Medical devices and methods coated with microsphere drugs

Abstract

This application relates generally to the field of materials and manufacturing methods, including single or multiple solvent-, excipient-, and polymer-free drug coating formulations, for producing microsphere-coated drug delivery technologies.

Description

[Technical Field]

[0001] This application relates to the field of materials and methods for manufacturing drug coating formulations that are free of anhydrous single or multiple solvents, excipients, and polymers, for generally producing drug delivery technologies coated with microspheres. [Background technology]

[0002] Balloon angioplasty is an established treatment for various arterial diseases. However, with the advent of stents and drug-releasing stents, balloon angioplasty has been relegated to the background. Recently, drug-coated angioplasty balloons (DCBs) have emerged as a viable alternative to uncoated balloons, or "POBA" (plain old balloon angioplasty). This emergence was initially driven by clinical data supporting the use of angioplasty balloons coated with antiproliferative paclitaxel incorporating excipients to treat in-stent restenosis (Chow et al., Interv Cardiol 7(2):169-180 (2015)).

[0003] Various drug forms, excipients, balloons, and coating methods of paclitaxel have been used in human clinical trials, but the results have been very mixed (Picard et al., Archives of Cardiovascular Disease 110:259-272 (2017)). More recently, sirolimus has been proposed for use with DCBs. Both paclitaxel and sirolimus are effective in preventing restenosis, but they differ in their biochemical mechanisms. Studies have shown that paclitaxel is potentially more toxic and has a narrower therapeutic range (Pires et al., Heart 93:722-727 (2007)). This understanding has led to great interest and numerous investigations into evaluating the use of sirolimus in both vascular stents and drug-coated balloons.

[0004] Currently, sirolimus and sirolimus derivatives ("limus") compounds are generally recognized as preferred drugs for use in coated vascular stents. However, the industry's demand for the development of limus-coated balloons has been more challenging. It is now understood that to obtain optimal results with these compounds, the drug needs to remain in the diseased tissue at therapeutic levels for at least one month. In attempts to address this requirement, various polymers and excipients have been used in conjunction with the physical forms of these drugs and various components. All of these attempt to avoid or delay drug loss from the balloon during insertion, enable drug migration and retention at the required site, minimize drug washout, and / or provide therapeutic amounts of drug and time to the tissue.

[0005] These requirements have led to complex Limus DCB coating compositions and manufacturing methods (Arpit et al., Trends Biomat Artif Organs 22(2):87-92 (2008)). Furthermore, it is now increasingly recognized that DCB coatings containing components in particulate and / or microsphere forms can aid in drug retention and timed release at the treatment site. These product requirements have led to the disclosure of a wide variety of drug forms and compositions.

[0006] Table 1 below lists several balloon designs coated with rims and the necessary coating additives they contain. [Table 1]

[0007] In-situ balloon formation of drug microspheres has been previously reported. For example, U.S. Patent No. 9,295,663 discloses several advantages of in-situ balloon microsphere formation over conventional balloon microsphere coating formulations. However, the disclosed materials and methods, required compositions, and necessary processes are quite complex. These materials and methods require balancing specific chemical substances with their chemical and physical properties, and using two different solvents. Then, specific drying requirements are utilized to obtain the desired results.

[0008] Such teachings in the art require that conventional optimization of drug coating formulations cannot produce a coating in which microspheres are formed in situ. Furthermore, in the relevant art, in order for drug microspheres to form properly, the formulation needs to use water as the primary solvent in a ratio of 30% to the secondary solvent. More importantly, if the evaporation of the coating formulation is too rapid, drug microspheres will not form.

[0009] It is evident that achieving the optimal physical and chemical drug composition to meet clinical requirements is challenging using polymers, foreign additives, and excipients. Various product additives can significantly increase manufacturing complexity and cost, and may negatively impact necessary packaging and product stability (shelf life). Furthermore, the addition of product components increases the risk of vascular and / or systemic toxicity in patients, all of which affect patient outcomes and total treatment costs. Improved limus DCB compositions and manufacturing processes are clearly needed in this field. [Overview of the project]

[0010] The present invention provides a method for coating a substrate surface to form a microsphere layer containing at least one drug, the method comprising (1) providing at least one hydrophobic material and at least one solvent, dissolving at least one hydrophobic material from (1) in at least one solvent from (1), (2) forming a dissolved product on the substrate surface, and (3) evaporating the dissolved product from the substrate surface to produce a microsphere layer. Alternatively, the at least one hydrophobic material contains at least one drug. Preferably, the at least one solvent is an alcohol. More preferably, the dissolved hydrophobic mixture is deposited onto the substrate by pipette or spray. Most preferably, the method does not involve the use of synthetic polymers in any of the steps defined above. Optionally, the substrate surface is selected from the group consisting of balloons, medical devices, and stents.

[0011] In another embodiment, the present invention provides a process for producing a microsphere composition comprising at least one drug, the process comprising the steps of: providing a hydrophobic mixture comprising at least one drug together with the hydrophobic mixture; dissolving the hydrophobic mixture in at least one solvent; depositing the dissolved hydrophobic mixture onto a substrate and evaporating the deposited dissolved hydrophobic mixture from the substrate to obtain a microsphere composition. Preferably, at least one solvent is an alcohol. More preferably, the dissolved hydrophobic mixture is deposited onto the substrate by pipette or spray. Most preferably, the process does not involve the use of synthetic polymers in any step. Optionally, the substrate is selected from the group consisting of balloons, medical devices, and stents.

[0012] Accordingly, one aspect of the present invention relates to a medical device having a coating layer comprising or comprising a plurality of drug microspheres as described herein.

