A drug coating, method of manufacture and drug balloon catheter

Abstract

The present application provides a drug coating, a preparation method and a drug balloon catheter, the drug coating comprises an active drug and an adhesive, the active drug is a crystal particle, and the active drug is sirolimus or a sirolimus derivative. The drug coating of the present application comprises an active drug in a crystal form, the drug coating has the advantages of good stability, when it is prepared in a drug balloon catheter, the influence of blood flow flushing on the active drug is small during the balloon expansion transfer process, the loss rate of the active drug during delivery is reduced, the physical force on the blood vessel wall during the balloon expansion process is increased, and the transfer rate of the active drug is increased; after the active drug is transferred to the blood vessel wall in the form of a crystal, the active drug is gradually dissolved and released, and then absorbed by surrounding tissue cells, so that long-term stable release and sustained drug efficacy can be achieved.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of medical devices, in particular to a drug coating, a preparation method and a drug balloon catheter. BACKGROUND

[0002] Drug-coated balloon is a combination of balloon dilatation and drug eluting technology, which attaches cell proliferation inhibiting drugs on the surface of the balloon. During the expansion process, the drugs on the balloon are delivered to the local blood vessel wall, achieving the effect of inhibiting smooth muscle cell proliferation and preventing vascular restenosis. Drug-coated balloon is an effective solution to intimal hyperplasia and restenosis, which can truly achieve the treatment concept of "intervention without implantation" and "intervention as implantation".

[0003] Drug-coated balloon (DCB) is composed of a balloon, an anti-proliferative drug (paclitaxel, sirolimus and its derivatives, etc.) and a drug carrier. By releasing the anti-proliferative drug to the target blood vessel wall, the effect of inhibiting vascular intimal hyperplasia is achieved. Compared with drug eluting stent (DES), DCB does not need long-term implantation, has no metal mesh residue, can reduce the inflammatory response at the intervention site, greatly reduces the risk of thrombosis, and can shorten the time of dual anti-platelet therapy. At the same time, DCB avoids the long-term placement of stents and other foreign objects, leaving the patient with the opportunity for follow-up treatment if necessary.

[0004] At present, there are many methods for preparing the drug coating of drug-coated balloon, but the therapeutic effect of most drug-coated balloons is not satisfactory. There are many factors affecting the therapeutic effect of drug-coated balloon, which usually include: the drug content and distribution on the surface of the balloon, the drug loading form, the particle size and its distribution of the drug, the firmness of the drug coating, the transfer efficiency of the drug on the blood vessel wall, the release period and half-life of the drug, etc. In order to increase the clinical effect of drug-coated balloon, the stability of the product during the shelf life should be ensured first, and the problem of drug coating shedding after entering the blood should be minimized. In order to achieve the above prerequisites, the preparation method of the drug coating needs to be optimized and improved, and the stability of the drug itself, the firmness of the drug coating and the uniformity of the drug distribution should be improved as much as possible.

[0005] Before the drug balloon product is mostly with paclitaxel as the active pharmaceutical ingredient of drug coating, paclitaxel has high lipophilicity, strong anti-proliferation effect and stable chemical properties, etc., which becomes the first choice of anti-proliferation drug in the previous DCB, but based on the narrow treatment window of paclitaxel and the concern of causing cytotoxicity, etc. At present, the drugs used at home and abroad are mostly sirolimus (Sirolimus, Rapamycin, abbreviated as RAP or RPM, also known as rapamycin) and its derivatives, which are natural macrolide antibiotics with strong anti-cell proliferation and immunosuppression effects. But the liposolubility and transfer rate of sirolimus is poor, which is difficult to adsorb to the surface of the balloon, and also affects the rapid absorption of the organization.

[0006] In order to achieve the balance between the adhesion of the drug coating and the surface of the balloon, the existing drug balloon is through the hydrophilic coating to adhere the drug on the surface of the balloon, and then through the contact between the expanded balloon and the blood vessel wall, so as to realize the loading of the drug. If the adhesion between the drug coating and the surface of the balloon is very strong, it is easy to cause low drug transfer rate, which cannot reach the ideal drug concentration; if the adhesion between the drug coating and the surface of the balloon is weak, the drug and the hydrophilic coating are easy to lose a lot in the transportation process.

[0007] And the drug utilization rate of drug balloon is mainly affected by two aspects: drug delivery and drug release. The existing research shows that more than 80% of the drug loss in the drug balloon occurs during the operation. In addition to the balloon delivery during the operation, during the short expansion (30-90s) of the balloon, the drug cannot be completely transferred from the balloon to the target blood vessel site, and 10% of the drug will remain on the balloon after the balloon is recovered. Because the use process of the drug coating balloon is very short, there is no efficient transfer technology, and the drug cannot transfer the drug from the surface of the balloon to the blood vessel wall in a short time of about one minute, which leads to a large amount of drug being washed away by blood flow or remaining on the balloon and cannot be released in the existing technology or product, so the drug release degree and utilization rate of the existing drug balloon product are not high.

[0008] As the core of the drug coating balloon, the drug coating is generally composed of active drug components and hydrophilic matrix. The commonly used anti-proliferation drugs are mostly liposoluble molecules, which are generally difficult to dissolve in water and easy to fall off, agglomerate and block, forming larger particles. These difficult-to-dissolve and easy-to-agglomerate drug particles are easy to be washed away by blood during transportation. On the one hand, these particles falling into the blood will reduce the efficiency of drug delivery; on the other hand, it may cause blockage of distal blood vessels, thrombosis and other adverse reactions.

[0009] Patent application number CN201711483968.4 discloses that by wrapping the drug in degradable polymer microspheres, then coating on the surface of the balloon, and finally coating a layer of hydrophilic coating on the surface of the balloon, the purpose of effectively reducing the initial drug concentration and stable release of the drug is achieved. But its long-term stable release of the drug is achieved by the way of polymer degradation, and the polymer may cause local inflammatory reaction during the degradation process. The shedding of the drug microspheres may also cause occlusion and embolism of the distal blood vessels.

[0010] Patent application number CN202011413585.1 discloses that through the form of double coating of hydrophilic coating and drug coating, the drug coating is ensured to be released rapidly after contacting the blood vessel, so that the drug microspheres in the drug layer are released into the blood vessel wall. The sustained release of the drug relies on the degradation of the degradable polymer, so as to achieve the effect of continuously inhibiting the restenosis of the blood vessel. But the dissolution rate of the hydrophilic coating is difficult to control, and the release of the drug layer relies on the adhesion of the amphiphilic substance to the drug microspheres, which cannot be stably adsorbed on the blood vessel wall, and may cause occlusion and embolism of the distal blood vessels.

[0011] Patent application number CN202110410650.3 discloses that the shock wave component is used to emit shock waves to the drug coating, so that the drug coating falls off from the outer surface of the balloon, so as to improve the drug utilization rate. But the use process is complex, the fallen coating cannot be guaranteed to be completely absorbed by the blood vessel wall, and its safety still needs to be considered.

