MEDICAL DEVICES INCLUDING THERAPEUTIC COATINGS FORMED FROM INDIVIDUALLY ENCAPSULATED THERAPEUTIC AGENT CRYSTALS

Abstract

A medical device may be coated with a therapeutic composition that includes everolimus. Everolimus crystals may be coated with a mixture of excipients to form encapsulated everolimus crystals suspended in a coating composition. The medical device may be contacted with the coating composition in order to form a coating on the medical device. Coating the everolimus crystals with a mixture of excipients to form encapsulated everolimus crystals suspended in a coating composition may include suspending everolimus crystals in a first solution that includes acetyl tri-butyl citrate (ATBC) and adding a second solution to the first solution, the second solution including ethyl cellulose (EC), the EC mixing with the ATBC and coating the everolimus crystals, thereby forming a coating suspension including coated everolimus crystals in the suspension.

Description

TECHNICAL FIELD

The present disclosure pertains to medical devices and more particularly to medical devices that include a therapeutic coating that is formed from encapsulated therapeutic agent crystals.

BACKGROUND

A wide variety of medical devices have been developed for medical use, for example, intravascular use. Some of these devices include guidewires, catheters, balloons, stents, and the like. These devices are manufactured by any one of a variety of different manufacturing methods and may be used according to any one of a variety of methods. Some of these medical devices may include a therapeutic agent. Of the known medical devices and methods, each has certain advantages and disadvantages. There is an ongoing need to provide alternative medical devices as well as alternative methods for manufacturing and using medical devices. This may include the formation of therapeutic agents that have a reduced drug dissolution rate in order to provide a prolonged therapeutic effect.

SUMMARY

The present disclosure pertains to medical devices and more particularly to medical devices that include a therapeutic coating that is formed from encapsulated therapeutic agent crystals. An example may be found in a method of coating a medical device with a therapeutic composition comprising everolimus. The method includes coating everolimus crystals with a mixture of excipients to form encapsulated everolimus crystals suspended in a coating composition. The medical device is contacted with the coating composition in order to form a coating on the medical device.

Alternatively or additionally, the mixture of excipients may include ethyl cellulose (EC).

Alternatively or additionally, the mixture of excipients may include acetyl tri-butyl citrate (ATBC).

Alternatively or additionally, the mixture of excipients may include EC and ATBC present in a range of 2 parts EC to 1 to 6 parts ATBC.

Alternatively or additionally, contacting the medical device with the coating composition may include spraying the coating composition onto the medical device.

Alternatively or additionally, coating everolimus crystals with a mixture of excipients to form encapsulated everolimus crystals suspended in a coating composition may include suspending everolimus crystals in a first solution that includes acetyl tri-butyl citrate (ATBC) and cyclohexane, and adding a second solution to the first solution, the second solution including ethyl cellulose (EC) and ethyl acetate, the EC mixing with the ATBC and coating the everolimus crystals, thereby forming a coating suspension including coated everolimus crystals in the suspension.

Alternatively or additionally, the medical device may include an inflatable balloon.

Alternatively or additionally, the medical device may include an expandable stent.

Another example may be found in a method of coating a medical device with encapsulated everolimus crystals. The method includes forming a coating suspension by suspending everolimus crystals in a first solution that includes acetyl tri-butyl citrate (ATBC), and adding a second solution to the first solution, the second solution including ethyl cellulose (EC), the EC mixing with the ATBC and encapsulating the everolimus crystals, thereby forming a coating suspension including encapsulated everolimus crystals. The coating suspension is applied to the medical device.

Alternatively or additionally, the method may further include converting amorphous everolimus into the everolimus crystals.

Alternatively or additionally, once the second solution has been added to the first solution, the EC and ATBC may be present in a range of 2 parts EC to 1 to 6 parts ATBC.

Alternatively or additionally, the medical device may include an inflatable balloon.

Alternatively or additionally, the medical device may include an expandable stent.

Another example may be found in a medical device that is adapted to be placed within a location within a vasculature. The medical device includes a surface that is adapted to be placed in contact with a vessel wall within the vasculature, and a therapeutic coating that is disposed on the surface. The therapeutic coating includes a plurality of everolimus crystals that are encapsulated within a coating that includes a synergistic combination of excipients.

Alternatively or additionally, the synergistic combination of excipients may include ethyl cellulose (EC).

Alternatively or additionally, the synergistic combination of excipients may include acetyl tri-butyl citrate (ATBC).

Alternatively or additionally, the synergistic combination of excipients may include two parts ethyl cellulose (EC) to one to six parts acetyl tri-butyl citrate (ATBC).

Alternatively or additionally, the medical device may include an inflatable balloon.

Alternatively or additionally, the medical device may include an expandable stent.

Alternatively or additionally, the therapeutic coating may be adapted to provide a 30 day tissue everolimus concentration of at least 1 nanogram per milligram.

Another example may be found in a method of coating a medical device with a therapeutic composition comprising everolimus. The method includes coating everolimus crystals with a mixture of excipients to form encapsulated everolimus crystals suspended in a coating solution. The medical device is contacted with the coating solution in order to form a coating on the medical device.

Alternatively or additionally, the mixture of excipients may include ethyl cellulose (EC).

Alternatively or additionally, the mixture of excipients may include acetyl tri-butyl citrate (ATBC).

Alternatively or additionally, the mixture of excipients may include EC and ATBC present in a range of 2 parts EC to 1 to 6 parts ATBC.

Alternatively or additionally, contacting the medical device with the coating solution may include spraying the coating solution onto the medical device.

Alternatively or additionally, coating everolimus crystals with a mixture of excipients to form encapsulated everolimus crystals suspended in a coating solution may include suspending everolimus crystals in a first solution that includes acetyl tri-butyl citrate (ATBC) and cyclohexane, and adding a second solution to the first solution, the second solution including ethyl cellulose (EC) and ethyl acetate, the EC mixing with the ATBC and coating the everolimus crystals, thereby forming a coating suspension including coated everolimus crystals in the suspension.

Alternatively or additionally, the medical device may include an inflatable balloon.

Alternatively or additionally, the medical device may include an expandable stent.

Another example may be found in a method of coating a medical device with encapsulated everolimus crystals. The method includes forming a coating suspension by suspending everolimus crystals in a first solution that includes acetyl tri-butyl citrate (ATBC), and adding a second solution to the first solution, the second solution including ethyl cellulose (EC), the EC mixing with the ATBC and encapsulating the everolimus crystals, thereby forming a coating suspension including encapsulated everolimus crystals. The coating suspension is applied to the medical device.

