Drug balloon catheter

Abstract

The utility model belongs to the field of drug delivery, and particularly relates to a drug balloon catheter. The utility model 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] This application belongs to the field of drug delivery, specifically relating to a drug balloon catheter. Background Technology

[0002] Drug-delivery balloons, commonly known as drug-coated balloons (DCBs), are innovative medical devices used for coronary artery interventional therapy. They work by coating the balloon surface with an anti-proliferative drug, which is rapidly and uniformly delivered to the vessel wall during balloon inflation to inhibit the proliferation of vascular smooth muscle cells and reduce restenosis. Compared to traditional drug-eluting stents (DES), DCBs offer the advantage of "intubation-free intervention," avoiding the presence of permanent metal implants and reducing potential implant-related risks. DCBs have demonstrated good efficacy and safety in treating in-stent restenosis (ISR) and small vessel lesions.

[0003] However, commercially available drug-eluting balloons typically face restenosis issues after about 6 months. Furthermore, most drug-eluting balloons use anti-proliferative drugs like rapamycin or paclitaxel, which have a fixed half-life determined by the drug itself. Therefore, after entering the body, the balloon releases a certain amount of drug into the target blood vessel, but not all of this drug is absorbed by the tissue. Tissue absorption reaches a saturation point, and the remaining drug adheres to the blood vessel wall.

[0004] According to drug elimination kinetics, drugs absorbed into tissues are eliminated over time, as are drugs adhering to blood vessel walls. Therefore, when the drug in tissues is completely metabolized, the drug on the blood vessel walls is also completely metabolized. This means that regardless of the initial drug loading capacity of commercially available drug-eluting balloons, since the initial concentration of drug absorbed into the tissue is constant, after a period of time, no drug will have any effect.

[0005] In summary, traditional drug delivery balloons suffer from low durability and cannot continue to function after a long period of drug delivery. Utility Model Content

[0006] Based on this, one embodiment of this application provides a drug balloon catheter that can continue to function after drug delivery for a long period of time.

[0007] This application provides a drug-eluting balloon catheter, comprising a balloon catheter and a drug reservoir layer and a drug coating layer sequentially covering the outer surface of the balloon catheter; the drug reservoir layer comprises one or more layers;

[0008] The drug reservoir contains PLGA drug-loaded microspheres encapsulated in 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 particle size of the PLGA drug-loaded microspheres is 30 μm to 60 μm.

[0011] In one embodiment, the drug reservoir layer has a multi-layer structure, and the particle size of the PLGA drug-loaded microspheres on each reservoir layer decreases sequentially from the inner layer to the outer layer.

[0012] In one embodiment, the drug reservoir layer has a gradient decreasing particle size of PLGA drug-loaded microspheres from the innermost layer to the outermost layer.

[0013] In one embodiment, the particle size gradient of the PLGA drug-loaded microspheres is 30 μm to 40 μm.

[0014] In one embodiment, the molecular weight of the PLGA in the drug-eluting balloon catheter is 40,000 Da to 45,000 Da.

[0015] In one embodiment, the molecular weight of the PLGA in the drug-eluting balloon catheter is 40,000 Da to 42,000 Da.

[0016] In one embodiment, the drug coating on the drug balloon catheter is released over a period of 2 to 4 minutes.

[0017] In one embodiment, the drug reservoir collapses after 180 to 200 days.

[0018] Details of one or more embodiments of this application are set forth in the following description, and other features, objects, and advantages of this application will become apparent from the specification and its claims. Attached Figure Description

[0019] To more clearly illustrate the technical solutions in the embodiments of this application and to more completely understand this application and its beneficial effects, the drawings used in the description of the embodiments will be briefly introduced below. Obviously, the drawings described below are only some embodiments of this application. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0020] Figure 1 Image of a drug-eluting balloon;

[0021] Figure 2 The morphology of the drug-loaded microspheres prepared in the PB experiment;

[0022] Figure 3 Pareto plot showing the effects of various factors on particle size (a), drug loading (b), and encapsulation efficiency (c);

[0023] Figure 4 To create response surface plots and contour plots based on the regression equations and the results of the analysis of variance of the regression model;

[0024] Figure 5 A schematic diagram of the collapse of chitosan-encapsulated PLGA drug-loaded microspheres provided in an embodiment of this application;

[0025] Figure 6 This is a schematic diagram of the collapse of other PLGA drug-loaded microspheres. Detailed Implementation