[0012] In summary, for the intravascular stenosis and restenosis, a new drug coating and its drug coating balloon are urgently needed in the clinic. On the one hand, the drug coating can be prevented from falling off and the risk of being washed away by the blood flow during the delivery process of the balloon; on the other hand, the transfer efficiency of the drug between the balloon and the blood vessel wall can be greatly improved, so that the drug coating remaining on the surface of the balloon can be prevented from falling off during the pressure relief and withdrawal process. Therefore, by improving the drug delivery efficiency, the expected therapeutic effect can be achieved and the clinical safety can be greatly guaranteed. SUMMARY

[0013] In view of the problems in the prior art, the purpose of the present application is to provide a drug coating solution and a preparation method thereof, and a drug balloon catheter, so as to reduce the risk of the active drug in the drug coating being washed away by the blood flow, reduce the loss rate of the drug, and improve the transfer efficiency of the drug.

[0014] The first aspect of the present application provides a drug coating, which comprises an active drug and an adhesion agent, the active drug is a crystal particle, and the active drug is sirolimus or a sirolimus derivative.

[0015] According to the first aspect of the present application, the size of the crystal particle in any dimension is 5nm-50μm.

[0016] According to the first aspect of the present application, the crystal particles are needle-shaped or flake-shaped.

[0017] According to the first aspect of the present application, the ratio of the size of the crystal particles in one dimension to the size in another dimension is greater than or equal to 5, or the ratio is less than or equal to 1 / 5.

[0018] According to the first aspect of the present application, the size of the crystal particles in one dimension is 5 μm to 50 μm, and the size in another dimension is 0.5 μm to 10 μm; or,

[0019] The size of the crystal particles in one dimension is 50 nm to 5000 nm, and the size in another dimension is 10 nm to 1000 nm.

[0020] According to the first aspect of the present application, the active drug is a sea urchin-shaped crystal formed by agglomeration of a plurality of the crystal particles, and the sea urchin-shaped crystal includes a plurality of radially outwardly extending whiskers.

[0021] According to the first aspect of the present application, the size of the sea urchin-shaped crystal in any dimension is 5 μm to 50 μm, the length of the whisker is 1 μm to 25 μm, and the width of the whisker is 0.2 μm to 2 μm.

[0022] According to the first aspect of the present application, the adhesive includes one or more of polyoxyethylene, carbomer, sucrose, sodium carboxymethyl cellulose, starch, hydroxyethyl methyl cellulose, trehalose, pectin, and shellac.

[0023] According to the first aspect of the present application, the mass ratio of the active drug to the adhesive is 1:4 to 4:1.

[0024] According to the first aspect of the present application, the thickness of the drug coating is 5 μm to 15 μm.

[0025] The second aspect of the present application provides a preparation method of a drug coating for preparing the drug coating, and the method includes the following steps:

[0026] A solute drug is provided and dissolved in a solvent to obtain a first solution;

[0027] An anti-solvent is added to the first solution, and the solution is stirred to obtain a second solution;

[0028] The second solution is centrifuged to obtain a solid precipitate;

[0029] The solid precipitate is dried at room temperature and in a vacuum environment to obtain the active drug;

[0030] The adhesive is provided, dissolved in water, and stirred to obtain a third solution;

[0031] The active drug is dispersed in the third solution to obtain a drug coating mixture;

[0032] The drug coating mixture is applied to the surface of the drug carrier;

[0033] The drug coating is dried.

[0034] According to a second aspect of the present application, the sirolimus derivative is everolimus.

[0035] According to the second aspect of the present application, the mass concentration of the adhesive in the third solution is 0.1% to 5%.

[0036] According to the second aspect of the present application, the adhesive includes one or more of polyoxyethylene, carbomer, sucrose, sodium carboxymethyl cellulose, starch, hydroxyethyl methyl cellulose, trehalose, pectin, and shellac.

[0037] The solvent includes one or more of ethyl acetate, dichloromethane, acetonitrile, and isopropyl alcohol.

[0038] The anti-solvent includes one or more of n-heptane, polyvinyl alcohol, and n-hexane.

[0039] According to the second aspect of the present application, the concentration of the solute drug in the solvent ranges from 25 mg / mL to 1000 mg / mL, and / or,

[0040] The volume ratio of the solvent to the anti-solvent is 1:100 to 1:4.

[0041] According to the second aspect of the present application, the solute drug is sirolimus, the solvent is dichloromethane, the anti-solvent is n-heptane, the stirring is performed, and the solid precipitate is urchin-shaped crystals, wherein the ratio of the solvent to the anti-solvent is 1:20, and the concentration of the solute drug in the solvent is 200 mg / mL; or,

[0042] The solute drug is sirolimus, the solvent is a mixed solvent of acetonitrile and isopropyl alcohol, the anti-solvent is polyvinyl alcohol, and the solid precipitate is urchin-shaped crystals; wherein the ratio of the solvent to the anti-solvent is 1:7, and the concentration of the solute drug in the solvent is 67 mg / mL; or,

[0043] The solute drug is everolimus, the solvent is a mixed solvent of acetonitrile and isopropyl alcohol, and the anti-solvent is polyvinyl alcohol; the solid precipitate is a sea urchin-shaped crystal; the ratio of the solvent to the anti-solvent is 1:7, and the concentration of the solute drug in the solvent is 67 mg / mL.

[0044] The third aspect of the present application provides a drug balloon catheter, comprising a balloon part and a catheter part connected, the balloon part comprising an expandable bare balloon and the drug coating disposed on the outer surface of the bare balloon.

[0045] According to the third aspect of the present application, the drug loading density of the bare balloon is 3 μg / mm 2 .

[0046] The drug coating solution, the preparation method thereof and the drug balloon catheter provided by the present application have the following advantages:

[0047] The active drug in the form of crystal has good stability, the influence of blood flow on the active drug during the expansion of the balloon of the drug balloon catheter is small, and the loss rate of the drug during delivery is reduced; the active drug in the form of crystal increases the physical force of the balloon on the blood vessel wall during expansion, and increases the transfer rate of the active drug; after the active drug is transferred to the blood vessel wall in the form of crystal, the active drug is gradually dissolved and released, and then is absorbed by the surrounding tissue cells, so that long-term stable release and sustained drug effect of the drug can be achieved. BRIEF DESCRIPTION OF DRAWINGS

[0048] Other features, objects and advantages of the present application will become more apparent from the following detailed description of non-limiting embodiments with reference to the attached drawings.

