A method for manufacturing beautiful limus crystals and its application

Abstract

The present invention provides a method for manufacturing Umilimus crystals and their application, comprising adding a good solvent and a poor solvent for Umilimus to the Umilimus API; performing sonication and stirring; centrifuging and drying; and then placing the crystals on a drug eluting balloon. The crystals have a small particle size and a wide range of applications.

Description

Technical Field

[0001] The present invention relates to the field of drug preparation, in particular to a method for preparing eumeilimus crystals and applications thereof. Background Art

[0002] The primary treatment for vascular stenosis is the implantation of a drug-eluting stent. However, patients require long-term oral antithrombotic medication, which can affect subsequent surgical treatment and poses the risk of late stent thrombosis. Therefore, the "intervention without implantation" concept, as a new interventional medical approach, is gaining acceptance among more clinicians and patients. The drug-eluting balloon (DCB) is a novel product within this interventional treatment concept.

[0003] As a novel intravascular drug delivery technology, drug-eluting balloons (DEBs) coat the balloon surface with an anti-proliferative drug. When the balloon reaches the diseased vessel and expands, contacting the vessel lining, the drug rapidly transfers to the vessel wall and remains there for a period of time, thereby inhibiting intimal hyperplasia. Amorphous drugs, due to their small particle size, are more rapidly lost from the lumen in the late stages. Modern research indicates that crystalline drugs more readily adhere to the vessel wall, becoming embedded within it to form a "drug reservoir" for sustained drug release. Therefore, the drugs carried by drug-eluting balloons are primarily crystalline.

[0004] Currently, the most commonly used anti-proliferative drugs are paclitaxel and rapamycin and their derivatives. Rapamycin is a natural macrolide antibiotic with strong anti-cell proliferative and immunosuppressive effects. It primarily acts on the G1 phase of mitosis in vascular smooth muscle cells, arresting mitosis at the G0 phase. Paclitaxel acts on the G2-M phase of mitosis in vascular smooth muscle cells, inhibiting their proliferation. While both prevent thrombosis by inhibiting excessive smooth muscle cell proliferation, they each have their own drawbacks. Rapamycin suffers from low lipid solubility, slow tissue absorption, short retention time, and poor stability; while paclitaxel has a cytotoxic mechanism of action and is less effective in terms of safety and anti-restenosis effects.

[0005] Patent US7220755B2 discloses Biolimus A9 (abbreviated as Umimus; 40-alkoxyalkyl rapamycin, Chinese name: Umimus), which is a rapamycin derivative obtained by modifying the hydroxyl side chain of rapamycin by alkylating the hydroxyl group at position 40 with an ethoxyethyl group.

[0006] Patent US9434744B2 discloses a synthetic production process for Umelimox. The resulting Umelimox crystals are approximately 20 μm in size, referred to as large crystals. Currently, Umelimox has been successfully used in China for the drug-eluting balloon "Umelimox-releasing Coronary Balloon Catheter." However, the large crystals used suffer from issues such as insufficient absorption capacity and uneven particle size. Compared to large crystals, nanocrystals or small crystals (1-2 μm) offer better absorption and a wider range of applications. However, methods for producing small crystals of Umelimox have not yet been reported.

[0007] Therefore, those skilled in the art have devoted themselves to developing a method for producing small crystals of beautiful limus and its application. Summary of the Invention

[0008] In view of the problems in the prior art, the present invention aims to provide a method for manufacturing beautiful limus crystals and their application, which have small crystal size and wide application range.

[0009] In one aspect of the present invention, a method for preparing beautiful limus crystals is provided, comprising the following steps:

[0010] Step 1, adding a good solvent for Umilimus to the Umilimus API;

[0011] Step 2, adding a poor solvent for Umilimus to the solution of step 1;

[0012] Step 3, mixing the solution obtained in step 2 uniformly;

[0013] Step 4, centrifuging and drying the solution obtained in step 3.

[0014] The good solvent in step 1 is one or more of isopropyl alcohol, isobutyl alcohol, toluene, chloroform, dichloromethane, methanol, acetone, and ethyl acetate.

[0015] Preferably, the good solvent in step 1 is ethyl acetate.

[0016] Preferably, the concentration of the Umilimus API in the good solvent in step 1 is 0.05 g / mL to 0.5 g / mL.

[0017] Preferably, the poor solvent in step 2 is one or more of cyclohexane, carbon tetrachloride, n-hexane, and heptane.

