A testing device and evaluation method for the coating adhesion and in vitro drug release rate of a balloon.

Abstract

This invention discloses a testing device and evaluation method for balloon coating adhesion and in vitro drug release rate, belonging to the technical field of vascular interventional device evaluation. It includes an in vitro release performance testing device; the in vitro release performance testing device comprises: a media liquid constant temperature circulation device, a pulse generator, a flow control unit, a testing operation platform, and an defoaming and particle capture unit connected in sequence. Based on the special circumstances of testing under simulated human body flow conditions, this invention uses a gas-driven diaphragm pulse generator and an electro-proportional valve to adjust and achieve a pulse flow environment under physical conditions.

Description

Technical Field

[0001] This invention discloses a testing device and evaluation method for balloon coating firmness and in vitro drug release rate, belonging to the technical field of vascular interventional device evaluation. Background Technology

[0002] Drug-coated balloons are widely used in the treatment of intravascular stenosis, small vessel disease, bifurcation disease, and in-stent restenosis, and their clinical usage rate is increasing year by year. The drugs in the coating are mainly paclitaxel and rapamycin derivatives. During use, the drug-coated balloon releases drugs to inhibit the growth of neointimal tissue, which can effectively reduce the occurrence of restenosis.

[0003] Coating adhesion testing and in vitro release rate testing examine coating detachment and drug release at the lesion site during simulated use, respectively. These are closely related to clinical efficacy, and particle detachment can also pose potential risks. Therefore, coating adhesion and in vitro drug release rate testing can provide data support for evaluating the safety and efficacy of products. Currently, there are no standard methods to examine these two performance aspects, and the simulation of application conditions is insufficient, resulting in poor correlation between in vitro tests and actual in vivo conditions.

[0004] Chinese patent document CN202111347834.6 discloses a method for evaluating the in vitro drug transfer efficiency of a balloon drug coating. This method involves releasing the drug from a test balloon according to actual usage, then measuring the drug content at the target blood vessel and comparing it to the standard drug content of the test balloon to calculate the in vitro drug transfer efficiency of the balloon drug coating. However, how to utilize an in vitro simulation system to track the shedding of the balloon coating and drug release during use, and establish an in vitro experimental evaluation method that provides test results close to human body temperature, blood flow velocity, and conditions, and further simulates the pulse physiological environment and pressure conditions of a beating heart, remains a technical problem of ongoing concern in this field. Summary of the Invention

[0005] To address the shortcomings of existing technologies, this invention discloses a testing device for the adhesion of a balloon coating and the in vitro drug release rate, providing temperature, pulse, pressure, blood flow velocity, and vascular models close to the intended use site to simulate the clinical use conditions of a drug-coated balloon.

[0006] The present invention also discloses a method for evaluating the coating adhesion and in vitro drug release rate of a balloon using the above-mentioned device. By simulating the balloon delivery process / delivery and expansion process, the detached particles are collected for counting; and the amount of drug remaining on the balloon is measured, and the percentage and difference are calculated with the labeled drug content to evaluate the coating detachment and drug release of the drug balloon in the above process.

[0007] The detailed technical solution of this invention is as follows:

[0008] A device for testing the coating firmness and in vitro drug release rate of a balloon includes: an in vitro release performance testing device;

[0009] The in vitro release performance testing device includes: a medium liquid constant temperature circulation device, a pulse generator, a flow control unit, a test operation platform, and a defoaming and particle capture unit connected in sequence;

[0010] The constant temperature circulation device for the medium liquid includes: a lifting medium tank, a circulation pump and a precision filter connected in sequence, and a water circulation heater and a temperature sensor are provided in the lifting medium tank.

[0011] The pulse generating device includes a connected gas-liquid pulsation generator and an electric proportional valve;

[0012] The test operation platform includes a 3D simulation path and an orifice plate for fixing the 3D simulation path. The 3D simulation path is connected to pipelines on both sides of the test operation platform, and a pressure sensor is provided on the outlet side of the 3D simulation path.

