Medical device and preparation method having an immediately mobile and permanently growth-inhibiting coating containing at least one type of limus substance

Abstract

The present invention provides medical devices having coatings for the local prevention and treatment of undesirable cell proliferation and vascular stenosis, as well as methods for coating the surface of medical devices. [Solution] A medical device is provided, comprising a coating on at least a portion of its surface, wherein the coating comprises at least one limus substance in an unencapsulated crystalline form, and the at least one unencapsulated limus substance is applied directly from a solvent mixture of at least one organic solvent and water. The formation of crystals of the limus substance can be brought about or enhanced by slowing the evaporation of the solvent mixture. In addition, a method for preparing the medical device is also provided.

Description

Technical Field

[0001] The present invention relates to a medical device having a coating on at least a part of its surface, the coating containing at least one limus substance in a non-encapsulated crystalline form, and a method for preparing the same.

Background Art

[0002] Hypoperfusion of various tissues is often a major cause of functional deficits and diseases in the elderly and is often a cause of death. Hypoperfusion is often caused by stenosis of the lumen of large blood vessels, which can be due to excessive growth of tissue that blocks the passageway that occurs during injury or even the healing process after surgery.

[0003] Uncontrolled and undesirable cell growth is the cause of many diseases, including those not related to tissue blood supply. Undesirable growth of cells and tissues is known to be affected by irradiation, by excessive tissue damage temperature, and by drug treatment. For the purpose of combating tumors, numerous substances from various classes of substances with various mechanisms of action can be used to inhibit cell growth. These are usually administered systemically, i.e., by intravenous injection or infusion, or orally. In contrast, the choice of pharmaceuticals for preventing stenosis of body passages is almost completely limited to two classes of substances: (a) macrolide antibiotics or limus substances (e.g., sirolimus = rapamycin) and (b) paclitaxel of the taxane class. The most prominent effect of these pharmaceuticals is the inhibition of cell growth.

[0004] Both substances or categories of substances are applied topically to achieve high concentrations in the target area with low systemic exposure. Limus substances are typically applied to coronary stents and released slowly from there to directly enter adjacent tissues. Paclitaxel is applied to the balloon of a balloon catheter and pressed against the adjacent vessel wall when the balloon is instantaneously inflated with high pressure. In both coronary arteries and other vessels, paclitaxel prevents rapid proliferation of vascular wall cells and immediate narrowing of the vascular lumen. Paclitaxel is also used on stents for peripheral arteries.

[0005] The clinical benefits of paclitaxel in reducing vascular stenosis are well recognized. Clinically relevant side effects of paclitaxel after use on balloon catheters have been a long-standing concern and suspicion, but none are publicly known, or at least not reproducibly demonstrated. Nevertheless, there is a growing consensus that topical application of paclitaxel can lead to systemic toxic effects and should be replaced with sirolimus or one of its derivatives whenever possible.

[0006] This has been shown and published many times over the years, with various changes, and is reflected in Table 1 below.

[0007] JPEG2026082826000001.jpg90170

[0008] Table 1 also reveals a problem: when applied topically as intended, the Limus substance is slowly absorbed by the tissue and does not remain in the tissue for as long as paclitaxel. This must be interpreted as suggesting insufficient efficacy when administered via a balloon that is inflated for only a short time at the treatment site. The development of an effective balloon catheter coated with Limus substance is difficult due to the following two facts: a) To date, almost all published animal studies on the inhibition of vascular stenosis by limus-coated balloon catheters have avoided comparisons with paclitaxel-coated balloon catheters. One possible reason for this is that limus may inhibit cell proliferation in pigs to a lower degree than in humans. b) Although sirolimus-coated balloon catheters are currently commercially available, no studies comparing their vascular stenosis inhibition with those of uncoated balloon catheters are known. A small number of clinical trials compared treatment using sirolimus-coated balloon catheters with treatment using paclitaxel-coated balloon catheters (Rosli MA, Abdul Kader MASK, Wan Ahmad WA, Ong TK, Liew HB, Al-Fazir Omar AF, Zuhdi ASM, Nuruddin AA, Schnorr B, Scheller B. Treatment of coronary drug-eluting stent restenosis by a sirolimus- or paclitaxel-coated balloon JACC:Cardiovasc Intervent, 2019:558-566).