[0018] Preferably, the volume ratio of the poor solvent to the good solvent is 8-15.

[0019] Preferably, the uniform mixing in step 3 includes placing the obtained solution in an ice-water bath, ultrasonicating it, and then magnetically stirring it; the number of ultrasonicating and stirring is ≥2.

[0020] Preferably, the centrifugation and drying in step 4 includes first centrifuging the solution obtained in step 3, then discarding the supernatant, and vacuum drying the lower layer of crystals.

[0021] Preferably, the particle size of the Umelimus crystals is 1 μm to 3 μm.

[0022] Another aspect of the present invention provides an application of the above-mentioned method for producing the umilimus crystals: the prepared umilimus crystals are placed on a drug eluting balloon.

[0023] The technical solution of this invention produces small crystals of eumanolimus, which are used for the first time as an antiproliferative drug in a drug-eluting balloon. Due to their small crystal size and large specific surface area, small eumanolimus crystals have a stronger ability to bind to the blood vessel wall and resist blood flow erosion. They are also easily endocytosed by the vascular intima and enter the vascular media, resulting in excellent tissue absorption. Furthermore, the small crystal size reduces the risk of embolism, expanding the application range of small eumanolimus crystals. BRIEF DESCRIPTION OF THE DRAWINGS

[0024] Other features, objects and advantages of the present invention will become more apparent from the following detailed description of non-limiting embodiments with reference to the accompanying drawings.

[0025] Figure 1 is a scanning electron microscope image of the small crystals of limus produced in Example 1;

[0026] Figure 2 This is a scanning electron microscope image of the large crystal of beautiful limus produced in Comparative Example 1. DETAILED DESCRIPTION

[0027] Example embodiments will now be described more fully with reference to the accompanying drawings. However, the example embodiments can be implemented in many forms and should not be construed as limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be comprehensive and complete and will fully convey the concepts of the example embodiments to those skilled in the art. Identical reference numerals in the figures represent identical or similar structures, and thus a repeated description thereof will be omitted.

[0028] In an embodiment of the present invention, a specific process for preparing Umelimus crystals is provided to prepare small Umelimus crystals, comprising the following steps:

[0029] Step 1: placing the amorphous Umilimus API in a centrifuge tube and adding a good solvent for Umilimus to dissolve it;

[0030] The Umilimus API produced by the existing process is amorphous. The production process of Umilimus API can be referred to patent US9434744B2.

[0031] A good solvent is a solvent that has a strong solubility for polymer solutes and an interaction parameter χ with polymer solutes that is less than 0.5.

[0032] The present invention compares the processes for preparing small crystals of umamiolimus using isopropyl alcohol, isobutyl alcohol, toluene, chloroform, dichloromethane, methanol, acetone, and ethyl acetate as good solvents. Among them, the good solvent, preferably ethyl acetate, has a better effect than other solvents.

[0033] The preferred ratio of the volume of ethyl acetate to the mass of the Umilimus bulk drug is 2 mL / g to 20 mL / g.

[0034] The concentration of the Umilimus API in the good solvent is 0.05 g / mL to 0.5 g / mL.

[0035] Step 2, adding a poor solvent for Umilimus to the solution obtained in Step 1, and vortex mixing;

[0036] A poor solvent is a solvent that has a weak solubility for polymer solutes and whose interaction parameter χ with polymer solutes is close to or greater than 0.5.

[0037] The present invention compares the processes for preparing small crystals of umamiolimus using n-hexane, heptane, cyclohexane and carbon tetrachloride as poor solvents. Among them, heptane and / or n-hexane are preferably used as the poor solvents, and their effects are better than those of other solvents.

[0038] The volume ratio of the poor solvent of Umilimus to the ethyl acetate in step 1 is preferably 8 to 15.

[0039] Step 3.1, placing the solution obtained in step 2 in an ice water bath and sonicating for a period of time;

[0040] The preferred ultrasonic time is 30 min to 2 h.

[0041] In step 3.2, remove the solution obtained in step 3.1 from the ice-water bath, add a rotor, and magnetically stir for a period of time;

[0042] The preferred magnetic stirring time is 1 h to 3 h.

[0043] In step 3.3, remove the rotor from the solution obtained in step 3.2, place the solution in an ice-water bath and sonicate again for a period of time;

[0044] The preferred second ultrasonication time is 10 min to 1 h.