[0013] In relation to the preceding aspects, the present invention relates to a medical device, preferably a balloon catheter having a balloon having a coating layer comprising or comprising a plurality of drug microspheres as described herein. One preferred embodiment of the above medical device relates to a balloon catheter having a balloon having a primer coating layer comprising a water-soluble material and a second layer comprising or comprising a plurality of drug microspheres as described herein. The primer layer used herein is to be applied to the surface of a substrate. For example, the primer layer of a balloon catheter is applied (coated) to the surface of the balloon.

[0014] The present invention also provides a method for producing drug microspheres containing at least one drug, comprising the steps of (1) dissolving at least one drug in at least one solvent to form a hydrophobic mixture, (2) depositing the dissolved hydrophobic mixture onto a substrate, and (3) evaporating the deposited and dissolved hydrophobic mixture from the substrate to obtain drug microspheres. The above method preferably includes an intermediate step (1b) applied before step (1), which includes applying a water-soluble material to a substrate and drying the water-soluble material. The application of step (1b) forms a primer layer of the water-soluble material on the substrate. Thus, the next step (2) is carried out, and the dissolved hydrophobic mixture is deposited on the substrate having the primer layer. [Brief explanation of the drawing]

[0015] The subject matter disclosed herein is best described in conjunction with the accompanying drawings. [Figure 1] Figure 1 shows SEM images of each coated balloon. (A) Balloon coated with 3.1 mg / mL CRC-015 in anhydrous methanol, (B) Balloon coated with 6.3 mg / mL CRC-015 in anhydrous methanol, (C) Balloon coated with 12.5 mg / mL CRC-015 in anhydrous methanol, and (D) Balloon coated with 25.0 mg / mL CRC-015 in anhydrous methanol. [Figure 2] Figure 2 shows paclitaxel spheres coated on a balloon. (A) Image of a balloon coated with a paclitaxel formulation in methanol at 25 mg / mL, (B) SEM image of drug microspheres. [Figure 3] Figure 3 shows spheres of CRC-015, paclitaxel, and gemcitabine coated on a balloon. (A) Image of a balloon coated by dissolving CRC-015, paclitaxel, and gemcitabine in methanol, (B) SEM image of drug formulation microspheres. [Figure 4] Figure 4 shows microspheres generated using CRC-015 in methanol (37.5 mg / mL) and 5% water. [Figure 5] Figure 5 shows microspheres generated using rapamycin in methanol (25 mg / mL) and 7% water. [Figure 6] Figure 6 shows microspheres generated using paclitaxel in methanol (10 mg / mL) and 4% water. [Figure 7] Figure 7 shows microspheres generated using everolimus in ethanol (45 mg / mL) and 1% water. [Figure 8] Figure 8 shows microspheres generated with a formulation comprising everolimus and alisertib in 34.2% (v / v) methanol and 56.8% (v / v) acetone. [Figure 9] Figure 9 shows microspheres generated with a formulation of CRC-015 in methanol coated on HSA. [Figure 10] Figure 10 shows microspheres produced with a formulation of CRC-015 in methanol coated on PVA. [Figure 11] Figure 11 shows in vivo data supporting a comparison of arterial vessel drug retention of CRC-015 DCB versus sirolimus DCB versus MagicTouch sirolimus DCB. [Modes for Carrying Out the Invention]

[0016] definition As used herein, the term “macrocyclic triene immunosuppressant compound” includes rapamycin (sirolimus), everolimus, zotalolimus, biolimus, novolimus, myolimus, temsirolimus, and the rapamycin derivatives described herein.

[0017] As used herein, the term “microsphere” or “microsphere-like” includes small, mostly spherical particles having a diameter ranging from nanometers to micrometers. The term “microsphere” or “microsphere-like” includes both hollow micelle structures and ball structures that are filled with material to the core without having a specific hollow space inside. This term directly refers to the term “particle” and can also mean partially hollow or completely filled.

[0018] The present invention provides materials and methods for the novel manufacture of drug microspheres for use in the treatment of specific diseases or conditions.

[0019] One aspect of the present invention provides a method for producing drug microspheres containing at least one drug, comprising the steps of (1) dissolving at least one drug in at least one solvent to form a hydrophobic mixture, (2) depositing the dissolved hydrophobic mixture onto a substrate, and (3) evaporating the deposited and dissolved hydrophobic mixture from the substrate to produce drug microspheres. The method described above may include an intermediate step (1b) applied before step (2), which includes applying a water-soluble material to the substrate and drying the water-soluble material. The water-soluble material in this step may be any material as defined herein as a water-soluble material. The substrate is preferably a medical device such as a balloon catheter or stent, but may be a pacemaker, an implantable cardioverter-defibrillator, or an implantable nerve stimulator. The method described herein may also include a step (1a) applied before step (1) or step (1b) (if present). Step (1a) provides washing and wetting the substrate, preferably the balloon of a balloon catheter, with an organic solvent as described herein. Preferably, step (1a) is carried out using acetone, pentane, hexane, ethanol, diethyl ether, or ethyl acetate. Performing step (1a) has the advantage that either the water-soluble material or the drug microspheres exhibit improved adhesion to the substrate. In addition, the substrate can be cleaned by plasma treatment before depositing the dissolved hydrophobic mixture onto the substrate. Preferably, the plasma treatment step is performed after cleaning and before applying step (1b). Plasma treatment can support the dissolution of the water-soluble material, thereby promoting faster migration of at least one drug.

[0020] Specific advantages of preferred embodiments of the present invention include, but are not limited to, increased drug yield on a milligram scale (even when using lipophilic drug compounds), reduced complexity associated with microsphere formation (including reductions in staff training and expensive equipment), dramatically reduced processing time (resulting in a decreased likelihood of drug degradation and reduced procedural costs), and removal of expensive materials (such as volatile compounds and expensive synthetic polymers) from the manufacturing stage.