[0049] Figure 1 is a flow chart of the preparation method of the drug coating of an embodiment of the present application;

[0050] Figure 2 is a morphology diagram of the sirolimus needle-shaped crystal of embodiment one of the present application;

[0051] Figure 3 is an XRD spectrum of the sirolimus needle-shaped crystal of embodiment two of the present application;

[0052] Figure 4 is a scanning electron microscope image of the everolimus needle-shaped crystal of embodiment three of the present application;

[0053] Figure 5 is a scanning electron microscope image of the nanocrystal of sirolimus of embodiment four of the present application;

[0054] Figure 6 is a scanning electron microscope image of the nanocrystal of sirolimus of embodiment five of the present application;

[0055] Figure 7 is a scanning electron micrograph of nanocrystals of everolimus according to an embodiment of the present application;

[0056] Figure 8 is an XRD pattern of needle-shaped crystals of everolimus according to an embodiment of the present application;

[0057] Figure 9 and Figure 10 is a scanning electron micrograph of sea urchin-shaped crystals of sirolimus according to an embodiment of the present application;

[0058] Figure 11 is a scanning electron micrograph of sea urchin-shaped crystals of sirolimus according to an embodiment of the present application;

[0059] Figure 12 is a scanning electron micrograph of amorphous nanospherical sirolimus according to a comparative example of the present application;

[0060] Figure 13 is an XRD pattern of sirolimus according to a comparative example of the present application;

[0061] Figure 14 is a scanning electron micrograph of amorphous nanospherical everolimus according to a comparative example of the present application;

[0062] Figure 15 is an XRD pattern of amorphous nanospherical everolimus according to a comparative example of the present application;

[0063] Figure 16 is a schematic diagram of a drug balloon catheter according to an embodiment of the present application;

[0064] Figure 17 is Figure 16 is a magnified view of the selected area in the square;

[0065] Figure 18 is a schematic diagram of a cross-sectional area of a blood vessel;

[0066] Figure 19 is a schematic diagram of a cross-sectional area of a blood vessel during expansion of a drug-coated intracranial balloon during an animal experiment;

[0067] Figure 20 is a schematic diagram of a cross-sectional area of a blood vessel after expansion of a drug-coated intracranial balloon during an animal experiment;

[0068] Figure 21 is a schematic diagram of a cross-sectional area of a blood vessel during expansion of a drug-coated intracranial balloon during an animal experiment;

[0069] Figure 22 is a schematic diagram of a model of in-vitro loss of delivery and ex-vivo release of a blood vessel;

[0070] Figure 23 to Figure 25This is a schematic diagram illustrating the interaction between the active drug and the blood vessel wall during balloon dilation.

[0071] Figure label:

[0072] 1. Bare balloon

[0073] 2. Drug coating

[0074] 21. Active drugs

[0075] 211 Sea urchin-like crystals

[0076] 212 Massive crystals

[0077] 213 Needle-like crystals

[0078] 22 Adhesive Coating

[0079] 3. Blood vessel wall Detailed Implementation

[0080] Exemplary embodiments will now be described more fully with reference to the accompanying drawings. However, these exemplary embodiments can be implemented in many forms and should not be construed as limited to the embodiments set forth herein; rather, they are provided so that the invention will be thorough and complete, and will fully convey the concept of the exemplary embodiments to those skilled in the art. The same reference numerals in the drawings denote the same or similar structures, and therefore repeated descriptions of them will be omitted. The words “or” and “or” in the specification may mean “and” or “or”.

[0081] To address the problems of existing technologies, this invention provides a drug coating comprising an active drug and an adhesive, wherein the active drug is crystalline particles, and the active drug is sirolimus or a sirolimus derivative. The size of the crystal in any dimension of this invention refers to the distance between the two farthest points in that dimension. Figures 2 to 16 As shown, the active pharmaceutical ingredient crystals are crystalline particles, such as micron-sized or nano-sized crystals; the crystalline particles of the active pharmaceutical ingredient are needle-shaped or plate-shaped. In this invention, "needle-shaped" refers to a crystal whose size in one spatial dimension is significantly larger than its size in other spatial dimensions, and can also be called rod-shaped or strip-shaped; "plate-shaped" refers to a crystal whose size is similar in at least two spatial dimensions, and can also be called plate-shaped or block-shaped. The active pharmaceutical ingredient crystals may also appear urchin-like under a scanning electron microscope. The urchin-shaped crystals described in this invention refer to crystal clusters formed by the aggregation of needle-shaped and / or plate-shaped crystals, which appear as spherical shapes with multiple outward protrusions under a scanning electron microscope, resembling the shape of a sea urchin; including multiple outwardly protruding whiskers.

[0082] The drug exists in crystalline form in the drug coating, which can achieve high drug delivery efficiency and high release rate.

[0083] Specifically, the adhesive can include one or more of polyoxyethylene, carbomer, sucrose, sodium carboxymethyl cellulose, starch, hydroxyethyl methyl cellulose, trehalose, pectin and shellac. The mass ratio of the active drug to the adhesive is 1:4-4:1. The ratio of the size of the crystal particles in one dimension to the size in another dimension is greater than or equal to 5, or the ratio is less than or equal to 1 / 5. For example, the active drug is a microneedle-shaped crystal, the length of the microneedle-shaped crystal is 5-50 μm, and the width is 0.5-10 μm; or the active drug is a nanoneedle-shaped crystal, the length of the nanoneedle-shaped crystal is 50-5000 nm, and the width is 10-1000 nm; or the active drug is a sea urchin-shaped crystal, the diameter of the sea urchin-shaped crystal is 5-50 μm, the length of the whisker of the sea urchin-shaped crystal is 1-25 μm, and the width of the whisker is 0.2-2 μm. The thickness of the drug coating is 5-15 μm.

[0084] The application also provides a method for preparing a drug coating, Figure 1 The flow chart of the method for preparing a drug coating according to an embodiment of the application, specifically, the method includes the following steps:

[0085] S100: providing a solute drug, dissolving the solute drug in a solvent to obtain a first solution; the solute drug is sirolimus (RAP) or a sirolimus derivative, and the sirolimus derivative is preferably Biolimus A9, also known as BA9. The solvent includes one or more of ethyl acetate, dichloromethane, acetonitrile and isopropyl alcohol; the concentration of the solute drug in the solvent is 25-1000 mg / mL,

[0086] S200: adding an anti-solvent to the first solution, stirring to obtain a second solution; the anti-solvent includes one or more of n-heptane, polyvinyl alcohol and n-hexane. The volume ratio of the solvent to the anti-solvent is 1:100-1:4.

[0087] S300: centrifuging the second solution to obtain a solid precipitate;

[0088] S400: drying the solid precipitate at room temperature and in a vacuum environment to obtain the active drug; the active drug and the solute drug are different in microscopic morphology but the same in composition.

[0089] S500: providing an adhesive, dissolving the adhesive in water, stirring to obtain a third solution; the adhesive includes one or more of polyoxyethylene, carbomer, sucrose, sodium carboxymethyl cellulose, starch, hydroxyethyl methyl cellulose, trehalose, pectin and shellac; the mass concentration of the adhesive in the third solution is 0.1%-5%.

[0090] S600: dispersing the active drug in the third solution to obtain a drug coating mixture; the mass ratio of the active drug to the adhesion agent is 4:1-1:4;

[0091] S700: applying the drug coating mixture to the surface of the drug carrier;

[0092] S800: drying to obtain the drug coating.