[0045] In step 3.4, remove the solution obtained in step 3.3 from the ice-water bath, add a rotor, and magnetically stir for a period of time;

[0046] The preferred magnetic stirring time is 5 h to 24 h.

[0047] The present invention has conducted multiple studies and experiments and found that small crystals can be produced by two ice-water bath ultrasound and magnetic stirring.

[0048] Step 4: Remove the rotor from the solution obtained in step 3.4, centrifuge the solution at 6000 rpm for 10 min, pour out the supernatant, place the lower layer of crystals in a vacuum drying oven, and dry at room temperature for 24 h to obtain the final product.

[0049] In this embodiment of the present invention, Umelimox is dissolved in a good solvent for Umelimox, and then a poor solvent for Umelimox is added to supersaturate the solution, thereby precipitating Umelimox crystals. Based on the principle of secondary nucleation, a production process involving "ice-water bath ultrasound-magnetic stirring-ice-water bath ultrasound-magnetic stirring" was designed to produce small Umelimox crystals.

[0050] The present invention is described below with specific embodiments:

[0051] Example 1

[0052] 1. Weigh 200 mg of amorphous Umdolimus API into a 50 mL centrifuge tube and dissolve in 1 mL of ethyl acetate.

[0053] 2. Add 12 mL of heptane to the solution in step (1) and vortex to mix;

[0054] 3. Place the solution obtained in step (2) in an ice-water bath and sonicate for 1 h;

[0055] 4. Remove the solution obtained in step (3) from the ice-water bath, add a rotor, and stir magnetically for 1 h;

[0056] 5. Remove the rotor from the solution obtained in step (4), place the solution in an ice-water bath and sonicate again for 30 minutes;

[0057] 6. Remove the solution obtained in step (5) from the ice-water bath, add a rotor, and stir magnetically for 16 h;

[0058] 7. Remove the rotor from the solution obtained in step (6), centrifuge the solution at 6000 rpm for 10 minutes, discard the supernatant, and place the lower layer of Umelimus crystals in a vacuum drying oven at room temperature for 24 hours. The resulting crystals have a particle size range of 1 to 3 μm, with an average particle size of 1.92 μm, indicating small Umelimus crystals.

[0059] Example 2

[0060] 1. Weigh 500 mg of amorphous Umdolimus API into a 100 mL centrifuge tube and dissolve in 4 mL of ethyl acetate.

[0061] 2. Add 60 mL of n-hexane to the solution in step (1) and vortex mix;

[0062] 3. Place the solution obtained in step (2) in an ice-water bath and sonicate for 1 h;

[0063] 4. Remove the solution obtained in step (3) from the ice-water bath, add a rotor, and stir magnetically for 2 h;

[0064] 5. Remove the rotor from the solution obtained in step (4), place the solution in an ice-water bath and sonicate again for 30 minutes;

[0065] 6. Remove the solution obtained in step (5) from the ice-water bath, add a rotor, and stir magnetically for 12 h;

[0066] 7. Remove the rotor from the solution obtained in step (6), centrifuge the solution at 6000 rpm for 10 minutes, discard the supernatant, and place the lower layer of Umelimus crystals in a vacuum drying oven at room temperature for 24 hours. The resulting crystals have a particle size range of 1 to 3 μm, with an average particle size of 2.11 μm, indicating small Umelimus crystals.

[0067] Example 3

[0068] 1. Weigh 1000 mg of amorphous Umdolimus API into a 50 mL centrifuge tube and dissolve in 5 mL of ethyl acetate.

[0069] 2. Add 55 mL of heptane to the solution in step (1) and vortex to mix;

[0070] 3. Place the solution obtained in step (2) in an ice-water bath and sonicate for 1.5 h;

[0071] 4. Remove the solution obtained in step (3) from the ice-water bath, add a rotor, and stir magnetically for 2 h;

[0072] 5. Remove the rotor from the solution obtained in step (4), place the solution in an ice-water bath and sonicate again for 10 minutes;

[0073] 6. Remove the solution obtained in step (5) from the ice-water bath, add a rotor, and stir magnetically for 16 h;

[0074] 7. Remove the rotor from the solution obtained in step (6), centrifuge the solution at 6000 rpm for 10 minutes, discard the supernatant, and place the lower layer of Umelimus crystals in a vacuum drying oven at room temperature for 24 hours. The resulting crystals have a particle size range of 1 to 3 μm, with an average particle size of 1.83 μm, indicating small Umelimus crystals.