[0009] German Patent Application Publication No. 102013110294 discloses the application of mixed-size limus crystals to the balloon surface of a medical device using polar and nonpolar organic solvents. [Overview of the project]

[0010] The object of the present invention is to provide a medical device having a coating for the local prevention and treatment of undesirable cell proliferation and vascular stenosis. Such a medical device can have similar efficacy in humans as paclitaxel-coated medical devices and can offer the advantages of the "Limus" substance shown in Table 1.

[0011] The above objectives are achieved by medical devices and by methods for preparing medical devices having the features of the independent claims.

[0012] Advantageous embodiments of the present invention are characterized in the dependent claims.

[0013] The present invention provides a medical device having a coating on at least a portion of its surface, wherein the coating comprises at least one limous substance in a non-encapsulated crystalline form, and the at least one crystalline non-encapsulated limous substance is applied directly from a solution of a water-miscible organic solvent or a mixture of a water-miscible organic solvent and water.

[0014] Nonpolar solvents are not miscible with water, and the solution contains no nonpolar solvent whatsoever.

[0015] The present invention provides a medical device having a coating on at least a portion of its surface, wherein the coating comprises at least one limus substance in a non-encapsulated crystalline form, and the crystalline non-encapsulated limus substance is applied as a suspension consisting of a water-miscible organic solvent or a mixture of a water-miscible organic solvent and water.

[0016] The suspension does not contain any nonpolar, water-immiscible organic solvents.

[0017] The degree of crystallinity and solution properties of a crystal are determined by the crystallization and coating conditions.

[0018] In the above modification, water and organic solvents, or the individual organic solvents used, can be mixed without phase formation.

[0019] The medical device according to the present invention is novel and is characterized by a method for preparing a coating.

[0020] Preferably, the drying of at least one limousine substance applied as a solution or suspension is carried out slowly or inhibited.

[0021] The formation of crystals of the limus substance can be achieved or enhanced by slowing down or suppressing the evaporation of the solvent mixture.

[0022] The limus substance is a macrolide active ingredient. Preferably, sirolimus, everolimus, zotarolimus and biolimus are used.

[0023] The medical device according to the present invention is inserted into a patient's body and can thereby come into temporary or permanent contact with a part of the body.

[0024] Preferably, the coating is applied to at least a part of the surface of the medical device, and after the medical device is introduced into the human body, the effect is brought about by contact with the tissue at the treatment site.

[0025] The medical device is, for example, preferably used to stabilize the lumen of a blood vessel or other passageway, preferably a short-term indwelling medical device such as an angioplasty balloon catheter and a temporary stent, preferably a medium-term indwelling medical device such as an indwelling catheter, or preferably a long-term indwelling implant such as a stent.

[0026] The medical device is preferably coated in a state where its surface is maximally available for the coating, for example, a stent in a fully expanded state, a balloon of a balloon catheter in an inflated form, etc.

[0027] The balloon of a folded balloon catheter that is ready for use can be inflated before being coated and can be folded after being coated, but may also be coated in a loosely or tightly folded state.

[0028] Alternatively, although not preferred, medical devices, in the state in which they are introduced into the body, are usually in a compressed or tightly folded form, usually already in an introducer catheter, or balloons with or without a pre-attached stent can be coated.

[0029] The active ingredients used for coating are locally effective. To achieve locally and systemically acceptable dosages, the dosages used on medical devices are within a relatively wide range depending on the product and application, preferably 0.1 - 20 μg / mm² of the surface of the medical device. 2 That is.

[0030] The coating containing the active ingredient is generally applied to the medical device in a defined dosage as a solution or suspension by a micro - dosing unit such as a microsyringe or a pump, and is uniformly distributed over the entire surface.

[0031] As long as the solvent used contains highly volatile components, the contact with the gas phase in the metering device should be limited to the outlet opening as much as possible.

[0032] A general feature of the medical device according to the present invention is a coating with a dosage of a drug that is effective on the contacted tissue. The coating is applied as completely as possible to the site of action, and at that site, the coating is released from the medical device quickly and completely. A part of the substance released at the site of action forms a reservoir to ensure a long - term effect.