Alternatively or additionally, the method may further include converting amorphous everolimus into the everolimus crystals.

Alternatively or additionally, once the second solution has been added to the first solution, the EC and ATBC may be present in a range of 2 parts EC to 1 to 6 parts ATBC.

Alternatively or additionally, the medical device may include an inflatable balloon.

Alternatively or additionally, the medical device may include an expandable stent.

Another example may be found in a medical device that is adapted to be placed within a location within a vasculature. The medical device includes a surface that is adapted to be placed in contact with a vessel wall within the vasculature, and a therapeutic coating that is disposed on the surface. The therapeutic coating includes a plurality of everolimus crystals that are encapsulated within a coating that includes a synergistic combination of excipients.

Alternatively or additionally, the synergistic combination of excipients may include ethyl cellulose (EC).

Alternatively or additionally, the synergistic combination of excipients may include acetyl tri-butyl citrate (ATBC).

Alternatively or additionally, the synergistic combination of excipients may include two parts ethyl cellulose (EC) to one to six parts acetyl tri-butyl citrate (ATBC).

Alternatively or additionally, the medical device may include an inflatable balloon.

Alternatively or additionally, the medical device may include an expandable stent.

Alternatively or additionally, the therapeutic coating may be adapted to provide a 30 day tissue everolimus concentration of at least 1 nanogram per milligram.

The above summary of some embodiments is not intended to describe each disclosed embodiment or every implementation of the present disclosure. The Figures, and Detailed Description, which follow, more particularly exemplify these embodiments.

BRIEF DESCRIPTION OF THE DRAWINGS

The disclosure may be more completely understood in consideration of the following detailed description in connection with the accompanying drawings, in which:

FIG. 1 is a schematic side view of an example drug delivery balloon catheter.

FIG. 2 is a cross-sectional view taken through line 2-2 in FIG. 1.

FIG. 3 depicts an example drug-coated stent in a collapsed or delivery configuration.

FIG. 4 depicts an example drug-coated stent in an expanded or deployed configuration.

FIG. 5 schematically depicts a drug coating disposed along an outer or abluminal surface of an example drug-coated stent.

FIG. 6 schematically depicts a drug coating disposed along an inner or luminal surface of an example drug-coated stent.

FIG. 7 schematically depicts the drug coating disposed along both an outer or abluminal surface of an example drug-coated stent and along an inner or luminal surface of the example drug-coated stent.

FIG. 8 is a graphical representation of experimental data.

While the disclosure is amenable to various modifications and alternative forms, specifics thereof have been shown by way of example in the drawings and will be described in detail. It should be understood, however, that the intention is not to limit the invention to the particular embodiments described. On the contrary, the intention is to cover all modifications, equivalents, and alternatives falling within the spirit and scope of the disclosure.

DETAILED DESCRIPTION

For the following defined terms, these definitions shall be applied, unless a different definition is given in the claims or elsewhere in this specification.

All numeric values are herein assumed to be modified by the term “about”, whether or not explicitly indicated. The term “about” generally refers to a range of numbers that one of skill in the art would consider equivalent to the recited value (e.g., having the same function or result). In many instances, the terms “about” may include numbers that are rounded to the nearest significant figure.

The recitation of numerical ranges by endpoints includes all numbers within that range (e.g. 1 to 5 includes 1, 1.5, 2, 2.75, 3, 3.80, 4, and 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 employed in its sense including “and/or” unless the content clearly dictates otherwise.

It is noted that references in the specification to “an embodiment”, “some embodiments”, “other embodiments”, etc., indicate that the embodiment described may include one or more particular features, structures, and/or characteristics. However, such recitations do not necessarily mean that all embodiments include the particular features, structures, and/or characteristics. Additionally, when particular features, structures, and/or characteristics are described in connection with one embodiment, it should be understood that such features, structures, and/or characteristics may also be used connection with other embodiments whether or not explicitly described unless clearly stated to the contrary.

The following detailed description should be read with reference to the 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.

Drug coated medical devices such as drug coated stents, drug coated balloons, and the like may be used to treat small vessel occlusions and/or vascular disease. Drug coated medical devices may include a drug or other therapeutic agent applied to the surface of the medical device. The application of the drug to the medical device may include applying a crystalline form of the drug to the surface of the medical devices. In at least some instances, the manufacturing process may include converting an amorphous form of the drug into a crystalline form. Disclosed herein are methods for converting an amorphous form of a material (e.g., a drug) into a crystalline form. Disclosed herein are methods for encapsulating crystals of the crystalline drug, for example in order to provide an extended release profile for the crystalline drug. In addition, disclosed herein are medical devices with such a coating applied thereto, methods for coating, etc.

Some specific beneficial agents include anti-thrombotic agents, anti-proliferative agents, anti-inflammatory agents, anti-migratory agents, agents affecting extracellular matrix production and organization, antineoplastic agents, anti-mitotic agents, anesthetic agents, anti-coagulants, vascular cell growth promoters, vascular cell growth inhibitors, cholesterol-lowering agents, vasodilating agents, and agents that interfere with endogenous vasoactive mechanisms.

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, Actinomycin D, Resten-NG, Ap-17, abciximab, clopidogrel, Ridogrel, beta-blockers, bARKct inhibitors, phospholamban inhibitors, and SERCA 2 gene/protein, resiquimod, imiquimod (as well as other imidazoquinoline immune response modifiers), human apolipoproteins (e.g., AI, AII, AIII, AIV, AV, etc.), vascular endothelial growth factors (e.g., VEGF-2), as well as derivatives of the forgoing, among many others.