[0026] The present application will be further described in detail below with reference to the embodiments and examples. It should be understood that these embodiments and examples are for illustrative purposes only and are not intended to limit the scope of the present application. The purpose of providing these embodiments and examples is to enable a more thorough and comprehensive understanding of the disclosure of the present application. It should also be understood that the present application can be implemented in many different forms and is not limited to the embodiments and examples described herein. Those skilled in the art can make various modifications or alterations without departing from the spirit of the present application, and the equivalent forms obtained also fall within the protection scope of the present application. Furthermore, numerous specific details are set forth in the following description to provide a more complete understanding of the present application. It should be understood that the present application can be implemented without one or more of these details.

[0027] Unless otherwise defined, all technical and scientific terms used in this application have the same meaning as commonly understood by one of ordinary skill in the art to which this application pertains.

[0028] the term

[0029] Unless otherwise stated or in case of contradiction, the terms or phrases used herein shall have the following meanings:

[0030] The terms "and / or," "or / and," and "and / or" as used herein include any one of two or more of the related listed items, as well as any and all combinations of the related listed items. These 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 connected by "logical AND," and also undoubtedly includes technical solutions connected by "logical OR." For example, "A and / or B" includes three parallel solutions: 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, a technical solution that is connected by "logical OR"), as well as any and all combinations of A, B, C, and D, that is, combinations of any two or three of A, B, C, and D, and also combinations of all four of A, B, C, and D (that is, a technical solution that is connected by "logical AND").

[0031] In this application, the terms "multiple", "various", "multiple times", "multi-dimensional", etc., unless otherwise specified, refer to a quantity greater than or equal to 2. For example, "one or more" means one or more than or equal to two.

[0032] The terms “combinations of,” “any combination of,” and “any combination of” used in this article include all suitable combinations of any two or more of the listed items.

[0033] In this document, the term "suitable" as used in phrases such as "suitable combination," "suitable method," and "any suitable method" refers to the ability to implement the technical solution of this application, solve the technical problem of this application, and achieve the expected technical effect of this application.

[0034] In this application, terms such as "further," "even further," and "particularly" are used to describe purposes and indicate differences in content, but should not be construed as limiting the scope of protection of this application.

[0035] In this application, "optionally," "optionally," and "optional" mean that something is optional, that is, it means that it is selected from either "with" or "without." If there are multiple "optional" entries in a technical solution, unless otherwise specified, and there are no contradictions or mutual constraints, each "optional" entry shall be independent.

[0036] In this application, the technical features described in an open-ended manner include both closed technical solutions consisting of the listed features and open technical solutions that include the listed features.

[0037] In this application, numerical intervals (i.e., numerical ranges) are involved. Unless otherwise specified, the selected numerical distributions within the aforementioned numerical intervals are considered continuous and include the two endpoints (i.e., the minimum and maximum values) of the numerical range, as well as every value between these two endpoints. Unless otherwise specified, when a numerical interval refers only to integers within that interval, it includes the two endpoint integers of the numerical range, as well as every integer between the two endpoints. In this document, this is equivalent to directly listing every integer. For example, if t is an integer selected from 1 to 10, it means that t is any integer selected from the group of integers consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10. Furthermore, when multiple ranges are provided to describe features or characteristics, these ranges can be merged. In other words, unless otherwise specified, the ranges disclosed herein should be understood to include any and all subranges to which they are included.

[0038] Unless otherwise specified, the temperature parameters in this application are permitted to be either constant-temperature treatment or variations within a certain temperature range. It should be understood that the constant-temperature treatment allows temperature fluctuations within the precision range of the instrument control, such as ±5℃, ±4℃, ±3℃, ±2℃, or ±1℃.

[0039] In this application, % (w / w) and wt% both represent weight percentage, % (v / v) refers to volume percentage, and % (w / v) refers to mass-volume percentage.

[0040] All references to documents mentioned in this application are incorporated herein by reference as if each document were individually incorporated herein by reference. Unless they conflict with the inventive purpose and / or technical solution of this application, all cited documents are incorporated herein by reference in their entirety and for all purposes. When citing documents in this application, the definitions of relevant technical features, terms, nouns, phrases, etc., are also incorporated herein by reference. When citing documents in this application, examples and preferred embodiments of the cited technical features may also be incorporated herein by reference, but only to the extent that they enable the implementation of this application. It should be understood that when the cited content conflicts with the description in this application, this application shall prevail or modifications shall be made adaptably to the description in this application.