[0033] The coating preferably contains at least one or more antioxidants selected from the group consisting of ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, nordihydroguaiaretic acid, probucol, propyl gallate, and resveratrol.

[0034] At least one organic solvent is preferably selected from the group consisting of methanol, ethanol, isopropanol, tetrahydrofuran, and / or acetone.

[0035] Furthermore, the coating may contain additional excipients and / or additives, the proportion of which may vary within the coating and be determined by the intended function.

[0036] Furthermore, a further layer containing additional excipients and / or additives can preferably be provided on the coating.

[0037] Excipients or antioxidants are used to improve the adhesion or delivery of the active ingredient to the tissue, preferably in proportion to more than 5 wt% of the limus substance. Antioxidants may be used in proportion to 1 wt% or less of the limus substance to chemically stabilize it.

[0038] In one preferred embodiment, the excipient is an oily substance such as a fatty acid salt or provitamin B5 (dexpanthenol) in the range of 0.5 to 50 wt% of the limus substance.

[0039] To coat at least a portion of the surface of a medical device with a suspension containing at least one crystalline limous material, the method according to the present invention includes the following steps:

[0040] A step of dissolving at least one Rimus substance in at least one organic solvent. A step of adding at least one water-miscible organic solvent, in which the Rimus substance loses solubility, to the Rimus solution until the mixture becomes Rimus supersaturated.

[0041] Such solutions or suspensions are not used for coating, but solely for generating Rimus crystals.

[0042] A step of initiating the crystallization of at least one type of limus substance to obtain a crystal-containing suspension.

[0043] The initiation of crystallization or crystallization itself can be achieved by storage at low temperatures and / or by ultrasonic exposure of the preparation.

[0044] Preferably, before or immediately after the first crystal formation, the preparation is cooled and left in a refrigerator (approximately +4°C) or freezer (approximately -20°C) for 30 minutes to several days.

[0045] Preferably, the step of isolating crystals of at least one lims substance from the suspension and resuspending the crystals in a water-miscible organic solvent or in a mixture of a water-miscible organic solvent and water having a water content of preferably 30-50 vol%.

[0046] A step of coating medical devices using a suspension. The liquid in the suspension does not contain water-immiscible organic solvents.

[0047] A step of applying a suspension to the surface of a medical device and drying it, wherein the suspended crystals are uniformly distributed and the dissolved portion crystallizes due to the evaporation of the solvent.

[0048] Below, we will again describe in detail one preferred variation for preparing the coating suspension.

[0049] To prepare the coating suspension, in the first step, the true solution in ethyl acetate, for example, can be prepared from any (amorphous or crystalline) limus substance or a mixture of limus substances, and the concentration of the limus substance in the solution is preferably 10 to 300 mg / ml, and particularly preferably about 100 mg / ml.

[0050] The antioxidant is preferably BHT (=butylated hydroxytoluene), which can be added to the solution at a concentration of 0.1 to 10 mg / ml.

[0051] Since the Rimus substance is very poorly soluble, an organic solvent such as n-hexane or n-heptane is slowly added to the solution with stirring in a ratio of 1 to 3 parts, for example, 1 part Rimus solution to n-hexane, to initiate the crystallization of the Rimus substance.

[0052] Preferably, before or immediately after the formation of the first crystals, the solution is cooled, preferably left in a refrigerator (approximately +4°C) or freezer (approximately -20°C) for 30 minutes to several days.

[0053] Crystallization can be initiated by ultrasonic treatment of the solution before cooling, or while it is pre-cooled with ice, and the crystal aggregates (not crystals) can then be broken.

[0054] The crystals can be removed by centrifugation or filtration and slowly dried at room temperature in a stream of air or nitrogen. Wet crystals can also be used.

[0055] In the second step, water is added to a mixture of water-miscible organic solvents or organic solvents, respectively, until the solubility of the limus substance at room temperature is preferably less than 30 mg / ml of mixture, more preferably less than 10 mg / ml, but always less than 50 mg / ml.

[0056] The crystals from the first step are preferably added to the solvent mixture in an amount of 10 to 100 mg / ml.

[0057] Alternatively or supplementary, the process of forming or preparing crystals can be carried out after the medical device has been coated.