[0013] The defoaming and particle capture unit includes: a bubble eliminator and a particle capture device connected sequentially in the liquid outlet direction of the test operation platform, and a float flow meter is provided between the bubble eliminator and the particle capture device.

[0014] The flow control unit includes a flow control valve installed on the inlet side of the 3D simulation path;

[0015] The particulate trap is connected to the lifting medium tank via a circulation pipeline, and a first control valve is installed on the circulation pipeline.

[0016] According to a preferred embodiment of the present invention, the testing device further includes a pipeline cleaning device, comprising: a vacuum generator and a collection tank respectively connected to the outlet of the float flowmeter and the particulate trap; the float flowmeter is connected to the inlet of the circulation pipeline and the inlet of the particulate trap respectively via a bypass valve; the vacuum generator is connected to the inlet of the circulation pipeline via a branch pipe; and a second control valve is provided on the branch pipe.

[0017] According to a preferred embodiment of the present invention, a one-way valve is provided at the liquid inlet of the 3D simulated path.

[0018] According to a preferred embodiment of the present invention, the electro-proportional valve is further connected to a filter and a silent air compressor.

[0019] According to a preferred embodiment of the present invention, the lifting medium tank includes a tank body and a drive motor for driving the tank body to move up and down; the water circulation heater is used to add hot liquid medium contained in the tank body. This design controls the pressure of the medium fluid by raising and lowering the tank body to create different height differences between the tank body and the test operation platform; it has high temperature protection, low temperature alarm, and low liquid level alarm functions, and uses coil heat exchange to avoid direct electric heating of the medium liquid, thus avoiding local overheating of the medium and salt precipitation.

[0020] According to a preferred embodiment of the present invention, the bubble eliminator includes a gas outlet rigid pipe and an exhaust valve above the tapered resin hose to eliminate bubbles generated in the pipeline and avoid affecting the normal operation of the particulate trap and flow meter. Therefore, the venturi structure adopted in this technical modification is used to eliminate bubbles in the system.

[0021] According to a preferred embodiment of the present invention, the gas-liquid pulsation generator includes a gas-driven diaphragm pulse generator, which adjusts the simulated pulse physiological environment required for the evaluation test through electro-proportional program control.

[0022] According to a preferred embodiment of the present invention, the testing device further includes a control module, wherein operating software is loaded in the control module to enable the user to set parameters, perform evaluation operations, and store data during the evaluation test through the control module.

[0023] A method for evaluating the adhesion of a balloon coating and the in vitro drug release rate using the above-mentioned device includes: evaluating the coating adhesion according to steps S1, S2, S3, S4, S7, and S8.

[0024] S1. Add the release medium into the lifting medium tank of the device. First, turn on the water circulation heating device and set the temperature of the medium. Then turn on the gas-liquid pulsation generator and set the pulse flow rate. Then turn on the circulation pump, bubble eliminator, and float flow meter. Open the particle trap channel. Make the entire test device circulate and fill with the medium and reach the test constant temperature, preferably 37℃.

[0025] S2. Insert the guiding catheter and guidewire into the designated test site of the 3D simulation path, i.e. the designated test site of the vascular model.

[0026] S3. Insert the balloon along the guidewire into the guiding catheter and deliver it to the designated test site of the 3D simulation path. After the predetermined time is reached, remove and cut off the balloon.

[0027] S4. Immerse the cut balloons in the extraction solvent. After complete extraction, measure the amount of drug remaining on the balloons. The method for calculating the firmness is as follows:

[0028] Firmness = (1 - Drug content on balloon / Nominal drug content) * 100%;

[0029] S7. Collect the sample collected at the particulate trap for testing;

[0030] S8. After the test, drain the liquid from the test device.

[0031] A method for evaluating the adhesion of a balloon coating and the in vitro drug release rate using the above-mentioned device includes: evaluating the in vitro drug release rate by performing steps S1, S2, S5, S6, S7, and S8.

