples, in another example, the first premix may include cyclohexane.

[0026] As an alternative to or supplement to any of the above examples, in another example, the second premix may include ethyl acetate.

[0027] The foregoing description of some implementations is not intended to describe every disclosed implementation or every embodiment of this disclosure. The following figures and detailed descriptions illustrate these implementations in more detail. Brief description of the attached figures

[0028] This disclosure can be more fully understood in conjunction with the following detailed description of the embodiments, in conjunction with the accompanying drawings, in which:

[0029] Figure 1 This is a schematic side view of an exemplary drug delivery balloon catheter.

[0030] Figure 2 It is along Figure 1 A cross-sectional view taken from line 2-2 in the middle.

[0031] Figure 3 An exemplary drug-coated scaffold in a contraction or delivery configuration is depicted.

[0032] Figure 4 An exemplary drug-coated scaffold in an expanded or deployed configuration is depicted.

[0033] Figure 5 A drug coating is schematically depicted along the outer surface or the distal lumen side surface of an exemplary drug-coated stent.

[0034] Figure 6 The drug coating is schematically depicted along the inner surface or near-nuclear side surface of an exemplary drug-coated stent.

[0035] Figure 7 The illustration schematically depicts a drug coating disposed along the outer surface or distal lumen side surface of an exemplary drug-coated stent and along the inner surface or proximal lumen side surface of an exemplary drug-coated stent.

[0036] Figure 8 It is a graphical representation of experimental data.

[0037] While the embodiments are readily adaptable to various modifications and alternatives, their details have been illustrated by way of example in the accompanying drawings and will be described in detail. Nevertheless, it should be understood that the invention is not limited to the specific embodiments described. Rather, it is intended to cover all modifications, equivalents, and alternatives falling within the spirit and scope of this disclosure. Detailed Implementation

[0038] The following definitions shall apply to terms unless otherwise defined in the claims or elsewhere in this specification.

[0039] Whether explicitly stated or not, all numerical values ​​herein are considered to be modified by the term "approximately". The term "approximately" generally refers to a range of numbers that a person skilled in the art would consider equivalent to the value stated (e.g., having the same function or result). In many cases, the term "approximately" may include numbers rounded to the nearest significant figure.

[0040] The range of values ​​listed by endpoints includes all values ​​within that range (for example, 1 to 5 includes 1, 1.5, 2, 2.75, 3, 3.80, 4, and 5).

[0041] As used in this specification and the appended claims, the singular forms “a” and “the”, and where no quantifier is used, include plural indicators, unless otherwise expressly stated. As used in this specification and the appended claims, the term “or” is generally used in the sense that it includes “and / or”, unless otherwise expressly stated.

[0042] Note that references to "one embodiment," "some embodiments," "other embodiments," etc., in the specification indicate that the described embodiment may include one or more specific features, structures, and / or characteristics. However, such descriptions do not necessarily mean that all embodiments include that specific feature, structure, and / or characteristic. Furthermore, when a specific feature, structure, and / or characteristic is described in conjunction with an embodiment, it should be understood that these features, structures, and / or characteristics may also be used in conjunction with other embodiments, whether explicitly described or not, unless explicitly stated otherwise.

[0043] The following detailed description should be read with reference to the accompanying drawings, in which similar elements in different drawings are numbered the same. The drawings (which are not necessarily to scale) depict illustrative embodiments and are not intended to limit the scope of the invention.

[0044] The body includes various channels, such as blood vessels and body cavities. These channels sometimes become blocked (e.g., by tumors or plaques). To widen blocked blood vessels, balloon catheters can be used, for example, in angioplasty. In some implementations, a balloon catheter may comprise an inflatable and deflateable balloon carried by a long, narrow catheter body. The balloon may initially be 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 is delivered to a target location in the blood vessel, such as a plaque-occluded portion, by passing the balloon catheter through a guidewire previously positioned in the vessel. The balloon is then inflated, for example, by introducing fluid (such as gas or liquid) into its interior. Inflating the balloon causes the vessel to expand radially, allowing for increased blood flow rates. After use, the balloon is typically deflated and removed from the body. In some cases, it may be desirable to coat, laminate, or otherwise apply an elutable drug or therapeutic agent to the outer surface of a balloon to deliver and / or administer the drug or therapeutic agent to the inner wall of the lumen during balloon inflation. Therefore, it may be desirable to efficiently transfer the drug coating to the target area and retain the drug coating at the target area. Further anticipated is the need for the drug coating to be durable so as to be easily handled during the manufacturing process, especially during repackaging when the balloon protector is placed on the drug coating. However, the elutable drug coating should balance durability and transferability (e.g., the ability of the drug coating to transfer to the vessel wall), which can be driven by the coating composition or excipients provided in the drug coating. For example, the elutable coating composition or drug coating may be durable enough that most of the drug remains within the drug coating before inflation at the target treatment site, and most of the drug can be transferred from the medical device to the target treatment site. This document discloses coating compositions that provide improved durability, transfer efficiency, and drug retention. This document further discloses methods for converting amorphous materials (e.g., drugs) into crystalline forms and methods for encapsulating crystals of crystalline drugs to provide an extended release profile of the crystalline drug. Furthermore, this article discloses medical devices coated with this coating, coating methods, etc. Although the therapeutic coatings described herein are discussed in relation to balloons and balloon catheters and stents, it is contemplated that the therapeutic coatings can be applied to and / or used in combination with other medical devices, such as, but not limited to, embolization filters, implantable devices, therapeutic devices, etc.

[0045] Medical devices may include a washable therapeutic coating disposed on their surface, the coating comprising multiple everolimus crystals encapsulated within a coating comprising a synergistic combination of excipients. The synergistic combination of excipients can be understood as a combination of multiple excipients that, when used together, provide improved outcomes relative to the use of any single excipient alone. The synergistic combination of excipients provides better protection for the everolimus crystals, meaning that the everolimus crystals dissolve more slowly over time, thus providing a delay in drug release or drug dissolution. This provides a longer-lasting tissue drug concentration. While the drug coating composition is described as containing everolimus, it is anticipated that the drug coating composition may include therapeutic agents other than or alternative to everolimus.

[0046] Surprisingly, some combinations of excipients have been found to provide better protection than the expected effect of the excipient combination. For example, in some cases, synergistic combinations of excipients include polycaprolactone (PCL) and acetylated tributyl citrate (ATBC). In another example, the synergistic combination of excipients includes poloxamer and acetylated tributyl citrate (ATBC). In some cases, the excipients may contain acetylated trihexyl citrate (ATHC). In yet another example, the synergistic combination of excipients includes polycaprolactone and acetylated tributyl citrate (ATHC). In yet another example, the synergistic combination of excipients includes poloxamer and acetylated tributyl citrate (ATHC). In yet another example, the synergistic combination of excipients includes ethyl cellulose and acetylated tributyl citrate (ATHC).

[0047] Figure 1 This is a schematic side view of the drug delivery balloon catheter 10. A cross-sectional view of the drug delivery balloon catheter 10 is shown in [the diagram / illustration]. Figure 2 In the depicted embodiment, catheter 10 may include an elongated shaft 12, an inflatable balloon 14 coupled to or coupled to a distal portion 16 of shaft 12, and other components. The elongated shaft 12 may include a tubular member having a proximal portion 18 and one or more lumens extending between the proximal portion 18 and the distal portion 16. The elongated shaft 12 may be configured to have a substantially circular cross-section; however, it may be configured to have other suitable cross-sectional shapes, such as elliptical, oval, polygonal, irregular, etc. Additionally, the elongated shaft 12 may be flexible along its entire length or adapted to bend only along a portion of its length. The desired degree of flexibility of the elongated shaft 12 may be predetermined based on its intended navigation to a target vascular channel and the amount of inertial force required to advance the elongated shaft 12 through the vascular channel. The catheter 10 may be configured as an over-the-wire (OTW) catheter, a single-operator exchange (SOE) catheter, a fixed-wire catheter, and / or similar types.

[0048] The cross-sectional dimensions of the elongated shaft 12 can be varied depending on the desired application. Typically, the cross-sectional dimensions of the elongated shaft 12 can be designed to be smaller than the size of a typical blood vessel in which the catheter 10 will be used. The length of the elongated shaft 12 can vary depending on the location of the vascular access required for drug delivery. In some cases, a 6F or 5F catheter can be used as the elongated shaft 12, where "F" is also known as the French catheter scale and is a unit for measuring catheter diameter (1F = 1 / 3 millimeter (mm)). Additionally, the elongated shaft 12, or a portion thereof, can be selectively manipulated. If desired, mechanisms such as drawstrings and / or other actuators can be used to selectively manipulate the elongated shaft 12.