In some embodiments, the drug may be a macrolide immunosuppressive (limus) drug. In some embodiments, the macrolide immunosuppressive drug is rapamycin, biolimus (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-dioxolan-4(S)-yl)-prop-2′-en-1′-yl]-rapamycin, (2′:E,4′S)-40-O-(4′,5′-Dihydroxypent-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-Dimethyldioxolan-3-yl]methyl-rapamycin, 40-O-[(2S)-2,3-Dihydroxyprop-1-yl]-rapamycin, 40-O-(2-Acetoxy)ethyl-rapamycin, 40-O-(2-Nicotinoyloxy)ethyl-rapamycin, 40-O-[2-(N-Morpholino)acetoxy]ethyl-rapamycin, 40-O-(2-N-Imidazolylacetoxy)ethyl-rapamycin, 40-O-[2-(N-Methyl-N′-piperazinyl)acetoxy]ethyl-rapamycin, 39-O-Desmethyl-39,40-O,O-ethylene-rapamycin, (26R)-26-Dihydro-40-O-(2-hydroxy)ethyl-rapamycin, 28-O-Methyl-rapamycin, 40-O-(2-Aminoethyl)-rapamycin, 40-O-(2-Acetaminoethyl)-rapamycin, 40-O-(2-Nicotinamidoethyl)-rapamycin, 40-O-(2-(N-Methyl-imidazo-2′-ylcarbethoxamido)ethyl)-rapamycin, 40-O-(2-Ethoxycarbonylaminoethyl)-rapamycin, 40-O-(2-Tolylsulfonamidoethyl)-rapamycin, 40-O-[2-(4′,5′-Dicarboethoxy-1′,2′,3′-triazol-1′-yl)-ethyl]-rapamycin, 42-Epi-(tetrazolyl)rapamycin (tacrolimus), 42-[3-hydroxy-2-(hydroxymethyl)-2-methylpropanoate]rapamycin (temsirolimus), (42S)-42-Deoxy-42-(1H-tetrazol-1-yl)-rapamycin (zotarolimus), or derivative, isomer, racemate, diastereoisomer, prodrug, hydrate, ester, or analog thereof. Other drugs may include anti-inflammatory agents such as dexamethasone, prednisolone, corticosterone, budesonide, estrogen, sulfasalazine, mesalamine, and analogues thereof; antineoplastic/antiproliferative/anti-miotic agents such as paclitaxel, 5-fluorouracil, cisplatin, vinblastine, vincristine, epothilones, endostatin, angiostatin, thymidine kinase inhibitors, and analogues thereof; anesthetic agents such as lidocaine, bupivacaine, ropivacaine, and analogues thereof; anti-coagulants; and growth factors.

In some cases, everolimus may be the drug used. Everolimus, which is also known as 40-O-(2-Hydroxyethyl)rapamycin, has the following chemical structure:

In some instances, providing a drug coated medical device with a drug coating that is adapted to permit an extended release profile may be beneficial in treating small vessel occlusions and/or vascular disease. In some instances, improved results may be achieved in cases where the extended release profile means that a useful fraction of the drug remains for an extended period of time, thereby increasing the efficacy of the drug in treating whatever condition is being treated, at least in part because a useful fraction of the drug remains for a longer period of time. In some instances, a drug coating with an extended release profile may mean that not as much drug is required in the coating in order to achieve a desired effect, for example.

In some instances, a therapeutic coating including encapsulated everolimus crystals may provide a 30 day tissue everolimus concentration of at least 0.5 nanograms per milligram. In some cases, a therapeutic coating including encapsulated everolimus crystals may provide a 30 day tissue everolimus concentration of at least 0.6 nanograms per milligram. In some cases, a therapeutic coating including encapsulated everolimus crystals may provide a 30 day tissue everolimus concentration of at least 0.7 nanograms per milligram. In some cases, a therapeutic coating including encapsulated everolimus crystals may provide a 30 day tissue everolimus concentration of at least 0.8 nanograms per milligram. In some cases, a therapeutic coating including encapsulated everolimus crystals may provide a 30 day tissue everolimus concentration of at least 0.9 nanograms per milligram. In some cases, a therapeutic coating including encapsulated everolimus crystals may provide a 30 day tissue everolimus concentration of at least 1 nanogram per milligram.

In some instances, the drug coating may include individual drug particles that are encapsulated with one or more excipients. The drug particles may include crystals of the drug, for example. Drug crystals may be formed in a variety of ways, for example. In some cases, a drug or other therapeutic agent may be available in an amorphous form, and a variety of processes may be used to convert an amorphous drug or other therapeutic agent into a crystalline drug or other therapeutic agent. One illustrative process for converting an amorphous drug such as amorphous everolimus into a crystalline drug such as crystalline everolimus is described herein.

A medical device may be coated with a therapeutic composition. As an example, the therapeutic composition may include everolimus. Everolimus crystals may be coated with a mixture of excipients in order to form encapsulated everolimus crystals that are suspended in a coating composition. In some instances, the medical device may be contacted with the coating composition in order to form a coating on the medical device. In some instances, the medical device or a portion thereof may be dipped into the coating composition. In some cases, vapor deposition may be used to transfer the coating composition to the medical device. In some cases, a roller coating process may be used to transfer the coating composition to the medical device. These are just examples. In some cases, the coating composition may be sprayed onto the medical device, or may be sprayed onto a particular portion or region of the medical device.

When the medical device includes an inflatable balloon, for example, the coating composition may be sprayed onto at least a portion of outer surface of the inflatable balloon in order to be able to subsequently transfer at least a portion of the drug coating to blood vessel walls. Alternative coating processes may be used such as dip coating, roller coating, vapor deposition, and/or the like, and/or other suitable coating processes. There may be little or no benefit to applying the coating composition to other portions of the medical device such as a balloon catheter shaft because the balloon catheter shaft may make incidental contact at best with the blood vessel walls, for example.

When the medical device is or includes an expandable stent, the coating composition may be sprayed onto at least a portion of the outer surface of the expandable stent in order to be able to subsequently transfer at least a portion of the drug coating to blood vessel walls. There may be reduced benefit to applying the coating composition to an interior surface of the expandable stent because the interior surface of the expandable stent is unlikely to contact the blood vessel walls. There may be some benefit to transferring at least a portion of the drug coating to blood flowing through the expandable stent, as the blood will subsequently contact the blood vessel walls, particularly downstream of where the expandable stent is deployed.

In some instances, the mixture of excipients may include two or more different excipients. An example excipient may include ethyl cellulose (EC), which is a derivative of cellulose in which some of the hydroxyl groups on the repeating glucose units are converted into ethyl ether groups. The relative number of ethyl ether groups can vary depending on the particular manufacturer. EC has the following chemical structure:

Another example excipient may include acetyl tri-butyl citrate (ATBC), which in some cases may be referred to by its IUPAC name of tributyl 2-acetyloxypropane-1,2,3-tricarboxylate. ATBC has the following chemical structure:

In some cases, the mixture of excipients may optionally include one or more additional excipients. In some instances, the mixture of excipients may include only EC and ATBC. In some instances, for example, the mixture of excipients may include two parts EC to one to six parts ATBC. As an example, coating everolimus crystals with a mixture of excipients to form encapsulated everolimus crystals suspended in a coating composition may include suspending everolimus crystals in a first solution that includes ATBC. A second solution may be added to the first solution, the second solution including EC. When the second solution including EC is added to the first solution that includes the suspended everolimus crystals and ATBC, the EC mixes with the ATBC and coats the everolimus crystals. This forms a coating composition that includes encapsulated everolimus crystals held within a suspension. In some examples, individual everolimus crystals may have a coating that is less than 1 micron thick.

