Drug balloon catheter and preparation method thereof

Abstract

The invention belongs to the field of drug delivery, and particularly relates to a drug balloon catheter and a preparation method thereof. The invention provides a medicine balloon catheter. The medicine balloon catheter comprises a balloon catheter body, a medicine storage layer and a medicine coating, wherein the outer surface of the balloon catheter body is sequentially coated with the medicine storage layer and the medicine coating. The medicine storage layer comprises one or more layers; when the drug balloon catheter is used for delivery, drugs on the outermost layer enter blood vessels preferentially and are continuously absorbed and metabolized and eliminated along with the half-life period and elimination kinetics of the drugs, and the anti-proliferation effect of the drugs is achieved. The first layer of the microspheres in the storage layer preferentially enters tissues and reaches saturation concentration, so that most of the microspheres are attached to the blood vessel wall, the modification of chitosan increases the contact between the PLGA microspheres and the blood vessel wall, a large amount of medicine is released after the structure of the storage layer collapses, and the released large amount of medicine enters the blood vessel to play a role.

Description

Technical Field

[0001] The present application belongs to the field of drug delivery, and specifically relates to a drug balloon catheter and a preparation method thereof. Background Art

[0002] Drug delivery balloon, commonly known as drug-coated balloon (DCB), is an innovative medical device used for coronary intervention. It coats the surface of the balloon with anti-proliferative drugs, and delivers the drugs quickly and evenly to the blood vessel wall when the balloon is expanded, so as to inhibit the proliferation of vascular smooth muscle cells and reduce the occurrence of vascular restenosis. Compared with traditional drug-eluting stents (DES), DCB has the advantage of "intervention without implantation", avoiding permanent metal implants in the patient's body and reducing the potential risks associated with implants. DCB shows good efficacy and safety in the treatment of in-stent restenosis (ISR) and small vessel lesions.

[0003] However, drug-eluting balloons on the market generally face the problem of restenosis in about 6 months, and most of the drugs in drug-eluting balloons are anti-proliferative drugs such as rapamycin or paclitaxel. Since drugs have a certain half-life, which is determined by the drug and cannot be changed, the drug-eluting balloon releases a certain amount of drugs to the target blood vessels after entering the human body, but these drugs will not be completely absorbed by the tissues. The absorption in the tissues will reach a saturation value, and the remaining drugs will adhere to the blood vessel wall.

[0004] According to the elimination kinetics of drugs, drugs absorbed in tissues will be eliminated over time, and drugs attached to blood vessel walls will also be eliminated over time. Therefore, when drugs in tissues are consumed and metabolized, drugs on blood vessel walls are also consumed and metabolized. This results in that no matter how much the initial drug loading value of drug balloons on the market is, since the concentration of drugs absorbed by tissues is constant at the beginning, after a period of time, no drug will take effect.

[0005] In summary, drug delivery balloons in traditional technologies have low durability and cannot continue to work after a long period of drug delivery. Summary of the invention

[0006] Based on this, an embodiment of the present application provides a drug balloon catheter and a preparation method thereof, wherein the drug balloon catheter can continue to function after drug delivery for a long period of time.

[0007] On one hand, the present application provides a drug balloon catheter, comprising a balloon catheter and a drug storage layer and a drug coating sequentially coated on the outer surface of the balloon catheter; the drug storage layer comprises one or more layers;

[0008] The drug storage layer contains PLGA drug-loaded microspheres wrapped with chitosan.

[0009] In one embodiment, the particle size of the PLGA drug-loaded microspheres is 1 μm to 100 μm.

[0010] In one embodiment, the drug storage layer is a multi-layer structure, and the drug storage layer is from the inner layer to the outer layer, and the particle size of the PLGA drug-loaded microspheres on each of the storage layers decreases from the inside to the outside.

[0011] In one embodiment, the particle size of the PLGA drug-loaded microspheres on each of the drug storage layers decreases in a gradient from the inner layer to the outer layer;

[0012] Optionally, the particle size gradient of the PLGA drug-loaded microspheres is 30 μm to 40 μm. In one embodiment, the drug balloon catheter meets at least one of the following conditions:

[0013] (1) The molecular weight of PLGA in the PLGA drug-loaded microspheres is 40000Da~45000Da;

[0014] (2) The monomer compounds in the PLGA preparation material in the PLGA drug-loaded microspheres include lactide and glycolide in a mass ratio of (1-17):1;

[0015] (3) The mass ratio of PLGA to the loaded drug in the PLGA drug-loaded microspheres is (5-20):1;

[0016] (4) The mass ratio of the chitosan to the PLGA drug-loaded microspheres is (0.8~2): (0.8~2).

[0017] In one embodiment, the drug in the drug coating includes one or more of paclitaxel, rapamycin and everolimus.

[0018] In one embodiment, the release time of the drug coating on the drug balloon catheter is 2 minutes to 4 minutes, and the drug storage layer collapses after 180 days to 200 days.

[0019] On the other hand, the present application provides a method for preparing a medicated balloon catheter, the method comprising the following steps:

[0020] A drug storage slurry containing chitosan-wrapped PLGA drug-loaded microspheres is coated on part of the outer surface of the balloon catheter, and a drug storage layer is obtained after drying; and a drug slurry is coated on at least part of the outer surface of the drug storage layer, and a drug coating is obtained after drying.