[0093] Preferably, in one embodiment, the third solution is a polyethylene oxide (PEO) solution, i.e., the adhesion agent is PEO, and the preparation of the drug coating includes the following steps:

[0094] 200 mg of PEO is weighed and dispersed in 10 ml of purified water, and after magnetic stirring to completely dissolve the PEO;

[0095] 50 mg of the active drug is added, and the active drug is uniformly dispersed in the PEO solution by means of shaking, vortexing, ultrasonic, etc., to obtain a drug coating solution with an active drug composition concentration of 5 mg / ml and a mass ratio of the active drug to the adhesion agent of 1:4.

[0096] Preferably, in another embodiment, the third solution is a polyethylene oxide (PEO) solution, and the preparation of the drug coating solution includes the following steps:

[0097] 200 mg of PEO is weighed and dispersed in 10 ml of purified water, and after magnetic stirring to completely dissolve the PEO, a PEO aqueous solution with a concentration of 20 mg / ml is obtained;

[0098] 200 mg of the active drug is weighed and added to a sample bottle containing 10 ml of water for injection, and the active drug is uniformly dispersed in the water by means of shaking, vortexing, ultrasonic, etc., to obtain a suspension of the active drug;

[0099] The PEO aqueous solution and the suspension of the active drug composition are mixed at a volume ratio of 1:1, and the active drug is uniformly dispersed in the PEO solution by means of shaking, vortexing, ultrasonic, etc., to obtain a drug coating solution with an active drug composition concentration of 5 mg / ml and a mass ratio of the active drug to the adhesion agent of 1:1. The preparation of the active drug provided in the present application will be described in detail below in combination with specific embodiments.

[0100]

Example One

[0101] The preparation of sirolimus needle-shaped crystals by the anti-solvent method includes the following steps:

[0102] Step S100a: 50 mg of sirolimus was weighed in a sample bottle, 1 mL of ethyl acetate was measured as a solvent, and the solvent was added to the sample bottle, and after shaking and stirring, the sirolimus was completely dissolved to obtain a sirolimus solution;

[0103] Step S200a: 10 mL of anti-solvent n-heptane was measured and quickly added to the sample bottle, and the liquid in the sample bottle was uniformly mixed by ultrasonic, and magnetically stirred for 24 h.

[0104] Step S300a: centrifugation to obtain a solid precipitate of sirolimus;

[0105] Step S400a: vacuum drying of the sirolimus solid precipitate at room temperature to obtain needle-shaped sirolimus crystals as shown Figure 2 , which are elongated needle-shaped or irregular flaky under a scanning electron microscope.

[0106]

Example Two

[0107] The preparation of sirolimus needle-shaped crystals by anti-solvent method includes the following steps:

[0108] Step S100b: 100 mg of sirolimus was weighed in a sample bottle, 1 mL of ethyl acetate was measured as a solvent, and the solvent was added to the sample bottle, and after shaking and stirring, the sirolimus was completely dissolved;

[0109] Step S200b: 15 mL of anti-solvent n-hexane was measured and quickly added to the sample bottle, and the liquid in the sample bottle was uniformly mixed by ultrasonic, and magnetically stirred for 24 h.

[0110] Step S300b: centrifugation to obtain a solid precipitate of sirolimus;

[0111] Step S400b: vacuum drying of the sirolimus solid precipitate at room temperature, Figure 3 to obtain the XRD characterization spectrum of the solid precipitate, which includes the characteristic peaks of sirolimus, and the half-peak width of XRD is small, i.e. the obtained sirolimus has good crystallinity, which is sirolimus needle-shaped crystals.

[0112]

Example Three

[0113] The preparation of sirolimus needle-shaped crystals by anti-solvent method includes the following steps:

[0114] Step S100c: 100 mg of sirolimus was weighed in a sample bottle, 0.2 mL of ethyl acetate was measured as a solvent, and the solvent was added to the sample bottle, and after shaking and stirring, the sirolimus was completely dissolved;

[0115] Step S200c: 12 mL of anti-solvent n-heptane was quickly added into the sample bottle, and the liquid in the sample bottle was mixed uniformly by ultrasonic. After 2 h of ultrasonic, a milky white suspension was obtained;

[0116] Step S300c: centrifugation to obtain a solid precipitate of everolimus;

[0117] Step S400c: vacuum drying of the solid precipitate of everolimus at room temperature to obtain a needle-shaped crystal of everolimus as shown in FIG. 4, which is rod-shaped under a scanning electron microscope. Figure 4

[0118]

Example Four

[0119] Preparation of a crystal of sirolimus by an anti-solvent method, including the following steps:

[0120] Step S100d: 100 mg of sirolimus was weighed in a sample bottle, 0.5 mL of ethyl acetate was measured as a solvent, and the solvent was added to the sample bottle. After shaking and stirring, the sirolimus was completely dissolved;

[0121] Step S200d: 10 mL of anti-solvent n-heptane was quickly added into the sample bottle, and the sample bottle was placed in an ultrasonic cleaner for continuous ultrasonic for 2 h;

[0122] Step S300d: centrifugation to obtain a solid precipitate of sirolimus;

[0123] Step S400d: vacuum drying of the solid precipitate of sirolimus at room temperature to obtain a crystal of sirolimus as shown in FIG. 4, which is nanoscale rod-shaped or irregular flaky under a scanning electron microscope. Figure 5

[0124]

Example Five

[0125] Preparation of a crystal of sirolimus by an anti-solvent method, including the following steps:

[0126] Step S100e: 100 mg of sirolimus was weighed in a sample bottle, 1 mL of acetonitrile was measured as a solvent, and the solvent was added to the sample bottle. After shaking and stirring, the sirolimus was completely dissolved. Then 0.5 mL of dichloromethane was added to the sample bottle and mixed;

[0127] Step S200e: 10 mL of anti-solvent n-heptane was quickly added into the sample bottle, and the sample bottle was placed in an ultrasonic cleaner for continuous ultrasonic for 2 h;

[0128] Step S300e: centrifugation to obtain a solid precipitate of sirolimus;

[0129] ​​Step S400e: vacuum drying the solid precipitate of sirolimus at room temperature to obtain sirolimus crystals as shown in FIG. 4E, which are rhombic needle-shaped or irregular flake-shaped under scanning electron microscope. Figure 6

[0130] Example Six

[0131] The preparation of everolimus crystals by anti-solvent method includes the following steps:

[0132] Step S100f: weighing 100 mg of everolimus (manufacturer: Bosheng International) in a sample bottle, measuring 0.2 mL of ethyl acetate as a solvent, and adding the solvent into the sample bottle, and after shaking and stirring, the everolimus is completely dissolved;

[0133] Step S200f: measuring 6 mL of anti-solvent n-heptane, quickly adding it into the sample bottle, and placing the sample bottle in an ultrasonic cleaner for 1 h of continuous ultrasonic treatment;

[0134] Step S300f: centrifuging to obtain the solid precipitate of everolimus;

[0135] Step S400f: vacuum drying the solid precipitate of everolimus at room temperature to obtain everolimus crystals as shown in FIG. 4F, which are needle-shaped or elongated flake-shaped under scanning electron microscope. Figure 7