[0049] The proximal portion 18 of the elongated shaft 12 may include a handle 20, which can be used to manually manipulate the distal portion 16 of the elongated shaft 12. The handle 20 may include one or more ports for introducing any suitable medical device, fluid, or other intervention. For example, the handle 20 may include a guidewire port communicating with the guidewire lumen 22 (in the resection portion at the distal end of the catheter 10 and also in…) Figure 2 As shown in the diagram, the guidewire lumen 22 can be used to introduce a guidewire of appropriate thickness (diameter) into the elongated shaft 12, which can guide the elongated shaft 12 to a target location inside the artery. Furthermore, the handle 20 may include an inflation port configured to connect to an inflation fluid source for delivering inflation fluid through the inflation lumen of the catheter shaft 12 to an inflatable balloon 14. In some embodiments, the elongated shaft 12 may include one or more additional lumens, which may be configured for various purposes, such as delivering medical devices or for providing fluid (e.g., saline) to a target location.

[0050] The inflatable balloon 14 can be operatively coupled to or attached to the distal portion 16 of the elongated shaft 12. Specifically, the proximal portion or waist 24 of the inflatable balloon 14 can be secured to the distal portion 16 of the elongated shaft 12, such as the outer tubular member 26 of the elongated shaft 12. Furthermore, the distal portion or waist 28 of the inflatable balloon 14 can be secured to the distal portion 16 of the elongated shaft 12, such as the inner tubular member 30 extending through the outer tubular member 26 of the elongated shaft 12. Suitable securing methods can be used to join the two structures as needed, including but not limited to adhesive bonding, thermal bonding (e.g., hot clamping, laser welding, etc.) or other bonding techniques. The inflatable balloon 14 can be configured to expand from a constricted state to an inflated state by delivering an inflatable fluid (e.g., saline) through an inflatable lumen passing through the catheter shaft 12. The balloon 14 can contract during the insertion of the catheter into the patient's body, and once the balloon 14 reaches the target site inside the body's blood vessels, the balloon 14 can inflate.

[0051] The inflatable balloon can be manufactured or otherwise formed from any suitable material, including polymeric materials such as polyamide, polyether block amide (PEBA), polyester, nylon, etc. As shown in the exemplary embodiment, the inflatable balloon 14 can have a generally cylindrical construction with a circular cross-section. However, in other embodiments, the inflatable balloon 14 can have another suitable construction or shape if desired.

[0052] The inflatable balloon 14 may include a balloon wall 32 to which a drug coating 34 is disposed. In some cases, the drug coating or coating composition 34 may include encapsulated crystalline everolimus, as will be described in more detail herein. The drug coating 34 may be disposed along substantially the entire length and / or circumference of the balloon 14 or along one or more portions of the balloon 14. For example, the drug coating 34 may be disposed along the central portion or body portion of the balloon 14. The drug coating 34 disposed on the balloon 14 / balloon wall 32 may have an average thickness, for example, ranging from about 1 micrometer to about 50 micrometers.

[0053] Figure 3-4 Depicting structures in contraction or delivery ( Figure 3 ) or in an expansion or deployment structure ( Figure 4 An exemplary drug-coated stent 110 is shown. Typically, the stent 110 can be delivered to a suitable target area via a catheter / delivery system while in a contractile configuration. Upon reaching the target area, the stent 110 can expand or be expanded into an expandable configuration. The stent 110 can be self-expanding (e.g., the stent 110 can be formed of a shape memory material such as nitinol) or it can be balloon expandable. When the stent 110 is self-expanding, the stent 110 can be held / constrained in a contractile configuration during delivery and then unconstrained to allow the stent 110 to expand (e.g., self-expand) into an expandable configuration. When the stent 110 is balloon expandable, the stent 110 can be constrained and coiled onto a delivery device / catheter and then expand at or near the target area (e.g., via an expandable member or balloon).

[0054] The support 110 may include a support frame 136. The support frame 136 may define one or more peak or vertex regions 138 and / or one or more connecting regions 140. Intermediate regions 142 may interconnect the vertex regions 138 and / or the connecting regions 140. In some cases, the support 110 may be formed by cutting (e.g., laser cutting) a tube. In this case, the structural arrangement of the vertex regions, connecting regions 140, and / or intermediate regions 142 may be determined by the cutting pattern. It is understood that a wide variety of patterns / arrangements can be used for the support 110. In other cases, the support 110 may be a woven or braided support, a support formed from a flat sheet of material that is rolled, molded, cast, etc.

[0055] The drug coating or coating composition 134 may be disposed along the support frame 136. For example, Figure 5 A drug coating 134 is schematically depicted along the outer surface or distal inner lumen side surface (outer inner lumen surface) 144 of the stent 110 (e.g., along the outer surface or distal inner lumen side surface 144 of the strut frame 136). Figure 6 A drug coating 134 is schematically depicted along the inner surface or near-nuclear side (inner surface) of the stent 110 (e.g., along the inner surface or near-nuclear side surface 146 of the strut frame 136). Figure 7 A drug coating 134 is schematically depicted along both the outer surface or distal lumen side surface 144 of the stent 110 and the inner surface or proximal lumen side surface 146 of the stent 110 (e.g., along both the outer surface or distal lumen side surface 144 and the inner surface or proximal lumen side surface 146 of the strut frame 136). Although not explicitly shown, in some examples, the drug coating 134 may additionally or alternatively be disposed along the lateral side (edge) of the strut frame 136, the lateral side extending between the outer surface or distal lumen side surface 144 and the inner surface or proximal lumen side surface 146. It should be noted that Figure 5-7 Cross-sectional views are intended to schematically represent a portion (e.g., a single region or section of the strut) of the strut frame 136. In these views, the strut frame 136 is drawn in a partially arcuate shape. This is intended to correspond to the generally cylindrical shape of the stent 110, for example, when the stent 110 is in an expanded configuration. In some cases, the drug coating 134 may comprise encapsulated crystalline everolimus, as will be described in more detail herein. The drug coating 134 disposed on the strut frame 136 may have an average thickness, for example, ranging from about 1 micrometer to about 50 micrometers.

[0056] The terms “therapeutic agent,” “drug,” “bioactive agent,” “pharmaceutical,” “pharmaceutical active agent,” and other related terms are used interchangeably herein and include genetic therapeutic agents, non-genetic therapeutic agents, and cells. Therapeutic agents can be used alone or in combination. The devices of the present invention can use various therapeutic agent loadings, wherein the pharmaceutically effective amount is readily determined by those skilled in the art and ultimately depends on, for example, the condition to be treated, the nature of the therapeutic agent itself, the tissue to which the dosage form is introduced, etc.

[0057] Drug coatings 34 and 134 may include therapeutic agents, including everolimus. However, other beneficial agents may include antithrombotic agents, antiproliferative agents, anti-inflammatory agents, antimigration agents, agents affecting extracellular matrix production and tissues, antitumor agents, antimitotic agents, anesthetics, anticoagulants, angiocyte growth promoters, angiocyte growth inhibitors, cholesterol lowering agents, vasodilators, and agents that interfere with endogenous vasoactivity mechanisms.

[0058] More specific drugs or therapeutic agents include paclitaxel, rapamycin, sirolimus, everolimus, tacrolimus, heparin, diclofenac, aspirin, Epo D, dexamethasone, estradiol, halofoponone, cilostazol, geldmycin, ABT-578 (Abbott Laboratories), tramidil, liprostin, actinomycin D, Resten-NG, Ap-17, abciximab, clopidogrel, lidogre, beta-blockers, bARKct inhibitors, phospholamban inhibitors and SERCA 2 gene / protein, imiquimod, imiquimod (and other imidazoquinoline immunomodulators), human apolipoproteins (e.g., AI, AII, AIII, AIV, AV, etc.), vascular endothelial growth factor (e.g., VEGF-2), and derivatives thereof.