[0021] In one embodiment, the preparation method further comprises the following steps:

[0022] Before coating at least a portion of the outer surface of the balloon catheter with the drug reserve slurry, the balloon catheter is inflated.

[0023] In one embodiment, the preparation method further comprises the following steps:

[0024] The preparation method of the drug reserve slurry comprises the steps of:

[0025] Stirring and mixing the water phase and the oil phase;

[0026] The aqueous phase comprises polyvinyl alcohol, and the oil phase comprises an aqueous solution containing PLGA and dichloromethane loaded with drugs; the mixed solution after stirring and mixing is subjected to centrifugal drying, and the PLGA and the loaded drugs are compounded to form PLGA drug-loaded microspheres; and the PLGA drug-loaded microspheres are subjected to ultrasonic dispersion treatment, and the PLGA drug-loaded microspheres after ultrasonic dispersion treatment are mixed with an acetic acid aqueous solution containing chitosan to obtain a mixed solution;

[0027] Liquid paraffin containing Tween is added to the mixed solution for emulsification, and then a cross-linking agent is added for cross-linking.

[0028] In one embodiment, the concentration of the PLGA drug-loaded microspheres in the mixed solution is controlled to be 180 mg / mL to 200 mg / mL.

[0029] In one embodiment, the stirring and mixing process includes at least one of mechanical stirring and magnetic stirring;

[0030] Wherein, the preparation method of the drug balloon catheter meets at least one of the following conditions:

[0031] (1) The mechanical stirring time is 5h~10h; the magnetic stirring time is 5h~10h, and the rotation speed is 360rpm~720rpm;

[0032] (2) The rotation speed of the centrifugal treatment is 7500r / min~8000r / min, and the centrifugal time is 10min~20min;

[0033] (3) The drying process includes vacuum drying, wherein the vacuum drying time is 80h~120h.

[0034] In one embodiment, the method for preparing the drug slurry comprises:

[0035] Dissolving the API in an organic solvent to obtain a drug slurry; wherein the organic solvent comprises one or more of ethanol, acetone and methanol;

[0036] Optionally, the API includes one or more of paclitaxel, rapamycin, and everolimus;

[0037] Optionally, the concentration of the active drug in the drug slurry is 25 mg / mL to 50 mg / mL.

[0038] In one embodiment, the coating process has one or more of the following technical features:

[0039] (1) coating at least a portion of the outer surface of the balloon catheter with a drug reserve slurry containing chitosan-coated PLGA drug-loaded microspheres by ultrasonic atomization spraying;

[0040] (2) Coating the drug slurry on at least a portion of the outer surface of the drug storage layer by ultrasonic atomization spraying.

[0041] In one embodiment, the parameters of the ultrasonic atomization spraying have one or more of the following technical features:

[0042] (1) Power is 0.8W~1.2W;

[0043] (2) Drainage air flow rate is 1psi~4psi;

[0044] (3) Temperature is 20℃~25℃;

[0045] (4) Humidity: 30%~50%;

[0046] (5) Flow rate: 0.03 mL / min~2 mL / min;

[0047] (6) The feeding speed of the balloon catheter is 2 mm / s~4 cm / s;

[0048] (7) The rotation speed of the balloon catheter is 100 REV / min~200 REV / min;

[0049] (8) The ultrasonic atomization spraying is repeated 1 to 30 times, and the drying time between adjacent ultrasonic atomization sprayings is 50 s to 70 s.

[0050] The details of one or more embodiments of the present application are set forth in the description which follows, and other features, objects, and advantages of the present application will be apparent from the description and its claims. BRIEF DESCRIPTION OF THE DRAWINGS

[0051] In order to more clearly illustrate the technical solutions in the embodiments of the present application and to more completely understand the present application and its beneficial effects, the following is a brief introduction to the drawings required for the description of the embodiments. Obviously, the drawings described below are only some embodiments of the present application, and those skilled in the art can obtain other drawings based on these drawings without creative work.

[0052] Figure 1 Actual picture of drug-eluting balloon;

[0053] Figure 2 The morphology of drug-loaded microspheres prepared in the PB experiment;

[0054] Figure 3 Pareto diagram of the effects of various factors on particle size (a), drug loading (b) and encapsulation efficiency (c);

[0055] Figure 4 To prepare response surface plots and contour plots based on the results of variance analysis of the regression equation and regression model;

[0056] Figure 5 A schematic diagram of the collapse of chitosan-coated PLGA drug-loaded microspheres provided in one embodiment of the present application;

[0057] Figure 6 Schematic diagram of the collapse of other PLGA drug-loaded microspheres. DETAILED DESCRIPTION

[0058] Below in conjunction with embodiment and example, the application is further described in detail.It should be understood that these embodiments and examples are only used to illustrate the application and are not used to limit the scope of the application, and the purpose of providing these embodiments and examples is to make the understanding of the disclosure of the application more thorough and comprehensive.It should also be understood that the application can be implemented in many different forms, is not limited to the embodiment and example described herein, and those skilled in the art can make various changes or modifications without violating the connotation of the application, and the equivalent form obtained also falls within the protection scope of the application.In addition, in the description below, a large number of specific details are given in order to provide a more comprehensive understanding of the application, and it should be understood that the application can be implemented without one or more of these details.