[0021] The present invention relates to a method and processing steps for providing the formation of drug microspheres after solubilizing at least one drug or drug composition (or multiple drug compositions) in at least one solvent or a variety of solvents. Following this solubilization or dissolution step, the resulting mixture is dispensed onto a substrate. Figure 1 shows one embodiment of a method by which the mixture is dispensed onto a particular substrate. Preferably, a syringe is used to dispense the dissolved drug mixture onto the substrate. Alternatively, a pipette, needle, or cannula can be used in a similar manner.

[0022] As described above, various solvents can be used in this application. Preferred solvents are organic solvents that have been dried before use. Preferably, only one solvent is used in the solubilization or dissolution step, but since various solvents are also used, solvent mixtures can be used. The solvent must be dry. It should be understood that means have been applied to remove water from the dry solvent. The degree of removal can range from simple distillation of the solvent to treatment and preservation of the solvent with a drying agent such as sodium, potassium, or NaAlH4 after or during distillation. Preferably, the solvent contains less than 7% water, more preferably less than 3% water, even more preferably less than 1% water, and most preferably less than 0.01% water. In this regard, it is preferable that water is present in the solvent in amounts up to about 7%. In this preferred embodiment, an unmet need for solutions in the art that utilize water-free formulations containing a single or multiple solvents that rapidly form drug microspheres is met, and when water is present in amounts up to about 7%, microsphere formation proceeds rapidly even at ambient temperature.

[0023] It is even more preferable if the solvent has a water content of less than 1%. Suitable solvents are organic solvents such as alcohols, especially C1-C3 aliphatic alcohols, acetone, ethers, especially diethyl ether, chloroform, dichloromethane, acetonitrile, hexane, and pentane. Particularly preferred are C1-C3 alcohols, such as methanol or ethanol.

[0024] After depositing a mixture of solvent and drug onto a substrate, the mixture is evaporated, forming drug microspheres on the substrate surface. Optimizing production conditions can lead to specific improvements in the final product, such as controlling sphere size or automating processing steps. The step of evaporating at least one solvent is preferably carried out without means to accelerate evaporation, for example, by a slight wind or airflow. When evaporation occurs slowly, a narrow particle size distribution is observed. If stronger means to accelerate evaporation are applied, such as a stronger gas flow or heating the solvent near or above the boiling point of at least one solvent, the formation of microspherical hydrophobic material is not observed. With respect to the gas flow, it is preferable that the gas moves more slowly than 0.2 m / s across the surface of the solution.

[0025] The concentration of the hydrophobic drug composition in at least one solvent is considered to be in the range of 0.1 to 200 mg / ml. In a preferred embodiment, the concentration is in the range of 10 to 100 mg / ml. Within the aforementioned range, a narrow particle size distribution is observed. Furthermore, as defined above, at higher drug concentrations, better adhesion of the microsphere-like hydrophobic material to the substrate was observed. Although not bound by the following theory, it is thought that as the concentration increases, the diameter of the microsphere-like particles tends to increase, and as the diameter increases, the surface area contributing to adhesion between the particles and the surface also increases.

[0026] Preferably, at least one drug used in the present invention is a macrocyclic triene immunosuppressive compound selected from the group consisting of rapamycin (sirolimus), everolimus, zotalolimus, biolimus, novolimus, myolimus, temsirolimus and rapamycin derivatives, which includes any pharmaceutically acceptable salts and hydrates, as well as any stereoisomers, mixtures of stereoisomers and racemates. More preferably, a macrocyclic triene immunosuppressive compound comprising any pharmaceutically acceptable salts and hydrates, as well as any stereoisomers, mixtures of stereoisomers and racemates, has the following structure: [ka] Here, R is C(O)-(CH2) n -X, where n is 0, 1, or 2, and X is a cyclic hydrocarbon having 3 to 8 carbon atoms, optionally containing one or more unsaturated bonds. In the most preferred embodiment, C(O)-(CH2) n -X has one of the following structures: [ka]

[0027] In one embodiment, the drug microsphere comprises a macrocyclic triene immunosuppressive compound comprising any pharmaceutically acceptable salts and hydrates, as well as any stereoisomers, stereoisomers, and racemates, as defined above. In another embodiment, the drug microsphere comprises a macrocyclic triene immunosuppressive compound comprising any pharmaceutically acceptable salts and hydrates, as well as any stereoisomers, stereoisomers, and racemates, as defined above. One particularly preferred embodiment comprises a drug microsphere formed from a macrocyclic triene immunosuppressive compound and aricertib, comprising any pharmaceutically acceptable salts and hydrates, as well as any stereoisomers, stereoisomers, and racemates, as defined above. The ratio of the two compounds varies by weight from 5:95 to 95:5. In the preferred embodiment, the drug microsphere has an aricertib content of less than 50% by weight.

[0028] A more preferred embodiment relates to a drug microsphere comprising or comprising rapamycin or its derivatives and paclitaxel as defined herein. In a particular embodiment, the drug microsphere comprises paclitaxel and a macrocyclic triene immunosuppressant, which comprises any pharmaceutically acceptable salts and hydrates, as well as any stereoisomers, stereoisomers and racemates, the macrocyclic triene immunosuppressant having the following structure: [ka] Here, R is C(O)-(CH2)n -X, where n is 0, 1, or 2, and X is a cyclic hydrocarbon having 3 to 8 carbon atoms, optionally containing one or more unsaturated bonds. In the most preferred embodiment, C(O)-(CH2) n -X has one of the following structures: [ka]

[0029] One further aspect of the present invention relates to a medical device, preferably a balloon catheter, having a coating layer comprising or comprising a plurality of drug microspheres as described and defined herein. One preferred embodiment of the above medical device relates to a balloon catheter having a balloon having a primer coating layer comprising a water-soluble material and a second layer comprising or comprising a plurality of drug microspheres as described and defined herein. The primer layer used herein is to be applied to the surface of a substrate. For example, the primer layer of a balloon catheter is applied to the surface of the balloon.