[0136] Example Seven

[0137] The preparation of everolimus crystals by anti-solvent method includes the following steps:

[0138] Step S100g: weighing 100 mg of everolimus in a sample bottle, measuring 0.1 mL of ethyl acetate as a solvent, and adding the solvent into the sample bottle, and after shaking and stirring, the everolimus is completely dissolved;

[0139] Step S200g: measuring 10 mL of anti-solvent n-hexane, quickly adding it into the sample bottle, and placing the sample bottle in an ultrasonic cleaner for 3 h of continuous ultrasonic treatment;

[0140] Step S300g: centrifuging to obtain the solid precipitate of everolimus;

[0141] Step S400g: vacuum drying the solid precipitate of everolimus at room temperature to obtain everolimus nanoneedle-shaped crystals. As shown in FIG. 4G, the XRD characterization spectrum confirms that the obtained solid precipitate is everolimus nanoneedle-shaped crystals. Figure 8

[0142] Example Eight

[0143] The preparation of sirolimus crystals by anti-solvent method includes the following steps:​​​

[0144] Step S100h: 100 mg of sirolimus was weighed in a sample bottle, 0.5 mL of dichloromethane was measured as solvent, and the solvent was added to the sample bottle, and sirolimus was completely dissolved after shaking and stirring;

[0145] Step S200h: 10 mL of anti-solvent n-heptane was measured and quickly added to the sample bottle, and the sample bottle was placed in an ultrasonic cleaner for 2 h of continuous ultrasonic cleaning;

[0146] Step S300h: centrifugation to obtain a solid precipitate of sirolimus;

[0147] Step S400h: vacuum drying of the solid precipitate of sirolimus at room temperature to obtain sea urchin-shaped crystals of sirolimus as shown in Figure 9 and Figure 10 Crystal measurement results show that the average particle size (diameter) of the sea urchin-shaped crystals of sirolimus is 9.1 μm, and the particle size distribution range is 6 μm-12 μm; the length of the whiskers is 3 μm-5 μm, and the average width is 0.32 μm.

[0148]

Example Nine

[0149] The preparation of sirolimus crystals by the anti-solvent method includes the following steps:

[0150] Step S100i: 100 mg of sirolimus was weighed in a sample bottle, 1 mL of acetonitrile and 0.5 mL of isopropyl alcohol were measured as solvents, and the solvents were added to the sample bottle, and sirolimus was completely dissolved after shaking and stirring;

[0151] Step S200i: 10 mL of anti-solvent polyvinyl alcohol (PVA, 0.5% wt / vol) was measured and quickly added to the sample bottle, and magnetic stirring was performed for 16-24 h;

[0152] Step S300i: centrifugation to obtain a solid precipitate of sirolimus;

[0153] Step S400i: vacuum drying of the solid precipitate of sirolimus at room temperature to obtain sea urchin-shaped crystals of sirolimus as shown in Figure 11 Crystal measurement results show that the average particle size (diameter) of the sea urchin-shaped crystals of sirolimus is 5.2 μm, and the particle size distribution range is 4.0 μm-7.0 μm; the length of the whiskers is 2.0 μm-4.5 μm, and the width range is 0.2 μm-0.60 μm.

[0154]

Example Ten

[0155] The preparation of everolimus crystals by the anti-solvent method includes the following steps:

[0156] Step S100j: 100 mg of everolimus was weighed in a sample bottle, 1 mL of acetonitrile and 0.5 mL of isopropyl alcohol were measured as solvents, and the solvents were added to the sample bottle, and the everolimus was completely dissolved after shaking and stirring;

[0157] Step S200j: 10 mL of anti-solvent polyvinyl alcohol (PVA) was quickly added to the sample bottle, and magnetic stirring was performed for 16-24 h;

[0158] Step S300j: centrifugation to obtain a solid precipitate of everolimus;

[0159] Step S400j: vacuum drying of the solid precipitate of everolimus at room temperature to obtain urchin-shaped crystals of everolimus. The crystal measurement results showed that the average particle size (diameter) of the urchin-shaped crystals of everolimus was 4.1 μm, and the particle size distribution range was 2.8 μm-6.3 μm; the length of the whisker was 1.6 μm-3.8 μm, and the whisker was wide and flat.

[0160] Example XI

[0161] The preparation of everolimus crystals by the anti-solvent method includes the following steps:

[0162] Step S100k: 80 mg of everolimus was weighed in a sample bottle, 2 mL of ethyl acetate was measured as a solvent, and the solvent was added to the sample bottle, and the everolimus was completely dissolved after shaking and stirring;

[0163] Step S200k: 15 mL of anti-solvent n-heptane was quickly added to the sample bottle, the liquid in the sample bottle was uniformly mixed by ultrasonic, and magnetic stirring was performed for 24 h.

[0164] Step S300k: centrifugation to obtain a solid precipitate of everolimus;

[0165] Step S400k: vacuum drying of the solid precipitate of everolimus at room temperature to obtain needle-shaped crystals of everolimus.

[0166] According to Examples 1-3, needle-shaped crystals of sirolimus and everolimus were obtained, the size of the needle-shaped crystals was in the micron range, the length of the micron needle-shaped crystals was 5 μm-50 μm, and the width was 0.5 μm-5 μm; in the preparation of the micron needle-shaped crystals, the concentration of the solute drug in the solvent was in the range of 25 mg / mL-1000 mg / mL, and the volume ratio of the solvent ethyl acetate to the anti-solvent (n-heptane, n-hexane) was 1:4-1:100.

[0167] The nanocrystals of sirolimus and everolimus prepared in Examples 4-7 have sizes and dimensions in the nanometer range, wherein the length of the nanoneedle crystals is 50 nm-5000 nm and the width is 100 nm-2000 nm. In the preparation of the nanocrystals, the concentration of the solute drug in the solvent is 25 mg / mL-1000 mg / mL; the volume ratio of the solvent (ethyl acetate, acetonitrile) to the anti-solvent (n-heptane, n-hexane) is 1:4-1:100.

[0168] The urchin-like crystals of sirolimus and everolimus prepared in Examples 8-10 have sizes and dimensions in the micrometer range, wherein the diameter of the urchin-like crystals is 5 μm-50 μm, and there are tens to hundreds of whiskers of different angles around the urchin-like crystals, the length of the whiskers is 1 μm-25 μm, and the width is 0.5 μm-2 μm. In the preparation of the urchin-like crystals, the concentration of the solute drug in the solvent is 25 mg / mL-500 mg / mL; the volume ratio of the solvent (acetonitrile, isopropanol, dichloromethane, etc.) to the anti-solvent (n-heptane, polyvinyl alcohol) is 1:4-1:100.