[0059] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs.

[0060] the term

[0061] Unless otherwise specified or incompatible herewith, the terms and phrases used herein shall have the following meanings:

[0062] The terms "and / or", "or / and", and "and / or" used in this article include any one of two or more related listed items, and also include any and all combinations of related listed items, and the arbitrary and all combinations include any two related listed items, any more related listed items, or a combination of all related listed items. It should be noted that when at least three items are connected by at least two conjunctions selected from "and / or", "or / and", and "and / or", it should be understood that in this application, the technical solution undoubtedly includes technical solutions that are all connected by "logical and", and undoubtedly includes technical solutions that are all connected by "logical or". For example, "A and / or B" includes three parallel solutions of A, B and A+B. For example, the technical solution of "A, and / or, B, and / or, C, and / or, D" includes any one of A, B, C, and D (that is, the technical solution that is all connected by "logical OR"), and also includes any and all combinations of A, B, C, and D, that is, the combination of any two or any three of A, B, C, and D, and also includes the combination of four of A, B, C, and D (that is, the technical solution that is all connected by "logical AND").

[0063] In the present application, "plurality", "multiple", "multiple times", "multiples", etc., unless otherwise specified, refer to a number greater than 2 or equal to 2. For example, "one or more" means one or greater than or equal to two.

[0064] As used herein, "combination thereof", "any combination thereof", "any combination thereof" etc. include all suitable combinations of any two or more of the listed items.

[0065] Herein, the “suitable” mentioned in “suitable combination”, “suitable method”, “any suitable method”, etc., shall be based on the ability to implement the technical solution of this application, solve the technical problems of this application, and achieve the expected technical effects of this application.

[0066] In the present application, "further", "further", "particularly" and the like are used for descriptive purposes to indicate differences in content, but should not be construed as limiting the scope of protection of the present application.

[0067] In this application, "optionally", "optional", and "optional" mean optional or dispensable, that is, any one of the two parallel schemes of "yes" or "no". If multiple "options" appear in a technical solution, unless otherwise specified and there is no contradiction or mutual restriction, each "optional" is independent.

[0068] In the present application, the technical features described in an open manner include closed technical solutions composed of the listed features, and also include open technical solutions containing the listed features.

[0069] In the present application, when it comes to numerical intervals (i.e., numerical ranges), unless otherwise specified, the optional numerical distribution is considered continuous within the above numerical interval, and includes the two numerical endpoints (i.e., the minimum and maximum values) of the numerical range, and each numerical value between the two numerical endpoints. Unless otherwise specified, when the numerical interval only refers to the integers within the numerical interval, it includes the two endpoint integers of the numerical range, and each integer between the two endpoints. In this article, it is equivalent to directly listing each integer, such as t is an integer selected from 1 to 10, indicating that t is any integer selected from the integer group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10. In addition, when multiple ranges are provided to describe features or characteristics, these ranges can be combined. In other words, unless otherwise specified, the ranges disclosed herein should be understood to include any and all sub-ranges included therein.

[0070] The temperature parameters in this application, unless otherwise specified, are allowed to be either constant temperature treatment or to vary within a certain temperature range. It should be understood that the constant temperature treatment allows the temperature to fluctuate within the accuracy range controlled by the instrument. Fluctuations within the range of ±5°C, ±4°C, ±3°C, ±2°C, and ±1°C are allowed.

[0071] In the present application, % (w / w) and wt% both represent weight percentage, % (v / v) refers to volume percentage, and % (w / v) refers to mass volume percentage.

[0072] All documents mentioned in this application are cited as references in this application, just as each document is cited as reference separately. Unless they conflict with the invention purpose and / or technical solution of this application, the cited documents involved in this application are cited with all contents and all purposes. When the cited documents are involved in this application, the definitions of relevant technical features, terms, nouns, phrases, etc. in the cited documents are also cited. When the cited documents are involved in this application, the examples and preferred methods of the cited relevant technical features can also be incorporated into this application as references, but are limited to the implementation of this application. It should be understood that when the cited content conflicts with the description in this application, the present application shall prevail or be modified adaptively according to the description of this application.

[0073] The term "PLGA" PLGA (polylactic-co-glycolic acid) is a biodegradable polymer material commonly used in drug delivery systems, including drug-coated balloons (DCBs). Drug-coated balloons are an interventional medical device used to treat vascular diseases. The surface of the drug is coated with drugs, which can deliver drugs directly to the lesion site during intravascular expansion, reducing the risk of restenosis.

[0074] PLGA (polylactic-co-glycolic acid) drug-loaded microspheres are a type of controlled-release drug carrier widely used in the biomedical field. They are biodegradable, biocompatible, and have high drug-loading capacity. The degradation rate and drug release characteristics of the microspheres can be regulated by changing the ratio of lactic acid to glycolic acid in PLGA.

[0075] On one hand, the present application provides a drug balloon catheter, comprising a balloon catheter and a drug storage layer and a drug coating sequentially coated on the outer surface of the balloon catheter; the drug storage layer comprises one or more layers;

[0076] The drug storage layer contains PLGA drug-loaded microspheres wrapped with chitosan. The present application increases the contact between the PLGA microspheres and the blood vessel wall through the modification of chitosan, which is conducive to the adsorption of each discrete microsphere on the blood vessel wall and avoids the aggregation and agglomeration of the microspheres.