[0030] To facilitate drug transfer from the medical device to the patient's tissue, it is within the scope of the present invention to provide a medical device having the microspheres described herein as an outer layer. In one embodiment, the layer of microspheres can be applied directly to the surface of the device. In a more preferred embodiment, an additional layer, but preferably one, a primer layer, may be introduced between the surface of the medical device and the layer of microspheres.

[0031] Preferably, the primer coating layer contains or consists of a water-soluble material and forms a first coating layer on the surface of the balloon catheter. This primer coating layer is preferably applied by immersion coating, in which the balloon catheter is placed in a solution containing the water-soluble material applied to the surface of the balloon catheter. Other suitable methods such as spraying or applying the solution with thread, needle, cannula, sponge or cloth can be used in the coating procedure. Following the application of this primer coating layer, the balloon catheter is removed from the solution or application device and allowed to dry for, for example, less than 24 hours at ambient temperature.

[0032] The water-soluble material, meaning the majority of the primer coating layer, is a polymer or protein having a molecular weight of approximately 50 to 200 kD. In one embodiment, the water-soluble material is a protein preferably selected from water-soluble human serum proteins or water-soluble blood proteins, preferably having a molecular weight of approximately 50 to 200 kD. In another embodiment, the water-soluble material is a polymer or protein having a molecular weight of approximately 65 to 70 kD, preferably a globular serum protein having a molecular weight of approximately 65 to 70 kD. In a further embodiment, the water-soluble material is selected from blood proteins such as globulins and / or fibrinogen having a molecular weight up to approximately 160 kD. More preferably, the water-soluble material is human fibrinogen or immunoglobulin. Most preferably, the water-soluble material is a human serum protein having at least 90% identity to the following sequences: [ka]

[0033] In the most preferred embodiment of the present invention, the water-soluble material is human serum albumin. The use of human serum albumin is preferable because, since the compound is of human origin, it does not impose an unnecessary drug or compound burden on patients treated with the balloon catheter described herein. This reduces unnecessary contamination of the patient. When used and applied as a primer layer, human serum albumin may contain small amounts of stabilizing compounds in the range of impurities. In embodiments in which the primer layer is considered to consist of human serum albumin or any other suitable protein, it is considered that these small amounts are covered by the wording "consists of" and is within the meaning of the present invention and the embodiments presented herein.

[0034] As described above, drug microspheres are small, mostly spherical particles with diameters ranging from nanometers to micrometers. In one embodiment, drug microspheres are in the micrometer range with an average diameter of 1–20 μm. In a preferred embodiment, drug microspheres have an average diameter of 3–10 μm. In this range, a synergistic effect was observed in that, when used on a balloon catheter, the microspheres exhibited strong adhesion to the substrate, while simultaneously achieving highly effective drug elution into the tissue. Although not bound by this theory, it is thought that diameters clearly outside the nanoscope have a relatively high surface area that contributes to adhesion between the particle and the surface, while still having a large overall surface area necessary for effective drug transfer.

[0035] Furthermore, as described above, the burden of exogenous compounds on the patient is kept to a minimum, preferably by not using any layers other than the drug microsphere layer or the human serum albumin layer. In particular, these embodiments allow for the application of higher drug doses than other layer combinations in which binders, excipients, or surfactants are typically applied in addition to the API, in order to provide an efficient implantation procedure with effective drug elution / transfer. For example, the typical drug load for a balloon catheter is 0.3-1.2 mg / mm³. 2It is maintained at a low level. Contamination is low according to the embodiments described herein, so 1.5 to 3.0 mg / mm³ 2 A higher drug load can be applied during this period.

[0036] In embodiments where the medical device is a balloon catheter, improved particle adhesion has been observed when the balloon is made of a polyamide material, particularly when the drug microspheres contain at least one compound described herein as CRC-15 (see Table 1 below). Balloon materials exhibiting good adhesion include polyamides such as nylon 6, nylon 66, nylon 11, and nylon 12, segmented polyamide-polyether-polyester block copolymers marketed under the trademark Pebax®, or nylon elastomers that are block copolymers having nylon 6, nylon 66, nylon 11, and nylon 12. The combination of polyamide-based balloon materials with drug microspheres containing or comprising CRC-15 is advantageous because the microsphere particles exhibit good adhesion, while the polyamide material has improved flexibility compared to, for example, polycarbonate. In this case, a balloon catheter having a balloon made from a polyamide-based material and having a microsphere coating as described herein, particularly a microsphere drug coating comprising or containing at least one CRC-15 as described herein, has an improved profile for use in small, winding vessels such as coronary arteries. This is because the flexibility of the material allows passage through these vessels, and the excellent adhesion minimizes material loss to these hard-to-reach locations. Furthermore, in embodiments without a primer layer, the balloon catheter exhibits a very small diameter, facilitating passage to very small locations.