In some instances, the encapsulated everolimus crystals may be considered as including from 0 to 30 weight percent ATBC, from 0 to 30 weight percent EC and from 70 to 100 weight percent everolimus. In some instances, the encapsulated everolimus crystals may be considered as including from 5 to 20 weight percent ATBC, from 5 to 20 weight percent EC and from 60 to 90 weight percent everolimus. Compositions within these ranges were found to have improved dissolution rates relative to formulations that only used EC or ATBC as a single excipient. In some instances, the encapsulated everolimus crystals may include about 85 weight percent everolimus and about 15 weight percent excipient, with the excipient being a combination of ATBC and EC. As an example, the excipient may be more than half ATBC and less than half EC. As an example, the excipient may include two parts ATBC and one part EC.

In some instances, the first solution may include a singular solvent, and preparing the first solution may be as simple as placing the solvent in a suitable container and adding the crystalline everolimus and the ATBC. When the solvent includes a mixture of materials, preparing the first solution may include combining or mixing two or more solvents prior to adding the crystalline everolimus and the ATBC.

In at least some instances, the solvent used for forming the first solution may include alcohols such as methanol, ethanol (EtOH), isopropanol (IPA), n-butanol, isobutyl alcohol or t-butyl alcohol; acetonitrile (ACN); ethers such as tetrahydrofuran (THF), isopropyl ether (IPE), diethyl ether (DEE); ketone solvents such as acetone, 2-butanone (MEK), or methyl isobutyl ketone (MIBK); halogenated solvents such as dichloromethane (DCM), monofluorobenzene (MFB), α,α,α-trifluorotoluene (TFT), nitromethane (NM), ethyl trifluoroacetate (ETFA); aliphatic or alicyclic hydrocarbons such as hexane, heptane, cyclohexane or the like; aromatic hydrocarbons, such as toluene or xylenes; and ester solvents such as ethyl acetate. Mixed solvents such as ethyl acetate/heptane, acetone/water, IPA/water, IPA/THF, methanol/water, IPA/heptane, or THF/heptane can also be used, for example. Other solvent systems are also contemplated. In some cases, the solvent used for forming the first solution may include cyclohexane.

In some instances, the process of forming the first solution may take place at ambient temperature and at atmospheric pressure. In some instances, the first solution may be formed as part of the process of converting the amorphous everolimus into crystalline everolimus. In some instances, ATBC may be added to the suspension that results from the crystallization process, for example.

In some instances, the first solution may include crystalline everolimus suspended in a solvent such as cyclohexane. In some instances, other solvents such as isopropanol, ethanol or similar alcohols, acetone, tetrahydrofuran or acetonitrile may be used. In some instances, the first solution may also include other additives such as BHT (butylated hydroxytoluene), for example. It will be appreciated that the crystalline everolimus will minimally dissolve in the solvent, and thus will be a suspension. The ATBC should at least partially dissolve in the solvent.

In some instances, the second solution may include a singular solvent, and preparing the second solution may be as simple as placing the solvent in a suitable container and adding the EC. When the solvent includes a mixture of materials, preparing the second solution may include combining or mixing two or more solvents prior to adding the EC.

In at least some instances, the solvent used for forming the second solution may include alcohols such as methanol, ethanol (EtOH), isopropanol (IPA), n-butanol, isobutyl alcohol or t-butyl alcohol; acetonitrile (ACN); ethers such as tetrahydrofuran (THF), isopropyl ether (IPE), diethyl ether (DEE); ketone solvents such as acetone, 2-butanone (MEK), or methyl isobutyl ketone (MIBK); halogenated solvents such as dichloromethane (DCM), monofluorobenzene (MFB), α,α,α-trifluorotoluene (TFT), nitromethane (NM), ethyl trifluoroacetate (ETFA); aliphatic hydrocarbons such as hexane, heptane, or the like; aromatic hydrocarbons, such as toluene or xylenes; and ester solvents such as ethyl acetate. Mixed solvents such as ethyl acetate/heptane, acetone/water, IPA/water, methanol/water, IPA/heptane, or THF/heptane can also be used, for example. Other solvent systems are also contemplated. In some cases, the solvent used for forming the second solution may include ethyl acetate.

In some instances, the process of forming the second solution may take place at ambient temperature and at atmospheric pressure. The second solution may include EC and one or more solvents. In some instances, the second solution may include EC dissolved in a solvent such as ethyl acetate, although other solvents such as heptane or similar alkanes, or even water, may be used. The EC will dissolve in the ethyl acetate, providing a solution.

In some cases, after the first solution and the second solution have been formed, the second solution may be added to the first solution. As a result, the ATBC and the EC mix together and coat the individual crystals of everolimus, resulting in encapsulated everolimus crystals. In some cases, the process may occur quickly. In some cases, the process may occur more slowly. The first solution may include a volume of cyclohexane and the second solution may include a volume of ethyl acetate to provide a ratio of ethyl acetate to cyclohexane of about 1 to 4 when the second solution is added to the first solution. It will be appreciated that having too much everolimus solubility will dissolve the everolimus crystals. It will be appreciated that the stated process of forming the first solution, forming the second solution and then combining the first solution and the second solution is merely illustrative, and other processes are contemplated.

A medical device may be adapted to be placed within a location with a vasculature. In some cases, a medical device may be adapted to be placed within an artery or a vein, for example. The medical device may include a surface that is adapted to be placed in contact with a vessel wall within the vasculature. The medical device may include a therapeutic coating that is disposed on the surface, the therapeutic coating including a plurality of everolimus crystals that are encapsulated within a coating that includes a synergistic combination of excipients. A synergistic combination of excipients may be understood to be a combination of excipients that, when used together, provide improved results relative to using either excipient by itself. A synergistic combination of excipients provides better protection for the everolimus crystals, meaning that the everolimus crystals dissolve more slowly over time, providing a delay in drug release or drug dissolution. This provides a tissue drug concentration that lasts longer over time.

Surprisingly, it has been found that some combinations of excipients provide better protection than what would be expected by a combination of excipients. For example, in some instances, the synergistic combination of excipients includes ethyl cellulose (EC). In these and other instances, the synergistic combination of excipients include acetyl tri-butyl citrate (ATBC). In an example, the synergistic combination of excipients may include two parts ethyl cellulose (EC) to one to six parts acetyl tri-butyl citrate (ATBC).