[0077] It is understandable that the drug storage layer can be one or more layers, and the particle size of the PLGA drug-loaded microspheres is 1 μm to 100 μm, for example, 1 μm, 5 μm, 10 μm, 15 μm, 20 μm, 25 μm, 30 μm, 40 μm, 50 μm, 60 μm, 70 μm, 80 μm, 90 μm, and 100 μm.

[0078] In a specific example, the drug storage layer is a multi-layer structure, and the drug storage layer is from the inner layer to the outer layer, and the particle size of the PLGA drug-loaded microspheres on each of the storage layers decreases from the inside to the outside.

[0079] Optionally, the particle size of the PLGA drug-loaded microspheres on each of the drug storage layers decreases in a gradient from the inner layer to the outer layer;

[0080] Further optionally, the particle size gradient of the PLGA drug-loaded microspheres is 30 μm to 40 μm.

[0081] For example, there can be more and more reserve layers, distributed according to the gradient of microsphere size. For example, the first reserve layer is about 60μm in size; the second reserve layer is about 60-30μm in size, and so on. However, the total volume cannot be greater than 100μm, as there is a risk of causing thrombosis.

[0082] After the drug balloon catheter of the present application delivers the drug to the blood vessel wall, it protects the drug and releases it at different times, so that the drug can exert its effect in the tissue for a longer period of time and can continuously deliver the drug to the tissue.

[0083] The outermost layer is the drug, which preferentially enters the blood vessels to reach saturation concentration and exerts an anti-proliferative effect. The inner reserve layer is PLGA nano-microspheres wrapped with chitosan, which are attached to the blood vessel wall and serve as a reserve for the first layer of drugs. After the first layer of drugs is fully absorbed and metabolized in the blood vessels, the second layer of microspheres slowly releases the drugs and enters the blood vessel wall again to exert an anti-proliferative effect.

[0084] Optionally, the concentration of the chitosan-coated PLGA drug-loaded microspheres is 180 mg / mL to 200 mg / mL.

[0085] In a specific example, the molecular weight of the PLGA is 40000Da~45000Da; the monomer compound of the PLGA includes lactide and glycolide in a mass ratio of (1~17):1.

[0086] Optionally, in the chitosan-coated PLGA drug-loaded microspheres, the mass ratio of PLGA to loaded drug is (5-20):1.

[0087] In a specific example, the mass ratio of the chitosan to the PLGA drug-loaded microspheres is (0.8~1.2): (0.8~1.2).

[0088] In a specific example, the drug in the drug layer includes, but is not limited to, one or more of paclitaxel, rapamycin, and everolimus.

[0089] Among them, the release time of the drug coating on the drug balloon catheter is 2 minutes to 4 minutes, and the drug storage layer collapses after 180 days to 200 days, further releasing the drugs in the drug storage layer.

[0090] Another aspect of the present application provides a method for preparing a medicated balloon catheter, the method comprising:

[0091] Coating a drug reserve slurry containing chitosan-coated PLGA drug-loaded microspheres on at least a portion of the outer surface of the balloon catheter, and obtaining a drug reserve layer after drying; and

[0092] The drug slurry is coated on at least part of the outer surface of the drug storage layer, and the drug coating is obtained after drying.

[0093] In a specific example, the preparation method comprises the following steps: before coating at least a portion of the outer surface of the balloon catheter with the drug reserve slurry, inflating the balloon catheter.

[0094] Optionally, the method for preparing the drug reserve slurry comprises the steps of:

[0095] The aqueous phase and the oil phase are stirred and mixed, wherein the aqueous phase includes polyvinyl alcohol, and the oil phase includes an aqueous solution containing PLGA and dichloromethane loaded with drugs; the mixed solution after the stirring and mixing treatment is centrifuged and dried, and the PLGA and the loaded drugs are compounded to form PLGA drug-loaded microspheres; polyvinyl alcohol is conducive to uniform dispersion of the microspheres; dichloromethane can dissolve PLGA and drugs, and has a low boiling point and fast volatilization, which is conducive to the formation of microsphere emulsions.

[0096] Performing ultrasonic dispersion treatment on the PLGA drug-loaded microspheres, and mixing the PLGA drug-loaded microspheres after the ultrasonic dispersion treatment with an acetic acid aqueous solution containing chitosan to obtain a mixed solution;

[0097] Liquid paraffin containing Tween is added to the mixed solution for emulsification, and then a cross-linking agent is added for cross-linking.

[0098] Optionally, the cross-linking agent is sodium tripolyphosphate.

[0099] In a specific example, the mechanical stirring time is 5h~10h, and the rotation speed is 360~720rpm; the magnetic stirring time is 5h~10h; the combination of mechanical stirring and magnetic stirring can make the water phase and the oil phase mix more fully, and also make the PLGA drug-loaded microspheres more uniform.