[0041] The term "PLGA" refers to polylactic-co-glycolic acid copolymer, a biodegradable polymer commonly used in drug delivery systems, including drug-coated balloons (DCBs). A drug-coated balloon is an interventional medical device used to treat vascular diseases. Its surface is coated with medication, allowing it to be delivered directly to the lesion site as the blood vessel expands, reducing the risk of restenosis.

[0042] PLGA (polylactic acid-glycolic acid copolymer) drug-loaded microspheres are a widely used controlled-release drug carrier in the biomedical field. They are characterized by biodegradability, good biocompatibility, and high drug loading capacity. The degradation rate and drug release characteristics of the microspheres can be controlled by changing the ratio of lactic acid to glycolic acid in the PLGA.

[0043] This application provides a drug-eluting balloon catheter, comprising a balloon catheter and a drug reservoir layer and a drug coating layer sequentially covering the outer surface of the balloon catheter; the drug reservoir layer comprises one or more layers;

[0044] The drug reservoir layer contains PLGA drug-loaded microspheres encapsulated in chitosan. This application increases the contact between the PLGA microspheres and the blood vessel wall through chitosan modification, which facilitates the adsorption of individual discrete microspheres to the blood vessel wall and prevents microsphere aggregation and clustering.

[0045] It is understood that the drug reservoir layer can be one or more layers, and the particle size of the PLGA drug-loaded microspheres is 1μm to 100μm. For example, 1μm, 5μm, 10μm, 15μm, 20μm, 25μm, 30μm, 40μm, 50μm, 60μm, 70μm, 80μm, 90μm, and 100μm.

[0046] In a specific example, the drug reservoir layer has a multi-layer structure, and the particle size of the PLGA drug-loaded microspheres on each reservoir layer decreases sequentially from the inside to the outside.

[0047] 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;

[0048] Further optionally, the particle size variation gradient of the PLGA drug-loaded microspheres is 30 μm to 40 μm.

[0049] For example, the number of reserve layers can increase, distributed according to the size gradient of microspheres. For instance, the first reserve layer is about 60 μm in size; the second reserve layer is about 60-30 μm in size, and so on. However, the total volume cannot exceed 100 μm, as this poses a risk of thrombosis.

[0050] The drug-eluting balloon catheter of this application delivers the drug to the blood vessel wall and protects the drug from release at different times, thus enabling the drug to exert its effect in the tissue for a longer period of time and continuously deliver the drug into the tissue.

[0051] The outermost layer is the drug, which preferentially enters the blood vessel to reach a saturation concentration and exerts an anti-proliferative effect. The inner reserve layer is PLGA nanospheres encapsulated in chitosan, which adhere 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 vessel, the second layer of microspheres slowly releases the drugs and re-enters the blood vessel wall to exert an anti-proliferative effect.

[0052] Optionally, the concentration of the chitosan-encapsulated PLGA drug-loaded microspheres is 180 mg / mL to 200 mg / mL.

[0053] In a specific example, the molecular weight of the PLGA is 40,000 Da to 45,000 Da; the monomeric compounds of the PLGA include lactide and glycolide in a mass ratio of (1 to 17):1.

[0054] Optionally, in the chitosan-encapsulated PLGA drug-loaded microspheres, the mass ratio of PLGA to the loaded drug is (5~20):1.

[0055] In one specific example, the mass ratio of chitosan to PLGA drug-loaded microspheres is (0.8~1.2):(0.8~1.2).

[0056] In one specific example, the drugs in the drug layer include, but are not limited to, one or more of paclitaxel, rapamycin, and everolimus.

[0057] The drug coating on the drug-eluting balloon catheter releases drugs in 2 to 4 minutes, and the drug reserve layer collapses after 180 to 200 days, further releasing the drug from the reserve layer.

[0058] This application also provides a method for preparing a drug-eluting balloon catheter, the method comprising:

[0059] A drug storage slurry containing chitosan-encapsulated PLGA drug-loaded microspheres was coated onto at least a portion of the outer surface of a balloon catheter, and dried to obtain a drug storage layer; and

[0060] A drug slurry is coated onto at least a portion of the outer surface of the drug reservoir layer, and after drying, a drug coating is obtained.