[0059] In some embodiments, the drug may be a macrolide immunosuppressant (mustard). In some embodiments, the macrolide immunosuppressant is rapamycin, biolimus A9, 40-O-(2-hydroxyethyl)rapamycin (everolimus), 40-O-benzyl-rapamycin, 40-O-(4'-hydroxymethyl)benzyl-rapamycin, 40-O-[4'-(1,2-dihydroxyethyl)]benzyl-rapamycin, 40-O-allyl-rapamycin, 40-O-[3'-(2,2-dimethyl-1,3-dioxolane-4(S)-yl)-propyl-2'-en-1'-yl]-rapamycin, (2':E,4'S)-40-O-(4',5'-dihydroxypentan-2'-en-1'-yl)-rapamycin, 40-O-(2-hydroxy)ethoxycarbonylmethyl -Rapamycin, 40-O-(3-hydroxy)propyl-rapamycin, 40-O-(6-hydroxy)hexyl-rapamycin, 40-O-[2-(2-hydroxy)ethoxy]ethyl-rapamycin, 40-O-[(3S)-2,2-dimethyldioxolane-3-yl]methyl-rapamycin, 40-O-[(2S)-2,3-dihydroxypropyl-1-yl]-rapamycin, 40-O-(2-acetoxy)ethyl-rapamycin, 40-O-(2-nicotinoxy)ethyl-rapamycin, 40-O-(2-(N-morpholino)acetoxy]ethyl-rapamycin, 40-O-(2-N-imidazole (26R)-26-dihydro-40-O-(2-hydroxy)ethyl-rapamycin, 40-O-[2-(N-methyl-N'-piperazinyl)acetoxy]ethyl-rapamycin, 42-O-demethyl-39,40-O,O-ethylene-rapamycin, (26R)-26-dihydro-40-O-(2-hydroxy)ethyl-rapamycin, 28-O-methylrapamycin, 40-O-(2-aminoethyl)-rapamycin, 40-O-(2-ethylaminoethyl)-rapamycin, 40-O-(2-nicotinamide ethyl)-rapamycin, 40-O-(2-(N-methyl-imidazol-2'-methylformamide)ethyl)-rapamycin, 40-O-(2-ethylaminoethyl)-rapamycin, 40-O-(2-ethylaminoethyl)-rapamycin, 40-O-(2-nicotinamide ethyl)-rapamycin, 40-O-(2-ethylamino ... (Oxycarbonylaminoethyl)-rapamycin, 40-O-(2-toluenesulfonylaminoethyl)-rapamycin, 40-O-[2-(4',5'-diethoxycarboxyl-1',2',3'-triazol-1'-yl)-ethyl]-rapamycin, 42-epi-(tetrazolyl)rapamycin (tacrolimus) and 42-[3-hydroxy-2-(hydroxymethyl)-2-methylpropionate]rapamycin (tesimolimus), (42S)-42-deoxy-42-(1H-tetrazol-1-yl)-rapamycin (zotamox), or derivatives thereof, isomers, racemates, diastereomers, prodrugs, hydrates, esters or analogs thereof.Other medications may include anti-inflammatory agents such as dexamethasone, prednisolone, corticosteroids, budesonide, estrogens, sulfasalazine, mesalazine, and their analogues; antitumor / antiproliferative / antimiotic agents such as paclitaxel, 5-fluorouracil, cisplatin, vincristine, epoch-forming alkaloids, endostatin, angiostatin, thymidine kinase inhibitors, and their analogues; anesthetics such as lidocaine, bupivacaine, ropivacaine, and their analogues; anticoagulants; and growth factors.

[0060] In some cases, everolimus can be the drug used. Everolimus, also known as 40-O-(2-hydroxyethyl)rapamycin, has the following chemical structure:

[0061] In some cases, medical devices 10, 110 providing a drug coating 34, 134 suitable for allowing a prolonged release profile can be beneficial in treating small vessel occlusion and / or vascular diseases. In some cases, where a prolonged release profile means that the useful portion of the drug remains for an extended period, improved results can be achieved, thereby increasing the efficacy of the drug in treating any condition, at least in part because the useful portion of the drug remains for a longer period. In some cases, for example, a drug coating with a prolonged release profile may mean that less drug is needed in the coating to achieve the desired effect.

[0062] In some cases, a therapeutic coating including encapsulated everolimus crystals can provide a 30-day tissue everolimus concentration of at least 0.5 nanograms of everolimus per milligram of tissue. In some cases, a therapeutic coating including encapsulated everolimus crystals can provide a 30-day tissue everolimus concentration of at least 0.6 nanograms of everolimus per milligram of tissue. In some cases, a therapeutic coating including encapsulated everolimus crystals can provide a 30-day tissue everolimus concentration of at least 0.7 nanograms of everolimus per milligram of tissue. In some cases, a therapeutic coating including encapsulated everolimus crystals can provide a 30-day tissue everolimus concentration of at least 0.8 nanograms of everolimus per milligram of tissue. In some cases, a therapeutic coating including encapsulated everolimus crystals can provide a 30-day tissue everolimus concentration of at least 0.9 nanograms of everolimus per milligram of tissue. In some cases, therapeutic coatings, including encapsulated everolimus crystals, can provide a 30-day tissue everolimus concentration of at least 1 nanogram of everolimus per milligram of tissue.

[0063] In some cases, a drug coating may comprise individual drug particles encapsulated with one or more excipients. For example, the drug particles may comprise crystals of the drug. Drug crystals may be formed in various ways. In some cases, drugs or other therapeutic agents may be obtained in an amorphous form, and various methods may be used to convert amorphous drugs or other therapeutic agents into crystalline drugs or other therapeutic agents. This document describes an exemplary method for converting an amorphous drug (e.g., amorphous everolimus) into a crystalline drug (e.g., crystalline everolimus).

[0064] Medical devices 10, 110, or portions thereof, may be coated with therapeutic compositions 34, 134. For example, the therapeutic composition may contain everolimus. Everolimus crystals may be coated with a mixture of excipients to form encapsulated everolimus crystals suspended in the coating compositions 34, 134. In some cases, medical devices 10, 110, or portions thereof may be in contact with the coating composition to form a coating on the medical device. In some cases, medical devices 10, 110, or portions thereof may be immersed in the coating composition. In some cases, vapor deposition may be used to transfer the coating composition to medical devices 10, 110. In some cases, a roll coating process may be used to transfer the coating composition to medical devices 10, 110. These are merely examples. In some cases, the coating composition may be sprayed onto medical devices 10, 110, or onto specific portions or areas of medical devices 10, 110.

[0065] For example, when the medical device 10 includes an inflatable balloon 14, a coating composition can be sprayed onto at least a portion of the outer surface of the inflatable balloon 14 to enable subsequent transfer of at least a portion of the drug coating 34 to the vessel wall. Alternative coating methods, such as dip coating, roll coating, vapor deposition, etc., and / or other suitable coating methods, can be used. Applying the coating composition to other parts of the medical device (e.g., the balloon catheter shaft) may offer little or no benefit, as the balloon catheter shaft, for example, may at most come into accidental contact with the vessel wall.

[0066] For example, when the medical device is or includes an expandable stent 110, a coating composition can be sprayed onto at least a portion of the outer surface 144 of the expandable stent 110 to enable subsequent transfer of at least a portion of the drug coating to the vessel wall. The benefit of applying the coating composition to the inner surface 146 of the expandable stent 110 may be reduced because the inner surface of the expandable stent 110 is less likely to come into contact with the vessel wall. Transferring at least a portion of the drug coating to the blood flowing through the expandable stent may have some benefits because the blood will subsequently come into contact with the vessel wall, particularly downstream of the location where the expandable stent 110 is deployed. Therefore, the coating composition can be applied to the inner surface 146 and / or the lateral sidewalls of the expandable stent 110.

[0067] In addition to the therapeutic agent, the coating compositions 34 and 134 may also include one or more excipients. Excipients may be used to enhance the durability of the drug coatings 34 and 134, promote drug delivery to the lesion, and / or control drug dissolution. Exemplary excipients may include polycaprolactone (PCL), a biodegradable polyester. PCL has the following chemical structure:

[0068] Another exemplary excipient may include acetylacetic acid tributyl ester (ATBC), which in some cases may be referred to by its IUPAC name 2-acetoxypropane-1,2,3-tricarboxylic acid tributyl ester. ATBC has the following chemical structure:

[0069] Another exemplary excipient may include poloxamer, which is a nonionic triblock copolymer. The triblock may comprise a hydrophobic polyoxypropylene (poly(propylene oxide)) central chain and a hydrophilic polyoxyethylene (poly(ethylene oxide)) chain on either side thereof. The lengths of the polymer blocks can be varied or customized to produce many different poloxamers with different properties. Poloxamer may be more commonly referred to as… (Manufactured by BASF in Ludwigshafen, Germany). Poloxamer can have the following general chemical structures: Where x, y, and z are the number of repeating units in each block (e.g., the degree of aggregation).

[0070] Another exemplary excipient may include acetyl citrate trihexyl ester (ATHC), which in some cases may be referred to by its IUPAC name 2-(acetoxy)propane-1,2,3-tricarboxylic acid trihexyl ester. ATHC has the following chemical structure:

[0071] In some cases, one or more excipients may optionally comprise two or more excipients or mixtures of excipients. In a first example, the mixture of excipients may include PCL and ATBC. In some examples, additional components may also be used in coating compositions 34, 134. In some cases, antioxidants, such as, but not limited to, butylated hydroxytoluene (BHT), may be used in the composition. As an example, coating everolimus crystals with an excipient mixture to form encapsulated everolimus crystals suspended in the coating composition may include suspending the everolimus crystals in a first premix comprising ATBC. A second premix comprising PCL may be added to the first premix. When the second premix comprising PCL is added to the first premix comprising suspended everolimus crystals and ATBC, the PCL mixes with the ATBC and coats the everolimus crystals. This forms a coating composition comprising encapsulated everolimus crystals retained within the suspension. In some examples, each individual everolimus crystal may have a coating less than 1 micrometer thick (e.g., a coating formed of PCL and ATBC).

[0072] PCL can have molecular weights in the range of about 10,000 g / mol or less. It is anticipated that PCL with a molecular weight less than 10,000 g / mol may increase the tendency of PCL to remain in solution and / or to be dispersible in organic solvent systems that will also disperse everolimus.

