A coating liquid containing crystalline drug molecules, a preparation method thereof, and applications thereof

Abstract

The present invention discloses a coating solution containing crystalline drug molecules, a preparation method and an application thereof. The coating solution comprises a good solvent solution of an active drug, a nucleating agent and a non-solvent. The good solvent solution of the active drug is formed by dissolving the active drug in a good solvent. The non-solvent is a non-solvent for the active drug and the nucleating agent. The good solvent and the non-solvent are mutually soluble. The nucleating agent comprises active drug crystal microparticles and / or polymer drug-loaded microparticles. The coating solution containing crystalline drug molecules of the present invention has a preset crystal size range for the crystalline drug contained therein, and can better control its uniformity, making the properties of the obtained drug-loaded coating more predictable and reproducible.

Description

Technical Field

[0001] The present invention relates to the technical field of medical devices, and more particularly to a coating solution containing crystalline drug molecules, a preparation method thereof, and an application thereof. Background Art

[0002] Drug-coated medical devices are generally designed to directly deliver drugs to the site of device implantation or intervention. This local treatment method minimizes systemic side effects and enhances the therapeutic effect at the target site. Drug-eluting stents and drug-coated balloons applied to angioplasty are the two main application fields of the above drug coatings. The drug coatings of these devices can be used to inhibit the hyperplasia (restenosis) of surrounding tissues caused by possible damage during angioplasty of vascular tissues.

[0003] Whether it is vascular restenosis, or the healing process or endothelialization process of vascular tissues after angioplasty, it is a gradual process. Preventing the occurrence of restenosis requires a continuous inhibitory effect on cell proliferation. Sustained drug delivery can ensure the maintenance of drug therapeutic activity for a long time, thereby reducing the risk of late restenosis; at the same time, prolonging the drug delivery time can also ensure that the drug remains active during the critical period of vascular healing. Therefore, a certain degree of long-acting drug delivery is the key formulation strategy for such drug coatings, which can slowly and continuously release active drug ingredients.

[0004] The drug coatings of existing stents usually adopt a polymer matrix system: the polymer entraps the drug in the entire coating, and the drug release is controlled by selecting or adjusting the properties of the polymer, the drug content, the coating thickness, etc. to achieve the purpose of long-acting drug delivery. The structure of this kind of drug-coated stent is usually a relatively firm polymer drug film, and its effectiveness and safety are guaranteed by confining the drug coating of the stent between the closely attached vascular wall and the outer surface of the stent. Therefore, such coatings are not suitable for application on the coatings of drug-coated balloons.

[0005] Currently, various balloon drug coating schemes mainly adopt active drug crystals, and utilize the property that the dissolution rate of crystalline drugs is slower than that of amorphous drugs to achieve the purpose of long-acting drug delivery. However, for this drug coating technology that uses active drug crystals to achieve long-acting drug delivery, the content and crystal size of the active drug crystals in the coating are uncontrollable, and the variability of crystal size and morphology may lead to a decrease in the predictability of product performance. Summary of the Invention

[0006] In order to overcome the defects of the prior art, the purpose of the present invention is to provide a coating solution containing crystalline drug molecules. The crystalline drug contained in the coating solution has a preset crystal size range, which can better control its uniformity, making the performance of the obtained drug-coated stent more predictable and repeatable.

[0007] To achieve the above object, the present invention discloses a coating liquid containing crystalline drug molecules, which includes a good solvent solution of the active drug, a nucleating agent, and a non-solvent of the active drug. The good solvent solution of the active drug is formed by dissolving the active drug in a good solvent. The non-solvent is a non-solvent for both the active drug and the nucleating agent. The good solvent and the non-solvent are mutually soluble. The nucleating agent includes active drug crystal microparticles and / or polymer drug-loaded microparticles.