[0169] To describe the performance of the drug coating of the present application including active drugs in the form of crystal particles, the specification lists Comparative Example 1 and Comparative Example 2 of amorphous nanospheres of sirolimus and everolimus respectively, wherein the diameters of the amorphous nanospheres are 200 nm-2000 nm. The morphology of the nanospheres of sirolimus of Comparative Example 1 is shown in Figure 12 The XRD characterization spectrum shown in Figure 13 confirms that it is amorphous nanospheres of sirolimus, i.e. non-crystal. Similarly, the nanospheres of everolimus of Comparative Example 2 are shown in Figure 14 The XRD characterization spectrum shown in Figure 15 confirms that it is amorphous everolimus.

[0170] As shown in Figure 16 and Figure 17 , the present application also provides a drug balloon catheter, which includes a balloon part and a catheter part connected together, the balloon part includes an expandable bare balloon 1 and a drug coating 2 disposed on the outer surface of the bare balloon. The drug coating 2 includes active drugs 21 in the form of crystals and an adhesive coating 22. As shown in Figures 18 to 21 , the active drugs 21 include urchin-like crystals 211, block-like crystals 212 and needle-like crystals 213. When the bare balloon 1 expands, the drug coating 2 adheres to the blood vessel wall, thereby realizing the transfer and release of the active drugs 21 to the blood vessel wall 3. In other embodiments, the drug carrier can also be other medical devices, such as a vascular stent, etc.

[0171] The method for preparing the drug balloon catheter comprises the following steps:

[0172] The drug quality required by the corresponding balloon model is calculated according to the outer surface area of the balloon body and the theoretical drug loading density of the active drug, the drug coating solution volume is obtained by dividing the drug quality by the determined drug concentration, the corresponding volume of the drug coating solution is taken by the micro-sampler, and is uniformly coated on one wing of the surface of the folded balloon, and is dried under natural conditions for 1-3 hours; then the balloon is rotated, the corresponding volume of the drug coating solution is taken by the micro-sampler again, and is uniformly coated on one wing of the surface of the bare balloon 1, and is dried under natural conditions for 1-3 hours. The balloon is rotated again, and the remaining one wing of the balloon surface is uniformly coated with the fixed volume of the drug coating solution, and is dried under natural conditions for 6-24 hours. The dried balloon is sequentially subjected to pressing, heat setting, vacuum drying, packaging, sterilization and the like, and the drug coating balloon is obtained.

[0173] Preferably, in one embodiment, 3 μg / mm 2 of the theoretical drug loading density is selected, and the drug balloon is prepared by using the active drug to form a drug coating solution with a concentration of 5 mg / mL and a mass ratio of the active drug 21 to the adhesive coating 22 of 1:4. As in Example Seven, the nanoneedle crystal of sirolimus is prepared to form a coating drug solution containing 5 mg / mL of the drug crystal and 20 mg / mL of PEO. The corresponding volume of the drug coating solution is taken by the micro-sampling sampler, and is uniformly coated on one wing of the surface of the folded balloon, and is dried under natural conditions for 1.5-2.5 hours; the balloon is rotated, the corresponding volume of the uniformly mixed drug coating solution is taken by the micro-sampling sampler again, and is uniformly coated on the other wing of the balloon surface, and is dried under natural conditions for 1.5-2.5 hours; the balloon is rotated again, and the remaining one wing of the balloon surface is uniformly coated with the fixed volume of the drug coating solution, and is dried under natural conditions for 14-18 hours. According to the mass of the drug coating and the surface area of the balloon (theoretical drug loading density), the average coating thickness of the obtained drug balloon surface is calculated to be about 12-15 μm according to the density of PEO (1.15-1.26 g / cm 3 3 3

[0174] Preferably, in another embodiment, 3 μg / mm 2 ​​​Theoretical drug loading density, the active pharmaceutical ingredient concentration of 10 mg / mL, the active pharmaceutical ingredient and the adhesive mass ratio of 1:1 of the drug coating solution for the preparation of the drug balloon catheter. As the example seven of the rapamycin nanoneedle crystal, the preparation of 10 mg / mL of the drug crystals and 10 mg / mL of PEO coating solution. The corresponding volume of the drug coating solution is taken by the micro-syringe, which is uniformly coated on one wing of the folded balloon surface, and dried for 1.5-2.5 hours under natural conditions; the balloon is rotated, and the corresponding volume of the mixed drug coating solution is selected by the micro-syringe, which is uniformly coated on the other wing of the balloon surface, and dried for 1.5-2.5 hours under natural conditions; the balloon is rotated again, and the corresponding volume of the mixed drug coating solution is uniformly coated on the other wing of the balloon surface, and dried for 14-18 hours under natural conditions. Finally, the dried balloon is pressed, heat-set, vacuum dried, packaged, sterilized, and the like, to obtain the drug balloon. According to the mass of the drug coating and the surface area of the balloon (theoretical drug loading density), the average coating thickness of the obtained drug balloon surface is about 5-7 μm, according to the density of PEO (1.15 g / cm 3 -1.26 g / cm 3 ) and the density of rapamycin (1.18 g / cm 3 ).

[0175] To determine the stability of the drug balloon, the preparation method of comparative example two, example three, six and ten is used to obtain different crystal forms of rapamycin (BA9) solute drugs, and the drug content and impurities of the four active drugs with different crystal forms are tested after being placed at room temperature for 1 year. See Table 1 for details. Table 1 shows the stability test results of rapamycin raw drug and various forms of rapamycin at 25°C for 1 year. The test results are as follows:

[0176] Table 1

[0177]

[0178] According to the above Table 1, it can be obtained that the drug composition of each crystal form of rapamycin obtained after the crystallization process of the rapamycin raw drug does not change much during the stability investigation period, and no obvious impurities are generated; the amorphous nanosphere rapamycin and the raw drug rapamycin appear a large amount of decrease in the main component under the room temperature condition for one year, accompanied by the generation of impurities with RRT=1.34 and the generation of other unknown impurities. It is shown that the stability of the active drug composition of the three forms of micrometer needle-shaped crystal, nanometer needle-shaped crystal and micrometer urchin-shaped crystal obtained by recrystallizing the rapamycin raw drug is obviously improved.

[0179] Further, the in vitro drug transfer efficiency of the drug balloon catheter was evaluated. The drug balloon catheter coated with the drug coating solution of the active drug prepared in the above examples was evaluated for in vitro delivery loss and drug transfer. The drug coating on the bare balloon surface was selected to have a theoretical drug loading density of 3 μg / mm 2 The drug balloon catheter was prepared using a drug coating solution having an active drug concentration of 5 mg / ml and a mass ratio of active drug to adhesive of 1:1. The in vitro delivery loss and drug transfer were evaluated under a simulated in vivo physiological environment.