[0073] In some cases, the encapsulated everolimus crystals may be considered to comprise 0 to 30 wt% ATBC, 0 to 30 wt% PCL, and 70 to 100 wt% everolimus. If provided, BHT has 0.5% or less of the weight percentage of everolimus (or the therapeutic agent). In some cases, the encapsulated everolimus crystals may be considered to comprise 5 to 20 wt% ATBC, 5 to 20 wt% PCL, and 60 to 90 wt% everolimus. In some cases, the encapsulated everolimus crystals may comprise about 80 wt% everolimus and about 20 wt% excipients, wherein the excipients are a combination of ATBC and PCL. For example, the excipients may be approximately equal amounts of ATBC and PCL. In other examples, the weight ratio of excipients may range from about 1:10 ATBC to PCL to about 10:1 ATBC to PCL. In one illustrative example, the final coating composition may have a therapeutic agent to ATBC to PCL weight ratio of 8:1:1.

[0074] In some cases, the first premix may comprise a single solvent, and preparing the first premix may include placing the solvent in a suitable container and adding crystalline everolimus and ATBC. When the solvent comprises a mixture of materials, preparing the first premix may include combining or mixing two or more solvents prior to adding crystalline everolimus and ATBC. In some examples, ATBC may be mixed with the solvent before adding the ATBC / solvent premix to the therapeutic agent. This may help prevent the therapeutic agent from completely dissolving in the first premix.

[0075] In at least some cases, the solvent used to form the first premix may include alcohols, such as, but not limited to, methanol, ethanol (EtOH), isopropanol (IPA), n-butanol, isobutanol, or tert-butanol; acetonitrile (ACN); ethers, such as, but not limited to, tetrahydrofuran (THF), isopropyl ether (IPE), or diethyl ether (DEE); ketone solvents, such as, but not limited to, acetone, 2-butanone (MEK), or methyl isobutyl ketone (MIBK); halogenated solvents, such as, but not limited to, dichloromethane (DCM), monofluorobenzene (MFB), α,α,α-trifluorotoluene (TFT), nitromethane (NM), or ethyl trifluoroacetate (ETFA); aliphatic or alicyclic hydrocarbons, such as, but not limited to, hexane, heptane, cyclohexane, etc.; aromatic hydrocarbons, such as, but not limited to, toluene or xylene; and ester solvents, such as, but not limited to, ethyl acetate. For example, mixed solvents such as, but not limited to, ethyl acetate / heptane, acetone / water, IPA / water, IPA / THF, methanol / water, IPA / heptane, or THF / heptane can also be used. Other solvent systems have also been considered. In some cases, the solvent used to form the first premix may include cyclohexane.

[0076] In some embodiments, the process of forming the first premix can be carried out at ambient temperature and atmospheric pressure. In some cases, the first premix can be formed as part of a process for converting amorphous everolimus into crystalline everolimus. Alternatively or additionally, ATBC can be added to a suspension, for example, produced by a crystallization process. In other examples, the first premix can be formed by first mixing ATBC with a solvent and then adding crystalline everolimus (or by adding the ATBC / solvent premix to crystalline everolimus).

[0077] In some cases, the first premix may include crystalline everolimus suspended in a solvent (e.g., cyclohexane). Alternatively, other solvents may be used, such as isopropanol, ethanol or similar alcohols, acetone, tetrahydrofuran, or acetonitrile. In some cases, the first premix may also include other additives, such as, but not limited to, BHT. BHT can prevent the degradation of the therapeutic agent before the coatings 34 and 134 are deployed in the body. It should be understood that crystalline everolimus can be minimally dissolved in the solvent, thus forming a suspension. Therefore, when suspended in the first solvent, crystalline everolimus can maintain its crystal size. ATBC should be at least partially dissolved in the solvent.

[0078] In some cases, the second premix may comprise a single solvent, and preparing the second premix may include placing the solvent in a suitable container and adding PCL. When the solvent comprises a mixture of materials, preparing the second premix may include combining or mixing two or more solvents prior to adding PCL.

[0079] In at least some cases, the solvent used to form the second premix may include: alcohols, such as but not limited to methanol, ethanol (EtOH), isopropanol (IPA), n-butanol, isobutanol, or tert-butanol; acetonitrile (ACN); ethers, such as but not limited to tetrahydrofuran (THF), isopropyl ether (IPE), or diethyl ether (DEE); ketone solvents, such as but not limited to acetone, 2-butanone (MEK), or methyl isobutyl ketone (MIBK); halogenated solvents, such as but not limited to dichloromethane (DCM), monofluorobenzene (MFB), α,α,α-trifluorotoluene (TFT), nitromethane (NM), and ethyl trifluoroacetate (ETFA); aliphatic hydrocarbons, such as but not limited to hexane, heptane, etc.; aromatic hydrocarbons, such as but not limited to toluene or xylene; and ester solvents, such as but not limited to ethyl acetate. For example, mixed solvents, such as ethyl acetate / heptane, acetone / water, IPA / water, methanol / water, IPA / heptane, or THF / heptane, may also be used. Other solvent systems are also considered. In some cases, the solvent used to form the second premix may include ethyl acetate.

[0080] In some cases, the process of forming the second premix can be carried out at ambient temperature and atmospheric pressure. The second premix may include PCL and one or more solvents. In some cases, the second premix may include PCL dissolved in a solvent (e.g., ethyl acetate), but other solvents may also be used, such as heptane or similar alkanes or even water. The PCL will dissolve in ethyl acetate to provide a solution.

[0081] It is anticipated that at least one of the first or second premixes may include a polar solvent, and the other of the first or second premixes may include a nonpolar solvent. For example, the first premix may include cyclohexane as a nonpolar solvent, and the second premix may include ethyl acetate as a polar solvent. The combination of polar and nonpolar solvents can facilitate the dispersion of everolimus crystals. The dispersion of everolimus crystals can facilitate the distribution of controlled, consistent amounts on a medical device to produce a pharmaceutical coating composition. The organic solvent (e.g., cyclohexane and ethyl acetate in the examples given above) evaporates during the coating manufacturing process. Thus, the pharmaceutical coatings 34, 134 on the medical device may include a drug, one or more excipients, and optionally an antioxidant.

[0082] In some cases, the second premix can be added to the first premix after the first and second premixes have been formed. In another example, crystalline everolimus can be added to a container, followed by the first premix containing ATBC and any other additives. Next, the second premix containing PCL can be added to the everolimus / ATBC mixture. As a result, ATBC and PCL mix together and coat the individual crystals of everolimus, producing encapsulated everolimus crystals. In some cases, this process can occur rapidly. In some cases, the process can occur more slowly. The first premix may include a volume of cyclohexane, and the second premix may include a volume of ethyl acetate to provide an ethyl acetate to cyclohexane ratio in the range of about 1:4 to about 1:10 when the second premix is ​​added to the first premix. It should be understood that excessively high everolimus solubility will dissolve the everolimus crystals. It should be understood that the described process of forming the first premix, forming the second premix, and then combining the first and second premixes is merely illustrative, and other processes may be considered.

[0083] Surprisingly, some combinations of excipients have been found to provide better protection than the expected effect of the excipient combination. For example, in some cases, synergistic combinations of excipients include polycaprolactone (PCL). In these and other cases, synergistic combinations of excipients include acetylated tributyl citrate (ATBC). In one example, a synergistic combination of excipients may include a single-component polycaprolactone (PCL) to a single-component acetylated tributyl citrate (ATBC). PCL is a bioabsorbable excipient that can provide coating durability, adhesion to the vessel wall, allow for a longer residence time of the drug coating 34, 134, and a dissolution barrier (e.g., inhibiting or slowing the dissolution of the therapeutic agent). Over time, PCL may be reabsorbed into the body. ATBC can be a plasticizer or a thickener that hardens the coating composition and can slow the dissolution of the therapeutic agent.

[0084] In another example, the mixture of excipients may include poloxamer and ATBC. In some examples, additional components may also be used in coating compositions 34, 134. In some cases, antioxidants, such as, but not limited to, butylated hydroxytoluene (BHT), may be used in the composition. As an example, coating everolimus crystals with an excipient mixture to form encapsulated everolimus crystals suspended in the coating composition may include suspending the everolimus crystals in a first premix containing ATBC. A second premix comprising poloxamer may be added to the first premix. When the second premix comprising poloxamer is added to the first premix comprising suspended everolimus crystals and ATBC, the poloxamer is mixed with the ATBC and coated onto the everolimus crystals. This forms a coating composition containing encapsulated everolimus crystals retained within the suspension. In some examples, each individual everolimus crystal may have a coating less than 1 micrometer thick (e.g., a coating formed from poloxamer and ATBC).