[0058] To coat at least a portion of the surface of a medical device with a solution and preferably produce at least one crystalline rim material by slow drying, the method according to the present invention includes the following steps:

[0059] A step of dissolving at least one lims substance in at least one water-miscible organic solvent and water, wherein the water content is preferably at least 10%. The at least one organic solvent does not contain a water-immiscible organic solvent.

[0060] A step of applying the solution to the surface of a medical device. Preferably, a step of drying, which is preferably carried out by slow drying. Preferably, slow drying is carried out by suppressing air exchange, by low temperature, and / or by a suitable composition of the gas phase in the environment of the medical device (e.g., enrichment of solvent vapor).

[0061] It is particularly preferable to optionally temporarily suppress these evaporations by covering the solution / suspension with a protective cover that is closed at one end and formed from, for example, Teflon®, polypropylene, or a similar synthetic material.

[0062] In one preferred embodiment, at least one additional layer of additives / excipients is applied to the dried layer in the final step.

[0063] Furthermore, the solution or suspension may contain an antioxidant, preferably BHT, at a concentration of 0.01 to 5 mg / ml, and any pharmaceutically acceptable additives, such as a stabilizer for the suspension, a chemical stabilizer for the active ingredient, a binder for the limus crystals on the surface of the medical device, and an excipient to improve the transfer of pharmaceutically active substances from the medical device to or within the tissue.

[0064] Such substances are well known and preferably amphiphilic substances such as iodized X-ray contrast agents, urea, fatty acids and fatty acid salts, citric acid and citrate esters, dexpanthenol, and lecithin.

[0065] The appropriate concentration of excipients in the coating suspension is 0.1–30% (m / v) relative to the limus material in the preparation.

[0066] Alternatively or supplementary, the process of forming or preparing crystals can be carried out after the medical device has been coated.

[0067] A known process is "vapor annealing," in which a dry drug on the surface of a medical device is exposed to the vapor of a suitable solvent for a relatively long period of time. Under the influence of the solvent vapor, the desired physical form of the active ingredient is formed. The process is labor-intensive and time-consuming. Therefore, the conversion of such amorphous (dry) coatings to crystalline coatings by subsequent introduction of the solvent into the gas phase of the coated medical device for crystalline conversion (annealing) is not within the scope of this invention.

[0068] As previously described in the present invention (International Publication Nos. 2011 / 131258, 2011 / 131259, 2011 / 131678, 2014 / 173748, and 2015 / 039969), a true solution or suspension of crystals containing a dissolved active-ingredient component can be used for coating. To promote the crystallization of the active ingredient or the growth of existing crystals, the drying of the liquid on the medical device can be carried out slowly. This can be achieved, for example, by selecting only low-volatility solvents; by applying the coating solution, which is a diluted form to start with and a highly concentrated form in subsequent coating stages to prevent the crystallized product formed in the initial coating stage from redissolving, in portion by portion; by avoiding airflow; by the specific composition of the ambient atmosphere; and by the specific temperature of the medical device or environment. Preferably, the medical device is packed into a container with a very small opening to a material or environment with limited permeability, shortly after the lims preparation is applied and before the solvent is completely dry after coating. A very simple and preferred method is to place a protective cover over the newly coated balloon while it is still not completely dry. If the balloon is coated while inflated and not folded, the balloon membrane can be folded and at the same time minimize the balloon diameter.

[0069] The particularly notable advantages of the medical devices and coatings described herein are the simple and inexpensive preparations and the surface area of ​​the medical device (mm²) required for limus activity. 2 The advantages include the potential to achieve a relatively high amount of active ingredient per unit, stability during storage, inhibition of luminal stenosis and stenosis formation due to neointimal proliferation, long-lasting efficacy with respect to the mentioned parameters, and good local tolerability.

[0070] Advantageously, compared to conventional technologies, it achieves faster and more complete tissue absorption and longer tissue retention, and in particular, can achieve stronger efficacy in animal studies compared to known lims coatings.

[0071] The in vitro measurable requirement for strong, persistent inhibition of excessive and undesirable neointima-proliferation as a result of long-term tissue retention (see Table 1) is the slow dissolution of the limus substance in an aqueous medium (see Example 5).