[0061] In one specific example, the preparation method includes the following steps: inflating the balloon catheter before coating at least a portion of its outer surface with the drug storage slurry.

[0062] Optionally, the method for preparing the drug storage slurry includes the following steps:

[0063] The aqueous phase and oil phase are stirred and mixed, wherein the aqueous phase includes polyvinyl alcohol, and the oil phase includes an aqueous solution containing PLGA and drug-loaded dichloromethane; the mixed solution after stirring and mixing is centrifuged and dried, and the PLGA and drug-loaded compound form PLGA drug-loaded microspheres; polyvinyl alcohol is beneficial for uniform dispersion of microspheres; dichloromethane can dissolve PLGA and drug, and has a low boiling point and fast volatilization, which is conducive to the formation of microsphere emulsion.

[0064] The PLGA drug-loaded microspheres were ultrasonically dispersed, and the ultrasonically dispersed PLGA drug-loaded microspheres were mixed with an aqueous solution of acetic acid containing chitosan to obtain a mixed solution.

[0065] Liquid paraffin containing Tween was added to the mixed solution for emulsification, and then a crosslinking agent was added for crosslinking.

[0066] Optionally, the crosslinking agent is sodium tripolyphosphate.

[0067] 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 aqueous phase and oil phase mix more thoroughly, and also make the PLGA drug-loaded microspheres more uniform.

[0068] In a specific example, the centrifugation speed is 7500 r / min to 8000 r / min, and the centrifugation time is 10 min to 20 min;

[0069] In a specific example, the drying process includes vacuum drying, wherein the vacuum drying time is 80h~120h.

[0070] In a specific example, the method for preparing the drug coating solution includes:

[0071] The active pharmaceutical ingredient is dissolved in an organic solvent to obtain a drug slurry; wherein the organic solvent includes one or more of ethanol, acetone and methanol;

[0072] Optionally, the active pharmaceutical ingredient includes one or more of paclitaxel, rapamycin, and everolimus;

[0073] Optionally, after the active pharmaceutical ingredient is dissolved in the organic solvent, the concentration of the active pharmaceutical ingredient in the pharmaceutical slurry is 25 mg / mL to 50 mg / mL.

[0074] In one specific example, an ultrasonic atomization spraying method is used to coat at least a portion of the outer surface of a balloon catheter with a drug stock slurry containing chitosan-encapsulated PLGA drug-loaded microspheres. It is understood that other spraying methods may also be used.

[0075] Optionally, a drug slurry may be coated onto at least a portion of the outer surface of the drug reservoir using an ultrasonic atomization spraying method.

[0076] In a specific example, the ultrasonic atomization spraying power is 0.8W~1.2W.

[0077] Optionally, the ultrasonic atomization spraying airflow rate is 1 psi to 4 psi.

[0078] Optionally, the ultrasonic atomization spraying temperature is 20℃~25℃.

[0079] In a specific example, the humidity of ultrasonic atomization spraying is 30%~50%.

[0080] In a specific example, the ultrasonic atomization spraying flow rate is 0.03 mL / min to 1 mL / min.

[0081] Optionally, the feed rate of the ultrasonic atomization sprayed balloon catheter is 2 cm / s to 4 cm / s.

[0082] Optionally, the rotation speed of the ultrasonic atomizing balloon catheter is 100 REV / min to 200 REV / min.

[0083] Optionally, the ultrasonic atomization spraying is repeated 20 to 30 times, and the drying time between adjacent ultrasonic atomization sprayings is 50 to 70 seconds.

[0084] This application provides a drug delivery balloon catheter, comprising a balloon catheter and one or more drug reservoir layers and drug coating layers sequentially covering the outer surface of the balloon catheter. The drug reservoir layer contains chitosan-encapsulated PLGA drug-loaded microspheres. During delivery, the outermost drug layer preferentially enters the blood vessel, reaching a saturation concentration within the tissue. Subsequently, the drug is continuously absorbed and metabolized according to its half-life and elimination kinetics, exerting its anti-proliferation effect.

[0085] Specifically, because the first layer of microspheres preferentially enters the tissue and reaches saturation concentration, most of the reserve layer microspheres adhere to the blood vessel wall. Chitosan further enhances the contact between the PLGA microspheres and the blood vessel wall, facilitating the adsorption of individual microspheres and preventing aggregation. Furthermore, the reserve layer collapses around 180 days, releasing a large amount of drug. By this time, the drug from the first layer has been almost completely absorbed, leaving virtually no active drug available, and endothelial cells begin to proliferate. The entry of the reserve layer then fills this gap, allowing the released drug to enter the blood vessels and exert its effect.