Some example drug coated medical devices, and portions thereof, are shown in FIGS. 1-7. For example, FIG. 1 is a schematic side view of a drug delivery balloon catheter 10. A cross-sectional view of the drug delivery balloon catheter 10 is shown in FIG. 2. In the illustrated embodiment, the catheter 10, along with other components, may include an elongated shaft 12, an inflatable balloon 14 coupled at or to a distal portion 16 of the shaft 12. 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. In addition, the elongated shaft 12 may be flexible along its entire length, or adapted for flexure only along portions of its length. The required degree of flexibility of the elongated shaft 12 may be predetermined based on its intended navigation to a target vascular passage, and the amount of inertial force required for advancing the elongated shaft 12 through the vascular passage. 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 the like.

The cross-sectional dimensions of the elongated shaft 12 may vary according to the desired application. Generally, the cross-sectional dimensions of the elongated shaft 12 may be sized smaller than the typical blood vessel in which the catheter 10 is to be used. The length of the elongated shaft 12 may vary according to the location of the vascular passage where drug delivery is desired. In some instances, a 6F or a 5F catheter may be used as the elongated shaft 12, where “F,” also known as French catheter scale, is a unit to measure catheter diameter (1F=⅓ mm). In addition, the elongated shaft 12 or a portion thereof may be selectively steerable. Mechanisms such as, pull wires and/or other actuators may be used to selectively steer the elongated shaft 12, if desired.

The proximal portion 18 of the elongated shaft 12 may include a handle 20 usable to manually maneuver the distal portion 16 of the elongated shaft 12. The handle 20 may include one or more ports that may be used to introduce any suitable medical device, fluid or other interventions. For example, the handle 20 may include a guidewire port in communication with a guidewire lumen 22 (shown in the cut-away portion at the distal end of the catheter 10 and also in FIG. 2) which may be used to introduce a guidewire having an appropriate thickness into the elongated shaft 12, which may guide the shaft 12 to the target location within an artery. Furthermore, the handle 20 may include an inflation port configured to be coupled to a source of inflation fluid for delivering an inflation fluid through an inflation lumen of the catheter shaft 12 to the inflatable balloon 14. In certain embodiments, the elongated shaft 12 may include one or more additional lumens, which may be configured for a variety of purposes, such as delivering medical devices or for providing fluids, such as saline, to a target location.

The inflatable balloon 14 may be operably coupled at or to the distal portion 16 of the elongated shaft 12. In particular, a proximal portion or waist 24 of the inflatable balloon 14 may be secured to the distal portion 16 of the elongated shaft 12, such as an outer tubular member 26 of the elongated shaft 12. Furthermore, a distal portion or waist 28 of the inflatable balloon 14 may be secured to the distal portion 16 of the elongated shaft 12, such as an inner tubular member 30 of the elongate shaft 12 extending through the outer tubular member 26. A suitable securing method(s) may be employed to couple the two structures, including but not limited to adhesive bonding, thermal bonding (e.g., hot jaws, laser welding, etc.) or other bonding technique, as desired. The inflatable balloon 14 may be configured to be expanded from a deflated state to an inflated state through delivery of an inflation fluid (e.g., saline) through the inflation lumen of the catheter shaft 12. The balloon 14 may be deflated during introduction of the catheter inside the patient's body, whereas the balloon 14 may be inflated once it reaches the target site within the body vessel.

The inflatable balloon may be manufactured using or otherwise formed of any suitable material, including polymer materials, such as polyamide, polyether block amide (PEBA), polyester, nylon, etc. The inflatable balloon 14 may have a substantially cylindrical configuration with a circular cross-section, as shown in the illustrative embodiment. However, in other embodiments the inflatable balloon 14 may have another suitable configuration or shape, if desired.

The inflatable balloon 14 may include a balloon wall 32 have a drug coating 34 disposed thereon. In some cases, the drug coating 34 may include encapsulated crystalline everolimus as disclosed herein, for example that is encapsulated with a mixture of EC and ATBC. The drug coating 34 may be disposed along substantially the entire length of the balloon 14 or along one or more portions of the balloon 14. For example, the drug coating 34 may be disposed along a central or body portion of the balloon 14. The drug coating 34 disposed on the balloon 14/balloon wall 32 may have an average thickness in the range of about 1 micron to about 50 microns, for example.

FIGS. 3-4 illustrate an example drug-coated stent 110 in either a collapsed or delivery configuration (FIG. 3) or in an expanded or deployed configuration (FIG. 4). In general, the stent 110 may be delivered to a suitable target region via a catheter/delivery system while in the collapsed configuration. Upon reaching the target region, the stent 110 may expand or be expanded into the expanded configuration. The stent 110 may be self-expanding (e.g., the stent 110 may be formed from a shape memory material such as nitinol) or may be balloon expandable. When the stent 110 is self-expanding, the stent 110 may be held/constrained in the collapsed configuration during delivery and then unconstrained to allow the stent 110 to expand (e.g., self-expand) to the expanded configuration. When the stent 110 is balloon-expandable, the stent 110 may be constrained crimped onto a delivery device/catheter and then expanded (e.g., via an expandable member or balloon) when at/adjacent the target region.

The stent 110 may include strut framework 136. The strut framework 136 may define one or more peaks or apex regions 138 and/or one or more connecting regions 140. Intermediate regions 142 may interconnect the apex regions 138 and/or the connecting regions 140. In some instances, the stent 110 may be formed from a cut (e.g., laser cut) tube. In such instances, the structural arrangement of the apex regions, connecting regions 140, and/or intermediate regions 142 may be determined by the cut pattern. It can be appreciated that a wide variety of patterns/arrangement may be used for the stent 110. In other instances, the stent 110 may be a woven or braided stent, a stent formed from a flat sheet of material that is rolled into a stent formation, molded, cast, and/or the like.