[0180] In vitro release evaluation method: a blood vessel model as shown in Figure 22 was selected as the path for balloon delivery, and the entire blood vessel model was immersed in purified water or physiological saline at 37°C, and a middle catheter and guide wire were placed therein, and the catheter was filled with purified water or physiological saline at 37°C. After the test environment was stabilized, the drug balloon catheter was subjected to negative pressure, passed through the guide wire via the middle catheter, and passed through the blood vessel model, and the balloon body was placed in a silicone tube (3 mm in inner diameter) having a diameter consistent with the designated balloon diameter, and was pressed to a designated pressure of 6 atm, and was maintained at the pressure for 1 min, and after the pressure was removed, the balloon was removed, and the silicone tube was immediately removed. Then, the silicone tube was placed in an appropriate volume of acetonitrile, and was allowed to stand for 5-10 min, and the drug content in the silicone tube was measured, and the in vitro release degree of the drug balloon in the in vitro model was obtained (drug content in the silicone tube / theoretical drug loading amount*100%). Table 2 shows the in vitro evaluation results of the balloon coated with different forms of everolimus (BA9) according to the above method.

[0181] Table 2

[0182]

[0183] According to Table 2, it can be seen that:

[0184] (1) Under the same coating and test conditions, the delivery loss rate of the nanoscale BA9 was higher than that of the microscale active drug component, and the drug loss rate of the drug in the form of a crystal on the balloon was significantly lower than that of the drug balloon in the form of an amorphous substance.

[0185] (2) The drug release degree of the drug balloon on the silicone tube wall showed that the urchin-shaped crystal having a three-dimensional configuration was more easily transferred to the silicone tube.

[0186] Further, the in vitro drug transfer efficiency of the drug balloon catheter was evaluated. The drug balloon catheter coated with the drug coating solution of the active drug prepared in the above examples was evaluated for in vitro delivery loss and drug transfer. The drug coating on the bare balloon surface was selected to have a theoretical drug loading density of 3 μg / mm 2Based on the theoretical drug loading density, a drug coating solution with a BA9 concentration of 5 mg / ml and a mass ratio of active drug to adhesive of 1:1 was selected for the preparation of drug-coated balloon catheters.

[0187] In this experiment, Labrador Retrievers were selected as animal subjects for intracranial vascular experiments. The basilar artery and vertebral artery were chosen as target vessels. Five Labrador Retrievers, approximately 6 months old, were used as subjects. Four dogs underwent in vivo drug release via four different types of BA9 drug-coated balloon catheters, while the remaining dog served as a blank control. During the experiment, each dog was subjected to general anesthesia, blood samples were collected, vascular access was established, vital signs were monitored, and angiography was performed. Then, drug-coated balloons were placed sequentially in the basilar artery and the left and right vertebral arteries. An appropriate drug-coated balloon size was selected with an expansion ratio of 1.2, and the target vessels were dilated for 60 seconds. After dilation, the balloons were withdrawn, and the remaining drug content in the balloons was measured.

[0188] One hour post-surgery, five experimental dogs were euthanized according to protocol, and the corresponding blood vessels were removed for bioanalytical analysis. Specifically, vascular resistance values ​​were processed and analyzed to determine the drug content at the target vessel site. Table 3 shows the efficacy evaluation results of different forms of BA9 drug balloons in dogs. Table 4 shows the drug transfer rate of different forms of BA9 drug balloons in dogs.

[0189] Table 3

[0190]

[0191] Table 4

[0192]

[0193] Drug content testing revealed the following levels of residual bacitralimus (BA9) in the balloon and the BA9 levels on the walls of various arteries in the dogs, as shown in Tables 3 and 4. The results showed that the balloon containing micron-sized sea urchin-like crystals exhibited the highest drug absorption levels in the basilar and vertebral arteries of the dogs, with an average intravascular drug content of 2417 ng / mg. The balloon containing micron-sized needle-like crystals showed an absorption level one order of magnitude lower in the basilar and vertebral arteries, with an average intravascular drug content of 157 ng / mg. The balloon containing nano-needle-like crystals showed a lower absorption level than the micron-sized needle-like crystals in the basilar and vertebral arteries, with an average intravascular drug content of 62 ng / mg. The balloon containing nano-amorphous microspheres showed the lowest absorption level in the basilar and vertebral arteries, with an average intravascular drug content of 16 ng / mg. The drug transfer rate of the balloon followed the same trend as the average drug content, from high to low: micron-sized sea urchin-like crystals, micron-sized needle-like crystals, nano-needle-like crystals, and nano-amorphous microspheres.

[0194] Preferably, the minipig is again selected as the animal experimental object of the coronary blood vessel, and three coronary blood vessels (anterior descending branch, circumflex branch, and right coronary artery) of the minipig are selected as the target blood vessels. Five 6-month-old minipigs are selected, and four of them are subjected to in-vivo drug release of the four forms of sirolimus (RAP) drug-coated balloon catheters, and the remaining one is used as a blank control. According to the conventional experimental procedure, each minipig is subjected to general anesthesia, blood sample collection, blood vessel access construction, monitoring of the pig's physical signs, angiography, and the like in turn, and the drug-coated balloon is placed in the anterior descending branch, circumflex branch, and right coronary artery in turn, and the appropriate drug balloon size is selected according to a dilatation ratio of 1.2, and the target blood vessel site is dilated for 60 seconds. After dilatation, the balloon is withdrawn, and the remaining drug content of the balloon is measured.

[0195] After 1 hour of post-operation, the five minipigs are euthanized according to the procedure, and the corresponding blood vessels are removed for biological analysis and detection, and the blood vessel tissue is processed and analyzed to obtain the drug content of the target blood vessel site.

[0196] Table 5

[0197]

[0198] Table 6

[0199]

[0200] According to the drug content test, the remaining sirolimus (RAP) of the balloon and the sirolimus drug content on the walls of the coronary arteries in the minipigs are shown in Tables 5 and 6. The results show that the drug absorption level of the drug balloon containing micron urchin-shaped crystals in the coronary arteries of the minipigs is the highest, and the average drug content in the blood vessels is 2766 ng / mg; the drug absorption level of the drug balloon containing micron needle-shaped crystals in the coronary arteries of the minipigs is the second, and the average drug content in the blood vessels is 1512 g / mg; the drug absorption level of the drug balloon containing nanometer needle-shaped crystals in the coronary arteries of the minipigs is lower than that of the micron needle-shaped crystals, and the average drug content in the blood vessels is 245 ng / mg; the drug absorption level of the drug balloon containing nanometer amorphous microspheres in the coronary arteries of the minipigs is the lowest, and the average drug content in the blood vessels is 36 ng / mg. The drug transfer rate of the balloon is consistent with the trend of the average drug content, and from high to low, it is micron urchin-shaped crystals, micron needle-shaped crystals, nanometer needle-shaped crystals, and nanometer amorphous microspheres, which is consistent with the results of the basilar artery and vertebral artery of the dog.