[0008] Compared with the prior art, the coating liquid containing crystalline drug molecules of the present invention includes a good solvent solution of the active drug, a nucleating agent, and a non-solvent. The nucleating agent includes active drug crystal microparticles and / or polymer drug-loaded microparticles. A nucleating agent is added to the coating liquid to replace the crystal nuclei originally generated by spontaneous nucleation. The nucleating agent provides a surface for the dissolved drug to grow as seeds. The number and size of the crystal microparticles in the coating liquid can be regulated by the number and size of the added nucleating agent, achieving the advantage that the crystalline drug has a preset crystal size. At the same time, the process step of adding the nucleating agent provides an opportunity to add nucleating agents with the same mass, size, and crystal form in batches at exactly the same temperature or time point. Therefore, essentially, adding the nucleating agent can ensure the same starting point from one batch to the next batch, thereby providing higher repeatability for the process. Therefore, in the coating liquid containing crystalline drug molecules of the present invention, the contained crystalline drug has a preset crystal size range, and its uniformity can be better controlled, making the performance of the obtained drug-loaded coating more predictable and repeatable.

[0009] Correspondingly, the present invention also provides a preparation method of a coating liquid containing crystalline drug molecules, which includes the following steps:

[0010] (1) Dissolve the active drug in a good solvent to prepare a good solvent solution of the active drug;

[0011] (2) Add the nucleating agent to the non-solvent of the active drug and the nucleating agent, and stir evenly to obtain a mixed solution;

[0012] (3) Mix the good solvent solution of the active drug and the mixed solution to form a coating liquid. Description of the Drawings

[0013] Figure 1 Show the results of the in vitro simulation test of the product in Example 6 of the present invention. Detailed Embodiments

[0014] To describe the technical content, structural features, achieved objects, and effects of the present invention in detail, the following is described in detail in combination with the embodiments and accompanied by the drawings.

[0015] The present invention provides a coating solution containing crystalline drug molecules, which comprises a good solvent solution of the active drug, a nucleating agent, and a non-solvent of the active drug. The good solvent solution of the active drug is formed by dissolving the active drug in a good solvent. The non-solvent is a non-solvent for both the active drug and the nucleating agent. The good solvent and the non-solvent are mutually soluble. The nucleating agent includes active drug crystal particles and / or polymer drug-loaded particles.

[0016] The coating solution of the present invention is used as all or part of the drug-loaded coating solution for preparing a drug-loaded coating on the outer surface of a medical device, providing at least one long-acting drug delivery method, and is particularly suitable for a drug-loaded coating with the goal of instantaneous drug delivery, especially a drug-coated balloon or stent system. This coating solution can better control the content and size of the active drug crystals, thereby ensuring the uniformity of the active drug crystals in the prepared drug coating, making the performance of the prepared drug-loaded coating more predictable and repeatable.

[0017] The good solvent solution of the active drug in the present invention is formed by dissolving the active drug in a good solvent. The active drug is dissolved in a selected good solvent or a mixed solvent good solvent and then added to the coating solution preparation system. The good solvent varies depending on the selected active drug. The good solvent can provide a high solubility of drug molecules, is conducive to being removed under relatively mild process conditions, and is mutually soluble with the non-solvent of the active drug and the nucleating agent. Among them, the active drug is selected from paclitaxel or mTOR drugs. By way of example, the mTOR drugs are selected from sirolimus, zotarolimus, everolimus, biolimus, and their derivatives. Preferably, the active drug is selected from sirolimus.

[0018] The good solvent of the present invention can be selected from alcohols, such as methanol, ethanol, isopropanol, ethyl acetate, acetone, dichloromethane, chloroform, etc., or a mixed solvent. By way of example, the good solvent is methanol or dichloromethane, but it is not limited thereto.

[0019] The non-solvent of the active drug in the present invention is selected from at least one of water, n-hexane, n-heptane, and petroleum ether, and the good solvent and the non-solvent of the active drug form a mutually soluble system.

[0020] In a preferred embodiment, on the basis of satisfying stable mutual solubility, the volume ratio of the good solvent to the non-solvent of the active drug in the above coating solution is controlled to control the percentage content of the crystalline active drug in the coating solution. Preferably, the volume ratio of the good solvent to the non-solvent is 1:5 to 1:50. Optionally, the volume ratio of the good solvent to the non-solvent is 1:10 to 1:50, about 1:10 to 1:40, about 1:10 to 1:30.