A drug coating 134 may be disposed along the strut framework 136. For example, FIG. 5 schematically depicts the drug coating 134 disposed along an outer or abluminal surface 144 of the stent 110 (e.g., along the outer or abluminal surface 144 of the strut framework 136). FIG. 6 schematically depicts the drug coating 134 disposed along an inner or luminal surface 146 of the stent 110 (e.g., along the inner or luminal surface 146 of the strut framework 136). FIG. 7 schematically depicts the drug coating 134 along both an outer or abluminal surface 144 of the stent 110 and the inner or luminal surface 146 of the stent 110 (e.g., along both the outer or abluminal surface 144 of the strut framework 136 and the inner or luminal surface 146 of the strut framework 136). While not explicitly shown, in some examples, the drug coating 134 may be additionally or alternatively disposed along the lateral sides of the strut framework 136, the lateral sides extending between the outer or abluminal surface 144 and the inner or luminal surface 146. It is noted that FIGS. 5-7 are intended to represent, schematically, a cross-sectional view of a portion (e.g., a singular region or portion of a strut) of the strut framework 136. In these views, the strut framework 136 is depicted as being partially arcuate in shape. This is intended to correspond to the generally cylindrical shape of the stent 110, for example when the stent 110 is in the expanded configuration. In some cases, the drug coating 134 may include encapsulated crystalline everolimus as disclosed herein, for example that is encapsulated with a mixture of EC and ATBC. The drug coating 134 disposed on the strut framework 136 may have an average thickness in the range of about 1 micron to about 50 microns, for example.

Process for Forming Crystalline Everolimus

Some example processes for converting an amorphous form of a drug into a crystalline form may generally include (a) preparing a suitable solvent, (b) preparing a nucleation initiator with the solvent, (c) combining/mixing the nucleation initiator with an amorphous form of a 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 to the crystalline form of the drug. The use of a suitable surfactant with the drug precursor dispersion/suspension may allow for the formation of drug crystals having a desirable morphology, allow for the formation of drug crystals having a desirable size and/or shape and/or aspect ratio, allow for the formation of coating suspensions with desirable stability, combinations thereof, and/or the like. Thus, at least some of the processes 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 the surfactant with the solvent, (c) preparing a nucleation initiator with the solvent, (d) combining/mixing the nucleation initiator with the surfactant solution and with an amorphous form of a drug to form a drug precursor dispersion/suspension and (c) incubating the drug precursor dispersion/suspension to allow the amorphous form of the drug to convert to the crystalline form of the drug. Other processes are also contemplated for converting the amorphous form of the drug into the crystalline form of the drug.

As indicated herein, example processes for converting an amorphous form of a drug into a crystalline form include preparing a suitable solvent. When the solvent is a singular material, preparing a suitable solvent may be as simple as placing the solvent in a suitable container. When the solvent is a mixture of materials, preparing a suitable solvent may include combining or mixing the solvents.

In at least some instances, the solvent may include alcohols such as methanol, ethanol (EtOH), isopropanol (IPA), n-butanol, isobutyl alcohol or t-butyl alcohol; acetonitrile (ACN); ethers such as tetrahydrofuran (THF), isopropyl ether (IPE), diethyl ether (DEE); ketone solvents such as acetone, 2-butanone (MEK), or methyl isobutyl ketone (MIBK); halogenated solvents such as dichloromethane (DCM), monofluorobenzene (MFB), α,α,α-trifluorotoluene (TFT), nitromethane (NM), ethyl trifluoroacetate (ETFA); aliphatic hydrocarbons such as hexane, heptane, or the like; aromatic hydrocarbons, such as toluene or xylenes; and ester solvents such as ethyl acetate. Mixed solvents such as ethyl acetate/heptane, acetone/water, IPA/water, IPA/THF, methanol/water, IPA/heptane, or THF/heptane can also be used, for example.

When mixtures of solvents are utilized, the mixture may have a suitable ratio of each material. For example, some example 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 ratios are contemplated. Thus, in some instances the process 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.

The process for converting an amorphous form of a drug into a crystalline form may include preparing a surfactant solution (e.g., preparing a surfactant solution with the solvent). In at least some instances, the surfactant may include TWEEN 20™ (e.g., polysorbate 20, polyoxyethylene (20) sorbitan monooleate, or PEG (20) sorbitan monooleate), TWEEN 80™ (e.g., polysorbate 80, polyoxyethylene (80) sorbitan monooleate, or PEG (80) sorbitan monooleate), SPAN™ 80, SPAN™ 20, TRITON™ X-100, TRITON™ 400, a non-ionic surfactant, and/or the like. 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).

The process for converting an amorphous form of a drug into a crystalline form may include preparing a nucleation initiator (e.g., preparing a nucleation initiator with the solvent). This process or step may also be termed “seeding”. In at least some instances, the nucleation initiator may include a crystalline form of the drug suspended in a suitable solvent (e.g., which may or may not be the same solvent that is used to dissolve the amorphous form of the drug). When the drug utilized is everolimus, the nucleation initiator may include a suitable quantity of crystalline everolimus in a suitable solvent. The concentration of the crystalline everolimus in the solvent may be in the ratio of about 0.1-10%, or about 0.1-2%, or about 0.5%. The crystalline everolimus may include everolimus microcrystals formed as described herein. Alternatively, the crystalline everolimus may include everolimus crystals having a different morphology.

The process for converting an amorphous form of a drug into a crystalline form may include mixing and/or combining the nucleation initiator with the surfactant solution and with an amorphous form of a drug to form a drug precursor dispersion/suspension. The amount of the amorphous form of the drug added may vary. For example, about 0.5-100 milligrams of everolimus may be added/dispersed per milliliter (e.g., per milliliter of solvent), or about 1-50 milligrams of everolimus may be added/dispersed per milliliter, or about 10-30 milligrams of everolimus may be added/dispersed per milliliter, or about 20 milligrams of everolimus may be dissolved per milliliter. In at least some instances, the drug dispersion solution may be termed and/or resemble a slurry.

The drug precursor dispersion/suspension may be incubated so that the amorphous form of the drug may convert to the crystalline form. In some instances, incubation may occur over a suitable time period on the order of a number of hours to a number of days. For example, incubation may occur over 24 hours. In some of these and in other instances, incubation may include a high-temperature or warm-temperature incubating step at a suitable temperature (e.g., at about 20° C. to 80° C., or at about 40° C. to 60° C., or at about 50° C.). In some instances, the high-temperature incubating may include agitating the drug precursor dispersion (e.g., using a suitable device such as an orbital shaker). However, in other instances, the high-temperature incubating step is free from agitating/agitation. The high-temperature incubating step may occur over a suitable time period on the order of a number of hours to a number of days. For example, incubation may occur over approximately two days. In some of these and in other instances, incubation may also include a low-temperature or cool-temperature incubating step at a suitable temperature (e.g., at about −10° C. to 10° C., or at about 0° C. to 5° C., or at about 4° C.). The low-temperature incubating step may occur over a suitable time period on the order of a number of hours to a number of days. For example, incubation may occur over several days.

