Drug coating for expandable balloon catheters and method for preparing same - Patents.com

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 medicine, in particular to the field of composite materials for coated catheters under IPC classification number A61L29 / 12, specifically to a drug coating for expandable balloon catheters and its preparation method. [Background technology]

[0002] Expandable balloons are a novel interventional therapy device that delivers drug-coated drugs to the target location by inflating the balloon after reaching the "destination", allowing the drug-coated drugs to adhere to the endothelium of the blood vessel, thus achieving effective local drug release. Currently, expandable balloons coated with drug coating are considered one of the representative treatment options for "intervention without implantation", which has become a "competitive field" with great market potential in the medical device industry.

[0003] At present, one example of a commercially available drug balloon is Sequent please developed by Braun, which uses taxol as the active drug and iopromide as the carrier, which is obtained by spraying it on the surface of the balloon after preparation. There are also Admiral Xtreme drug balloon, Lutonix035 drug balloon, etc., most of them use taxol as the active drug and use different carrier technology to prepare the drug coating. However, the utilization rate of traditional drug balloons is low, on the one hand, during delivery, the blood washout leads to the drug coating being separated from the surface of the balloon, and most of the drug is lost before being delivered to the target location, on the other hand, during the expansion stage, some of the drug still remains on the surface of the balloon, does not adhere to the vascular wall, and does not release. In addition, because interventional therapy brings certain damage to the human body, multiple treatments cannot be performed at short intervals, and the effect of one treatment is limited, and there is a large but limited nature, which means there are higher requirements for the controlled release of drug coding.

[0004] The prior art CN 110292701B discloses a drug-eluting balloon catheter, which is made by mixing phospholipid-encapsulated drugs and hydrophilic excipient I in the inner layer and spraying hydrophobic excipient II on the outer layer to form a drug coating, thereby improving the availability of drugs and realizing rapid drug release. However, after the particles of phospholipid-encapsulated drugs come into contact with the vascular wall, the phospholipids are easily fused with the cell membrane, resulting in burst release, and no long-term sustained release effect can be achieved. 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 release of the drug.

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

[0007] In order 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, in parts by weight, 20-80 parts by weight of drug, 10-70 parts by weight of phospholipid, 5-60 parts by weight of excipient, and 5-60 parts by weight of co-polymerized 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 phospholipids in the outer layer play a protective role in the blood, preventing the coating layer from being washed away by blood during balloon delivery; since the composition of phospholipids and cell membranes is similar, when the balloon is expanded, the carding layer adheres to the blood vessel wall, and due to its affinity with the phospholipid cell membrane, the drug is retained at the target location and biocompatibility is improved; in this case, PEG, a hydrophilic excipient, absorbs water in the blood vessel, making the surface of the drug coating and the surface of the balloon easily peelable, and the surface of the drug coating can be peeled 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 8,000, and the number average molecular weight of PLGA is 5,000 to 60,000, and more preferably, the number average molecular weight of mPEG in the mPEG-PLGA block copolymer is 550 to 5,000.

[0016] The present invention specifically selects a block copolymer composed of mPEG with a number average molecular weight of 200-8000, preferably 550-5000, and PLGA with a number average molecular weight of 5000-60000 as a copolymerization excipient, which can form a cover on the surface of the drug droplet and realize the controlled release of the drug as the drug decomposes at the target location. The inventor unexpectedly found that the smaller the molecular weight of mPEG, the slower the drug release rate, and the larger the molecular weight of mPEG, the faster the drug release rate, and when the molecular weight of mPEG reaches 8000, there is an obvious burst release. Based on this creative development, the drug coding of the present invention can realize the adjustment to the drug release rate by adjusting the molecular weight of mPEG of the copolymerization excipient mPEG-PLGA block copolymer according to the actual use needs and drug properties, thereby improving the universality of the 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 1-5:1.