[0100] In a specific example, the rotation speed of the centrifugal treatment is 7500r / min~8000r / min, and the centrifugal time is 10min~20min;

[0101] In a specific example, the drying process includes vacuum drying, wherein the vacuum drying time is 80h~120h

[0102] In a specific example, the method for preparing the drug coating solution includes:

[0103] Dissolving the API in an organic solvent to obtain a drug slurry; wherein the organic solvent comprises one or more of ethanol, acetone and methanol;

[0104] Optionally, the API includes one or more of paclitaxel, rapamycin, and everolimus;

[0105] Optionally, after the drug substance is dissolved in the organic solvent, the concentration of the active drug in the drug slurry is 25 mg / mL to 50 mg / mL.

[0106] In a specific example, a drug reserve slurry containing chitosan-coated PLGA drug-loaded microspheres is coated on at least a portion of the outer surface of the balloon catheter by ultrasonic atomization spraying. It is understandable that other spraying methods may also be used.

[0107] Optionally, the drug slurry is coated on at least a portion of the outer surface of the drug storage layer by ultrasonic atomization spraying.

[0108] In a specific example, the ultrasonic atomization spray power is 0.8W~1.2W.

[0109] Optionally, the ultrasonic atomization spray drainage air flow rate is 1psi ~4psi.

[0110] Optionally, the ultrasonic atomization spraying temperature is 20°C~25°C.

[0111] In a specific example, the ultrasonic atomization spraying humidity is 30% to 50%.

[0112] In a specific example, the ultrasonic atomization spray flow rate is 0.03 mL / min~1 mL / min.

[0113] Optionally, the feeding speed of the ultrasonic atomization spray balloon catheter is 2 cm / s~4 cm / s.

[0114] Optionally, the rotation speed of the ultrasonic atomization spray balloon catheter is 100 REV / min ~200 REV / min.

[0115] Optionally, the ultrasonic atomization spraying is repeated 20 to 30 times, and the time for the drying treatment between adjacent ultrasonic atomization spraying is 50s to 70s.

[0116] The present application provides a drug balloon catheter, comprising a balloon catheter and one or more drug storage layers and drug coatings sequentially coated on the outer surface of the balloon catheter, wherein the drug storage layer contains PLGA drug-loaded microspheres wrapped with chitosan. When the drug balloon catheter is delivered, the outermost layer of the drug preferentially enters the blood vessel, reaches a saturated concentration in the tissue, and begins to be continuously absorbed and metabolized and eliminated along with the half-life and elimination kinetics of the drug, thereby exerting its anti-proliferation effect.

[0117] Specifically, because the first layer of microspheres in the reserve layer enters the tissue first and has reached saturation concentration, most of them are attached to the blood vessel wall, including chitosan, which increases the contact between the PLGA microspheres and the blood vessel wall, which is conducive to the adsorption of each discrete microsphere on the blood vessel wall and avoids the aggregation and agglomeration of microspheres. Furthermore, the structure of the reserve layer collapses around 180 days, and a large amount of drugs are released. At this time, the drugs that entered the tissue in the first layer have been completely absorbed, and there are basically no active drugs that can play a role, and endothelial cells begin to proliferate. Therefore, the entry of the reserve layer just fills this gap, and a large amount of released drugs enter the blood vessels and play a role.

[0118] The embodiments of the present application will be described in detail below in conjunction with examples. It should be understood that these examples are only used to illustrate the present application and are not intended to limit the scope of the present application. The experimental methods for which specific conditions are not specified in the following examples are preferably referred to the guidance provided in the present application, and can also be based on the experimental manual or normal conditions in this area, can also be based on the conditions recommended by the manufacturer, or refer to experimental methods known in the art.

[0119] In the following specific embodiments, the measured parameters of raw material components may have slight deviations within the range of weighing accuracy unless otherwise specified. For temperature and time parameters, acceptable deviations caused by instrument test accuracy or operation accuracy are allowed.

[0120] It should be understood that in the various embodiments of the present application, the size of the serial numbers of the above-mentioned processes does not mean the order of execution. The execution order of each process should be determined by its function and internal logic, and should not constitute any limitation on the implementation process of the embodiments of the present application.

[0121] Example 1

[0122] This embodiment provides a drug balloon catheter, comprising a balloon catheter and a drug storage layer and a drug coating sequentially coated on the outer surface of the balloon catheter;

[0123] The drug in the drug storage layer is chitosan-coated PLGA drug-loaded microspheres, the particle size of the chitosan-coated PLGA drug-loaded microspheres is 35 μM, the concentration is 180 mg / mL, and the mass ratio of PLGA to the loaded drug is 20:1.

[0124] The molecular weight of PLGA is 45000Da, and the monomer compounds of PLGA include lactide and glycolide in a mass ratio of 10:1.

[0125] The drug layer is rapamycin, and the concentration of the active drug in the drug layer is 25 mg / mL.

[0126] Example 2

[0127] This embodiment provides a drug balloon catheter, comprising a balloon catheter and a drug storage layer and a drug coating sequentially coated on the outer surface of the balloon catheter;

[0128] The drug in the drug storage layer is chitosan-coated PLGA drug-loaded microspheres, the particle size of the chitosan-coated PLGA drug-loaded microspheres is 30 μM, the concentration is 200 mg / mL, and the mass ratio of PLGA to the loaded drug is 10:1.