[0037] Accordingly, in a particular embodiment, the present invention relates to a balloon catheter having a balloon made of a polyamide material as defined herein, having a coating layer applied to the balloon surface comprising or comprising rapamycin (sirolimus), everolimus, zotalolimus, biolimus, novolimus, myolimus, temsirolimus and / or rapamycin derivatives (including any pharmaceutically acceptable salts and hydrates, and mixtures of any stereoisomers, stereoisomers and racemates), and macrocyclic triene immunosuppressive compounds (including any pharmaceutically acceptable salts and hydrates, and mixtures of any stereoisomers, stereoisomers and racemates), wherein the macrocyclic triene immunosuppressive compound has the following structure: [ka] Here, R is C(O)-(CH2) n -X, where n is 0, 1, or 2, and X is a cyclic hydrocarbon having 3 to 8 carbon atoms, optionally containing one or more unsaturated bonds. In the most preferred embodiment, C(O)-(CH2) n -X has one of the following structures: [ka]

[0038] Most preferably, in this embodiment, the drug comprises or consists of any pharmaceutically acceptable salts and hydrates, as well as any stereoisomers, mixtures of stereoisomers and racemates, of macrocyclic triene immunosuppressive compounds, as defined above.

[0039] In one embodiment, the present invention relates to a balloon catheter having a coating layer applied to the surface of a balloon, wherein the coating layer consists of drug microspheres, the drug microspheres consist of macrocyclic triene immunosuppressive compounds, which include any pharmaceutically acceptable salts and hydrates, as well as stereoisomers, stereoisomers and racemates, and the macrocyclic triene immunosuppressive compound has the following structure: [ka] Here, R is C(O)-(CH2) n -X, n is 0, 1 or 2, X is a cyclic hydrocarbon having 3 to 8 carbon atoms, optionally containing one or a plurality of unsaturated bonds. In the most preferred embodiment, C(O)-(CH2) n -X has one of the following structures:

Chemical Formula

[0040] This particular embodiment of the balloon catheter has only a single monolayer on the balloon surface composed of microspheres, as defined immediately above. This embodiment may have further limitations with respect to balloon material, particle size, and drug loading on the balloon, as defined herein.

[0041] A preferred embodiment relates to a balloon catheter having a primer layer and a coating layer composed of drug microspheres. The coating layer is applied over the primer layer. The primer layer is applied to the surface of the balloon of the balloon catheter. The primer layer consists of a water-soluble material, preferably a protein with a molecular weight of 50 to 200 kD, most preferably human serum albumin. The drug microspheres are composed of a macrocyclic triene immunosuppressive compound, which includes pharmaceutically acceptable salts and hydrates, as well as stereoisomers, mixtures of stereoisomers and racemates, and said macrocyclic triene immunosuppressive compound has the following structure:

Chemical Formula

Chemical Formula

[0042] This particular embodiment is thought to have only the two layers defined above. No further layers are applied to the balloon. This embodiment may have further limitations with respect to the balloon material, particle size, and drug loading on the balloon, as defined herein.

[0043] Further embodiments 1. A method for coating a substrate surface to form a microsphere layer containing at least one drug, comprising: (a) providing at least one hydrophobic material; (b) providing at least one solvent; (c) dissolving at least one hydrophobic material from (a) in at least one solvent from (b) to form a dissolved product on the substrate surface; and (d) evaporating the dissolved product from the substrate surface to produce a microsphere layer.

[0044] 2. The method of Embodiment 1, wherein at least one hydrophobic material comprises at least one drug.

[0045] 3. The method of Embodiment 1 or 2, wherein at least one solvent is an alcohol.

[0046] 4. A method of one of the embodiments described above, in which no excipients or synthetic polymers are used in any of the steps.

[0047] 5. A method of the above-described embodiment, wherein the substrate surface is selected from the group consisting of balloons, medical devices, and stents.

[0048] 6. A process for producing a microsphere composition comprising at least one drug, wherein at least one drug is contained in a hydrophobic mixture, the hydrophobic mixture is dissolved in at least one solvent, the dissolved hydrophobic mixture is deposited on a substrate, the deposited hydrophobic mixture is evaporated from the substrate to produce the microsphere composition.

[0049] 7. The process of Embodiment 6, wherein at least one solvent is an alcohol.

[0050] 8. The process of Embodiment 6 or 7, wherein the process does not involve the use of synthetic polymers or excipients in any step.

[0051] 9. A process according to Embodiments 6-8, wherein the substrate is selected from the group consisting of balloons, medical devices, and stents.

[0052] 10. A medical device comprising a primer coating layer containing a water-soluble material and a second layer containing multiple drug microspheres.

[0053] 11. A medical device according to embodiment 10, wherein a primer coating layer forms a first coating layer on the surface of the medical device.

[0054] 12. A medical device of embodiment 10 or 11, wherein the medical device is a balloon catheter.

[0055] 13. One medical device according to Embodiments 10-12, wherein the primer coating layer is applied via one selected from the group consisting of dipping coating, spray coating, thread, needle, cannula, sponge, and cloth piece.

[0056] 14. A medical device according to one of embodiments 10-13, wherein a water-soluble material constitutes the majority of the primer coating layer.

[0057] 15. One medical device according to Embodiments 10-14, wherein the water-soluble material is a polymer or protein having a molecular weight of 50-200 kD. [Examples]

[0058] Examples of drug formulations: The macrocyclic triene immunosuppressive compounds of the present invention may be described as having two or more embodiments and comprising at least one of the following species from Table 1: [Table 2]

[0059] Where used herein, CRC-015 is a term that encompasses the genus and is used to refer to each of the following species from Table 1: CRC-015a, CRC-015b, CRC-015c, CRC-015d, CRC-015e, CRC-015f, CRC-015g, and CRC-015h.

[0060] I. Balloon coated with CRC-015 sphere The ability of anhydrous CRC-015 formulations at concentrations of 25.0, 12.5, 6.3, and 3.1 mg / mL to generate spheres by the method of the present invention, as well as the role of drug concentration in relation to sphere size, were investigated.