[0085] In some cases, poloxamer can be either poloxamer 181 or poloxamer 188. Typically, the first two digits of the poloxamer number multiplied by 100 give the molecular weight of the polyoxypropylene core, and the last digit multiplied by 10 gives the percentage of polyethylene oxide content. Therefore, poloxamer 181 will contain polyoxypropylene with a molecular weight of 1800 (e.g., 18 x 100) and will also contain 10% polyethylene oxide (e.g., 1 x 10), while poloxamer 188 will contain polyoxypropylene with a molecular weight of 1800 (e.g., 18 x 100) and will also contain 80% polyethylene oxide (e.g., 8 x 10). However, in some cases, other grades of poloxamer can be used as needed. It is anticipated that poloxamers with smaller molecular weights may increase the tendency for poloxamer to remain in solution and / or to dispersible in organic solvent systems that will also disperse everolimus. For example, poloxamers can have molecular weights of less than 10,000 Daltons (Da). Poloxamer is known to gel at body temperature. It is anticipated that gelled poloxamer can act as a diffusion barrier. Furthermore, it is expected that the gelation can be thermally reversible.

[0086] In some cases, encapsulated everolimus crystals may be considered to comprise 0 to 30 wt% ATBC, 0 to 30 wt% poloxamer, and 70 to 100 wt% everolimus. If provided, BHT has 0.5% or less of the weight percentage of everolimus (or the therapeutic agent). In some cases, encapsulated everolimus crystals may be considered to comprise 5 to 20 wt% ATBC, 5 to 20 wt% poloxamer, and 60 to 90 wt% everolimus. Compositions within these ranges have been found to have improved dissolution rates relative to formulations using only ATBC as a single excipient. In some cases, encapsulated everolimus crystals may comprise about 80 wt% everolimus and about 20 wt% excipients, wherein the excipients are a combination of ATBC and poloxamer. For example, the excipients may be approximately equal amounts of ATBC and poloxamer. In other examples, the weight ratio of excipients can range from about 1:10 ATBC to poloxamer to about 10:1 ATBC to poloxamer. In one illustrative example, the final coating composition can have a weight ratio of therapeutic agent to ATBC to poloxamer of 8:1:1.

[0087] In some cases, the first premix may comprise a single solvent, and preparing the first premix may include placing the solvent in a suitable container and adding crystalline everolimus and ATBC. When the solvent comprises a mixture of materials, preparing the first premix may include combining or mixing two or more solvents prior to adding crystalline everolimus and ATBC. In some examples, ATBC may be mixed with the solvent before adding the ATBC / solvent premix to the therapeutic agent. This may help prevent the therapeutic agent from completely dissolving in the first premix.

[0088] In at least some cases, the solvent used to form the first premix may include alcohols, such as, but not limited to, methanol, ethanol (EtOH), isopropanol (IPA), n-butanol, isobutanol, or tert-butanol; acetonitrile (ACN); ethers, such as, but not limited to, tetrahydrofuran (THF), isopropyl ether (IPE), or diethyl ether (DEE); ketone solvents, such as, but not limited to, acetone, 2-butanone (MEK), or methyl isobutyl ketone (MIBK); halogenated solvents, such as, but not limited to, dichloromethane (DCM), monofluorobenzene (MFB), α,α,α-trifluorotoluene (TFT), nitromethane (NM), or ethyl trifluoroacetate (ETFA); aliphatic or alicyclic hydrocarbons, such as, but not limited to, hexane, heptane, cyclohexane, etc.; aromatic hydrocarbons, such as, but not limited to, toluene or xylene; and ester solvents, such as, but not limited to, ethyl acetate. For example, mixed solvents such as, but not limited to, ethyl acetate / heptane, acetone / water, IPA / water, IPA / THF, methanol / water, IPA / heptane, or THF / heptane can also be used. Other solvent systems have also been considered. In some cases, the solvent used to form the first premix may include cyclohexane.

[0089] In some embodiments, the process of forming the first premix can be carried out at ambient temperature and atmospheric pressure. In some cases, the first premix can be formed as part of a process for converting amorphous everolimus into crystalline everolimus. Alternatively or additionally, ATBC can be added to a suspension, for example, produced by a crystallization process. In other examples, the first premix can be formed by first mixing ATBC with a solvent and then adding crystalline everolimus (or by adding the ATBC / solvent premix to crystalline everolimus).

[0090] In some cases, the first premix may include crystalline everolimus suspended in a solvent (e.g., cyclohexane). Alternatively, other solvents may be used, such as isopropanol, ethanol or similar alcohols, acetone, tetrahydrofuran, or acetonitrile. In some cases, the first premix may also include other additives, such as, but not limited to, BHT. BHT can prevent the degradation of the therapeutic agent before the coatings 34 and 134 are deployed in the body. It should be understood that crystalline everolimus can be minimally soluble in the solvent and will therefore be a suspension. Thus, when suspended in the first solvent, crystalline everolimus can maintain its crystal size. ATBC should be at least partially dissolved in the solvent.

[0091] In some cases, the second premix may comprise a single solvent, and preparing the second premix may include placing the solvent in a suitable container and adding poloxamer. When the solvent comprises a mixture of materials, preparing the second premix may include combining or mixing two or more solvents prior to adding poloxamer.

[0092] In at least some cases, the solvent used to form the second premix may include alcohols, such as, but not limited to, methanol, ethanol (EtOH), isopropanol (IPA), n-butanol, isobutanol, or tert-butanol; acetonitrile (ACN); ethers, such as, but not limited to, tetrahydrofuran (THF), isopropyl ether (IPE), and diethyl ether (DEE); ketone solvents, such as, but not limited to, acetone, 2-butanone (MEK), or methyl isobutyl ketone (MIBK); halogenated solvents, such as, but not limited to, dichloromethane (DCM), monofluorobenzene (MFB), α,α,α-trifluorotoluene (TFT), nitromethane (NM), and ethyl trifluoroacetate (ETFA); aliphatic hydrocarbons, such as, but not limited to, hexane, heptane, etc.; aromatic hydrocarbons, such as, but not limited to, toluene or xylene; and ester solvents, such as, but not limited to, ethyl acetate. For example, mixed solvents, such as ethyl acetate / heptane, acetone / water, IPA / water, methanol / water, IPA / heptane, or THF / heptane, may also be used. Other solvent systems are also considered. In some cases, the solvent used to form the second premix may include ethyl acetate.

[0093] In some cases, the formation of the second premix can be carried out at ambient temperature and atmospheric pressure. The second premix may include poloxamer and one or more solvents. In some cases, the second premix may include poloxamer dissolved in a solvent (e.g., ethyl acetate), but other solvents may also be used, such as heptane or similar alkanes or even water. The poloxamer will be dissolved in ethyl acetate to provide a solution.

[0094] It is anticipated that at least one of the first or second premixes may include a polar solvent, and the other of the first or second premixes may include a nonpolar solvent. For example, the first premix may include cyclohexane as a nonpolar solvent, and the second premix may include ethyl acetate as a polar solvent. The combination of polar and nonpolar solvents can facilitate the dispersion of everolimus crystals. The dispersion of everolimus crystals can facilitate the distribution of controlled, consistent amounts on a medical device to produce a pharmaceutical coating composition. The organic solvent (e.g., cyclohexane and ethyl acetate in the examples given above) evaporates during the coating manufacturing process. Thus, the pharmaceutical coatings 34, 134 on the medical device may include a drug, one or more excipients, and optionally an antioxidant.

[0095] In some cases, the second premix can be added to the first premix after the first and second premixes have been formed. In another example, crystalline everolimus can be added to a container, followed by the first premix containing ATBC and any other additives to the container containing everolimus. Next, the second premix containing poloxamer can be added to the everolimus / ATBC mixture. As a result, ATBC and poloxamer mix together and coat the individual crystals of everolimus, producing encapsulated everolimus crystals. In some cases, this process can occur rapidly. In some cases, the process can occur more slowly. The first premix may include a volume of cyclohexane, and the second premix may include a volume of ethyl acetate to provide an ethyl acetate to cyclohexane ratio in the range of about 1:4 to about 1:10 when the second premix is ​​added to the first premix. It should be understood that excessive everolimus solubility will dissolve the everolimus crystals. It should be understood that the described process of forming the first premix, forming the second premix, and then combining the first and second premixes is merely illustrative, and other processes may be considered.

[0096] Surprisingly, some combinations of excipients have been found to provide better protection than the expected effect of the excipient combination. For example, in some cases, synergistic combinations of excipients include poloxamer. In these and other cases, synergistic combinations of excipients include acetyl tributyl citrate (ATBC). In one example, a synergistic combination of excipients may include a single-component poloxamer to a single-component acetyl tributyl citrate (ATBC). Poloxamer is a reversible thermogel excipient that can provide coating durability, adhesion to the blood vessel wall, allow for a longer residence time of the drug coating 34, 134, and a dissolution barrier (e.g., inhibiting or slowing the dissolution of the therapeutic agent). Poloxamer may be reabsorbed into the body over time. ATBC can be a plasticizer or thickener that hardens the coating composition and can slow the dissolution of the therapeutic agent.