[0032] S1. Add the release medium into the lifting medium tank of the device. First, turn on the water circulation heating device and set the temperature of the medium. Then turn on the gas-liquid pulsation generator and set the pulse flow rate. Then turn on the circulation pump, bubble eliminator, and float flow meter. Open the particle trap channel. Make the entire test device circulate and fill with the medium and reach the test constant temperature, preferably 37℃.

[0033] S2. Insert the guiding catheter and guidewire into the designated test site of the 3D simulation path, i.e. the designated test site of the vascular model.

[0034] S5. Insert the balloon along the guidewire into the guiding catheter and deliver it to the designated test site of the vascular model. Use the inflation device to slowly pressurize the balloon to the nominal pressure. After the predetermined time is reached, depressurize the balloon, remove it, and cut it off.

[0035] S6. Immerse the cut balloon in the extraction solvent and measure the remaining drug content on the balloon. The in vitro drug release rate is calculated as follows:

[0036] In vitro release rate = (1 - remaining drug content on the balloon / nominal drug content) * 100%;

[0037] S7. Collect the sample collected at the particulate trap for testing;

[0038] S8. After the test, drain the liquid from the test device.

[0039] According to a preferred embodiment of the present invention, after the liquid in the testing device is drained, the lifting medium tank is replaced with pure water, and the circulation pump is turned on to clean the entire in vitro release performance testing device.

[0040] The technical advantages of this invention are:

[0041] 1. This invention is based on the simulation of human blood flow conditions, using a pneumatic diaphragm pulse generator and an electric proportional valve to adjust and realize the pulse flow environment under physical conditions.

[0042] 2. This invention uses 3D simulation paths and well plates, which facilitates the placement and fixation of simulated blood vessels during the experiment. The simulated blood vessel path module can be replaced as needed to meet the requirements of different test paths in the experiment.

[0043] 3. The system's corresponding valves, filters, and dedicated degassing devices provide a clean fluid environment required for testing and avoid the influence of air bubbles in the flow path.

[0044] 4. The software allows for convenient parameter setting, experimental operation, and data storage.

[0045] 5. This invention also fully considers the difficulty of cleaning the pipeline after the evaluation test. In order to meet the future requirements for the analysis of particles that fall off during the test, the system is equipped with a particle trap and a dedicated fluid passage is reserved. Attached Figure Description

[0046] Figure 1 This is a connection diagram of the testing device described in this invention. Detailed Implementation

[0047] The present invention will now be described in detail with reference to the embodiments and the accompanying drawings, but is not limited thereto.

[0048] Example 1

[0049] A device for testing the coating firmness and in vitro drug release rate of a balloon includes: an in vitro release performance testing device;

[0050] The in vitro release performance testing device includes: a medium liquid constant temperature circulation device, a pulse generator and flow control unit, a test operation platform, and a defoaming and particle capture unit connected in sequence;

[0051] The constant temperature circulation device for the medium liquid includes: a lifting medium tank and a precision filter connected in sequence; a water circulation heater and a temperature sensor are installed in the lifting medium tank; and a liquid medium for holding the balloon for in vitro release and stability testing.

[0052] The pulse generating device includes a connected gas-liquid pulsation generator and an electric proportional valve; the circulating pump output power is adjusted and the float flow meter is adjusted to control the circulating flow rate of the medium liquid to about 80 ml / min as required for the test;

[0053] The testing platform includes a 3D simulation path and an orifice plate for fixing the 3D simulation path. The 3D simulation path is connected to pipelines on both sides of the testing platform, and a pressure sensor is installed at the outlet side of the 3D simulation path. The 3D simulation path is fabricated based on parameters such as the size, curvature, elasticity, and wall thickness of the blood vessels at the target site, and is made of silicone to simulate the blood vessel path traversed by the balloon. Figure 1As shown, the medium liquid is provided with 4 outlets as needed, fixed on the orifice plate, and each outlet is equipped with a corresponding switch valve, which can be connected to different lumens of the conduit. When connecting different conduit lumens, a clean RHV valve is used to prevent the conduit from passing through the simulated path and to prevent liquid backflow and overflow during the evacuation process; a movable pressure sensor is equipped at the outlet end of the 3D simulated path to monitor the fluid pressure at the far end of the path pipe, with a pressure measurement range of 0-10 psi and an accuracy of ≤1%FS;

[0054] The defoaming and particle capture unit includes: a bubble eliminator and a particle capture device connected sequentially in the liquid outlet direction of the test operation platform, and a float flow meter is provided between the bubble eliminator and the particle capture device.