In some instances, the process for converting an amorphous form of a drug into a crystalline form may include one or more of (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, some processes are contemplated that include filtering, washing, and drying the crystalline form of the drug. When doing so, the solvent, the surfactant, or both may be essentially completely removed from the drug crystals.

The crystalline form of the drug (e.g., the crystalline form of everolimus) formed by this process may result in crystals with a morphology, size, and shape that allow the formed crystals to be described as being microcrystals. In particular, the use of a surfactant in the crystallization process, along with a suitable solvent mixture, mixed at a suitable ratio, results in the formation of microcrystals. For the purposes of this disclosure, microcrystals may be understood to be crystals that could be described as relatively flat, thin sheets. Some example dimensions may include microcrystals having a width less than about 3 micrometers (e.g., having a non-zero width that is less than about 3 micrometers), a thickness less than about 1 micrometer (e.g., having a non-zero thickness that is less than about 1 micrometer), and a length less than about 10 micrometers (e.g., having a non-zero length that is less than about 10 micrometers). Microcrystals may be desirable for a number of reasons. For example, in some crystallization processes that form “larger”, rod-like, or “non-micro” crystals, the resultant crystals can rapidly settle when suspended in a coating material/dispersion. This may make it more challenging to apply the drug crystals to a medical device. The microcrystals formed by the process described herein can be, for example, suspended in a coating material/dispersion and remain in suspension for an extended period of time (e.g., on the order of months or longer).

Experimental Results

FIG. 8 is a graphical representation of experimental data providing relative drug release rates when using ATBC alone as an excipient, using EC alone as an excipient, and using a combination of ATBC and EC as the excipient. FIG. 8 shows drug release data for a first sample that includes crystalline everolimus that is encapsulated with EC only, shown graphically as a solid line. A second sample includes crystalline everolimus that is encapsulated with ATBC only, shown graphically as a dashed line. A third sample includes crystalline everolimus that is encapsulated with a mixture of EC and ATBC. It can be seen that the first sample and the second sample have both eluted about forty percent of the original quantity of everolimus after a period of about twenty hours. It can also be seen that using EC alone or using ATBC alone provides similar results. In comparison, the third sample, which includes both EC and ATBC as excipients, only eluted about twenty percent of the original quantity of everolimus after a period of about twenty hours.

The first sample tested was 85 weight percent everolimus and 15 weight percent ATBC. The second sample tested was 85 weight percent everolimus and 15 weight percent EC. The third sample tested was 85 weight percent everolimus, 10 weight percent ATBC and 5 weight percent EC. Since the combination of both ATBC and EC resulted in a loss of only about half as much drug over twenty hours, relative to using either excipient alone, and since each composition included the same total amount of excipient, it is appropriate to state that using a combination of ATBC and EC as the excipient may be considered as providing a synergistic improvement in drug release rate.

Tested Compositions

	Evero-				Cyclo-	Ethyl
	limus	ATBC	BHT	EC	hexane	acetate
Sample	(g)	(g)	(mg)	(g)	(ml)	(ml)
1	0.6137	0.1083	0.61	n/a	8	n/a
2	0.6124	n/a	0.61	0.1081	8	2
3	0.6129	0.0721	0.61	0.0361	8	2

Testing Procedure

A testing solution was made by dissolving Brij™ (a nonionic polyoxyethylene surfactant) in a sodium acetate buffer to form a test solution that is a 10 mM acetate buffer including 0.2 weight percent Brij™. A coated balloon was placed in a bottle and filled with the test medium, and was shaken at 120 rpm. The test solution was sampled at multiple time points (t=0.5 hours, 1 hour, 2 hours, 5 hours, and 24 hours. The collected samples were analyzed on HPLC (high performance liquid chromatography) to measure drug concentration, as the drug present in the test medium represents drug that has eluted from the coating on the balloon. The resulting concentrations were graphed, as seen in FIG. 8.

The materials that can be used for the various components of the medical devices described herein may include those commonly associated with medical devices. The medical devices described herein may include components that may be made from a metal, metal alloy, polymer (some examples of which are disclosed below), a metal-polymer composite, ceramics, combinations thereof, and the like, or other suitable material. Some examples of suitable metals and metal alloys include stainless steel, such as 304V, 304L, and 316LV stainless steel; mild steel; nickel-titanium alloy such as linear-elastic and/or super-elastic nitinol; other nickel alloys such as 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, and the like), nickel-copper alloys (e.g., UNS: N04400 such as MONEL® 400, NICKELVAC® 400, NICORROS® 400, and the like), nickel-cobalt-chromium-molybdenum alloys (e.g., UNS: R30035 such as MP35-N® and the like), 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, and the like; cobalt-chromium alloys; cobalt-chromium-molybdenum alloys (e.g., UNS: R30003 such as ELGILOY®, PHYNOX®, and the like); platinum enriched stainless steel; titanium; combinations thereof; and the like; or any other suitable material.

As alluded to herein, within the family of commercially available nickel-titanium or nitinol alloys, is a category designated “linear elastic” or “non-super-elastic” which, although may be similar in chemistry to conventional shape memory and super clastic varieties, may exhibit distinct and useful mechanical properties. Linear elastic and/or non-super-elastic nitinol may be distinguished from super elastic nitinol in that the linear elastic and/or non-super-elastic nitinol does not display a substantial “superelastic plateau” or “flag region” in its stress/strain curve like super elastic nitinol does. Instead, in the linear clastic and/or non-super-clastic nitinol, as recoverable strain increases, the stress continues to increase in a substantially linear, or a somewhat, but not necessarily entirely linear relationship until plastic deformation begins or at least in a relationship that is more linear that the super elastic plateau and/or flag region that may be seen with super elastic nitinol. Thus, for the purposes of this disclosure linear elastic and/or non-super-elastic nitinol may also be termed “substantially” linear elastic and/or non-super-elastic nitinol.

In some cases, linear elastic and/or non-super-elastic nitinol may also be distinguishable from super elastic nitinol in that linear elastic and/or non-super-elastic nitinol may accept up to about 2-5% strain while remaining substantially elastic (e.g., before plastically deforming) whereas super elastic nitinol may accept up to about 8% strain before plastically deforming. Both of these materials can be distinguished from other linear elastic materials such as stainless steel (that can also can be distinguished based on its composition), which may accept only about 0.2 to 0.44 percent strain before plastically deforming.