[0201] According to the results of the in-vivo experiments on dogs and small pigs, the drugs are made into micron urchin-shaped crystals and micron needle-shaped crystals, which are beneficial to the transfer of the drugs from the coating on the balloon surface to the blood vessel wall. The animal experiment results show that the drug transfer rate of the same drug-coated balloon on the coronary artery of a small pig is obviously higher than that on the intracranial / vertebral artery of a dog; the drug residue rate of the balloon after the expansion of the coronary artery of a small pig is obviously higher than that after the expansion of the intracranial / vertebral artery of a dog. This may be related to the length and tortuosity of the passageway. Different active drug compositions can cause greater differences in the drug content on the target blood vessel wall, which may be related to the physical structure of the active drug, as shown in Figure 23 、 Figure 24 and Figure 25 When the bare balloon 1 is under the same expansion pressure, the active drugs 21 of different structures are directly contacted with the blood vessel wall 3 (as shown in Figures 18 to 22 and Figures 23 to 25 ) after being affected by the expansion pressure, and the size of the contact point or surface is significantly different, which causes the micron urchin-shaped crystals and micron needle-shaped crystals to have greater force on the blood vessel wall, thereby having better physical puncture effect. The drugs enter the blood vessel wall through physical puncture, thereby entering the blood vessel and continuously releasing drug molecules in the blood vessel tissue, so as to achieve the effect of inhibiting intimal hyperplasia and preventing restenosis for a longer time.

[0202] The drug-coated balloon catheter provided by the application has the following advantages:

[0203] (1) The active drug in the drug coating exists in the form of crystals, and the active drug has high structural stability;

[0204] (2) The active drug is transferred, stored, dissolved and absorbed in the form of crystals, and is less affected by the flushing of the blood flow, so that the loss rate of the active drug delivery is low, the transfer efficiency is high, and the release efficiency is high;

[0205] (3) The needle-shaped or urchin-shaped drug crystals provided by the application are transferred to the inside of the blood vessel through physical puncture or adsorption, the drug is stored in the form of crystals in the blood vessel, and then the drug crystals are gradually dissolved and released and are absorbed by the surrounding tissue cells, so as to achieve the long-term stable release and sustained efficacy of the drug. The crystal form can improve the stability of the drug and increase the physical force of the drug on the blood vessel wall during the balloon expansion process, thereby increasing the drug transfer rate;

[0206] (4) The micron urchin-shaped drug crystals provided by the application can improve the drug transfer rate and also provide radial support force through the gaps between the whiskers, thereby greatly reducing the risk of proximal and distal vessel occlusion;

[0207] (5) The micron-sized urchin-like crystals, micron-sized needle-like crystals, nanometer needle-like crystals and nanometer amorphous microspheres provided by the application can have sizes adjusted by changing the amount of solvent, and the preparation process is simple.

[0208] The above is a further detailed description of the application in combination with specific preferred embodiments, and the specific implementation of the application should not be limited to these descriptions. For ordinary skilled persons in the art to which the application belongs, several simple deductions or substitutions can be made without departing from the concept of the application, and all of them should be considered as falling within the protection scope of the application.

Claims

1. A drug coating, characterized in that, The active drug is a sea urchin-like crystal, which is a crystal cluster formed by agglomeration of needle-like and / or flake-like crystals, and is spherical-like with multiple outward protruding whiskers under a scanning electron microscope. The sea urchin-like crystal has a size of 5 μm to 50 μm in any dimension, and includes multiple radially outward extending whiskers, the length of the whiskers being 1 μm to 25 μm, and the width of the whiskers being 0.2 μm to 2 μm. The active drug is sirolimus or a sirolimus derivative.

2. The drug coating of claim 1, wherein, The adhesive includes one or more of polyoxyethylene, carbomer, sucrose, sodium carboxymethyl cellulose, starch, hydroxyethyl methyl cellulose, trehalose, pectin, and shellac.

3. The drug coating of claim 1, wherein, The mass ratio of the active drug to the adhesive is 1:4 to 4:

1.

4. The drug coating of claim 1, wherein, The thickness of the drug coating is 5 μm to 15 μm.

5. A method of preparing a drug coating, characterized by, The method for preparing the drug coating as claimed in any one of claims 1 to 4 comprises the following steps: providing a solute drug, dissolving the solute drug in a solvent to obtain a first solution; adding an anti-solvent to the first solution, and stirring to obtain a second solution; centrifuging the second solution to obtain a solid precipitate; drying the solid precipitate at room temperature and in a vacuum environment to obtain the active drug; providing an adhesive, dissolving the adhesive in water, and stirring to obtain a third solution; dispersing the active drug in the third solution to obtain a drug coating mixture; applying the drug coating mixture to the surface of a drug carrier; and drying to obtain the drug coating.

6. The method of claim 5, wherein the drug coating is prepared by, The sirolimus derivative is everolimus.

7. The method of claim 6, wherein the drug coating is prepared by, The mass concentration of the adhesive in the third solution is 0.1% to 5%.

8. The method of claim 6, wherein the drug coating is prepared by, The adhesive includes one or more of polyoxyethylene, carbomer, sucrose, sodium carboxymethyl cellulose, starch, hydroxyethyl methyl cellulose, trehalose, pectin, and shellac. The solvent is one or more of dichloromethane, acetonitrile, and isopropanol. The anti-solvent includes one or more of n-heptane, polyvinyl alcohol, and n-hexane.

9. The method of claim 6, wherein the drug coating is prepared by, The concentration of the solute drug in the solvent ranges from 25 mg / mL to 1000 mg / mL, and / or The volume ratio of the solvent to the anti-solvent is 1:100 to 1:

4.

10. The method for preparing the drug coating of claim 6, wherein the solute drug is sirolimus, the solvent is dichloromethane, the anti-solvent is n-heptane, and the solid precipitate is a sea urchin-like crystal, wherein the ratio of the solvent to the anti-solvent is 1:20, and the concentration of the solute drug in the solvent is 200 mg / mL; or the solute drug is sirolimus, the solvent is a mixed solvent of acetonitrile and isopropanol, the anti-solvent is polyvinyl alcohol, and the solid precipitate is a sea urchin-like crystal, wherein the ratio of the solvent to the anti-solvent is 1:7, and the concentration of the solute drug in the solvent is 67 mg / mL; or the solute drug is sirolimus, the solvent is dichloromethane, the anti-solvent is n-heptane, and the solid precipitate is a sea urchin-like crystal, wherein the ratio of the solvent to the anti-solvent is 1:20, and the concentration of the solute drug in the solvent is 200 mg / mL; or the solute drug is sirolimus, the solvent is a mixed solvent of acetonitrile and isopropanol, the anti-solvent is polyvinyl alcohol, and the solid precipitate is a sea urchin-like crystal, wherein the ratio of the solvent to the anti-solvent is 1:7, and the concentration of the solute drug in the solvent is 67 mg / mL. The solute drug is everolimus, the solvent is a mixed solvent of acetonitrile and isopropyl alcohol, and the anti-solvent is polyvinyl alcohol; the solid precipitate is urchin-shaped crystals; wherein the ratio of the solvent to the anti-solvent is 1:7, and the concentration of the solute drug in the solvent is 67 mg / mL.

11. A drug balloon catheter, characterized by A balloon catheter comprising a balloon portion and a catheter portion connected together, the balloon portion comprising an expandable bare balloon and a drug coating as claimed in any one of claims 1 to 4 disposed on the outer surface of the bare balloon.

12. The drug balloon catheter of claim 11, wherein, The drug loading density of the bare balloon is 3 μg / mm 2 .

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