[0129] The molecular weight of PLGA is 40,000 Da, and the monomer compounds of PLGA include lactide and glycolide in a mass ratio of 15:1.

[0130] The drug layer is paclitaxel, and the concentration of the active drug in the drug layer is 30 mg / mL.

[0131] Example 3

[0132] This embodiment provides a drug balloon catheter, comprising a balloon catheter and a drug storage layer and a drug coating sequentially coated on the outer surface of the balloon catheter;

[0133] The drug in the drug storage layer is chitosan-coated PLGA drug-loaded microspheres, the particle size of the chitosan-coated PLGA drug-loaded microspheres is 40 μM, the concentration is 200 mg / mL, and the mass ratio of PLGA to the loaded drug is 10:1.

[0134] The molecular weight of PLGA is 45000Da, and the monomer compounds of PLGA include lactide and glycolide in a mass ratio of 5:1.

[0135] The drug layer is rapamycin, and the concentration of the active drug in the drug layer is 30 mg / mL.

[0136] Example 4

[0137] Another embodiment of the present application provides a method for preparing a drug balloon catheter, comprising:

[0138] 1. Preparation of ordinary PLGA drug-loaded microspheres

[0139] (1) Prepare the aqueous phase: Accurately weigh 100 mg of polyvinyl alcohol (PVA) and add it to deionized water. Stir magnetically and heat to dissolve to obtain PVA aqueous solutions with different mass fractions. Cool the solution at room temperature for later use.

[0140] (2) Preparation of oil phase: Accurately weigh 100 mg of PLGA and a certain mass of drug, add them into dichloromethane (DCM), and dissolve them at room temperature to obtain oil phases with different concentrations of PLGA and different dosing ratios.

[0141] (3) The oil phase was slowly added dropwise into the aqueous phase, sheared for 50 minutes, mechanically stirred for 10 hours, and then magnetically stirred at room temperature for 10 hours. After DCM was completely evaporated and the solution in the beaker gradually became clear, it was centrifuged in a high-speed centrifuge at 8000 r / min for 20 minutes, and then washed with deionized water. This was repeated three times, and finally vacuum dried for 120 hours to obtain PLGA drug-loaded microspheres.

[0142] The molecular weight of the PLGA is 45000Da, and the ratio of lactide to hexyl lactide is 17:1.

[0143] The drug dosage ratio refers to the mass ratio of PLGA to the drug, which is in the range of 20:1.

[0144] 2. Preparation of chitosan-modified PLGA microspheres

[0145] (1) The prepared PLGA microspheres were ultrasonically dispersed in deionized water and added to an aqueous solution of chitosan dissolved in low concentration acetic acid.

[0146] (2) Add to liquid paraffin containing Tween 80 and emulsify for several hours, then use sodium tripolyphosphate for cross-linking.

[0147] The prepared chitosan-coated PLGA drug-loaded microspheres were screened by molecular sieves, and the particle sizes below 30 μm and above 30 μm were distinguished, and the microspheres above 30 μm were used as microsphere particles of the reserve layer.

[0148] 3. Spraying

[0149] (1) After the balloon catheter is inflated, paclitaxel with a size of 15 μm or more is dissolved in an organic solvent under ultrasonic conditions to obtain a lower layer solution suspension, wherein the concentration of the active drug in the drug layer solution is 50 mg / mL and the concentration of the microspheres is 200 mg / mL;

[0150] (2) The lower layer solution obtained in step 1 is placed in a syringe with a stirring function to ensure that the microspheres in the syringe can be evenly dispersed in the suspension.

[0151] (3) applying the lower layer solution suspension obtained in step 1 to the outer surface of the balloon catheter by ultrasonic atomization spraying, and then repeating steps (1) to (3) after drying for a period of time to complete the spraying of the upper layer solution;

[0152] Among them, the upper solution is the raw material of the outermost coating; the lower solution is the reserve layer solution, which is chitosan-wrapped PLGA drug-loaded microspheres.

[0153] The process conditions of ultrasonic atomization spraying in step 3 include: power of 1.2W, drainage air flow of 4psi, temperature of 225°C, humidity of 50%, flow rate of 1mL / min, feeding speed of balloon catheter of 4cm / s, rotation speed of balloon catheter of 200REV / min, repetition number of ultrasonic atomization spraying of 30 times, drying time between adjacent ultrasonic atomization spraying of 70s, and the schematic diagram of the drug balloon catheter after final spraying is as shown in FIG. Figure 1 shown.

[0154] Verification results:

[0155] Research on production formula:

[0156] In order to explore the main influencing factors of the preparation process, a Plackett-Burman (PB) test was designed, with a total of 12 groups, A\B\C\D\E\F representing PLGA concentration, PVA concentration, water-oil ratio, dosing ratio, rotation speed, shear time, etc. A low level and a high level value were determined for each factor, and the particle size (Size), drug loading (DL) and encapsulation efficiency (EE) of PLGA-loaded rapamycin microspheres were used as response values. The design of the levels of each experimental factor is shown in the table below.