[0021] In a preferred embodiment, in order to control the number and geometric size of the active pharmaceutical crystal microparticles in the coating solution, a crystal nucleating agent is selected and added to the non-solvent system of the active pharmaceutical and the nucleating agent. The selection of the type, quantity, and size of the nucleating agent will determine the final content, crystal morphology, and geometric size of the active pharmaceutical crystal microparticles in the coating solution; preferably, the addition amount of the nucleating agent is 10,000 ppm to 10 ppm, about 10,000 ppm to 1000 ppm, about 10,000 ppm to 100 ppm, about 1000 ppm to 100 ppm, and preferably 1000 ppm to 25 ppm of the total active pharmaceutical in the coating solution.

[0022] In some embodiments, the size of the nucleating agent is controlled to be from 10 nanometers to 500 nanometers, about 10 nanometers to 400 nanometers, about 20 nanometers to 400 nanometers, and preferably 50 nanometers to 200 nanometers; in a preferred embodiment, the coating solution system can be used to prepare active pharmaceutical crystal microparticles with a size of less than 25 micrometers, particularly less than 10 micrometers, or more preferably less than 5 micrometers. Therefore, the content and size of the active pharmaceutical crystal microparticles in the coating solution of the present invention can be controlled, and the particle size distribution is narrow.

[0023] In a preferred embodiment, the nucleating agent can be a homogeneous nucleating agent or a heterogeneous nucleating agent. In some embodiments, the nucleating agent is a homogeneous nucleating agent. For example, the nucleating agent is an active pharmaceutical crystal microparticle, a tiny crystal composed of the same active pharmaceutical, used to provide a tiny solid structure as a template for guiding the formation and growth of new crystals.

[0024] In some embodiments, the nucleating agent is a heterogeneous nucleating agent, used to provide an attachment interface that is beneficial to the formation of crystal nuclei during the crystallization process of the active pharmaceutical. The heterogeneous nucleating agent can be one or more prefabricated crystal microparticles of the active pharmaceutical. By way of example, the coating solution contains prefabricated paclitaxel crystal microparticles, and at least part of the paclitaxel crystal microparticles are added to the coating solution as a heterogeneous nucleating agent for the crystallization of the first active pharmaceutical (such as sirolimus crystal microparticles). In this case, the coating composition solution contains at least two kinds of crystals of active therapeutic drugs (such as paclitaxel crystal microparticles, sirolimus crystal microparticles); it should be emphasized that the selection of the active pharmaceutical other than the main active pharmaceutical as the heterogeneous nucleating agent in this technology includes but is not limited to paclitaxel; in addition, it should be clarified that the heterogeneous nucleating agent is dispersed in the non-solvent of the first active pharmaceutical, and the non-solvent and the heterogeneous nucleating agent dispersed therein should maintain a relatively independent and stable state.

[0025] In some embodiments, the heterogeneous nucleating agent is a polymer drug-loaded microparticle. Preferably, the polymer drug-loaded microparticle can be a drug-loaded microparticle with a drug sustained-release and controlled-release function, i.e., a sustained-release polymer drug-loaded microparticle. All or at least part of the drug-loaded microparticle serves as a heterogeneous nucleating agent for the first active pharmaceutical crystal microparticles (such as sirolimus crystal microparticles) to provide an attachment interface that is conducive to the formation of crystal nuclei during the crystallization process of the active pharmaceutical. It should be noted that the active pharmaceutical loaded in the drug-loaded microparticle can be the first active pharmaceutical, or the second active pharmaceutical, or even the third active pharmaceutical. The first active pharmaceutical, the second active pharmaceutical, and the third active pharmaceutical can be the same or different. Preferably, the first active pharmaceutical, the second active pharmaceutical, and the third active pharmaceutical are different active pharmaceuticals. Therefore, the active pharmaceutical loaded in the drug-loaded microparticle can be one or more. Additionally, it should also be clarified that the heterogeneous nucleating agent is dispersed in the non-solvent of the first active pharmaceutical, and the non-solvent and the heterogeneous nucleating agent dispersed therein should maintain a relatively independent and stable state. Therefore, both the drug-loading matrix of the drug-loaded microparticle and the loaded active pharmaceutical should be compatible with the non-solvent system.

