Drug coating for expandable balloon catheter and method for preparing same

Abstract

The present invention belongs to the field of medicine, specifically relates to a drug coating for an expandable balloon catheter and its preparation method. The present invention selects two kinds of amphiphilic additives, phospholipid and PEG, in which the phospholipid in the outer layer prevents the coating layer from being washed away by blood during balloon delivery, and realizes drug retention at the target position due to its affinity with cell membrane, and improves biocompatibility; the hydrophilic excipient PEG makes the surface of the drug coating and the surface of the balloon in an easily peelable state, and the surface of the drug coating can be peeled off from the surface of the balloon, achieving a balance between adhesion and peeling; the present invention also creatively adds a specific molecular weight mPEG-PLGA block copolymer to realize controlled drug release, and obtains a drug coating with adjustable drug release rate by adjusting the molecular weight of mPEG, thus expanding the application scope of the drug coating.

Description

[Technical Field]

[0001] The present invention belongs to the field of pharmaceuticals, in particular to the field of composite materials for coated catheters under IPC classification number A61L29 / 12, specifically to drug coatings for expandable balloon catheters and methods for preparing same. [Background technology]

[0002] Expandable balloons are a novel interventional therapy device that delivers a drug-coated surface to the target location. After reaching the "destination," the balloon inflates and expands, adhering the drug coating to the endothelial membrane of the blood vessel for effective local drug release. Currently, expandable balloons coated with drug coatings are considered one of the leading treatment options for "interventions without implants," and have become a "competitive field" with great market potential in the medical device industry.

[0003] One example of a commercially available drug-coated balloon is the Sequent Please developed by Braun. It uses Taxol as the active drug and iopromide as the carrier, sprayed onto the balloon surface after preparation. Other examples include the Admiral Xtreme drug balloon and the Lutonix 035 drug balloon. Most of these use Taxol as the active drug and use different carrier technologies to prepare the drug coating. However, traditional drug balloons have low utilization rates. During delivery, blood washout causes the drug coating to detach from the balloon surface, resulting in the loss of most of the drug before it reaches the target location. During the expansion phase, some drug remains on the balloon surface and does not adhere to the vessel wall, preventing its release. Furthermore, interventional therapy inflicts certain damage on the human body, making multiple treatments in close intervals impossible. The effectiveness of a single treatment is limited, resulting in higher requirements for controlled drug release.

[0004] Prior art CN 110292701B discloses a drug-eluting balloon catheter, which has an inner layer made of a mixture of phospholipid-encapsulated drugs and a hydrophilic excipient I, and an outer layer sprayed with a hydrophobic excipient II to form a drug coating, thereby improving drug availability and achieving rapid drug release. However, after the phospholipid-encapsulated drug particles come into contact with the vascular wall, the phospholipids tend to fuse with the cell membrane, resulting in burst release and failing to achieve a long-term sustained release effect. Summary of the Invention

[0005] In response to the deficiencies of the prior art, it is an object of the present invention to provide a drug coating for an expandable balloon catheter that has high drug availability, is easy to prepare, and provides controlled drug release.

[0006] Meanwhile, an object of the present invention is to further provide a method for preparing the drug coating for the expandable balloon catheter, which requires mild conditions and is a simple process.

[0007] To achieve the above object of the invention, the present invention uses the following technical solutions:

[0008] A drug coating for an expandable balloon catheter, the preparation of which comprises, by weight, 20-80 parts by weight of a drug, 10-70 parts by weight of a phospholipid, 5-60 parts by weight of an excipient, and 5-60 parts by weight of a copolymerized excipient.

[0009] Preferably, the drug is selected from one or more of rapamycin, rapamycin derivatives, taxol, heparin and hirudin.

[0010] Preferably, the phospholipid is selected from soy lecithin or lecithin.

[0011] Preferably, the excipient is one or more of PEG (polyethylene glycol), hyaluronic acid, chitosan, iopromide, shellac, tannic acid, polylactide, and PLGA (poly(lactic-co-glycolic acid)).

[0012] More preferably, the number average molecular weight of the PEG is 8,000 to 30,000.