[0072] The present invention will be described in more detail below with reference to examples. [Examples]

[0073] [Example 1] (1) Preparation of silolimus crystals 200 mg of sirolimus was dissolved in 2 ml of ethyl acetate, and 2.5 ml of hexane was added to this solution in a 0.5 ml portion and mixed. A clear solution was obtained, which was first cooled in a freezer at -20°C for 10 minutes. Simultaneously, crystallization was initiated by sonication for 30 minutes while cooling with ice.

[0074] The sample was stored overnight at -20°C, then centrifuged at -9°C, and the supernatant was transferred.

[0075] The precipitate, consisting of silolimus crystals, was dried in a vacuum.

[0076] (2) Coating preparations The 50 mg of dried crystals produced as described above were added to 1 ml of a solution containing 5 mg / ml of dexpanthenol and 6.5 mg / ml of butylated hydroxytoluene in acetone / water 1:1 (v / v) and mixed to obtain a suspension.

[0077] (3) Coating Catheter: PTCA, rapid exchange, Creganna, balloon size 3.5 x 20 mm, inflated and coated with suspension. Sirolimus content / balloon = 5.8 ± 0.7 μg / mm 2 = 1469 ± 189 μg

[0078] [Example 2] (1) Preparation of silolimus crystals 500 mg of sirolimus was dissolved in 5 ml of ethyl acetate. 6.25 ml of n-hexane was added to this solution in 2 ml portions, with mixing after each portion. The solution remained clear. To form crystals, the solution was first stored at -20°C for 10 minutes, then sonicated for 30 minutes while cooling on ice, followed by standing at -20°C overnight and centrifugation at -9°C. The supernatant was transferred to another container. The sirolimus crystals were dried in a vacuum.

[0079] (2) Coating preparations Using these crystals, the following preparations were made for coating medical devices.

[0080] JPEG2026082826000002.jpg47170

[0081] (3) Coating We coated a temporary spur stent system (2nd generation) from ReFlow medical Inc. (San Clemente, USA).

[0082] JPEG2026082826000003.jpg88170

[0083] Figure 1 shows a spur (stent) coated with RFlimus-Q-50-DP-5-BHT-0.5.

[0084] [Example 3] <Comparison of three coatings according to the present invention and a commercially available sample (Magic Touch)>

[0085] JPEG2026082826000004.jpg157170

[0086] (Preparation of coating solution / suspension): (Preparation of the solution for A2 coating) A solvent mixture of 3.9 ml of tetrahydrofuran, 8.0 ml of acetone, and 90 μl of acetic acid was prepared. 6 mg of butylated hydroxytoluene (BHT) was dissolved in 9.0 ml of the mixture. 6 mg of magnesium stearate was dissolved in 3.6 ml of the BHT solution. 2.4 ml of water was added to this solution, and it was sonicated for 10 minutes. Then 40 mg of sirolimus was dissolved in 1 ml of the BHT / magnesium stearate solution.

[0087] (Preparation of suspensions for coatings C2 and C3) Sirolimus crystals were prepared as described in Example 2.

[0088] 6 mg of BHT was dissolved in 15 ml of methanol / water (70 / 30, v / v) (0.4 mg / ml), and 40 mg of SIR / ml was suspended in the solution.

[0089] (A2 coating): While continuously rotating the folded balloon around its vertical axis, 14 μl of the solution was applied to the balloon twice, with an interval of approximately 30 minutes between applications.

[0090] Immediately after coating, a wide protective cover (with an inner diameter of 1.3 mm) was pulled over the balloon.

[0091] After 16 hours, the wide protective cover was replaced with a narrower protective cover (with an inner diameter of 1.1 mm).

[0092] (C2 and C3 coatings): A protective cover with an inner diameter of approximately 1.2 mm was pushed up onto the catheter shaft, over the uncoated, still-folded balloon.

[0093] The balloons were inflated just before coating.

[0094] A suspension was applied to a balloon that was rotating relative to the vertical axis.

[0095] Next, the balloon was rotated for one minute to allow the coating to dry.

[0096] Next, the balloon was deflated using a vacuum, and the balloon membrane was folded again, with the protective cover pulled back onto the coated balloon.