[0055] The flow control unit includes a flow control valve installed on the inlet side of the 3D simulation path;

[0056] The particulate trap is connected to the lifting medium tank via a circulation pipeline, and a first control valve is installed on the circulation pipeline.

[0057] A one-way valve is installed at the liquid inlet of the 3D simulation path.

[0058] The electro-proportional valve is also connected to a filter and a silent air compressor.

[0059] The bubble eliminator includes a gas outlet rigid pipe and an exhaust valve above the tapered resin hose to eliminate bubbles generated in the pipeline and avoid affecting the normal operation of the particulate trap and flow meter. Therefore, this technical modification adopts a Venturi structure to eliminate bubbles in the system.

[0060] The gas-liquid pulsation generator includes a gas-driven diaphragm pulse generator, which uses an electro-proportional program control to adjust the simulated pulse physiological environment required for the evaluation test. The pulse flow has a pressure of 80-160 mmHg and a frequency of 72 bpm, which can simulate the actual working conditions to perform pulse flow impact on the stent or drug-eluting balloon. The impact waveform is similar to a sine wave.

[0061] Example 2

[0062] As described in Example 1, a testing device for the coating firmness and in vitro drug release rate of a balloon is provided. The testing device further includes a pipeline cleaning device, comprising: a vacuum generator and a collection tank respectively connected to the outlet of the float flowmeter and the particulate trap. The float flowmeter is connected to the inlet of the circulation pipeline and the inlet of the particulate trap respectively through a bypass valve. The vacuum generator is connected to the inlet of the circulation pipeline through a branch pipe, and a second control valve is provided on the branch pipe.

[0063] Example 3

[0064] As described in Examples 1 and 2, a testing device for the coating adhesion and in vitro drug release rate of a balloon includes a lifting medium tank comprising a tank body and a drive motor for moving the tank body up and down; a water circulation heater is used to add hot liquid medium contained in the tank body. This design uses the lifting of the tank body to create different height differences between the tank body and the testing platform, thereby controlling the pressure of the medium fluid; it has high-temperature protection, low-temperature alarm, and low liquid level alarm functions, and uses coil heat exchange, avoiding direct electric heating of the medium liquid to prevent local overheating and salt precipitation. In this embodiment, the medium tank volume is 5L, the temperature is controlled within 37℃±1℃, and a 0.2-micron precision filter is installed at the outlet to filter the medium liquid. The medium liquid tank design considers ease of cleaning, employing a separate tank body and measuring instruments, with the coil system separate. The medium tank is placed on the platform and can be lifted up and down by a small motor.

[0065] Example 4

[0066] As described in Examples 1, 2, and 3, a testing device for the coating adhesion and in vitro drug release rate of a balloon includes operating software loaded in the control module. This software allows users to set parameters, perform evaluation operations, and store data during the evaluation test. The operating software also features alarm prompts for abnormal conditions such as overpressure and overtemperature, and shutdown settings. Electrical components have protection functions against leakage, overload, overvoltage, undervoltage, phase loss, and phase reversal. The system includes an emergency stop button and three-color indicators to indicate the operating status.

[0067] Example 5

[0068] A method for evaluating the adhesion of a balloon coating and the in vitro drug release rate using the above-mentioned device, wherein the evaluation method for coating adhesion is performed according to steps S1, S2, S3, S4, S7, and S8.

[0069] S1. Add the release medium into the lifting medium tank of the device. First, turn on the water circulation heating device and set the temperature of the medium. Then turn on the gas-liquid pulsation generator and set the pulse flow rate. Then turn on the circulation pump, bubble eliminator, and float flow meter. Open the particle trap channel. Make the entire test device circulate and fill with the medium and reach the test constant temperature, preferably 37℃.

