Controllable drug release balloon catheter for urethrostenosis treatment and preparation method thereof

Abstract

The invention discloses a controllable drug release balloon catheter for treating urethrostenosis and a preparation method of the controllable drug release balloon catheter, and belongs to the technical field of medication for urinary diseases, two layers of coatings with different components are sprayed on the surface of a balloon, the coatings comprise a drug-loaded microcapsule complex coating and a quaternary ammonium salt modified silicon dioxide coating, and the drug-loaded microcapsule complex coating and the quaternary ammonium salt modified silicon dioxide coating are compounded through cooperation of the two coatings. The long-acting effect of the medicine can be guaranteed, the medicine is not prone to being washed away by blood flow and losing efficacy, the lubricity is good, the urethra of a patient is not prone to being damaged, and the local inhibition effect on urethrostenosis inflammation of the patient is achieved; the drug-loaded microcapsule complex coating on the inner layer has a certain swelling effect, the drug-loaded microcapsule complex coating absorbs water to swell in the urethra, the radial pressure generated by swelling can stretch the outer layer, gaps among silicon dioxide particles are enlarged, disulfide bonds are fully exposed, the fully exposed disulfide bonds are more easily in contact with acid metabolites and reducing agents at the urethritis part, and therefore the urethritis treatment effect is improved. The disulfide bond breaking efficiency is improved, and free release of quaternary ammonium salt is accelerated.

Description

Technical Field

[0001] This invention belongs to the field of urological drug technology, specifically a controlled-release balloon catheter for the treatment of urethral stricture and its preparation method. Background Technology

[0002] Percutaneous balloon angioplasty to reopen narrowed blood vessels is an innovation in vascular reconstruction. However, balloon angioplasty has significant drawbacks in long, narrow vessels and small vessels, and the reopened vessels are prone to restenosis. While stents in stent surgery provide mechanical support to the vessel and can eliminate the elastic recoil and subsequent negative vascular remodeling that often occur after simple balloon dilation, they can also lead to excessive inflammation, resulting in more intimal hyperplasia and in-stent restenosis.

[0003] Drug-eluting balloons are a novel intravascular drug release technology developed based on interventional techniques such as balloon dilation or balloon angioplasty. Anti-proliferative drugs, such as paclitaxel and rapamycin, are coated on the surface of the balloon. When the balloon reaches the diseased blood vessel and is inflated and comes into contact with the vessel wall's intima, the drug it carries is rapidly transferred to the vessel wall and remains there for a relatively long period. The drug inhibits intimal proliferation in the vessel wall, thereby preventing restenosis after surgery.

[0004] Many factors influence the efficacy of drug-eluting balloons, including the drug content and distribution on the balloon surface, drug loss during delivery, the ability of the drug to migrate to the vessel wall, and the drug's retention capacity under blood flow conditions. All of these factors are directly related to the morphology of the drug on the coating surface. The surface morphology of the drug in the coating not only affects drug loss during delivery and the ability of the drug to migrate to the vessel wall, but also influences the drug release rate and retention time at the site of the diseased vessel.

[0005] Chinese patent announcement CN104324421B discloses a method for preparing a drug coating for a therapeutic balloon dilation catheter. In this method, a paclitaxel drug solution is mixed with another incompatible interference solvent before ultrasonic spraying to change the morphology of the drug in the solution. Then, ultrasonic spraying is performed to control the particle size of the coating, increase the coating adhesion, and control the drug release rate. However, this method only uses paclitaxel and polyvinylpyrrolidone as carriers, which makes the active drug ingredient easily washed away by blood flow, resulting in the loss of paclitaxel and a reduction in efficacy. Summary of the Invention

[0006] The purpose of this invention is to provide a controlled-release balloon catheter for the treatment of urethral stricture and its preparation method. By spraying two layers of coatings with different compositions on the surface of the balloon, including a drug-loaded microcapsule complex coating and a quaternary ammonium salt modified silica coating, the synergistic effect of the two coatings can ensure the long-term efficacy of the drug, prevent it from being washed away by blood flow and lose its effectiveness, provide good lubrication and prevent damage to the patient's urethra, and have a local inhibitory effect on the inflammation of the patient's urethral stricture.

[0007] The objective of this invention can be achieved through the following technical solutions: A method for preparing a controlled-release balloon catheter for the treatment of urethral stricture includes the following steps: Step 1: Using the coordination assembly method, carboxymethyl chitosan, terephthalic acid and ferric chloride are self-assembled into microcapsules, which are then used to encapsulate antifibrotic drugs and anti-inflammatory drugs, thus obtaining drug-loaded microcapsule complex coatings.

[0008] Step 2: Treat the product with 3-mercaptopropyltrimethoxysilane to obtain mercaptosilica powder; 2-chloroethanethiol reacts with N,N-dimethyl-n-octylamine to obtain mercaptoquaternary ammonium salt, which is then oxidized with the mercaptosilica powder to obtain quaternary ammonium salt modified silica coating.

[0009] Step 3: Using nanoimprinting technology, a polylactic acid-glycolic acid copolymer solution is coated onto a template to obtain a capsule with micropores. The capsule is then sprayed with a drug-loaded microcapsule complex coating and a quaternary ammonium salt modified silica coating to obtain a controlled-release drug capsule.