[0157] Table 1 Experimental factors and levels

[0158]

[0159] Based on the above six-factor two-level PB experiment as a screening method, the experimental design and results are as follows:

[0160] Table 2

[0161]

[0162] The morphology of drug-loaded microspheres prepared in the PB experiment is as follows: Figure 2 As shown in the figure, it can be intuitively observed that, except for the microspheres in PB-8 with a large number of irregular shapes such as columns and oblate spheres, the microspheres in other formulations have good spheroidization, indicating that the experiment went smoothly. Next, a multivariate stepwise regression analysis was performed on the data in the above table to eliminate insignificant influencing factors and screen out factors with significant impact on the response value. The multivariate linear regression equations of the response values ​​R1, R2 and R3 with respect to A, B, C, D, E, and F were fitted:

[0163] R1=6.88+2.21A-0.1450B+0.1950C-0.1250D+0.0083E+0.2617F (R12=0.8885, P1<0.05);

[0164] R2=6.11+1.33A+1.68B+0.3650C+2.78D-0.4133E-0.0400F (R22=0.9352, P1<0.05);

[0165] R3=53.30+10.65A+11.67B+3.06C+0.0317D+0.1550E-1.04F (R32=0.9392, P1<0.05);

[0166] In order to verify the regression effect, the above regression equation was subjected to variance analysis, and the variance analysis results of the equation model were shown in Table 3. According to the statistical analysis results, the F values ​​of the three response values ​​were 6.64, 12.03, and 12.87 respectively; the P values ​​were all less than 0.05, indicating that the model was statistically significant.

[0167] Table 3

[0168]

[0169] The Pareto chart can determine the importance of each factor. If the bar chart of a factor exceeds the t value, it is called a significant influencing factor. Figure 3 The Pareto diagram of the influence of various factors on particle size (a), drug loading (b) and encapsulation efficiency (c) is shown in the figure. The most significant factor affecting the particle size of PLGA-loaded Rapa microspheres is PLGA concentration; the most significant factors affecting the drug loading are drug ratio, PVA concentration and PLGA concentration; the most significant factors affecting the encapsulation efficiency are PVA concentration and PLGA concentration.

[0170] Box-Behnken Design is a commonly used response surface design method. This experiment used Design-Expert 13 software to conduct a 3-factor 3-level experiment based on the results of the Plackett-Burman experiment. PLGA concentration, dosing ratio and PVA concentration were selected as independent variables, and were set to low, medium and high levels as shown in Table 4. The particle size (Size), drug loading (DL) and encapsulation efficiency (EE) of the microspheres were used as response values. There were a total of 17 groups of experiments, and the center point was repeated 5 times. The experimental design and results are shown in Table 5 below.

[0171] Table 4

[0172]

[0173] Table 5

[0174]

[0175] After analysis, we know:

[0176] Based on the results of the regression equation and the variance analysis of the regression model, response surface plots and contour plots were prepared to study the effects of PLGA concentration, dosing ratio, and PVA concentration on the particle size, drug loading, and encapsulation efficiency of PLGA drug-loaded microspheres. When one of the three factors is fixed, the interaction between the other two factors can be displayed through contour plots and response surface plots to evaluate their effects on the response values, as shown in the following figure. Figure 4 shown.

[0177] The response surface and contour plots have the ability to intuitively display the degree of influence of the interaction on the response value. The steepness of the surface and the tightness of the contours reflect the significance of the influence of the interaction between the factors on the response value, that is, the steeper the surface and the denser the contours, the more significant the influence. In addition, if the contours are closer to the elliptical shape, it means that the interaction between the two factors is stronger.

[0178] After determining the formulation parameters of PLGA, chitosan was wrapped to conduct a drug balloon manufacturing experiment. Multiple embodiments can be set by adjusting the spraying parameters to compare drug balloons with a layer of drug coating (available on the market)

[0179] Table 6

[0180]

[0181] The in vitro release rate of the drug balloon catheter of Example 1 of the present application was verified on the 30th day, 60th day, 90th day and 180th day after the delivery of the drug balloon catheter. The results showed that the drug balloon catheter of Example 1 of the present application could be stored for 180 days and then release the drug. Specifically, Figure 5 As shown in Figure 2, the commercially available drug balloon catheters have no drug residues and are not effective until 180 days. Figure 6 shown.

[0182] The above-described embodiments only express several implementation methods of the present application, which is convenient for understanding the technical solution of the present application in detail, but it cannot be understood as a limitation on the scope of protection of the patent application. It should be pointed out that for ordinary technicians in this field, without departing from the concept of the present application, several deformations and improvements can be made, which all belong to the protection scope of the present application. In addition, it should be understood that after reading the above-mentioned teaching content of the present application, the technicians in this field can make various changes or modifications to the present application, and the equivalent forms obtained also fall within the protection scope of the present application. It should also be understood that the technical solutions obtained by the technicians in this field through logical analysis, reasoning or limited experiments on the basis of the technical solutions provided in the present application are all within the protection scope of the claims attached to the present application. Therefore, the protection scope of the patent of the present application shall be based on the content of the attached claims, and the description and drawings can be used to explain the content of the claims.

Claims

1. A drug balloon catheter, It is characterized in that It comprises a balloon catheter and a drug storage layer and a drug coating sequentially coated on the outer surface of the balloon catheter; the drug storage layer comprises one or more layers; The drug storage layer contains PLGA drug-loaded microspheres wrapped with chitosan.