[0070] S2. Insert the guiding catheter and guidewire into the designated test site of the 3D simulation path, i.e. the designated test site of the vascular model.

[0071] S3. Insert the balloon along the guidewire into the guiding catheter and deliver it to the designated test site of the 3D simulation path. After the predetermined time is reached, remove and cut off the balloon.

[0072] S4. Immerse the cut balloons in the extraction solvent. After complete extraction, measure the amount of drug remaining on the balloons. The method for calculating the firmness is as follows:

[0073] Firmness = (1 - Drug content on balloon / Nominal drug content) * 100%;

[0074] S7. Collect the sample collected at the particulate trap for testing;

[0075] S8. After the test, drain the liquid from the test device.

[0076] Example 6

[0077] A method for evaluating the adhesion of a balloon coating and the in vitro drug release rate using the above-mentioned device includes: evaluating the in vitro drug release rate by performing steps S1, S2, S5, S6, S7, and S8.

[0078] S1. Add the release medium into the lifting medium tank of the device. First, turn on the water circulation heating device and set the temperature of the medium. Then turn on the gas-liquid pulsation generator and set the pulse flow rate. Then turn on the circulation pump, bubble eliminator, and float flow meter. Open the particle trap channel. Make the entire test device circulate and fill with the medium and reach the test constant temperature, preferably 37℃.

[0079] S2. Insert the guiding catheter and guidewire into the designated test site of the 3D simulation path, i.e. the designated test site of the vascular model.

[0080] S5. Insert the balloon along the guidewire into the guiding catheter and deliver it to the designated test site of the vascular model. Use the inflation device to slowly pressurize the balloon to the nominal pressure. After the predetermined time is reached, depressurize the balloon, remove it, and cut it off.

[0081] S6. Immerse the cut balloon in the extraction solvent and measure the remaining drug content on the balloon. The in vitro drug release rate is calculated as follows:

[0082] In vitro release rate = (1 - remaining drug content on the balloon / nominal drug content) * 100%;

[0083] S7. Collect the sample collected at the particulate trap for testing;

[0084] S8. After the test, drain the liquid from the test device.

[0085] According to a preferred embodiment of the present invention, after the liquid in the testing device is drained, the lifting medium tank is replaced with pure water, and the circulation pump is turned on to clean the entire in vitro release performance testing device.

[0086] Example 7

[0087] The method for evaluating the coating adhesion and in vitro drug release rate of the balloon using the above-mentioned device as described in Examples 5 and 6 includes: after draining the liquid in the test device, replacing the lifting medium tank with pure water, and turning on the circulation pump to clean the entire in vitro release performance test device.

Claims

1. A device for testing balloon coating firmness and drug release rate in vitro, characterized by, include: In vitro release performance testing device; The in vitro release performance testing device includes: a medium liquid constant temperature circulation device, a pulse generator, a flow control unit, a test operation platform, and a defoaming and particle capture unit connected in sequence; The constant temperature circulation device for the medium liquid includes: a lifting medium tank, a circulation pump and a precision filter connected in sequence. A water circulation heater and a temperature sensor are provided in the lifting medium tank. The lifting medium tank includes a tank body and a drive motor for driving the tank body to move up and down. The pulse generating device includes a connected gas-liquid pulsation generator and an electric proportional valve, wherein the gas-liquid pulsation generator includes a gas-driven diaphragm pulse generator; The gas-liquid pulsation generator adjusts the simulated pulse physiological environment required for the evaluation test through electro-proportional program control. The test operation platform includes a 3D simulation path and an orifice plate for fixing the 3D simulation path. The 3D simulation path is connected to pipelines on both sides of the test operation platform, and a pressure sensor is provided on the outlet side of the 3D simulation path. The defoaming and particle capture unit includes: a bubble eliminator and a particle capture device connected sequentially in the liquid outlet direction of the test operation platform, and a float flow meter is provided between the bubble eliminator and the particle capture device. The bubble eliminator includes a tapered resin hose, a gas outlet rigid pipe above the tapered resin hose, and an exhaust valve to eliminate bubbles generated in the pipe. The flow control unit includes a flow control valve installed on the inlet side of the 3D simulation path; The particulate trap is connected to the lifting medium tank via a circulation pipeline, and a first control valve is installed on the circulation pipeline.