[0026] It can be understood that the polymer drug-loaded microparticle is formed by embedding a drug with a polymer as a carrier. The polymer has biocompatibility and biodegradability. Preferably, the polymer is a non-hydrophilic biodegradable polymer. Further, the polymer is selected from at least one of polylactic acid, polyglycolic acid and its copolymers, and polydioxanone. More preferably, polylactic acid or a lactic acid-glycolic acid copolymer is an amorphous or partially crystalline polymer. It is worth mentioning that the method of forming a drug-loaded microparticle or a sustained-release polymer drug-loaded microparticle by embedding a drug with a polymer as a carrier can be prepared by any applicable existing polymer drug-embedding technology, such as microfluidics technology, membrane emulsification technology, etc., and will not be specifically elaborated herein.

[0027] In some embodiments, a stabilizer can also be added to the coating solution. The stabilizer can be a film-forming agent, a dispersing agent, an adhesive, such as PVP, HPMC, TWEEN, POLOXAMER, etc.

[0028] The coating solution of the present invention is placed on the outer surface of the medical device by methods such as drop coating or spraying to obtain a drug-loaded coating.

[0029] Correspondingly, the present invention also provides a preparation method of a coating solution containing crystalline drug molecules, including the following steps:

[0030] (1) Dissolve the active pharmaceutical in a good solvent to prepare an active pharmaceutical good solvent solution;

[0031] (2) Add the nucleating agent to the non-solvent of the active pharmaceutical and the nucleating agent, and stir evenly to obtain a mixture;

[0032] (3) Mix the active pharmaceutical good solvent solution with the mixture to form a coating solution.

[0033] Since a nucleating agent is added to the coating solution to replace the nuclei originally generated by spontaneous nucleation. The nucleating agent provides a surface on which the dissolved drug can grow as seeds. The number and size of the crystal particles in the coating solution can be regulated by the number and size of the added nucleating agent, achieving the advantage that the crystalline drug has a preset crystal size. At the same time, the process step of adding the nucleating agent provides an opportunity to add nucleating agents of the same mass, size and crystal form in batches at exactly the same temperature or time point. Therefore, essentially, adding a nucleating agent can ensure the same starting point from one batch to the next, thus providing higher repeatability for the process. Therefore, in the coating solution containing crystalline drug molecules of the present invention, the crystalline drug contained has a preset crystal size range, which can better control its uniformity, making the performance of the drug-loaded coating obtained more predictable and repeatable.

[0034] It can be understood that the nucleating agent is active pharmaceutical crystal particles, or the nucleating agent is polymer drug-loaded particles. The nucleating agent forms crystal particles with multiple active pharmaceuticals, or forms polymer drug-loaded particles with multiple active pharmaceuticals.

[0035] In a preferred embodiment, the nucleating agent is active pharmaceutical crystal particles. The preparation method of the coating solution containing crystalline drug molecules includes the following steps:

[0036] (1) Dissolve the active pharmaceutical in the good solvent to prepare the active pharmaceutical good solvent solution;

[0037] (2) Add the active pharmaceutical crystal particles to the non-solvent of the active pharmaceutical, stir evenly to obtain a mixture;

[0038] (3) Mix the active pharmaceutical good solvent solution with the mixture to form a coating solution,

[0039] The preparation steps of the active pharmaceutical crystal particles are as follows:

[0040] (1) Dissolve the active pharmaceutical in a solvent to prepare the active pharmaceutical good solvent solution;

[0041] (2) Add the active pharmaceutical good solvent solution to a non-solvent of the active pharmaceutical, and centrifuge, wash and freeze-dry to obtain the active pharmaceutical crystal particles.

[0042] The content and size of the active pharmaceutical crystal particles in the coating solution of the present invention can be regulated, and the particle size distribution is narrow.

[0043] In a preferred embodiment, the nucleating agent uses a variety of active drugs to form crystal microparticles. The preparation method of the coating liquid containing crystalline drug molecules includes the following steps:

[0044] (1) Dissolve the first active drug in the good solvent to make a first active drug good solvent solution;

[0045] (2) Add the second active drug crystal microparticles to the non-solvent of the second active drug and the first active drug, stir evenly to obtain a mixed solution;

[0046] (3) Mix the first active drug good solvent solution with the mixed solution to form a coating liquid,

[0047] wherein, the preparation steps of the second active drug crystal microparticles are as follows:

[0048] (1) Dissolve the second active drug in a good solvent of the second active drug to make a second active drug good solvent solution;

[0049] (2) Add the second active drug good solvent solution to a non-solvent of the second active drug, perform centrifugal separation, washing, and freeze-drying to obtain the second active drug crystal microparticles.