[0075] Example 4

[0076] 1. Weigh 200 mg of amorphous umamimus API into a 50 mL centrifuge tube and dissolve in 1 mL of ethyl acetate.

[0077] 2. Add 12 mL of heptane to the solution in step (1) and vortex to mix;

[0078] 3. Place the solution obtained in step (2) in an ice-water bath and sonicate for 30 minutes;

[0079] 4. Remove the solution obtained in step (3) from the ice-water bath, add a rotor, and stir magnetically for 3 h;

[0080] 5. Remove the rotor from the solution obtained in step (4), place the solution in an ice-water bath and sonicate again for 1 h;

[0081] 6. Remove the solution obtained in step (5) from the ice-water bath, add a rotor, and stir magnetically for 5 h;

[0082] 7. Remove the rotor from the solution obtained in step (6), centrifuge the solution at 6000 rpm for 10 min, pour off the supernatant, and place the lower layer of Umelimus crystals into a vacuum drying oven and dry at room temperature for 24 h.

[0083] The obtained crystals have a particle size range of 1 to 3 μm and an average particle size of 1.71 μm, and are small crystals of beautiful molybdenum.

[0084] Example 5

[0085] 1. Weigh 400 mg of amorphous Umdolimus API into a 50 mL centrifuge tube and dissolve in 1 mL of ethyl acetate.

[0086] 2. Add 12 mL of heptane to the solution in step (1) and vortex to mix;

[0087] 3. Place the solution obtained in step (2) in an ice water bath and sonicate for 2 h;

[0088] 4. Remove the solution obtained in step (3) from the ice-water bath, add a rotor, and stir magnetically for 3 h;

[0089] 5. Remove the rotor from the solution obtained in step (4), place the solution in an ice-water bath and sonicate again for 1 h;

[0090] 6. Remove the solution obtained in step (5) from the ice-water bath, add a rotor, and stir magnetically for 24 hours;

[0091] 7. Remove the rotor from the solution obtained in step (6), centrifuge the solution at 6000 rpm for 10 min, pour off the supernatant, and place the lower layer of Umelimus crystals into a vacuum drying oven and dry at room temperature for 24 h.

[0092] The obtained crystals have a particle size range of 1.5 to 3 μm and an average particle size of 2.24 μm, and are small crystals of beautiful molybdenum.

[0093] Example 6

[0094] A drug-loaded balloon catheter was prepared using the small crystals of Umelimus prepared in Example 1:

[0095] 1. Raw materials

[0096] 1. Drugs: such as Figure 1 As shown in the figure, the small crystals of Umeboshi prepared in Example 1 have an average particle size of 1.92 μm;

[0097] 2. Excipient: polyethylene oxide (PEO), molecular weight 1 million;

[0098] 3. Water, water for injection.

[0099] 4. Balloon catheter: Rapid exchange balloon catheter (matching 0.014" guidewire), catheter effective length 140cm, balloon diameter 2.0~4.0mm, balloon length 10.0~40mm.

[0100] 2. Preparation Method

[0101] 5. Weigh 100 mg of Umdelimus crystals into a 10 mL glass vial, add 10 mL of water, and cap the vial. Vortex for 10 seconds, then sonicate for 3 minutes. Repeat this process three times until the Umdelimus is completely dispersed.

[0102] 6. Weigh 400 mg of PEO into a 10 mL glass vial, add 10 mL of water, cap the vial, vortex, and then magnetically stir until the PEO is completely dissolved;

[0103] 7. Combine the solutions from step 1 and step 2, vortex mix, and ultrasonically disperse until the Umelimus crystals are completely dispersed and no Umelimus crystals are visible to the naked eye.

[0104] 8. After the balloon is treated with plasma, it is folded into three wings using a folding machine;

[0105] 9. Use needle coating to apply the coating solution into the V-shaped groove of the folded balloon;

[0106] 10. After the coating was dried at room temperature for 16 hours, a drug-coated balloon catheter was obtained. The drug loading rate of 3.0 μg / mm2 of umefaciens per unit surface area of ​​the balloon was obtained.

[0107] controlled trials

[0108] Comparative Example 1

[0109] Preparation of large crystals of Umelimum:

[0110] 1. Raw materials

[0111] 1. Drug: Amorphous Umelimus API;

[0112] 2.Solvent: isopropyl alcohol, n-hexane;

[0113] 2. Preparation Method

[0114] 1. Weigh 200 mg of amorphous Umedalimum API into a 50 mL centrifuge tube and dissolve in 4 mL of isopropanol.