[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 obtaining a drug micelle microsphere solution by ultrasonic wave; and spraying the drug micelle microsphere solution on the surface of the balloon of an expandable balloon catheter by ultrasonic wave 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 present 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 phospholipids in the outer layer prevent the coating layer from being washed away by blood during balloon delivery, and due to their affinity with cell membranes, they allow the drug to remain at the target location, improving biocompatibility;

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

[0027] 3. The drug coating of the present invention further comprises an mPEG-PLGA block copolymer with a specific molecular weight, and the molecular weight of mPEG is creatively expressed to affect the drug release rate, thereby realizing a controlled and long-term sustained release of the drug. [Brief description of the drawings]

[0028] [Figure 1] FIG. 2 is a SEM image of drug coding according to Example 1. [Diagram 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). [Diagram 3]FIG. 2 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 PREFERRED EMBODIMENTS

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

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

[0031] The copolymer excipient is mPEG-PLGA block copolymer, in which the number average molecular weight of mPEG is 550, the number average molecular weight of PLGA is 60000, and the molar ratio of mPEG to PLGA is 1:1. The mPEG-PLGA block copolymer is purchased from Yinchuang Special Chemical (Shanghai) Co., Ltd.

[0032] The organic solvent is acetone.

[0033] The present invention further provides a method for preparing the drug coating for the expandable balloon catheter, in which rapamycin, soybean lecithin, PEG, and mPEG-PLGA block copolymer are weighed in the above weight parts, dissolved in acetone, mixed uniformly, and then treated with 54 kHz ultrasonic for 30 minutes to obtain a drug micelle microsphere solution, and then sprayed with the drug micelle microsphere solution on the surface of the balloon of the expandable balloon catheter with ultrasonic, 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 expandable balloon catheter and its preparation method, the embodiment of which is the same as that of 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 Yinchuang 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 It is. Example 3

[0037] This example further provides a drug coating for expandable balloon catheter and its preparation method, the embodiment of which is the same as that of 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 Eichuang 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 It is. Comparative Example 1

[0039] This comparative example further provides a drug coating for expandable balloon catheter and its preparation method, the embodiment of which is the same as that of Example 1, with the following differences: the copolymerization excipient is mPEG-PLGA block copolymer, where the number average molecular weight of mPEG is 10000, 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 Jinan Jufukai Biological Technology Co., Ltd.

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

[0041] This comparative example further provides a drug coating for expandable balloon catheter and its preparation method, the embodiment of which is the same as that of Example 1, with the following differences: the copolymerization excipient is mPEG-PLGA block copolymer, where the number average molecular weight of mPEG is 20000, 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 Jinan Jufukai Biological Technology Co., Ltd.

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

[0043] Performance Testing

[0044] In the drug release test, in order to verify the sustained release effect of drug coating prepared by mPEG-PLGA with different molecular weights, the release rate of the drug coated in each example is detected by animal experiments. In this experiment, a miniature pig animal model is used, and drug coatings in Examples 1-3 and Comparative Examples 1-2 are used in the miniature pig body, respectively, and the timings are set as 0 (immediate), 1 day, 7 days, 14 days, 30 days, 60 days, and 90 days. Drug tests are performed on the blood vessels by extracting the pig blood vessel model.

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

[0046] The experimental product had a drug content of 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 to 2.

[0047] The experimental method is as follows.

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

Claims

1. A drug coating for an expandable balloon catheter, the preparation of which comprises, in parts 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 co-polymerized excipient.

2. 2. The drug coating for an expandable balloon catheter of 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, characterized in that the phospholipid is selected from soy lecithin or lecithin.

4. 2. The drug coating for an expandable balloon catheter according to claim 1, wherein the excipient is one or more of PEG, hyaluronic acid, chitosan, iopromide, shellac, tannic acid, polylactide, and PLGA.

5. The drug coating for an expandable balloon catheter according to claim 4, wherein the number average molecular weight of the PEG is 8,000-30,000.

6. 2. The drug coating for an expandable balloon catheter according to claim 1, wherein the copolymer excipient is selected from one or more of mPEG-PLGA block copolymers, PEG-PLGA block copolymers, and PEG-hyaluronic acid copolymers.

7. 7. The drug coating for an expandable balloon catheter according to claim 6, wherein the mPEG-PLGA block copolymer has a number average molecular weight of 200-8,000 and a number average molecular weight of 5,000-60,000.

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

1.

9. The method for preparing drug coating for expandable balloon catheter according to any one of claims 1 to 8, characterized in that it includes the steps of: dissolving the drug, phospholipid, excipient and copolymer excipient in organic solvent after weighing them by weight, mixing them uniformly, and obtaining a drug micelle microsphere solution by ultrasonic; and spraying the drug micelle microsphere solution on the surface of the balloon of the expandable balloon catheter by ultrasonic to obtain a drug coating.

10. The method for preparing a drug coating for an expandable balloon catheter according to claim 9, wherein the thickness of the drug coating is 1-10 microns.

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