[0086] The embodiments of this application will be described in detail below with reference to examples. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of this application. For experimental methods in the following embodiments where specific conditions are not specified, please refer to the guidelines given in this application, or follow experimental manuals or conventional conditions in the art, or follow the conditions recommended by the manufacturer, or refer to experimental methods known in the art.

[0087] In the specific embodiments described below, the measurement parameters involving raw material components may have slight deviations within the weighing accuracy range unless otherwise specified. Temperature and time parameters are subject to acceptable deviations due to instrument testing accuracy or operational precision.

[0088] It should be understood that in the various embodiments of this application, the order of the above-mentioned processes does not imply 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 this application.

[0089] Example 1

[0090] This embodiment provides a drug-eluting balloon catheter, including a balloon catheter and a drug reservoir layer and a drug coating layer sequentially covering the outer surface of the balloon catheter;

[0091] The drug in the drug reservoir is PLGA drug-loaded microspheres encapsulated in chitosan. The particle size of the 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.

[0092] PLGA has a molecular weight of 45,000 Da, and its monomeric compounds include lactide and glycolide in a mass ratio of 10:1.

[0093] The drug layer contains rapamycin, and the concentration of the active drug in the drug layer is 25 mg / mL.

[0094] Example 2

[0095] This embodiment provides a drug-eluting balloon catheter, including a balloon catheter and a drug reservoir layer and a drug coating layer sequentially covering the outer surface of the balloon catheter;

[0096] The drug in the drug reservoir is PLGA drug-loaded microspheres encapsulated in chitosan. The particle size of the 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.

[0097] PLGA has a molecular weight of 40,000 Da, and its monomeric compounds include lactide and glycolide in a mass ratio of 15:1.

[0098] The drug layer is paclitaxel, and the concentration of the active drug in the drug layer is 30 mg / mL.

[0099] Example 3

[0100] This embodiment provides a drug-eluting balloon catheter, including a balloon catheter and a drug reservoir layer and a drug coating layer sequentially covering the outer surface of the balloon catheter;

[0101] The drug in the drug reservoir is PLGA drug-loaded microspheres encapsulated in chitosan. The particle size of the chitosan-encapsulated 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.

[0102] PLGA has a molecular weight of 45,000 Da, and its monomeric compounds include lactide and glycolide in a mass ratio of 5:1.

[0103] The drug layer contains rapamycin, and the concentration of the active drug in the drug layer is 30 mg / mL.

[0104] Example 4

[0105] Another embodiment of this application provides a method for preparing a drug-eluting balloon catheter, comprising:

[0106] 1. Preparation of drug-loaded microspheres from conventional PLGA

[0107] (1) Preparation of 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. Let it cool at room temperature for later use.

[0108] (2) Preparation of oil phase: Accurately weigh 100mg PLGA and a certain mass of drug and add them to dichloromethane (DCM). Dissolve at room temperature to obtain oil phases with different concentrations of PLGA and different drug ratios.

[0109] (3) The oil phase was slowly added dropwise to the aqueous phase, sheared for 50 minutes, mechanically stirred for 10 hours, and then magnetically stirred at room temperature for 10 hours. After the 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, then washed with deionized water, repeated 3 times, and finally vacuum dried for 120 hours to obtain PLGA drug-loaded microspheres.

[0110] The PLGA has a molecular weight of 45,000 Da and a ratio of lactide to lactide of 17:1.

[0111] The drug dosage ratio refers to the mass ratio of PLGA to the drug, which ranges from 20:1.

[0112] 2. Preparation of chitosan-modified PLGA microspheres

[0113] (1) The prepared PLGA microspheres were ultrasonically dispersed in deionized water and added to a chitosan aqueous solution dissolved in low concentration acetic acid.

[0114] (2) Add to liquid paraffin containing Tween 80 and emulsify for several hours, then crosslink with sodium tripolyphosphate.

[0115] The prepared chitosan-encapsulated PLGA drug-loaded microspheres were screened using molecular sieves to distinguish between those with a particle size of less than 30 μm and those with a particle size of more than 30 μm. Microspheres with a particle size of more than 30 μm were used as microspheres for the reserve layer.