[0061] Materials: Anhydrous methanol; Sigma 900641-4x2ML sealed glass ampoules, lot SHBH9540 (0.001% water, Karl Fischer CERT). 4mL glass vial; heat-treated overnight at 140°C, then capped with a plastic PTFE-lined cap. Stainless steel spatula and 1mL glass pipette; heat-treated in the same manner as the glass vial. CRC-015; 0.47% moisture (Karl Fischer). 5.0x40mm Passeo35 balloon catheter (Biotronik Inc.).

[0062] Preparation method: An anhydrous formulation of CRC-015 was prepared by adding the required amount of drug to a tare vial using a stainless steel spatula. The required amount of anhydrous methanol was added using a glass measuring pipette, and the vial was immediately capped. The vial was briefly vortexed to dissolve the drug.

[0063] Balloon coating materials: Coating equipment; Adept Engineering Limited, P / N 768-01; Syringe pump; Sono-tek Syringe Pump Ti P / N 12-05-00144; Dispensing cannula; Stainless steel 55mm L x 1.5mm OD, 0.9mm ID x 0.7mm D side hole.

[0064] Balloon Coating Method: Each anhydrous formulation of CRC-015 was coated onto an inflated 5.0 × 40 mm Passeo35 balloon. The dispensing cannula was in direct contact with the balloon at either the proximal or distal end, and surfed along the balloon from end to end while dispensing 50 μL of the formulation solution horizontally across the inflated balloon as the balloon rotated around its axis. In these examples, the following process parameters were used: solution flow rate = 0.2 mL / min, dispensing time = 15 seconds to wet the balloon surface; rotation speed = 120 rpm, rotation time = 240 seconds to evaporate the solvent and form drug microspheres. The spherical coated balloons were kept at ambient temperature before image analysis. The coated balloons were imaged using a Hitachi TM-1000 benchtop scanning electron microscope (SEM). The drug-coated balloons were divided into three equal segments: distal, intermediate, and proximal. Each section was placed on a sample stage and then sputter-coated with gold. Next, the sample stage was placed in the sample chamber of a SEM for analysis. The size of the CRC-015 spheres present in the distal, middle, and proximal sections of the balloon was measured. Representative SEM images of each coated balloon are shown in Figure 1. The measured CRC-015 sphere sizes are shown in Table 2. No significant change in the size of the CRC-015 spheres was observed when the concentration of the drug formulation was increased from 3.1 mg / mL to 6.3 mg / mL and then to 12.5 mg / mL. However, when the concentration of CRC-015 was increased to 25 mg / mL, a statistically significant difference (P<0.0001 in the 95% confidence interval) in the size of the CRC-015 spheres was observed. [Table 3]

[0065] II. Balloons coated with paclitaxel spheres Paclitaxel (LC Laboratories P-3600, lot ASM-121) was formulated with methanol (EMD MXO488P-1, lot 59129) at 25 mg / mL, and balloons were coated using this solution in the same manner as in Example I. The resulting balloons were imaged (Figure 2(A)), and SEM analysis of the results showing the generated drug microspheres is shown in Figure 2(B).

[0066] III. Balloons coated with silolimus spheres Sirolimus (rapamycin) (LC Laboratories R-5000, lot ASW-134) was formulated as described in Example I, and drug spheres were generated on the balloon surface using this formulation.

[0067] IV. Balloons coated with Everolimus spheres Everolimus (LC Laboratories E4040, lot BDE-115) was formulated as described in Example I, and drug spheres were generated on the balloon surface using this formulation.

[0068] V. Balloons coated with biolimus spheres Biolimus was formulated as described in Example I, and drug spheres were generated on the balloon surface using this formulation.

[0069] VI. Balloons coated with Zotarolimus spheres Zotarolimus (Molcan, lot 10081) was formulated as described in Example I, and drug spheres were generated on the balloon surface using this formulation.

[0070] VII. Balloon coated with CRC-015 sphere CRC-015 was formulated as described in Example I, except that 100% ethanol (Sigma 459844, lot SHBJ8382) was used as the solvent. Drug spheres were generated on the surface of the balloon using this formulation.

[0071] VIII. Balloon coated with CRC-015, paclitaxel, and gemcitabine spheres. CRC-015, paclitaxel, and gemcitabine free base (LC Laboratories G4199, lot GMB-103) were dissolved together in methanol at the following concentrations: 20 mg / ml, 17 mg / ml, and 5.2 mg / ml, respectively. These solutions were used to coat balloons according to the method of Example I. The resulting balloons were imaged (Figure 3(A)), and the resulting drug spheres are shown in Figure 3(B).

[0072] The following formulations are examples of water-containing coatings.

[0073] IX. CRC-015 CRC-015 was dissolved in methanol to a concentration of 37.5 mg / mL. HPLC-grade water was added to prepare a coating solution containing water at a concentration of approximately 5 vol%. This coating solution was pipetteed onto the surface of a 5 × 120 mm balloon catheter and dried under ambient conditions for 30 seconds. The balloon surface was examined by SEM, and an SEM image showing the generated drug spheres was obtained (Figure 4).

[0074] X. Rapamycin Rapamycin was dissolved in methanol to a concentration of 25 mg / mL. HPLC-grade water was added to prepare a coating solution containing water at a concentration of approximately 7 vol%. Balloon coating and testing were performed in the same manner as in Example I. The resulting SEM image showing the generated drug spheres is shown (Figure 5).