[0050] In a preferred embodiment, the nucleating agent uses polymer drug-loaded microparticles. The preparation method of the coating liquid containing crystalline drug molecules includes the following steps:

[0051] (1) Dissolve the active drug in the good solvent to make the active drug good solvent solution;

[0052] (2) Add the polymer drug-loaded microparticles to the non-solvent of the active drug and the polymer microparticles, stir evenly to obtain a mixed solution;

[0053] (3) Mix the active drug good solvent solution with the mixed solution to form a coating liquid.

[0054] In a preferred embodiment, the preparation method of the coating liquid containing crystalline drug molecules includes the following steps:

[0055] (1) Dissolve the active drug in the good solvent to make the active drug good solvent solution;

[0056] (2) Add the first polymer drug-loaded microparticles to the non-solvent of the active drug and the first polymer drug-loaded microparticles, stir evenly to obtain a mixed solution;

[0057] (3) Mix the active drug good solvent solution with the mixed solution to form coating liquid A;

[0058] (4) Add the second polymer drug-loaded microparticles to the coating solution A to form a coating solution.

[0059] The preparation method of the coating solution containing crystalline drug molecules of the present invention will be further described below through specific examples, but not limited thereto.

[0060] Example 1

[0061] In this example, an active drug crystal microparticle is prepared as a preparation method of a homogeneous nucleating agent. The steps are as follows:

[0062] (1) Dissolve sirolimus in methanol to obtain a 12 mg / ml sirolimus methanol solution;

[0063] (2) Add 60 ml of deionized water to a 100 ml beaker and place it in a low-temperature controlled ultrasonic water bath for ultrasonic treatment;

[0064] (3) Add the sirolimus methanol solution dropwise to the deionized water at a small flow rate (0.2 ml / min) with a syringe pump at a volume ratio of 1:12;

[0065] (4) After the injection is completed, continue to maintain ultrasonic treatment for 10 minutes;

[0066] (5) Centrifuge at high speed, wash with deionized ice water, and then freeze-dry to obtain active drug crystal microparticles with an average particle size of 123 nm for standby.

[0067] Example 2

[0068] The preparation of a polymer drug-loaded microparticle belongs to the preparation of a heterogeneous nucleating agent. The steps are as follows:

[0069] (1) Prepare Solution 1: Dissolve 50 mg of polymer (PLGA) and 25 mg of sirolimus in 3 ml of acetone for use;

[0070] (2) Prepare Solution 2: Provide a 1 wt% PVA aqueous solution;

[0071] (3) Fill Solution 1 into a 3.0 ml syringe, control it by a precision syringe pump, and insert it into the center position of the container of Solution 2 through a 34G flat head injection needle;

[0072] (4) Pour 45 ml of the dispersion liquid (i.e., Solution 2) into a 100 ml beaker, with a magnetic stirring speed of 600 rpm, and inject Solution 1 into Solution 2 at a flow rate of 0.05 ml / min to obtain a suspension;

[0073] (5) Keep the obtained suspension under magnetic stirring for 30 minutes to ensure sufficient time for the solvent to migrate to the non-solvent water phase and form nanoparticles;

[0074] (6) After high-speed centrifugal separation, washing with deionized ice water, and freeze-drying, polymer drug-loaded microparticles with an average particle size of 350 nm were obtained and reserved for use.

[0075] Example 3

[0076] The preparation of a sustained-release polymer drug-loaded microparticle is as follows:

[0077] (1) Prepare Solution 1: Dissolve 300 mg of polymer (PLGA) and 60 mg of sirolimus in 10 ml of dichloromethane for later use.

[0078] (2) Prepare Solution 2: Provide a 2 wt% aqueous PVA solution.

[0079] (3) Prepare Solution 3: Provide a 1 wt% aqueous PVA solution.

[0080] (4) Add 2 ml of Solution 1 to 6 ml of Solution 2 and homogenize at 10,000 RPM for 1 minute to form Emulsion 1.

[0081] (5) Then add Emulsion 1 to 45 ml of Solution 3 and homogenize at 10,000 RPM for 3 minutes to form Emulsion 2.