[0097] In another example, the excipient may contain acetylated trihexyl citrate (ATBC). ATHC may be a plasticizer that hardens the coating composition and can slow the dissolution of the therapeutic agent. Because ATHC is more nonpolar than ATBC, it can slow the dissolution of the therapeutic agent to a greater extent than ATBC. In some examples, additional components may also be used in coating compositions 34, 134. In some cases, antioxidants, such as, but not limited to, butylated hydroxytoluene (BHT), may be used in the composition. As an example, coating everolimus crystals with an excipient to form encapsulated everolimus crystals suspended in the coating composition may include suspending the everolimus crystals in a first premix containing ATHC. A second premix or a second solvent may be added to the first premix. When the second premix is ​​added to the first premix comprising the suspended everolimus crystals and ATHC, the everolimus crystals are coated with ATBC. This forms a coating composition containing encapsulated everolimus crystals retained within the suspension. In some examples, each individual everolimus crystal may have a coating less than 1 micrometer thick (e.g., a coating formed by ATHC).

[0098] In some cases, encapsulated everolimus crystals may be considered to comprise about 0 to about 30% by weight of ATHC and about 70 to about 100% by weight of everolimus. If provided, BHT has 0.5% or less by weight of everolimus (or the therapeutic agent). In some cases, encapsulated everolimus crystals may be considered to comprise about 5 to 20% by weight of ATHC and about 80 to about 95% by weight of everolimus. Compositions within these ranges have been found to have improved dissolution rates relative to formulations using only ATBC as a single excipient. In some cases, encapsulated everolimus crystals may comprise about 85% by weight of everolimus and about 15% by weight of ATHC.

[0099] In some examples, the drug coatings 34, 134 may include another excipient, such as, but not limited to, ethylcellulose, polycaprolactone, and / or poloxamer. In some cases, the encapsulated everolimus crystals may include about 80% by weight everolimus and about 20% by weight excipients, wherein the excipients are a combination of ATHC and PCL or a combination of ATHC and poloxamer. For example, the excipients may be approximately equal parts of ATHC and PCL or equal parts of ATHC and poloxamer. In other examples, the weight ratio of excipients may range from about 1:10 ATHC to PCL to about 10:1 ATHC to PCL. In still other examples, the weight ratio of excipients may range from about 1:10 ATHC to poloxamer to about 10:1 ATHC to poloxamer. The final coating composition may have a therapeutic agent to ATHC to PCL weight ratio of 8:1:1. In another example, the excipients may be more than half ATHC and less than half EC. For example, excipients may include two parts ATHC and one part EC.

[0100] In some cases, the first premix may comprise a single solvent, and preparing the first premix may include placing the solvent in a suitable container and adding crystalline everolimus and ATHC. When the solvent comprises a mixture of materials, preparing the first premix may include combining or mixing two or more solvents prior to adding crystalline everolimus and ATHC. In some examples, ATHC may be mixed with the solvent before adding the ATHC / solvent premix to the therapeutic agent. This may help prevent the therapeutic agent from completely dissolving in the first premix.

[0101] In at least some cases, the solvent used to form the first premix may include alcohols, such as, but not limited to, methanol, ethanol (EtOH), isopropanol (IPA), n-butanol, isobutanol, or tert-butanol; acetonitrile (ACN); ethers, such as, but not limited to, tetrahydrofuran (THF), isopropyl ether (IPE), or diethyl ether (DEE); ketone solvents, such as, but not limited to, acetone, 2-butanone (MEK), or methyl isobutyl ketone (MIBK); halogenated solvents, such as, but not limited to, dichloromethane (DCM), monofluorobenzene (MFB), α,α,α-trifluorotoluene (TFT), nitromethane (NM), or ethyl trifluoroacetate (ETFA); aliphatic or alicyclic hydrocarbons, such as, but not limited to, hexane, heptane, cyclohexane, etc.; aromatic hydrocarbons, such as, but not limited to, toluene or xylene; and ester solvents, such as, but not limited to, ethyl acetate. For example, mixed solvents such as, but not limited to, ethyl acetate / heptane, acetone / water, IPA / water, IPA / THF, methanol / water, IPA / heptane, or THF / heptane can also be used. Other solvent systems have also been considered. In some cases, the solvent used to form the first premix may include cyclohexane.

[0102] In some embodiments, the process of forming the first premix can be carried out at ambient temperature and atmospheric pressure. In some cases, the first premix can be formed as part of a process for converting amorphous everolimus into crystalline everolimus. Alternatively or additionally, ATHC can be added to a suspension, for example, produced by a crystallization process. In other examples, the first premix can be formed by first mixing ATHC with a solvent and then adding crystalline everolimus (or adding the ATHC / solvent premix to crystalline everolimus).

[0103] In some cases, the first premix may include crystalline everolimus suspended in a solvent (e.g., cyclohexane). Alternatively, other solvents may be used, such as isopropanol, ethanol or similar alcohols, acetone, tetrahydrofuran, or acetonitrile. In some cases, the first premix may also include other additives, such as, but not limited to, BHT. BHT can prevent the degradation of the therapeutic agent before the coatings 34 and 134 are deployed in the body. It should be understood that crystalline everolimus can be minimally soluble in the solvent and will therefore be a suspension. Thus, when suspended in the first solvent, crystalline everolimus can maintain its crystal size. ATHC should be at least partially dissolved in the solvent.

[0104] In some cases, the second premix may comprise a single solvent-based compound without additional excipients, and preparing the second premix may include placing the solvent in a suitable container. When the solvent comprises a mixture of materials, preparing the second premix may include combining or mixing two or more solvents. It is contemplated that, in some embodiments, the second premix may include the addition of polycaprolactone or poloxamer to the solvent, such that the final drug coating 34, 134 comprises the therapeutic agent ATHC, polycaprolactone, and optionally BHT, or the therapeutic agent ATHC, poloxamer, and optionally BHT.

[0105] In at least some cases, the solvent used to form the second premix may include alcohols, such as, but not limited to, methanol, ethanol (EtOH), isopropanol (IPA), n-butanol, isobutanol, or tert-butanol; acetonitrile (ACN); ethers, such as, but not limited to, tetrahydrofuran (THF), isopropyl ether (IPE), and diethyl ether (DEE); ketone solvents, such as, but not limited to, acetone, 2-butanone (MEK), or methyl isobutyl ketone (MIBK); halogenated solvents, such as, but not limited to, dichloromethane (DCM), monofluorobenzene (MFB), α,α,α-trifluorotoluene (TFT), nitromethane (NM), and ethyl trifluoroacetate (ETFA); aliphatic hydrocarbons, such as, but not limited to, hexane, heptane, etc.; aromatic hydrocarbons, such as, but not limited to, toluene or xylene; and ester solvents, such as, but not limited to, ethyl acetate. For example, mixed solvents, such as ethyl acetate / heptane, acetone / water, IPA / water, methanol / water, IPA / heptane, or THF / heptane, may also be used. Other solvent systems are also considered. In some cases, the solvent used to form the second premix may include ethyl acetate.

[0106] In some cases, the process of forming the second premix can be carried out at ambient temperature and atmospheric pressure. The second premix may include one or more solvents. In some cases, the second premix may include a solvent (e.g., ethyl acetate), but other solvents may also be used, such as heptane or similar alkanes or even water. In some cases, another excipient may be added to the second premix, such as, but not limited to, ethyl cellulose, polycaprolactone, and / or poloxamer.

[0107] It is anticipated that at least one of the first or second premixes may include a polar solvent, and the other of the first or second premixes may include a nonpolar solvent. For example, the first premix may include cyclohexane as a nonpolar solvent, and the second premix may include ethyl acetate as a polar solvent. The combination of polar and nonpolar solvents can facilitate the dispersion of everolimus crystals. The dispersion of everolimus crystals can facilitate the distribution of controlled, consistent amounts on a medical device to produce a pharmaceutical coating composition. The organic solvent (e.g., cyclohexane and ethyl acetate in the examples given above) evaporates during the coating manufacturing process. Thus, the pharmaceutical coatings 34, 134 on the medical device may include a drug, one or more excipients, and optionally an antioxidant.