2. The drug balloon catheter according to claim 1, It is characterized in that The particle size of the PLGA drug-loaded microspheres is 1 μm to 100 μm; Optionally, the drug storage layer is a multi-layer structure, and the drug storage layer is from the inner layer to the outer layer, and the particle size of the PLGA drug-loaded microspheres on each of the storage layers decreases from the inside to the outside; Optionally, the particle size of the PLGA drug-loaded microspheres on each of the drug storage layers decreases in a gradient from the inner layer to the outer layer; Optionally, the particle size gradient of the PLGA drug-loaded microspheres is 30 μm to 40 μm.

3. The drug balloon catheter according to claim 1, It is characterized in that The drug balloon catheter meets at least one of the following conditions: (1) The molecular weight of PLGA in the PLGA drug-loaded microspheres is 40000Da~45000Da; (2) The monomer compounds in the PLGA preparation material in the PLGA drug-loaded microspheres include lactide and glycolide in a mass ratio of (1-17):1; (3) The mass ratio of PLGA to the loaded drug in the PLGA drug-loaded microspheres is (5-20):1; (4) The mass ratio of the chitosan to the PLGA drug-loaded microspheres is (0.8-1.2): (0.8-1.2).

4. The drug balloon catheter according to claim 1, It is characterized in that The drug in the drug coating includes one or more of paclitaxel, rapamycin and everolimus; Optionally, the release time of the drug coating on the drug balloon catheter is 2 minutes to 4 minutes, and the drug storage layer collapses after 180 days to 200 days.

5. A method for preparing a drug balloon catheter, It is characterized in that The preparation method comprises the following steps: A drug storage slurry containing chitosan-wrapped PLGA drug-loaded microspheres is coated on part of the outer surface of the balloon catheter, and a drug storage layer is obtained after drying; and a drug slurry is coated on at least part of the outer surface of the drug storage layer, and a drug coating is obtained after drying.

6. The method for preparing the drug balloon catheter according to claim 5, It is characterized in that The preparation method further comprises the following steps: Before coating at least a portion of the outer surface of the balloon catheter with the drug reserve slurry, inflating the balloon catheter; Optionally, the method for preparing the drug reserve slurry comprises the steps of: Stirring and mixing the water phase and the oil phase; The aqueous phase comprises polyvinyl alcohol, and the oil phase comprises an aqueous solution containing PLGA and dichloromethane loaded with drugs; the mixed solution after stirring and mixing is subjected to centrifugal drying, and the PLGA and the loaded drugs are compounded to form PLGA drug-loaded microspheres; and the PLGA drug-loaded microspheres are subjected to ultrasonic dispersion treatment, and the PLGA drug-loaded microspheres after ultrasonic dispersion treatment are mixed with an acetic acid aqueous solution containing chitosan to obtain a mixed solution; Adding liquid paraffin containing Tween to the mixed solution for emulsification, and then adding a cross-linking agent for cross-linking; Optionally, the concentration of the PLGA drug-loaded microspheres in the mixed solution is controlled to be 180 mg / mL to 200 mg / mL.

7. The method for preparing the drug balloon catheter according to claim 6, It is characterized in that The stirring and mixing process includes at least one of mechanical stirring and magnetic stirring; Wherein, the preparation method of the drug balloon catheter meets at least one of the following conditions: (1) The mechanical stirring time is 5h~10h; the magnetic stirring time is 5h~10h, and the rotation speed is 360rpm~720rpm; (2) The rotation speed of the centrifugal treatment is 7500r / min~8000r / min, and the centrifugal time is 10min~20min; (3) The drying process includes vacuum drying, wherein the vacuum drying time is 80h~120h.

8. A method for preparing a medical balloon catheter according to any one of claims 5 to 7, It is characterized in that The preparation method of the drug slurry comprises: Dissolving the API in an organic solvent to obtain a drug slurry; wherein the organic solvent comprises one or more of ethanol, acetone and methanol; Optionally, the API includes one or more of paclitaxel, rapamycin, and everolimus; Optionally, the concentration of the active drug in the drug slurry is 25 mg / mL to 50 mg / mL.

9. The method for preparing the medical balloon catheter according to any one of claims 5 to 7, It is characterized in that The coating process has one or more of the following technical features: (1) coating at least a portion of the outer surface of the balloon catheter with a drug reserve slurry containing chitosan-coated PLGA drug-loaded microspheres by ultrasonic atomization spraying; (2) Coating the drug slurry on at least a portion of the outer surface of the drug storage layer by ultrasonic atomization spraying.

10. The method for preparing the drug balloon catheter according to claim 9, It is characterized in that The parameters of the ultrasonic atomization spraying have one or more of the following technical features: (1) Power is 0.8W~1.2W; (2) Drainage air flow rate is 1psi ~4psi; (3) Temperature is 20℃~25℃; (4) Humidity: 30%~50%; (5) Flow rate: 0.03 mL / min~2 mL / min; (6) The feeding speed of the balloon catheter is 2 mm / s~4 cm / s; (7) The rotation speed of the balloon catheter is 100 REV / min~200 REV / min; (8) The ultrasonic atomization spraying is repeated 1 to 30 times, and the drying time between adjacent ultrasonic atomization sprayings is 50 s to 70 s.

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