[0082] (6) Stir Emulsion 2 magnetically at room temperature for at least 6 hours to remove the solvent dichloromethane, and then refrigerate (4 - 10 °C) for 60 minutes.

[0083] (7) Centrifuge and wash the microspheres with deionized ice water multiple times.

[0084] (8) Suspend the microspheres in 5 ml of deionized water, freeze-dry and store for later use.

[0085] Example 4

[0086] This example provides a method for preparing a coating solution containing crystalline drug molecules, including the following steps:

[0087] (1) Prepare an active drug good solvent solution

[0088] Dissolve sirolimus in methanol to prepare an active drug good solvent solution of 40 mg / ml, designated as Solution A.

[0089] (2) Prepare a mixture

[0090] Add active drug crystal microparticles (prepared in Example 1) equivalent to the weight of 125 ppm sirolimus to n-heptane 10 times that of methanol, and ultrasonically mix evenly, designated as Solution B.

[0091] (3) Mix Solution A and Solution B and continuously stir at room temperature for 24 hours to obtain the coating solution.

[0092] Example 5

[0093] This embodiment provides a method for preparing a coating solution containing crystalline drug molecules, comprising the following steps:

[0094] (1) Prepare a good solvent solution of the active drug

[0095] Dissolve sirolimus in methanol to prepare a 40 mg / ml good solvent solution of the active drug, called solution A;

[0096] (2) Prepare a mixed solution

[0097] Add polymer-drug nanoparticles (prepared in Example 2) equivalent to 350 ppm of the weight of sirolimus to n-heptane with a weight 10 times that of methanol and ultrasonically mix evenly to obtain solution B;

[0098] (3) Mix solution A and solution B and continuously stir at room temperature for 24 hours to obtain a coating solution.

[0099] Example 6

[0100] This embodiment provides a method for preparing a coating solution containing crystalline drug molecules, comprising the following steps:

[0101] (1) Prepare a good solvent solution of the active drug

[0102] Dissolve sirolimus in methanol to prepare a 40 mg / ml good solvent solution of the active drug, called solution A;

[0103] (2) Prepare a mixed solution

[0104] Add polymer-drug nanoparticles (prepared in Example 2) equivalent to 350 ppm of the weight of sirolimus to n-heptane with a weight 10 times that of methanol and ultrasonically mix evenly to obtain solution B;

[0105] (3) Prepare coating solution A

[0106] Mix solution A and solution B and continuously stir at room temperature for 24 hours to obtain coating solution A;

[0107] (4) Prepare coating solution B

[0108] Add sustained-release polymer drug-loaded microparticles (prepared in Example 3) with a weight equal to that of the active drug in solution A to coating solution A and continue to stir for 30 minutes to obtain coating solution B.

[0109] The coating liquid B prepared in Example 6 was filled into a syringe, and magnetic stirring was carried out by applying an electromagnetic field inside or outside the syringe. The uniformly stirred suspension was ultrasonically atomized and sprayed onto the outer surface of the rotating balloon body. After spraying, the balloon was dried, folded, and sterilized with ethylene oxide after being placed in a protective sleeve to form a drug-loaded coating. Taking the drug-coated balloon as an example, the drug release performance test of the drug-loaded coating was carried out:

[0110] Fresh porcine coronary blood vessels were provided and rinsed repeatedly with physiological saline to remove excess fat, connective tissue, and fascia. After cutting the blood vessels to an appropriate length, they were connected to the distal outlet of the ASTM F2394-07 curvature model blood vessel simulation channel. A 37°C physiological saline pipeline was connected to the proximal inlet of the blood vessel simulation channel through a three-way valve, and the flow rate of physiological saline was controlled by a peristaltic pump at 50 ml / min. The simulated blood vessel channel was pre-flushed with 37°C physiological saline.

[0111] The protective sleeve of the drug-loaded balloon was removed, and the balloon entered from the proximal end of the simulated blood vessel channel and reached the blood vessel through the simulated channel within 60 ± 10 seconds. It was pressurized to 8 atm and maintained for 60 seconds to release the drug-loaded coating to the blood vessel. After release, the balloon was evacuated and withdrawn along the simulated blood vessel channel; the simulated channel included the porcine blood vessel passage being flushed with 37°C physiological saline for 1 hour, 24 hours, and 72 hours respectively, with a flow rate of 50 ml / min.