[0075] XI. Paclitaxel Paclitaxel was dissolved in methanol to a concentration of 10 mg / mL. HPLC-grade water was added to prepare a coating solution containing approximately 4% water by volume. Balloon coating and testing were performed in the same manner as in Example I. The resulting SEM image showing the generated drug spheres is shown (Figure 6).

[0076] XII. Everolimus Everolimus was dissolved in 100% ethanol to a concentration of 45 mg / mL. HPLC-grade water was added to prepare a coating solution containing water at a concentration of approximately 1 vol%. Balloon coating was performed in the same manner as in Example 1, except that solvent drying was 45 seconds followed by SEM analysis. The resulting SEM image showing the generated drug spheres is shown (Figure 7).

[0077] These examples of microsphere formulations demonstrate that drug microspheres are rapidly generated using anhydrous solvent systems, yet the presence of varying amounts of water does not inhibit the microsphere formation process.

[0078] The following examples demonstrate coating formulations containing a mixture of multiple solvents and multiple compounds for the production of microspheres.

[0079] XIII. Multisolvent, multicompound mixture Everolimus and aricertib (MLN 8237) Adooq Bioscience 1028486-01-2, lot LI0004B007 were dissolved together in a 34.2% methanol and 65.8% acetone, v / v (EMD) solution to concentrations of 4.5 mg / mL and 2.5 mg / mL, respectively. The solutions were pipetteed onto the surface of an inflated balloon and allowed to dry for 30 seconds before SEM analysis. The microspheres obtained by SEM are shown in Figure 8.

[0080] The following examples show drug microspheres formed using the underlying layer.

[0081] XIV. Formation of drug microspheres with underlying layers Inflated 5.0 x 40 mm Passeo 35 balloons were cleaned by wiping the surface of the balloon with a Kimwipe moistened with acetone. The balloons were optionally pre-treated with plasma (including argon gas). The dried balloons were dipped in human serum albumin (HSA) by first inserting the distal end of the balloon into a tube containing a solution of 5% human serum albumin (HSA) (Albumedix P / N 200-010, Lot 2107, diluted to 5% with HPLC water). The dipped-coated balloon was removed from the tube and then inverted so that the distal end of the balloon was facing upward. Excess HSA that had flowed down to the proximal end of the balloon was removed with a Kimwipe. The HSA-coated balloons were dried under ambient conditions for 14–38 hours. CRC-015 was formulated and coated onto the HSA-coated balloons as described in Example I. Figure 9 shows an SEM image of the balloon surface, which was examined using a scanning electron microscope (SEM) and shows the generated drug spheres.

[0082] In another embodiment, an inflated 5.0 × 40 mm Passeo 35 balloon was dip-coated with a solution of 0.25% polyvinyl alcohol (PVA; EMD P / N 1.41350.1000, Lot K50570650, 85-89% hydrolysis, 3.4-4.6 mPa*s viscosity) prepared by adding PVA to a vial whose tare weight was measured using a stainless steel spatula. The required amount of HPLC-grade water was added to the vial using a glass measuring pipette. A stirring rod was added to the vial and the vial was capped. The PVA was dissolved by stirring the solution in an 80°C water bath for 3-4 hours. After the PVA cooled to ambient temperature, the balloon was dip-coated as described in Example XIV. CRC-015 was formulated and coated onto the PVA-coated balloon as described in Example I. The balloon surface was examined by SEM, and an SEM image showing the generated drug spheres is shown in Figure 10.

[0083] XV. In vivo data supporting balloons coated with CRC-015 microspheres The in vivo migration of the drug coating into arterial vessels was evaluated by treating the left and right deep (deep femoral artery) and superficial femoral artery (SFA) of Yucatan minipigs with CRC-015 DCB (Example XIV). This pig model has been recognized as a general predictor of human performance. Prior to treatment with CRC-015 DCB, the target vessels were pre-dilated with uncoated balloons to mimic surgical procedures commonly performed in human clinical settings. The carotid arteries of the animals were surgically exposed and ligated after administration of anesthesia. An 8F introducer sheath was inserted and secured. An 18000 guidewire and 8F guiding catheter were inserted through the introducer sheath and advanced to the target vessel. Angiographic images of the vessels were obtained using contrast agent, and vessel size was measured using calibration markers.

[0084] Under fluoroscopy, an uncoated, sterile 5.0 x 40 mm pre-inflated balloon catheter was inserted through a guide catheter onto a guidewire, advanced to the target site, and inflated for 30 seconds. The pre-inflated balloon was deflated and withdrawn. Next, a 5.0 x 40 mm drug-coated balloon catheter was advanced to the dilated vascular segment and inflated for 120 seconds. The drug-coated balloon was deflated and withdrawn. Angiograms of the contrast-enhanced vessels were obtained after each balloon inflation.

[0085] A total of six animals were treated with CRC-015 DCB. Three animals (six femoral arteries per test group) were euthanized on day 14, and three animals (six femoral arteries per test group) were euthanized on day 28. The treated blood vessels were recovered by autopsy, and the drug content was analyzed by HPLC quantification. The tissue drug retention of CRC-015 on days 14 and 28 was ng drug / mg tissue / μg / mm³ on the balloon. 2 Normalized as a function of drug dose, ng / mg / (μg / mm 2The arterial drug retention of CRC-015DCB was compared with the results reported for MagicTouch sirolimus DCB (Concept Medical, Cardiovascular Innovation Pipeline @ EuroPCR, May 26, 2010) and Selution sirolimus DCB (Zeller, et al. MAC, Dec 07-09, 2017), as shown in Figure 11.

[0086] These results demonstrate improved in vivo performance of the present invention's product compared to the referenced, more chemically complex and compounded product.