[0116] 3. Spraying

[0117] (1) After the balloon catheter is inflated, paclitaxel with a diameter of more than 15 μm is dissolved in an organic solvent under ultrasonic conditions to obtain a lower layer solution suspension, wherein the concentration of active drug in the drug layer solution is 50 mg / mL and the concentration of microspheres is 200 mg / mL.

[0118] (2) The lower layer solution obtained in step 1 is loaded into a syringe with a stirring function to ensure that the microspheres in the syringe can be uniformly dispersed in the suspension.

[0119] (3) The lower layer solution suspension obtained in step 1 is coated onto the outer surface of the balloon catheter by ultrasonic atomization spraying. After drying for a period of time, the steps (1) to (3) are repeated to complete the spraying of the upper layer solution.

[0120] The upper solution is the active pharmaceutical ingredient for the outermost coating layer; the lower solution is the reserve layer solution, which consists of chitosan-encapsulated PLGA drug-loaded microspheres.

[0121] The ultrasonic atomization spraying process conditions in step 3 include: power of 1.2W, drainage gas flow rate of 4psi, temperature of 225℃, humidity of 50%, flow rate of 1mL / min, balloon catheter feed speed of 4cm / s, balloon catheter rotation speed of 200REV / min, ultrasonic atomization spraying repeated 30 times, and drying time between adjacent ultrasonic atomization sprayings of 70s. A schematic diagram of the final sprayed drug-eluting balloon catheter is shown below. Figure 1 As shown.

[0122] Result verification:

[0123] Production formula research:

[0124] To investigate the main influencing factors of the preparation process, a Plackett-Burman (PB) experiment was designed, consisting of 12 groups. A, B, C, D, E, and F represent PLGA concentration, PVA concentration, water-oil ratio, drug ratio, rotation speed, and shear time, respectively. A low-level and high-level value was 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 experimental design for each factor level is shown in the table below.

[0125] Table 1 Experimental factors and levels

[0126]

[0127] Based on the above six-factor, two-level PB experiment as a screening method, the experimental design and results are shown in the table below:

[0128] Table 2

[0129]

[0130] The morphology of the drug-loaded microspheres prepared in the PB experiment is as follows: Figure 2 As shown in the figure, it can be clearly observed that, except for the microspheres in PB-8 which exhibit numerous irregular shapes such as columnar and oblate forms, the microspheres in other formulations show good sphericity, indicating that the experiment proceeded smoothly. Next, a multiple stepwise regression analysis was performed on the data in the table above to eliminate insignificant influencing factors and identify those that significantly affect the response values. The multiple linear regression equations for the response values ​​R1, R2, and R3 on A, B, C, D, E, and F were fitted:

[0131] R1=6.88+2.21A-0.1450B+0.1950C-0.1250D+0.0083E+0.2617F (R12=0.8885, P1<0.05);

[0132] R2=6.11+1.33A+1.68B+0.3650C+2.78D-0.4133E-0.0400F (R22=0.9352, P1<0.05);

[0133] R3=53.30+10.65A+11.67B+3.06C+0.0317D+0.1550E-1.04F (R32=0.9392, P1<0.05);

[0134] To verify the regression effect, an analysis of variance was performed on the above regression equation, and the results are shown in Table 3 below. According to the statistical analysis results, the F-values ​​for 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 is statistically significant.

[0135] Table 3

[0136]

[0137] Pareto charts can determine the importance of each factor. If the bar chart for a factor exceeds the t-value, it is called a significant factor. Figure 3 The Pareto plots show the effects of various factors on particle size (a), drug loading (b), and encapsulation efficiency (c). The most significant factor affecting the particle size of PLGA-loaded Rapa microspheres is the PLGA concentration; the most significant factors affecting the drug loading are the drug-to-particle ratio, PVA concentration, and PLGA concentration; and the most significant factors affecting the encapsulation efficiency are the PVA concentration and PLGA concentration.

[0138] Box-Behnken design is a commonly used response surface methodology. This experiment used Design-Expert 13 software to conduct a three-factor, three-level experiment based on the Plackett-Burman results. PLGA concentration, dosage ratio, and PVA concentration were selected as independent variables, set at low, medium, and high levels as shown in Table 4. Microsphere size, drug loading (DL), and encapsulation efficiency (EE) were used as response values. A total of 17 experiments were conducted, with five replicates at the center point. The experimental design and results are shown in Table 5 below.