[0112] The test results are as Figure 1 shown. The drug loading dose of the drug-loaded coating of this balloon is 1.5 μg / mm2. Taking the porcine coronary artery as a model and simulating flushing at 1 hour, 24 hours, and 72 hours after surgery, after providing a sufficient initial loading drug dose, over time, the drug content in the blood vessel showed a slow decay, meeting the design expectations of the coating liquid.

[0113] The above-disclosed are only the preferred embodiments of the present invention. Of course, the scope of the rights of the present invention cannot be limited thereby. Therefore, equivalent changes made according to the scope of the patent application of the present invention still fall within the scope covered by the present invention.

Claims

1. A coating solution containing crystalline drug molecules, characterized in that, It includes a good solvent solution of the active drug, a nucleating agent, and a non-solvent. The good solvent solution of the active drug is formed by dissolving the active drug in a good solvent. The non-solvent is a non-solvent for the active drug and the nucleating agent. The good solvent and the non-solvent are miscible. The volume ratio of the good solvent to the non-solvent for the active drug is 1:5 to 1:

50. The addition amount of the nucleating agent is 10,000 ppm to 10 ppm of the total active drug. The size of the nucleating agent is 10 nm to 500 nm. The nucleating agent is a heterogeneous nucleating agent, and the nucleating agent includes active drug crystal microparticles or polymer drug-loaded microparticles; The preparation method of the coating solution containing crystalline drug molecules includes the following steps: (1) Dissolve the active drug in a good solvent to prepare a good solvent solution of the active drug; (2) Add the nucleating agent to the non-solvent of the active drug and the nucleating agent, and stir evenly to obtain a mixed solution; (3) Mix the good solvent solution of the active drug with the mixed solution to form a coating solution.

2. The coating liquid containing crystalline drug molecules according to claim 1, characterized in that, It includes at least one of the following features (1) to (4): (1) The active drug is selected from paclitaxel or mTOR drugs; (2) The active drug is selected from mTOR drugs, and the mTOR drugs are selected from sirolimus, zotarolimus, everolimus, umbralisib, and their derivatives; (3) The good solvent is selected from at least one of methanol, ethanol, isopropanol, ethyl acetate, acetone, dichloromethane, chloroform; (4) The non-solvent for the active drug is selected from at least one of water, n-hexane, n-heptane, petroleum ether.

3. The coating liquid containing crystalline drug molecules as described in claim 1, characterized in that, It includes the following steps: (1) Dissolve the first active drug in the good solvent to prepare a good solvent solution of the first active drug; (2) Add the second active drug crystal microparticles to the non-solvent of the second active drug and the first active drug, and stir evenly to obtain a mixed solution; (3) Mix the good solvent solution of the first active drug with the mixed solution to form a coating solution, wherein, the preparation steps of the second active drug crystal microparticles are as follows: (1) Dissolve the second active drug in a good solvent of the second active drug to prepare a good solvent solution of the second active drug; (2) Drop the good solvent solution of the second active drug into a non-solvent of the second active drug, and perform centrifugal separation, washing, and freeze-drying to obtain the second active drug crystal microparticles.

4. The coating liquid containing crystalline drug molecules according to claim 1, characterized in that, It includes the following steps: (1) Dissolve the active drug in the good solvent to prepare the good solvent solution of the active drug; (2) Add the polymer drug-loaded microparticles to the non-solvent of the active drug and the polymer drug-loaded microparticles, and stir evenly to obtain a mixed solution; (3) Mix the good solvent solution of the active drug with the mixed solution to form a coating solution.

5. The coating solution containing crystalline drug molecules according to claim 1, wherein It includes the following steps: (1) Dissolve the active drug in the good solvent to prepare the good solvent solution of the active drug; (2) Add the first polymer drug-loaded microparticles to the non-solvent of the active drug and the first polymer drug-loaded microparticles, and stir evenly to obtain a mixed solution; (3) Mix the good solvent solution of the active drug with the mixed solution to form coating solution A; (4) Add the second polymer drug-loaded microparticles to coating solution A to form a coating solution.

6. Use of a coating solution containing a crystalline drug molecule as described in any one of claims 1-5 in a medical device.

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