In some embodiments, the linear elastic and/or non-super-elastic nickel-titanium alloy is an alloy that does not show any martensite/austenite phase changes that are detectable by differential scanning calorimetry (DSC) and dynamic metal thermal analysis (DMTA) analysis over a large temperature range. For example, in some embodiments, there may be no martensite/austenite phase changes detectable by DSC and DMTA analysis in the range of about −60 degrees Celsius (° C.) to about 120° C. in the linear elastic and/or non-super-elastic nickel-titanium alloy. The mechanical bending properties of such material may therefore be generally inert to the effect of temperature over this very broad range of temperature. In some embodiments, the mechanical bending properties of the linear elastic and/or non-super-elastic nickel-titanium alloy at ambient or room temperature are substantially the same as the mechanical properties at body temperature, for example, in that they do not display a super-elastic plateau and/or flag region. In other words, across a broad temperature range, the linear elastic and/or non-super-elastic nickel-titanium alloy maintains its linear elastic and/or non-super-elastic characteristics and/or properties.

In some embodiments, the linear elastic and/or non-super-elastic nickel-titanium alloy may be in the range of about 50 to about 60 weight percent nickel, with the remainder being essentially titanium. In some embodiments, the composition is in the range of about 54 to about 57 weight percent nickel. One example of a suitable nickel-titanium alloy is FHP-NT alloy commercially available from Furukawa Techno Material Co. of Kanagawa, Japan. Some examples of nickel titanium alloys are disclosed in U.S. Pat. Nos. 5,238,004 and 6,508,803, which are incorporated herein by reference. Other suitable materials may include ULTANIUM™ (available from Neo-Metrics) and GUM METAL™ (available from Toyota). In some other embodiments, a superelastic alloy, for example a superelastic nitinol can be used to achieve desired properties.

In at least some embodiments, portions or all of the medical devices described herein may also be doped with, made of, or otherwise include a radiopaque material. Radiopaque materials are understood to be materials capable of producing a relatively bright image on a fluoroscopy screen or another imaging technique during a medical procedure. This relatively bright image aids the user of the medical devices described herein in determining its location. Some examples of radiopaque materials can include, but are not limited to, gold, platinum, palladium, tantalum, tungsten alloy, polymer material loaded with a radiopaque filler, and the like. Additionally, other radiopaque marker bands and/or coils may also be incorporated into the design of the medical devices described herein to achieve the same result.

In some embodiments, a degree of Magnetic Resonance Imaging (MRI) compatibility is imparted into the medical devices described herein. For example, the medical devices described herein, or portions thereof, may be made of a material that does not substantially distort the image and create substantial artifacts (i.e., gaps in the image). Certain ferromagnetic materials, for example, may not be suitable because they may create artifacts in an MRI image. The medical devices described herein, or portions thereof, may also be made from a material that the MRI machine can image. Some materials that exhibit these characteristics include, for example, tungsten, cobalt-chromium-molybdenum alloys (e.g., UNS: R30003 such as ELGILOY®, PHYNOX®, and the like), nickel-cobalt-chromium-molybdenum alloys (e.g., UNS: R30035 such as MP35-N® and the like), nitinol, and the like, and others.

It should be understood that this disclosure is, in many respects, only illustrative. Changes may be made in details, particularly in matters of shape, size, and arrangement of steps without exceeding the scope of the disclosure. This may include, to the extent that it is appropriate, the use of any of the features of one example embodiment being used in other embodiments. The scope of the disclosure is, of course, defined in the language in which the appended claims are expressed.

Claims

1. A method of coating a medical device with a therapeutic composition comprising everolimus, the method comprising: coating everolimus crystals with a mixture of excipients to form encapsulated everolimus crystals suspended in a coating composition; andcontacting the medical device with the coating composition in order to form a coating on the medical device.

2. The method of claim 1, wherein the mixture of excipients comprise ethyl cellulose (EC).

3. The method of claim 1, wherein the mixture of excipients comprises acetyl tri-butyl citrate (ATBC).

4. The method of claim 1, wherein the mixture of excipients comprise EC and ATBC present in a range of 2 parts EC to 1 to 6 parts ATBC.

5. The method of claim 1, wherein contacting the medical device with the coating composition comprises spraying the coating composition onto the medical device.

6. The method of claim 1, wherein coating everolimus crystals with a mixture of excipients to form encapsulated everolimus crystals suspended in a coating composition comprises: suspending everolimus crystals in a first solution that includes acetyl tri-butyl citrate (ATBC) and cyclohexane; andadding a second solution to the first solution, the second solution including ethyl cellulose (EC) and ethyl acetate, the EC mixing with the ATBC and coating the everolimus crystals, thereby forming a coating suspension including coated everolimus crystals in the suspension.

7. The method of claim 1, wherein the medical device comprises an inflatable balloon.

8. The method claim 1, wherein the medical device comprises an expandable stent.

9. A method of coating a medical device with encapsulated everolimus crystals, the method comprising: forming a coating suspension by: suspending everolimus crystals in a first solution that includes acetyl tri-butyl citrate (ATBC);adding a second solution to the first solution, the second solution including ethyl cellulose (EC), the EC mixing with the ATBC and encapsulating the everolimus crystals, thereby forming a coating suspension including encapsulated everolimus crystals; andapplying the coating suspension to the medical device.

10. The method of claim 1, further comprising converting amorphous everolimus into the everolimus crystals.

11. The method of claim 9, wherein once the second solution has been added to the first solution, the EC and ATBC are present in a range of 2 parts EC to 1 to 6 parts ATBC.

12. The method of claim 9, wherein the medical device comprises an inflatable balloon.

13. The method claim 9, wherein the medical device comprises an expandable stent.

14. A medical device adapted to be placed within a location within a vasculature, the medical device comprising: a surface adapted to be placed in contact with a vessel wall within the vasculature; anda therapeutic coating disposed on the surface, the therapeutic coating comprising a plurality of everolimus crystals that are encapsulated within a coating that includes a synergistic combination of excipients.

15. The medical device of claim 14, wherein the synergistic combination of excipients comprises ethyl cellulose (EC).

16. The medical device of claim 14, wherein the synergistic combination of excipients comprises acetyl tri-butyl citrate (ATBC).

17. The medical device of claim 14, wherein the synergistic combination of excipients comprises two parts ethyl cellulose (EC) to one to six parts acetyl tri-butyl citrate (ATBC).

18. The medical device of claim 14, comprising an inflatable balloon.

19. The medical device of claim 14, comprising an expandable stent.

20. The medical device of claim 14, wherein the therapeutic coating is adapted to provide a 30 day tissue everolimus concentration of at least 1 nanogram per milligram.