[0097] [Example 4] <Deformed form of coating A2> (Preparation of solutions for coating variations A2a, A2b, A2c, A2d, and A2e): A solvent mixture of 3.9 ml of tetrahydrofuran, 8.0 ml of acetone, and 90 μl of acetic acid was prepared. 6 mg of butylated hydroxytoluene (BHT) was dissolved in 9.0 ml of the mixture. 6 mg of magnesium stearate was dissolved in 3.6 ml of the BHT solution. 2.4 ml of water was added to this solution, and it was sonicated for 10 minutes. Then, 40 mg of sirolimus was dissolved in 1 ml of the BHT / magnesium stearate solution.

[0098] (Preparation of solutions for coating modification forms A3b and A3e) A solvent mixture of 3.9 ml of tetrahydrofuran, 8.0 ml of acetone, and 90 μl of acetic acid was prepared. 6 mg of butylated hydroxytoluene (BHT) was dissolved in 10.3 ml of the mixture. 5.25 mg of magnesium stearate was dissolved in 3.6 ml of the BHT solution. 2.4 ml of water was added to this solution, and it was sonicated for 10 minutes. Then, 40 mg of sirolimus was dissolved in 1 ml of the BHT / magnesium stearate solution.

[0099] (Modification of the coating method):

[0100] JPEG2026082826000005.jpg246170

[0101] The results of the analysis of the modified forms are shown in Table 4 of Example 5.

[0102] [Example 5] <Differences in the dissolution rate of sirolimus in aqueous media> Please refer to Table 4 for the composition of the coating preparations (A1, A2, B1, and D1, columns 2-4; preparations for C1 and C2 contain the crystals according to Example 1, paragraph 1).

[0103] (coating): Balloons from groups A1, B1, C1, and D1 were inflated, and before coating, protective covers with an inner diameter of 1.05 mm were stretched from the distal to the proximal region of the balloon shaft. The balloons were inflated and continuously rotated while being coated with the preparations shown in Table 4 using a Hamilton microsyringe.

[0104] After coating, the balloons were deflated, the protective covers were carefully pulled distally, the balloon membranes were folded back to their original state (before inflation and coating), and the folded balloons were completely covered with the protective covers.

[0105] The coatings for groups A2 and C2 were carried out as described in Example 3.

[0106] <Result> Table 4 shows, (a) Appropriate dose for all coating deformations (3 μg / mm 2 The above is the coating for the 6th row. (b) Coating with Limus crystals reduces the dissolution rate of the active ingredient (7th column), (c) The transfer of the active ingredient onto or into the vascular wall was similar for all preparations (8th column). (d) In the case of crystalline coating, much higher drug concentrations were observed in arterial tissue 4 weeks after treatment (9th row). (e) In the case of coating A, the slow drying of the solvent after coating reduces the dissolution rate of the active ingredient in the aqueous medium (6th column). This indicates that.

[0107] JPEG2026082826000006.jpg254170JPEG2026082826000007.jpg255161JPEG2026082826000008.jpg255161

[0108] [Example 6] <Preparation and testing of coating C2> For animal testing methods, please refer to Example 4 and Clever YP, Peters D, Calisse J, Bettink S, Berg MC, Sperling C, Stoever M, Cremers B, Kelsch B, Bohm M, Speck U, Scheller B. Novel Sirolimus-coated balloon catheter. In vivo evaluation in a porcine coronary model. Circ Cardiovasc Interv. 2016;9:e003543. DOI:10.1161 / CIRCINTERVENTIONS.115.003543.

[0109] For information on preparing sirolimus crystals, please refer to Example 2.

[0110] Please refer to Table 5 for information on the coating solutions and results.

[0111] <Conclusion> (a) A coating that could be slowly dissolved by crystals from an aqueous solvent was possible (rows 5, 6, 8, 9, and 10). (b) Slow dissolution of the crystalline coating was observed (column 7).

[0112] JPEG2026082826000009.jpg98170

[0113] [Example 7] <Effects and Suitability> The coronary arteries of 20 young domestic pigs were treated with sirolimus-coated catheters according to Example 3(A2) and Example 4(C2). To promote neointimal proliferation caused by arterial hyperdilation, all balloons were fitted with Coro Large cobalt / chromium stents from Fortimedix, Netherlands, before sterilization. Immediately after treatment, the lumen diameter of the slightly hyperdilated coronary segments was measured, and the measurement was repeated after 4 weeks. The decrease in lumen diameter during the 4-week period was named "late lumen loss" (LLL) and characterized undesirable vascular stenosis due to neointimal proliferation. The desired inhibition of neointimal proliferation, and therefore inhibition of stenosis in the treated arterial segments, was partly attributable to the difference in LLL between arteries treated with uncoated balloons and those treated with sirolimus-coated balloons. The results are shown in Table 6.