[0108] In some cases, the second premix can be added to the first premix after the first and second premixes have been formed. In another example, crystalline everolimus can be added to a container, followed by the first premix containing ATHC and any other additives. Next, the second premix (or a second solvent) can be added to the everolimus / ATHC mixture. As a result, ATHC coats the individual crystals of everolimus, producing encapsulated everolimus crystals. In some cases, this process can occur rapidly. In some cases, the process can occur more slowly. The first premix may include a volume of cyclohexane, and the second premix may include a volume of ethyl acetate to provide an ethyl acetate to cyclohexane ratio in the range of about 1:4 to about 1:10 when the second premix is ​​added to the first premix. It should be understood that excessive everolimus solubility will dissolve the everolimus crystals. It should be understood that the described process of forming the first premix, forming the second premix, and then combining the first and second premixes is merely illustrative, and other processes may be considered. Methods for forming crystalline everolimus

[0109] Some exemplary methods for converting an amorphous form of a drug into a crystalline form may typically include (a) preparing a suitable solvent, (b) preparing a nucleation initiator with the solvent, (c) combining / mixing the nucleation initiator with the amorphous form of the drug to form a drug precursor dispersion / suspension, and (d) incubating the drug precursor dispersion / suspension to allow the amorphous form of the drug to convert into a crystalline form. Using a suitable surfactant with the drug precursor dispersion / suspension can allow the formation of drug crystals with a desired morphology, allow the formation of drug crystals with a desired size and / or shape and / or aspect ratio, allow the formation of coated suspensions with desired stability, and combinations thereof. Therefore, at least some of the methods for converting an amorphous form of a drug into a crystalline form include (a) preparing a suitable solvent, (b) preparing a surfactant solution by combining / mixing a surfactant with the solvent, (c) preparing a nucleating initiator with the solvent, (d) combining / mixing the nucleating initiator with the surfactant solution and the amorphous form of the drug to form a drug precursor dispersion / suspension, and (e) incubating the drug precursor dispersion / suspension to allow the amorphous form of the drug to convert into a crystalline form. Other methods for converting an amorphous form of a drug into a crystalline form are also considered.

[0110] As illustrated herein, exemplary methods for converting an amorphous form of a drug into a crystalline form include preparing a suitable solvent. When the solvent is a single material, preparing a suitable solvent may involve placing the solvent in a suitable container. When the solvent is a mixture of materials, preparing a suitable solvent may involve combining or mixing the solvents.

[0111] In at least some cases, the solvent may include alcohols, such as, but not limited to, methanol, ethanol (EtOH), isopropanol (IPA), n-butanol, isobutanol, or tert-butanol; acetonitrile (ACN); ethers, such as, but not limited to, tetrahydrofuran (THF), isopropyl ether (IPE), and diethyl ether (DEE); ketone solvents, such as, but not limited to, acetone, 2-butanone (MEK), or methyl isobutyl ketone (MIBK); halogenated solvents, such as, but not limited to, dichloromethane (DCM), monofluorobenzene (MFB), α,α,α-trifluorotoluene (TFT), nitromethane (NM), and ethyl trifluoroacetate (ETFA); aliphatic hydrocarbons, such as, but not limited to, hexane, heptane, etc.; aromatic hydrocarbons, such as, but not limited to, toluene or xylene; and ester solvents, such as, but not limited to, ethyl acetate. For example, mixed solvents, such as ethyl acetate / heptane, acetone / water, IPA / water, IPA / THF, methanol / water, IPA / heptane, or THF / heptane, may also be used.

[0112] When using a mixture of solvents, the mixture can have suitable proportions of each material. For example, some exemplary solvents may include a mixture of ethyl acetate and heptane. The ratio of ethyl acetate to heptane may be in the range of about 1:4 to 1:30, or about 1:4 to 1:20, or about 1:20. Other mixtures and / or proportions are considered. Therefore, in some cases, methods for converting an amorphous form of a drug into a crystalline form may include preparing a solvent, for example by mixing ethyl acetate with heptane.

[0113] Methods for converting amorphous forms of drugs into crystalline forms may include preparing surfactant solutions (e.g., preparing surfactant solutions with solvents). In at least some cases, the surfactant may include Tween 20. TM (e.g., polysorbate 20, polyoxyethylene (20) sorbitan monooleate or PEG (20) sorbitan monooleate), Tween 80 TM (e.g., polysorbate 80, polyoxyethylene (80) sorbitan monooleate or PEG (80) sorbitan monooleate), SPAN TM 80. SPAN TM 20. TRITON TM X-100, TRITON TM 400. Nonionic surfactants and / or their analogues. The surfactant solution may have a suitable concentration. For example, the concentration of the surfactant solution may be about 0.01-1% (by weight), about 0.05-0.5% (by weight), or about 0.1% (by weight).

[0114] Methods for converting an amorphous form of a drug into a crystalline form may include preparing a nucleating initiator (e.g., preparing a nucleating initiator with a solvent). This process or step may also be referred to as “inoculation.” In at least some cases, the nucleating initiator may comprise the crystalline form of the drug suspended in a suitable solvent (e.g., which may or may not be the same solvent used to dissolve the amorphous form of the drug). When the drug used is everolimus, the nucleating initiator may comprise a suitable amount of crystalline everolimus in a suitable solvent. The concentration of crystalline everolimus in the solvent may be about 0.1-10%, or about 0.1-2%, or about 0.5%. Crystalline everolimus may comprise everolimus microcrystals formed as described herein. Alternatively, crystalline everolimus may comprise everolimus crystals of different morphologies.

[0115] Methods for converting an amorphous form of a drug into a crystalline form may include mixing and / or combining a nucleating initiator with a surfactant solution and the amorphous form of the drug to form a drug prodrug dispersion / suspension. The amount of the amorphous form of the drug added may vary. For example, about 0.5-100 mg everolimus may be added / dispersed per milliliter (e.g., per milliliter of solvent), or about 1-50 mg everolimus may be added / dispersed per milliliter, or about 10-30 mg everolimus may be added / dispersed per milliliter, or about 20 mg everolimus may be dissolved per milliliter. In at least some cases, the drug dispersion solution may be referred to as and / or resemble a slurry.

[0116] Drug prodrug dispersions / suspensions can be incubated to allow the amorphous form of the drug to be converted into a crystalline form. In some cases, incubation can be carried out over a suitable time period of approximately several hours to several days. For example, incubation can be carried out for 24 hours. In some of these and other cases, incubation may include a high-temperature or warm-temperature incubation step at a suitable temperature (e.g., about 20°C to 80°C, or about 40°C to 60°C, or about 50°C). In some cases, high-temperature incubation may include agitation of the drug prodrug dispersion (e.g., using a suitable device, such as an orbital oscillator). However, in other cases, the high-temperature incubation step does not require stirring / agitation. High-temperature incubation steps can be carried out over a suitable time period of approximately several hours to several days. For example, incubation can be carried out for about two days. In some of these and other cases, incubation may also include a low-temperature or cold-temperature incubation step at a suitable temperature (e.g., about -10°C to 10°C, or about 0°C to 5°C, or about 4°C). Low-temperature incubation steps can be carried out over a suitable time period of approximately several hours to several days. For example, incubation can last for several days.

[0117] In some cases, methods for converting an amorphous form of a drug into a crystalline form may include one or more of the following: (a) filtering the crystalline form of the drug, (b) washing the crystalline form of the drug, and (c) drying the crystalline form of the drug. For example, methods are considered that include filtering, washing, and drying the crystalline form of the drug. When doing so, solvents, surfactants, or both can be removed substantially completely from the drug crystals.

[0118] The crystalline form of a drug formed by this method (e.g., the crystalline form of everolimus) can result in crystals having a morphology, size, and shape that allow the formed crystals to be described as microcrystals. In particular, the use of a surfactant and a suitable solvent mixture mixed in appropriate proportions during the crystallization process leads to the formation of microcrystals. For the purposes of this disclosure, microcrystals can be understood as crystals that can be described as relatively flat flakes. Some exemplary sizes may include microcrystals having a width of less than about 3 micrometers (e.g., a non-zero width of less than about 3 micrometers), a thickness of less than about 1 micrometer (e.g., a non-zero thickness of less than about 1 micrometer), and a length of less than about 10 micrometers (e.g., a non-zero length of less than about 10 micrometers). Microcrystals can be desirable for many reasons. For example, in some crystallization processes that form “larger,” rod-shaped, or “non-micrometer” crystals, the resulting crystals can settle rapidly when suspended in a coating / dispersion. This can make the application of drug crystals to medical devices more challenging. Microcrystals formed by the methods described herein can, for example, be suspended in a coating material / dispersion and remain in suspension for an extended period of time (e.g., about several months or longer). Experimental results

[0119] Figure 8 This is a graph illustrating experimental data on relative drug release rates when ATBC is used alone as an excipient, when a combination of ATBC and poloxamer is used as an excipient, and when a combination of ATBC and PCL is used as an excipient. The compositions tested are provided in Table 1 below. Figure 8 Drug release data for two samples, including crystalline everolimus encapsulated only with ATBC, are shown graphically as solid lines with triangles. Other samples included crystalline everolimus encapsulated with both ATBC and PCL, shown graphically as solid lines with circles, squares, or rhombuses. Further samples included crystalline everolimus encapsulated with a mixture of ATBC and poloxamer, shown graphically as thick solid lines, solid lines with solid circles, or dashed lines with solid circles. It can be seen that the sample using ATBC only as an excipient elutes approximately 40% of the initial amount of everolimus after approximately 20 hours. In contrast, samples including both PCL and ATBC as excipients, and some samples including both poloxamer and ATBC, elute only approximately 25% to approximately 35% of the initial amount of everolimus after approximately 20 hours.