[0013] The present invention selects an amphiphilic additive, and the phospholipid in the outer layer plays a protective role in the blood, preventing the coating layer from being washed away by the blood during balloon delivery. Since the structure of phospholipids is similar to that of cell membranes, when the balloon is expanded, the carding layer adheres to the blood vessel wall, and due to its affinity with the phospholipid cell membrane, it ensures drug retention at the target location and improves biocompatibility. In this case, the hydrophilic excipient PEG absorbs water in the blood vessel, making the surface of the drug coating and the surface of the balloon easily peelable, allowing the surface of the drug coating to peel off from the surface of the balloon, achieving a balance between adhesion and peeling.

[0014] Preferably, the copolymeric excipient is selected from one or more of mPEG-PLGA block copolymers, PEG-PLGA block copolymers, and PEG-hyaluronic acid copolymers.

[0015] Preferably, the number average molecular weight of mPEG (methoxypolyethylene glycol) in the mPEG-PLGA block copolymer is 200 to 8000, and the number average molecular weight of PLGA is 5000 to 60000, and more preferably, the number average molecular weight of mPEG in the mPEG-PLGA block copolymer is 550 to 5000.

[0016] Specifically, the present invention uses a block copolymer composed of mPEG with a number-average molecular weight of 200-8,000, preferably 550-5,000, and PLGA with a number-average molecular weight of 5,000-60,000, as the copolymer excipient. This copolymer forms a coating on the surface of drug droplets, achieving controlled drug release as the drug decomposes at the target site. The inventors unexpectedly found that the lower the molecular weight of mPEG, the slower the drug release rate; the higher the molecular weight of mPEG, the faster the drug release rate. When the molecular weight of mPEG reaches 8,000, there is a significant burst release. Based on this creative discovery, the drug coding of the present invention can adjust the molecular weight of mPEG in the copolymer excipient mPEG-PLGA block copolymer according to actual application needs and drug properties, thereby achieving drug release rate adjustment and improving the universality of drug coding.

[0017] Preferably, the molar ratio of mPEG to PLGA in the mPEG-PLGA block copolymer is 0.1 to 5:1, more preferably 1:1.

[0018] Preferably, the mass ratio of the phospholipid to the excipient is 1 to 5:1.

[0019] Meanwhile, the present invention provides a method for preparing a drug coating for the expandable balloon catheter, the method comprising: The method includes the steps of: measuring the drug, phospholipid, excipient and copolymer excipient by weight, dissolving them in an organic solvent, mixing them uniformly, and using ultrasound to obtain a drug micelle microsphere solution; and spraying the drug micelle microsphere solution onto the surface of the balloon of an expandable balloon catheter using ultrasound to obtain a drug coating.

[0020] Preferably, the organic solvent comprises one or more of ethanol, isopropanol, acetone, methylene chloride, chloroform, ethyl acetate, acetonitrile, butyl acetate, ether, and carbon tetrachloride.

[0021] Preferably, in the preparation method, the organic solvent is used in an amount of 15,000 to 25,000 parts by weight.

[0022] Preferably, the drug coating has a thickness of 1 to 10 microns.

[0023] Preferably, the drug micelle microspheres have a particle size of 10 microns or less.

[0024] Compared with the prior art, the present invention has the following beneficial effects:

[0025] 1. In the drug coating of the present invention, the phospholipid in the outer layer prevents the coating layer from being washed away by blood during balloon delivery, and its affinity with cell membranes allows the drug to remain at the target location, improving biocompatibility.

[0026] 2. PEG, a hydrophilic excipient of the present invention, absorbs water in the blood vessel, making the surface of the drug coating and the surface of the balloon easily peelable, allowing the surface of the drug coating to be peeled off from the surface of the balloon, and further improving the availability of the drug.