[0114] JPEG2026082826000010.jpg69170

[0115] JPEG2026082826000011.jpg159170

[0116] The animals showed no clinically apparent signs of intolerance, either acutely or during the 4-week observation period. ECG, blood pressure, angiography, and histological examinations confirmed the high level of tolerability of the coating. [Brief explanation of the drawing]

[0117] [Figure 1] Figure 1 shows a spur (stent) coated with RFlimus-Q-50-DP-5-BHT-0.5.

Claims

1. A medical device having a coating on at least a portion of its surface, wherein the coating is It comprises at least one limus material in an unencapsulated crystalline form, and at least one crystalline The unencapsulated lims substance contains a water-miscible organic solvent or a water-miscible organic solvent and water. A medical device that is applied directly from a solution containing a mixture of [the following].

2. A medical device having a coating on at least a portion of its surface, wherein the coating is It comprises at least one limous material in an unencapsulated crystalline form, and is a crystalline unencapsulated limous material. The substance consists of a mixture of water-miscible organic solvents or a mixture of water-miscible organic solvents and water. A medical device that is coated as a suspension.

3. Drying of the at least one lims substance applied as a solution or suspension is preferred. Or, by being placed inside a pipe or tube, it is characterized by being slowed or inhibited. A medical device according to claim 1 or 2.

4. The aforementioned coating is ascorbyl palmitate, butylated hydroxyanisole, Chilled hydroxytoluene, nordihydroguaiaretic acid, probucol, gallate It is characterized by containing one or more antioxidants selected from the group of ropil and resveratrol. A medical device as described in any one of claims 1 to 3, characterized by...

5. The above at least one water-miscible organic solvent is methanol, ethanol, isopropanol It is characterized by being selected from the group consisting of tetrahydrofuran, acetic acid, and / or acetone. A medical device according to any one of claims 1 to 4.

6. The coating is characterized by comprising further excipients and / or additives. A medical device described in any one of the requests 1 to 5.

7. A further layer containing further excipients and / or additives is applied. or a medical device according to any one of claims 1 to 6.

8. The excipient is characterized in that it is an antioxidant in a proportion of more than 5 wt% of the lims substance. or the medical device according to claim 6 or 7.

9. The excipient is characterized by being a fatty acid salt in the range of 0.5 to 50 wt% of the limus substance. A medical device as described in any one of claims 6 to 8.

10. Characterized by being an angioplasty balloon catheter, an indwelling catheter, or a stent. or a medical device according to any one of claims 1 to 9.

11. Coat at least a portion of the surface of a medical device with at least one type of crystalline rim material. A method, a) Dissolve at least one lims substance in at least one water-miscible organic solvent and water. Alternatively, the step of suspending to form a supersaturated solution or maintaining true solubility, and There, b1) Apply the supersaturated solution or true solution to the surface of the medical device and allow it to crystallize. The steps, or b2) Step of applying the suspension to the surface of the balloon. One of the following steps, c) The drying step and Methods that include...

12. The drying step according to claim 11 is characterized in that the drying step according to (c) is performed slowly. Method of loading.

13. Step c) to dry the medical device by placing it inside the pipe or tube. By suppressing air exchange, and / or the medical The method according to claim 12, characterized in that it is carried out slowly depending on the composition of the gas phase in the environment of the apparatus. Law.

14. As the final step d), apply at least one additional layer of additive / excipient. A method according to any one of claims 11 to 13, characterized by the above.

15. In addition to the above-mentioned at least one lims substance, preferably, ascorbyl palmitate, Butylated hydroxyanisole, butylated hydroxytoluene, nordihydroguaiale Select from the group consisting of tinic acid, probucol, propyl gallate, and / or resveratrol. Claims 11 to 14, characterized in that one or more antioxidants are applied. The method described in any one of the items.

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