[0139] Table 4

[0140]

[0141] Table 5

[0142]

[0143] Analysis shows that:

[0144] Based on the regression equation and the results of the analysis of variance of the regression model, response surface plots and contour plots were constructed to study the effects of PLGA concentration, drug-to-microsphere ratio, and PVA concentration on the particle size, drug loading, and encapsulation efficiency of PLGA-loaded microspheres. When one of the three factors was fixed, the interaction between the other two factors could be visualized using contour plots and response surface plots to assess their impact on the response value, as shown in the following figures. Figure 4 As shown.

[0145] Response surfaces and contour plots provide a visual representation of the impact of interactions on response values. The steepness of the surface and the density of the contour lines reflect the significance of the interaction between factors on the response value; that is, the steeper the surface and the denser the contour lines, the more significant the impact. Furthermore, the closer the contour lines are to an ellipse shape, the stronger the interaction between the two factors.

[0146] After determining the formulation parameters of PLGA, experiments were conducted to fabricate drug capsules by encapsulating chitosan. Multiple embodiments could be set up by adjusting the spraying parameters to compare drug capsules with a single drug coating (commercially available).

[0147] Table 6

[0148]

[0149] The in vitro release rate of the drug-eluting balloon catheter of Example 1 of this application was verified on days 30, 60, 90, and 180 after delivery. The results showed that the drug-eluting balloon catheter of Example 1 of this application can be stored for up to 180 days before releasing the drug. Specifically, as follows... Figure 5 As shown, commercially available drug-eluting balloon catheters generally have no drug residue and are ineffective up to 180 days later. Specifically, as... Figure 6 As shown.

[0150] The embodiments described above merely illustrate several implementation methods of this application to facilitate a detailed understanding of the technical solutions of this application, but should not be construed as limiting the scope of protection of the patent application. It should be noted that those skilled in the art can make various modifications and improvements without departing from the concept of this application, and these all fall within the scope of protection of this application. Furthermore, it should be understood that after reading the above teachings of this application, those skilled in the art can make various alterations or modifications to this application, and the equivalent forms obtained also fall within the scope of protection of this application. It should also be understood that technical solutions obtained by those skilled in the art based on the technical solutions provided in this application through logical analysis, reasoning, or limited experimentation are all within the scope of protection of the appended claims. Therefore, the scope of protection of this patent application should be determined by the content of the appended claims, and the specification and drawings can be used to interpret the content of the claims.

Claims

1. A drug-eluting balloon catheter, characterized in that, It includes a balloon catheter and a drug reservoir layer and a drug coating layer sequentially covering the outer surface of the balloon catheter; the drug reservoir layer may include one or more layers; The drug reservoir contains PLGA drug-loaded microspheres encapsulated in chitosan.

2. The drug-eluting balloon catheter according to claim 1, characterized in that, The particle size of the PLGA drug-loaded microspheres is 1μm~100μm.

3. The drug-eluting balloon catheter according to claim 2, characterized in that, The particle size of the PLGA drug-loaded microspheres is 30 μm to 60 μm.

4. The drug-eluting balloon catheter according to claim 1, characterized in that, The drug reservoir layer has a multi-layer structure, and the particle size of the PLGA drug-loaded microspheres on each reservoir layer decreases sequentially from the inner layer to the outer layer.

5. The drug-eluting balloon catheter according to claim 4, characterized in that, The drug reservoir layer consists of an inner layer and an outer layer, with the particle size of the PLGA drug-loaded microspheres on each reservoir layer decreasing in a gradient.

6. The drug-eluting balloon catheter according to claim 5, characterized in that, The particle size gradient of the PLGA drug-loaded microspheres is 30 μm to 40 μm.

7. The drug-eluting balloon catheter according to any one of claims 1 to 6, characterized in that, The molecular weight of PLGA in the drug-eluting balloon catheter is 40,000 Da to 45,000 Da.

8. The drug-eluting balloon catheter according to claim 7, characterized in that, The molecular weight of PLGA in the drug-eluting balloon catheter is 40,000 Da to 42,000 Da.

9. The drug-eluting balloon catheter according to any one of claims 1 to 6, characterized in that, The drug coating on the drug-eluting balloon catheter is released in 2 to 4 minutes.

10. The drug-eluting balloon catheter according to any one of claims 1 to 6, characterized in that, The drug reservoir collapsed after 180 to 200 days.

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