[0027] 3. The drug coating of the present invention further comprises an mPEG-PLGA block copolymer of a specific molecular weight, and the molecular weight of the mPEG creatively influences the drug release rate, thereby achieving controlled and long-term sustained release of the drug. [Brief explanation of the drawings]

[0028] [Figure 1] FIG. 1 is an SEM image of drug coding according to Example 1. [Figure 2] FIG. 1 shows the change in drug release rate over time for drug coatings prepared with mPEG-PLGA block copolymers having mPEG molecular weights of 550 (Example 1), 5000 (Example 2), and 8000 (Example 3). [Figure 3]FIG. 1 shows the change in drug release rate over time for drug coatings prepared with mPEG-PLGA block copolymers having mPEG molecular weights of 10,000 (Comparative Example 1) and 20,000 (Comparative Example 2). DETAILED DESCRIPTION OF THE INVENTION

[0029] Example 1 This example provides a drug coating for an expandable balloon catheter, the preparation of which includes, by weight, 40 parts by weight of rapamycin, 60 parts by weight of soy lecithin, 40 parts by weight of an excipient, 60 parts by weight of a copolymerizable excipient, and 20,000 parts by weight of an organic solvent.

[0030] The excipient is PEG, whose number average molecular weight is 10000, and is purchased from Guangzhou Xilong Fine Chemical Technology Co., Ltd.

[0031] The copolymer excipient is an mPEG-PLGA block copolymer, in which the number-average molecular weight of mPEG is 550, the number-average molecular weight of PLGA is 60,000, and the molar ratio of mPEG to PLGA is 1:1. The mPEG-PLGA block copolymer is purchased from Eichuan Special Chemical (Shanghai) Co., Ltd.

[0032] The organic solvent is acetone.

[0033] The present invention also provides a method for preparing the drug coating for an expandable balloon catheter, in which rapamycin, soybean lecithin, PEG, and mPEG-PLGA block copolymer are weighed out in the above weight parts, dissolved in acetone, and mixed uniformly. The mixture is then treated with 54 kHz ultrasound for 30 minutes to obtain a drug micelle microsphere solution. The drug micelle microsphere solution is then sprayed onto the surface of the balloon of an expandable balloon catheter using ultrasound, and dried at 40°C for 60 minutes to obtain a drug coating with a thickness of 10 microns.

[0034] The average particle size of the drug micelle microspheres in the drug coating obtained in this example was 8 microns, and the drug content of the coating was 7 μg / mm 2 and the scanning electron micrograph is shown in FIG. Example 2

[0035] This example further provides a drug coating for an expandable balloon catheter and a preparation method thereof, which is the same as that in Example 1, with the following differences: the copolymerization excipient is mPEG-PLGA block copolymer, where the number-average molecular weight of mPEG is 5000, the number-average molecular weight of PLGA is 60000, the molar ratio of mPEG to PLGA is 1:1, and the mPEG-PLGA block copolymer is purchased from Eichuan Special Chemical (Shanghai) Co., Ltd.

[0036] The average particle size of the drug micelle microspheres in the drug coating obtained in this example was 10 microns, and the drug content of the coating layer was 6 μg / mm 2 is. Example 3

[0037] This example further provides a drug coating for an expandable balloon catheter and a preparation method thereof, which is the same as that in Example 1, with the following differences: the copolymerization excipient is mPEG-PLGA block copolymer, where the number-average molecular weight of mPEG is 8000, the number-average molecular weight of PLGA is 60000, the molar ratio of mPEG to PLGA is 1:1, and the mPEG-PLGA block copolymer is purchased from Eichuan Special Chemical (Shanghai) Co., Ltd.

[0038] The average particle size of the drug micelle microspheres in the drug coating obtained in this example was 5 microns, and the drug content of the coating was 8 μg / mm 2 is. (Comparative Example 1)

[0039] This comparative example further provides a drug coating for an expandable balloon catheter and a preparation method thereof, which is the same as that of Example 1, with the following differences: the copolymerization excipient is an mPEG-PLGA block copolymer, where the number-average molecular weight of mPEG is 10,000, the number-average molecular weight of PLGA is 60,000, the molar ratio of mPEG to PLGA is 1:1, and the mPEG-PLGA block copolymer is purchased from Jinan Jufukai Biotechnology Co., Ltd.

[0040] The average particle size of the drug micelle microspheres in the drug coating obtained in this comparative example was 4 microns, and the drug content of the coating was 8 μg / mm 2 is. (Comparative Example 2)

[0041] This comparative example further provides a drug coating for an expandable balloon catheter and a preparation method thereof, which is the same as that of Example 1, with the following differences: the copolymerization excipient is an mPEG-PLGA block copolymer, where the number-average molecular weight of mPEG is 20,000, the number-average molecular weight of PLGA is 60,000, the molar ratio of mPEG to PLGA is 1:1, and the mPEG-PLGA block copolymer is purchased from Jinan Jufukai Biotechnology Co., Ltd.