[0115] 2. Add 32 mL of n-hexane to the solution in step (1) and vortex to mix;

[0116] 3. Add a rotor to the solution in step (2) and stir magnetically for 16 h;

[0117] 4. Remove the rotor from the solution obtained in step (3), centrifuge the solution at 6000 rpm for 10 min, discard the supernatant, and place the lower layer of Umega-limust crystals in a vacuum drying oven and dry them at room temperature for 24 h. The crystal particle size is 10 to 30 μm, with an average particle size of 17.6 μm, indicating large Umega-limust crystals.

[0118] The large crystals obtained through the above steps are used to prepare drug-loaded balloon catheters:

[0119] 1. Raw materials

[0120] 1. Drugs: such as Figure 2 As shown in , the obtained large crystals of Umeboshi have an average particle size of 17.6 μm;

[0121] 2. Excipient: polyethylene oxide (PEO), molecular weight 1 million;

[0122] 3. Water, water for injection.

[0123] 4. Balloon catheter: Rapid exchange balloon catheter (matching 0.014" guidewire), catheter effective length 140cm, balloon diameter 2.0~4.0mm, balloon length 10.0~40mm.

[0124] 2. Preparation Method

[0125] 5. Weigh 100 mg of large crystals of Umdelimus into a 10 mL glass vial, add 10 mL of water, and cap the vial. Vortex for 10 seconds, then sonicate for 3 minutes. Repeat this process three times until the Umdelimus is completely dispersed.

[0126] 6. Weigh 400 mg of PEO into a 10 mL glass vial, add 10 mL of water, cap the vial, vortex, and then magnetically stir until the PEO is completely dissolved;

[0127] 7. Combine the solutions from step 1 and step 2, vortex mix, and ultrasonically disperse until the Umelimus crystals are completely dispersed and no Umelimus crystals are visible to the naked eye.

[0128] 8. After the balloon is treated with plasma, it is folded into three wings using a folding machine;

[0129] 9. Use needle coating to apply the coating solution into the V-shaped groove of the folded balloon;

[0130] 10. After the coating was dried at room temperature for 16 hours, a drug-coated balloon catheter was obtained. The drug loading rate of 3.0 μg / mm2 of umefaciens per unit surface area of ​​the balloon was obtained.

[0131] Comparative experiment:

[0132] 1. Materials

[0133] The drug-eluting balloon catheters prepared in Example 6 and Comparative Example 1 were folded and coiled, covered with protective sheaths, and sterilized with ethylene oxide before animal experiments. The drug transfer / delivery characteristics and target tissue uptake in vivo were evaluated at 1 hour, 1 day, 7 days, and 28 days.

[0134] 2. Experimental Subjects

[0135] 1. Experimental Animals

[0136] Experimental animals: white pigs for experiments; gender: either male or female; weight: 35-40 kg.

[0137] The total number of experimental animals: 4 cases.

[0138] 2. Drug-eluting balloon

[0139] Model specifications: DCB-2530, DCB-3030, DCB-4030

[0140] 3. Experimental Methods

[0141] 1. Surgical Procedure

[0142] 4 pigs, 2 drug-eluting balloons were implanted in each pig, for a total of 8 drug-eluting balloons. The implantation locations for each pig were:

[0143] (1) Left circumflex artery (LCX)

[0144] (2) Right coronary artery (RCA)

[0145] Select an appropriate balloon based on an overexpansion ratio of 1.10 to 1.20, inflate the balloon for 60 seconds, and then retract it.

[0146] 2. Animal Handling

[0147] Routine blood tests and biochemical tests were performed before and after surgery at each time point. After balloon implantation, patients were treated with dual-antibody therapy until the end of the study. Tissue samples were obtained at each time point from the blood vessels at the balloon implantation site, with the sample length exceeding 0.3 cm both before and after the implantation site.

[0148] IV. Organization Testing

[0149] After sampling at each time point, the blood vessels were immediately stored in dry ice and sent to a third-party testing organization for analysis.