[0120] Since less drug loss occurs within 20 hours compared to using ATBC alone, the combination of ATBC and PCL, and some combinations of ATBC and poloxamer, and since each composition contains the same total amount of excipients, it can be appropriately stated that the use of ATBC and PCL, or the combination of ATBC and poloxamer as excipients, can be considered to provide a synergistic improvement in drug release rate. Tested composition Test program

[0121] The test solution was prepared as follows: by dissolving Brij TM A test solution is prepared in sodium acetate buffer containing 0.2% by weight of nonionic polyoxyethylene surfactant. TM 10 mM acetate buffer was used. The coated balloon was placed in a vial and filled with test medium at 37°C, and shaken at 120 rpm. Samples of the test solution were taken at multiple time points (t = 0.5 h, 1 h, 2 h, 5 h, and 24 h). The collected samples were analyzed by HPLC (High Performance Liquid Chromatography) to measure drug concentration, as the drug present in the test medium represents the drug eluted from the coating on the balloon. The resulting concentrations were plotted, as shown in the figure. Figure 8 As shown.

[0122] Materials that can be used for various components of the medical devices described herein may include those typically associated with medical devices. The medical devices described herein may include various components that may be made of metals, metal alloys, polymers (some examples of which are disclosed below), metal-polymer composites, ceramics, combinations thereof, or other suitable materials. Some examples of suitable metals and metal alloys include stainless steel, such as 304V, 304L, and 316LV stainless steel; low-carbon steel; nickel-titanium alloys, such as linearly elastic and / or hyperelastic nickel-titanium alloys; other nickel alloys, such as nickel-chromium-molybdenum alloys (e.g., UNS: N06625, such as...). 625, UNS: N06022, such as UNS: N10276, such as other Alloys, etc.), nickel-copper alloys (e.g., UNS: N04400, such as...) 400, 400, 400, etc.), nickel-cobalt-chromium-molybdenum alloys (e.g., UNS: R30035, such as...) (etc.), nickel-molybdenum alloys (e.g., UNS: 10665, such as...) 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.; cobalt-chromium alloys; cobalt-chromium-molybdenum alloys (e.g., UNS: R30003, for example). (etc.); platinum-rich stainless steel; titanium; combinations thereof; etc.; or any other suitable material.

[0123] As mentioned herein, within the family of commercially available nickel-titanium or nitinol alloys, there is a category designated as “linear elastic” or “non-hyperelastic”, which, while chemically similar to conventional shape memory and hyperelastic varieties, can exhibit distinct and useful mechanical properties. The difference between linear elastic and / or non-hyperelastic nitinol and hyperelastic nitinol lies in the fact that linear elastic and / or non-hyperelastic nitinol does not exhibit a substantial “hyperelastic plateau” or “flag region” in its stress / strain curve as hyperelastic nitinol does. In fact, in linear elastic and / or non-hyperelastic nitinol, stress continues to increase substantially linearly or slightly but not necessarily completely linearly with increasing recoverable strain until plastic deformation begins, or at least with a more linear relationship than the hyperelastic plateau and / or flag region observed in hyperelastic nitinol. Therefore, for the purposes of this disclosure, linear elastic and / or non-hyperelastic nitinol may also be referred to as “substantially” linear elastic and / or non-hyperelastic nitinol.

[0124] In some cases, linear elastic and / or non-hyperelastic nitinol can also be distinguished from hyperelastic nitinol because linear elastic and / or non-hyperelastic nitinol can accept up to about 2-5% strain while remaining essentially elastic (e.g., before plastic deformation), while hyperelastic nitinol can accept up to about 8% strain before plastic deformation. Both materials can also be distinguished from other linear elastic materials such as stainless steel (which can also be distinguished based on its composition), which can accept only about 0.2% to 0.44% strain before plastic deformation.

[0125] In some embodiments, linear elastic and / or non-hyperelastic nickel-titanium alloys are alloys that do not exhibit any martensitic / austenitic phase transformations detectable by differential scanning calorimetry (DSC) and dynamic metallographic analysis (DMTA) over a wide temperature range. For example, in some embodiments, martensitic / austenitic phase transformations detectable by DSC and DMTA may be absent in linear elastic and / or non-hyperelastic nickel-titanium alloys in the range of about -60°C to about 120°C. Therefore, the mechanical bending properties of such materials can generally be inert to temperature effects over this very wide temperature range. In some embodiments, the mechanical bending properties of linear elastic and / or non-hyperelastic nickel-titanium alloys at ambient temperature or room temperature are substantially the same as their mechanical properties at body temperature, for example, they do not exhibit hyperelastic plateaus and / or flag-shaped regions. In other words, linear elastic and / or non-hyperelastic nickel-titanium alloys retain their linear elastic and / or non-hyperelastic properties and / or characteristics throughout the wide temperature range.

[0126] In some embodiments, the linear elastic and / or non-hyperelastic nickel-titanium alloy may be about 50 to about 60 wt% nickel, with the remainder being substantially titanium. In some embodiments, the composition is about 54 to about 57 wt% nickel. An example of a suitable nickel-titanium alloy is the FHP-NT alloy, commercially available from Furukawa Techno Material Co., 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 may include ULTANIUM. TM (Available from Neo-Metrics) and GUM METAL TM (Available from Toyota). In some other embodiments, a superelastic alloy (e.g., superelastic nitinol) can be used to achieve the desired properties.

[0127] In at least some embodiments, part or all of the medical device described herein may be doped with, made of, or otherwise include a radiopaque material. A radiopaque material should be understood as a material capable of producing a relatively bright image on a fluorescent screen or other imaging technique during medical procedures. This relatively bright image helps the user of the medical device described herein to determine their location. Some examples of radiopaque materials may include, but are not limited to, gold, platinum, palladium, tantalum, tungsten alloys, polymeric materials loaded with radiopaque fillers, etc. Additionally, other radiopaque marking strips and / or coils may be incorporated into the design of the medical device described herein to achieve the same result.

[0128] In some embodiments, a degree of magnetic resonance imaging (MRI) compatibility is imparted to the medical devices described herein. For example, the medical devices or portions thereof described herein may be made of materials that substantially do not distort images and do not produce significant artifacts (i.e., gaps in the image). For example, certain ferromagnetic materials may be unsuitable because they may produce artifacts in MRI images. The medical devices or portions thereof described herein may also be made of materials that an MRI machine can image. Some materials exhibiting these properties include, for example, tungsten, cobalt-chromium-molybdenum alloys (e.g., UNS: R30003, such as...). (etc.), nickel-cobalt-chromium-molybdenum alloys (e.g., UNS: R30035, such as...) (etc.), nickel-titanium, etc., and other materials.

[0129] It should be understood that this disclosure is merely illustrative in many respects. Changes in detail may be made, particularly in terms of shape, size, and arrangement of steps, without departing from the scope of this disclosure. To the appropriate extent, this may include the use of any feature of an exemplary embodiment used in other embodiments. Of course, the scope of this disclosure is defined by the language of the appended claims.

Claims

1. An elutable coating composition comprising: a mixture of excipients comprising a bioabsorbable polymer or a thermogelling polymer and a plasticizer; and a therapeutic agent; wherein the bioabsorbable polymer or the thermogelling polymer is selected from polycaprolactone (PCL) or a poloxamer.

2. The elutable coating composition of claim 1, wherein the plasticizer comprises acetyl tri-butyl citrate (ATBC) or acetyl tri-hexyl citrate (ATHC).

3. The elutable coating composition of any one of claims 1-2, wherein the mixture of excipients comprises polycaprolactone.

4. The elutable coating composition of claim 3, wherein the polycaprolactone has a molecular weight of about 10,000 grams per mole (g / mol) or less.

5. The elutable coating composition of any one of claims 1-4, wherein the mixture of excipients comprises about an equal portion of polycaprolactone and acetyl tri-butyl citrate (ATBC).

6. The elutable coating composition of any one of claims 1-2, wherein the mixture of excipients comprises a poloxamer.

7. The elutable coating composition of claim 6, wherein the poloxamer comprises poloxamer 181 or poloxamer 188.

8. The elutable coating composition of any one of claims 1-2 or 6-7, wherein the mixture of excipients comprises about an equal portion of poloxamer and acetyl tri-butyl citrate (ATBC).

9. The elutable coating composition of any one of claims 1-8, wherein the mixture of excipients comprises about 10% to about 40% by weight of the elutable coating composition.

10. The elutable coating composition of any one of claims 1-9, wherein the therapeutic agent comprises about 60% to about 90% by weight of the elutable coating composition.

11. The elutable coating composition of any one of claims 1-10, wherein the therapeutic agent comprises about 60% to about 90% by weight of the elutable coating composition, the bioabsorbable polymer or the thermogelling polymer comprises about 5% to about 20% by weight of the elutable coating composition, and the plasticizer comprises about 5% to about 20% by weight of the elutable coating composition.

12. The elutable coating composition of any one of claims 1-11, wherein the therapeutic agent comprises everolimus.

13. The elutable coating composition of any one of claims 1-12, further comprising an antioxidant.

14. A medical device comprising a medical device component at least partially covered by a layer of the elutable coating composition of claim 1.

15. The medical device of claim 14, wherein the medical device component is an expandable balloon or an expandable stent.

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