[0087] In a further embodiment of the present invention, coating of the sphere-forming composition can be achieved by spraying, rolling, brushing, dip coating, direct fluid or inkjet application of the solution onto the substrate. The present invention also enables the production of drug spheres containing two or more drugs together on a medical device for treating various disease conditions.

[0088] The inventions described herein exemplary can be adequately implemented without any elements (singular or plural) or limitations (singular or plural) not specifically disclosed herein. Therefore, terms such as “comprising,” “including,” and “containing” should be read broadly and without limitation. Furthermore, the terms and expressions used herein are for illustrative purposes only, not limitation, and in the use of such terms and expressions, there is no intention to exclude any future equivalents or parts thereof shown or described. It is recognized that various modifications are possible within the scope of the invention as described in the claims. Therefore, although the invention has been specifically disclosed by preferred embodiments and optional features, those skilled in the art should understand that modifications and variations of the invention disclosed herein can be made, and such modifications and variations should be considered within the scope of the invention disclosed herein. The invention has been described broadly and generally herein. Each of the narrower groups of species and subgenerics that fall within the scope of the general disclosure also forms part of these inventions. This includes a general description of each invention, but with provisos or negative limitations that remove the subject matter from the genre, regardless of whether the excluded materials are specifically present therein.

[0089] Furthermore, where features or aspects of the invention are described from the perspective of the Markush Group, a person skilled in the art will recognize that the invention is also described from the perspective of any individual member or subgroup of a member of the Markush Group. It should also be understood that the above description is intended to be illustrative and not limiting. Many embodiments will be apparent to a person skilled in the art upon consideration of the above description. Therefore, the scope of the invention should not be determined by reference to the above description, but by reference to the appended claims, and together with the entire scope of equivalents to which such claims are entitled. All disclosures of papers and references, including patent publications, are incorporated herein by reference.

[0090] In light of the above teachings, it will be apparent to those skilled in the art that numerous modifications and variations are possible of the described examples and embodiments. The disclosed examples and embodiments may include some or all of the features disclosed herein. Therefore, it is intended to cover all such modifications and alternative embodiments that fall within the true scope of the invention.

Claims

1. The substrate is coated with rapamycin (sirolimus), everolimus, zotalolimus, biolimus, novolimus, myolimus, and / or temsirolimus, including any pharmaceutically acceptable salts and hydrates thereof, as well as any stereoisomers, mixtures of stereoisomers and racemates, and the following structures: 【Chemistry 1】 (Here, R is C(O)-(CH ２ ) ｎ A method for forming a microsphere layer comprising at least one drug selected from a macrocyclic triene immunosuppressive compound having -X (where n is 0, 1, or 2, and X is a cyclic hydrocarbon having 3 to 8 carbon atoms, and optionally containing one or more unsaturated bonds), which includes any pharmaceutically acceptable salts and hydrates, as well as any stereoisomers, mixtures of stereoisomers and racemates, The method comprises (1) dissolving the at least one drug in at least one solvent containing less than 7% water at a concentration in the range of 10 to 100 mg / ml to form a hydrophobic mixture; (2) depositing the dissolved hydrophobic mixture onto a substrate; and (3) evaporating the deposited and dissolved hydrophobic mixture from the substrate such that a gas flow moves over the substrate at a rate slower than 0.2 m / s to obtain a microsphere layer, wherein the microspheres in the microsphere layer have an average diameter of 1 to 20 μm, and the method further comprises (1b) prior to step (2) applying a water-soluble material to the substrate and drying the water-soluble material to form a primer layer, wherein the water-soluble material is a protein selected from water-soluble human serum proteins.

2. At least one solvent is C １ ~C ３ The method according to claim 1, selected from aliphatic alcohols.

3. The method according to claim 1 or 2, further comprising the step (1a) of washing a substrate with an organic solvent.

4. The method according to any one of claims 1 to 3, wherein the water-soluble material is human serum albumin.

5. The method according to any one of claims 1 to 4, further comprising a plasma cleaning step prior to step (1b) or (2).

6. A medical device having a coating layer consisting of multiple drug microspheres having an average diameter of 1 to 20 μm, wherein the drug microspheres include rapamycin (sirolimus), everolimus, zotarolimus, biolimus, novolimus, myolimus, and / or temsirolimus, any pharmaceutically acceptable salts and hydrates thereof, as well as stereoisomers, mixtures of stereoisomers and racemates, and the following structures: 【Chemistry 2】 (R is C(O)-(CH ２ ) ｎ A macrocyclic triene immunosuppressive compound having -X (where n is 0, 1, or 2, and X is a cyclic hydrocarbon having 3 to 8 carbon atoms, optionally containing one or more unsaturated bonds), comprising at least one of any pharmaceutically acceptable salts and hydrates, as well as any stereoisomers, mixtures of stereoisomers and racemates, The medical device comprises a primer layer made of a water-soluble material, wherein the water-soluble material is a protein selected from water-soluble human serum proteins.

7. The medical device according to claim 6, wherein the medical device is a balloon catheter having a balloon.

8. The medical device according to claim 6 or 7, wherein the microspheres have an average diameter of 3 to 10 μm.

9. The medical device according to any one of claims 6 to 8, wherein the water-soluble material is a protein having a molecular weight of 50 to 200 kD.

10. The medical device according to any one of claims 6 to 9, wherein the water-soluble material is human serum albumin.

11. The medical device according to any one of claims 7 to 10, wherein the balloon of the balloon catheter is made of polyamide material.

12. The medical device according to any one of claims 7 to 11, wherein the medical device is a balloon catheter having a balloon, a primer layer is applied on the balloon, a coating layer consisting of drug microspheres is applied on the primer layer, and the balloon does not have any additional layers.

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