[0150] 1. Instruments and Equipment

[0151] Instrument: Triple quadrupole mass spectrometer (LC / MS / MS), model: AB Sciex QTRAP 5500

[0152] Chromatographic column: Kinetex 2.6μC18 100A (50mm×3.00mm)

[0153] Mobile phase: Mobile phase A: 5 mM ammonium acetate (containing 0.05% formic acid); Mobile phase B: acetonitrile (containing 0.05% formic acid);

[0154] 2. Test results

[0155] The drug absorption results are shown in Table 1.

[0156] Table 1: Drug tissue absorption results

[0157]

[0158] As can be seen from the table above, at the 1 hour post-implantation time point, the main test was the drug's adhesion to the vascular wall (anti-blood flow scour ability). The tissue drug concentration of Comparative Example 1 was 96.30 μg / g, while the tissue drug concentration of the small crystals of eumanolimus prepared in Example 6 of the technical solution of the present invention was 43.81 μg / g.

[0159] The drug absorption effect was mainly investigated at the 1-day implantation time point. The tissue drug concentration of Comparative Example 1 was 32.90 μg / g, and the tissue drug concentration of the small crystals of Umefibroxine prepared in Example 6 of the technical solution of the present invention was 53.52 μg / g.

[0160] 7 days after balloon implantation, the tissue drug concentration of Comparative Example 1 was 7.62 μg / g, and the tissue drug concentration of small crystals of Umedalimum prepared in Example 6 of the technical solution of the present invention was 18.33 μg / g;

[0161] 28 days after balloon implantation, the tissue drug concentration of Comparative Example 1 was 0.071 μg / g, and the tissue drug concentration of the small crystals of Umedalimum prepared in Example 6 of the technical solution of the present invention was 1.31 μg / g.

[0162] It can be seen that the small crystals of eumanolimus in the technical solution of the present invention have good blood vessel adhesion and strong resistance to blood flow erosion. The small crystals of eumanolimus are easily endocytosed by the vascular endothelium and enter the vascular middle layer. Therefore, eumanolimus is retained in the tissue for a long time. At 28 days, the tissue drug concentration is still as high as 1.31μg / g.

[0163] In summary, the manufacturing method and application of Umelimus crystals according to an embodiment of the present invention adopts the "ice-water bath ultrasound-magnetic stirring-ice-water bath ultrasound-magnetic stirring" method, as well as good solvents and poor solvents for Umelimus, to produce small Umelimus crystals. The small Umelimus crystals are then used in drug balloons, and the tissue absorption effect is significantly better than that of large Umelimus crystals.

[0164] The above is a further detailed description of the present invention in conjunction with specific preferred embodiments, and the specific implementation of the present invention should not be considered to be limited to these descriptions. For those skilled in the art of the present invention, without departing from the concept of the present invention, several simple deductions or substitutions can be made, which should be considered to fall within the scope of protection of the present invention.

Claims

1. A method for producing beautiful limus crystals, characterized by: The following steps are involved: Step 1, adding a good solvent for Umilimus to the Umilimus API, wherein the good solvent in step 1 is ethyl acetate; Step 2, adding a poor solvent for Umilimus to the solution of Step 1, wherein the poor solvent in Step 2 is one or both of n-hexane and heptane; Step 3, mixing the solution obtained in step 2 uniformly; the mixing in step 3 comprises placing the obtained solution in an ice water bath, ultrasonicating it, and then magnetically stirring it; the number of ultrasonication and stirring in step 3 is ≥ 2; Step 4, centrifuging and drying the solution obtained in step 3.

2. The method for producing beautiful limus crystals according to claim 1, wherein: The ratio of the volume of the ethyl acetate to the mass of the Umilimus API is 2 mL / g to 20 mL / g.

3. The method for producing beautiful limus crystals according to claim 1, wherein: In the step 1, the concentration of the Umilimus API in the good solvent is 0.05 g / mL to 0.5 g / mL.

4. The method for producing beautiful limus crystals according to claim 1, wherein: The volume ratio of the poor solvent to the good solvent is 8-15.

5. The method for producing beautiful limus crystals according to claim 1, wherein: The centrifugation and drying in step 4 includes first centrifuging the solution obtained in step 3, then discarding the supernatant, and vacuum drying the lower layer of crystals.

6. The method for producing beautiful limus crystals according to claim 1, wherein: The particle size of the Umelimus crystals is 1 μm to 3 μm.

7. Use of the method for producing Umelimus crystals according to any one of claims 1 to 6, characterized in that: The prepared Umelimus crystals were placed on a drug eluting balloon.

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