2. The device for testing the balloon coating firmness and drug release rate in vitro according to claim 1, wherein, The testing device also includes a pipeline cleaning device, comprising: a vacuum generator and a collection tank respectively connected to the outlet of the float flowmeter and the particulate trap; the float flowmeter is connected to the inlet of the circulation pipeline and the inlet of the particulate trap respectively through a bypass valve; the vacuum generator is connected to the inlet of the circulation pipeline through a branch pipe; and a second control valve is provided on the branch pipe.

3. The device for testing the balloon coating firmness and drug release rate in vitro according to claim 1, wherein, A one-way valve is installed at the inlet of the 3D simulation path.

4. The device for testing the balloon coating firmness and drug release rate in vitro according to claim 1, wherein, The electro-proportional valve is also connected to a filter and a silent air compressor.

5. The device for testing the balloon coating firmness and drug release rate in vitro according to claim 1, wherein The water circulation heater is used to heat the liquid medium contained in the tank.

6. The testing device for the coating firmness and in vitro drug release rate of a balloon according to claim 1, characterized in that, The testing device also includes a control module, which is loaded with operating software to enable users to set parameters, perform evaluation operations, and store data during evaluation tests.

7. A method for evaluating the adhesion of a balloon coating and the in vitro drug release rate using the device as described in any one of claims 1 to 6, comprising: The evaluation method for coating adhesion is performed according to steps S1, S2, S3, S4, S7, and S8. S1. Add the release medium into the lifting medium tank of the device. First, turn on the water circulation heater and set the temperature of the medium. Then, turn on the gas-liquid pulsation generator and set the pulse flow rate. Then, turn on the circulation pump, bubble eliminator, and float flow meter. Open the particle trap channel. Make the entire test device circulate and fill with the medium and reach the test constant temperature. S2. Insert the guiding catheter and guidewire into the designated test site along the 3D simulated path in sequence; S3. Insert the balloon along the guidewire into the guiding catheter and deliver it to the designated test site along the 3D simulated path. After the predetermined time has elapsed, remove and cut off the balloon. S4. Immerse the cut balloons in the extraction solvent. After complete extraction, measure the amount of drug remaining on the balloons. The method for calculating the firmness is as follows: Firmness = (1 - Drug content on balloon / Nominal drug content) × 100%; S7. Collect the sample collected at the particulate trap for testing; S8. After the test, drain the liquid from the test device.

8. A method for evaluating the adhesion of a balloon coating and the in vitro drug release rate using the device as described in any one of claims 1 to 6, comprising: The method for evaluating the in vitro release rate of the drug is performed according to steps S1, S2, S5, S6, S7, and S8. S1. Add the release medium into the lifting medium tank of the device. First, turn on the water circulation heater and set the temperature of the medium. Then, turn on the gas-liquid pulsation generator and set the pulse flow rate. Then, turn on the circulation pump, bubble eliminator, and float flow meter. Open the particle trap channel. Make the entire test device circulate and fill with the medium and reach the test constant temperature. S2. Insert the guiding catheter and guidewire into the designated test site along the 3D simulated path in sequence; S5. Insert the balloon along the guidewire into the guiding catheter and deliver it to the designated test site of the vascular model. After the predetermined time has elapsed, depressurize the balloon, remove it, and cut it off. S6. Immerse the cut capsules in the extraction solvent and measure the remaining drug content on the capsules. The in vitro drug release rate is calculated as follows: In vitro release rate = (1 - remaining drug content on the balloon / nominal drug content) × 100%; S7. Collect the sample collected at the particulate trap for testing; S8. After the test, drain the liquid from the test device; After the liquid in the testing device is drained, the lifting medium tank is replaced with pure water, and the circulation pump is turned on to clean the entire in vitro release performance testing device.

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