[0042] The average particle size of the drug micelle microspheres in the drug coating obtained in this comparative example was 4 microns, and the drug content of the coating was 8 μg / mm 2 is.

[0043] Performance Test

[0044] In the drug release test, the sustained release effect of drug coatings prepared with mPEG-PLGA of different molecular weights was verified by animal experiments to detect the drug release rate of the coating in each example. This experiment used a miniature pig animal model, and drug coatings from Examples 1-3 and Comparative Examples 1-2 were used in the miniature pig's body, respectively, with the following timings set: 0 (immediate), 1 day, 7 days, 14 days, 30 days, 60 days, and 90 days. The pig vascular model was then removed and drug testing was performed on the blood vessels.

[0045] The experimental subjects were miniature pig models weighing approximately 25 to 45 kg.

[0046] The experimental product contained 1 to 10 μg / mm 2 1 shows drug coatings prepared using mPEG-PLGA with different molecular weights in Examples 1 to 3 and Comparative Examples 1 and 2.

[0047] The experimental method is as follows.

[0048] (1) Seven pig animal models were selected for each group, corresponding to the timings of 0 (immediately), 1 day, 7 days, 14 days, 30 days, 60 days, and 90 days. The balloons of the expandable balloon catheters sprayed with drug coatings in Examples 1 to 3 and Comparative Examples 1 and 2 were implanted into the cardiovascular RCA, LCX, and LAD of the pig animal models in each group.

[0049] (2) At the timing of 0 (immediately), 1 day, 7 days, 14 days, 30 days, 60 days, and 90 days, the pigs are killed, and the blood vessels are removed to measure the drug content.

[0050] The experimental results are as follows: Based on the obtained drug content, a drug release curve (see Figures 2 and 3) was drawn, and the drug release rate on the vertical axis is the ratio of the drug content in the vascular wall to the drug content on the surface of the balloon before implantation.

Claims

1. 1. A drug coating for an expandable balloon catheter, comprising a preparation material comprising, by weight, 20 to 80 parts by weight of a drug, 10 to 70 parts by weight of a phospholipid, 5 to 60 parts by weight of an excipient, and 5 to 60 parts by weight of a copolymerized excipient, wherein the excipient is PEG, and the copolymerized excipient is an mPEG-PLGA block copolymer, the PEG having a number average molecular weight of 8,000 to 30,000, and in the mPEG-PLGA block copolymer, the mPEG has a number average molecular weight of 200 to 8,000, and the PLGA has a number average molecular weight of 5,000 to 60,000.

2. 2. The drug coating for an expandable balloon catheter according to claim 1, wherein the drug is selected from one or more of rapamycin, rapamycin derivatives, taxol, heparin, and hirudin.

3. 2. The drug coating for an expandable balloon catheter according to claim 1, wherein the phospholipid is selected from soy lecithin or lecithin.

4. The drug coating for an expandable balloon catheter according to claim 1, wherein the mass ratio of the phospholipid to the excipient is 1-5:

1.

5. 5. The method for preparing a drug coating for an expandable balloon catheter according to claim 1, further comprising the steps of: weighing the drug, phospholipid, excipient, and copolymerized excipient by weight, dissolving them in an organic solvent, mixing them uniformly, and using ultrasound to obtain a drug micelle microsphere solution; and spraying the drug micelle microsphere solution onto the surface of the balloon of the expandable balloon catheter using ultrasound to obtain a drug coating, wherein the excipient is PEG, the copolymerized excipient is mPEG-PLGA block copolymer, and the number average molecular weight of the PEG is 8,000-30,000. In the mPEG-PLGA block copolymer, the number average molecular weight of the mPEG is 200-8,000, and the number average molecular weight of the PLGA is 5,000-60,000.

6. 6. The method for preparing a drug coating for an expandable balloon catheter according to claim 5, wherein the thickness of the drug coating is 1-10 microns.

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