[0010] Step 4: The controlled-release balloon and the inflation chamber of the polyetheretherketone catheter are sealed together using a heat-sealing process to obtain a controlled-release balloon catheter for the treatment of urethral stricture.

[0011] Furthermore, the specific preparation steps of the drug-loaded microcapsule complex coating are as follows: The therapeutic drug, acetonitrile, and acetone were added to a reaction vessel at a ratio of 5-6 g: 300-400 mL: 300-400 mL. The mixture was stirred for 20-30 min at 20-25°C and 500-600 rpm to form the organic phase. Carboxymethyl chitosan and deionized water were added to the reaction vessel at a ratio of 30-40 g: 1.5-2 L. The mixture was stirred for 20-30 min at 20-25°C and 500-600 rpm to form the aqueous phase. The organic phase was then added to the aqueous phase at a 1:1 mass ratio and homogenized for 3-4 minutes at 4000-4200 rpm. A homogeneous emulsion was obtained. The homogeneous emulsion, terephthalic acid, and ferric chloride were added to a reaction vessel and stirred for 20-30 min at 20-25℃ and 500-600 r / min. Then, a mixed solution of sodium hexadecyl sulfate and 60-70 wt% ethanol was added and stirred for 24-26 h at 120-130℃ and 500-600 r / min. The mixture was then centrifuged for 3-5 min at 10000-12000 r / min, filtered, and the precipitate was washed 2-3 times with deionized water and anhydrous ethanol. The precipitate was then vacuum dried at 60-70℃ for 1-2 h to obtain the drug-loaded microcapsule complex coating.

[0012] Furthermore, the ratio of homogenized emulsion, terephthalic acid, ferric chloride, sodium hexadecyl sulfate, and ethanol solution is 70-80 mL: 20-30 g: 12-15 g: 0.2-0.4 g: 20-30 mL.

[0013] Furthermore, the specific preparation steps for mercapto silica powder are as follows: Add silica powder, 3-mercaptopropyltrimethoxysilane, anhydrous ethanol, and deionized water to a reaction vessel in a ratio of 10-12 g: 12-14 mL: 50-60 mL: 400-500 mL. Adjust the pH to 3-4 with hydrochloric acid solution. Stir for 24-26 h at 20-25 °C and 500-600 r / min. Filter the mixture, wash the precipitate 2-3 times with deionized water and anhydrous ethanol, and dry it under vacuum at 60-70 °C for 1-2 h to obtain mercaptosilica powder.

[0014] Furthermore, the specific preparation steps for quaternary ammonium salt modified silica coatings are as follows: Mercaptosilica powder, mercaptoquaternary ammonium salt, dimethyl sulfoxide and deionized water are added to a reaction vessel and stirred for 4-5 hours at 20-25℃ and 500-600 r / min. After filtration, the precipitate is washed 2-3 times with deionized water and anhydrous ethanol and dried under vacuum at 60-70℃ for 1-2 hours to obtain quaternary ammonium salt modified silica coating.

[0015] Furthermore, the ratio of mercapto silica powder, mercapto quaternary ammonium salt, acetonitrile, dimethyl sulfoxide and deionized water is 20-30g: 22-24g: 50-60mL: 500-600mL.

[0016] Furthermore, the specific preparation steps of the thiol quaternary ammonium salt are as follows: 2-Chloroethanethiol, N,N-dimethyl-n-octylamine, and acetonitrile were added to a reaction vessel at a ratio of 30-50 g: 50-60 g: 100-120 mL. The mixture was stirred at 20-25 °C and 500-600 r / min for 6-7 h. After filtration, the precipitate was washed 2-3 times with deionized water and anhydrous ethanol and dried under vacuum at 60-70 °C for 1-2 h to obtain mercaptoquaternary ammonium salt.

[0017] Furthermore, the specific preparation steps of the controlled-release drug-eluting balloon are as follows: The drug-loaded microcapsule complex coating was sprayed onto the capsules at a flow rate of 0.1-0.2 mL / min for 0.5-1 min. After spraying, the capsules were removed and dried at 30-40℃ and 60-70% relative humidity for 30-40 min. Then, the quaternary ammonium salt modified silica coating was sprayed onto the capsules a second time at a flow rate of 0.1-0.2 mL / min for 0.5-1 min. The capsules were removed and dried under the same conditions for 30-40 min. After folding, tube filling, sterilization, and packaging, the controlled-release drug capsules were obtained.

[0018] Furthermore, the specific preparation steps of the balloon are as follows: Polylactic acid-glycolic acid copolymer and dichloromethane were added to a reaction vessel at a ratio of 800-900g:1-2L. The mixture was stirred at 20-25℃ and 500-600r / min for 30-40min to obtain a polylactic acid-glycolic acid copolymer solution. The polylactic acid-glycolic acid copolymer solution was coated onto a template using nanoimprinting technology. The template was dried at 20-25℃ for 24-26h and cured at 60-70℃ for 12-14h to obtain a 2.0×20mm microporous balloon.

[0019] The beneficial effects of this invention are: 1. The controlled-release balloon catheter prepared by the present invention, by spraying two layers of coatings with different compositions on the surface of the balloon, including a drug-loaded microcapsule complex coating and a quaternary ammonium salt modified silica coating, can ensure the long-term effect of the drug through the synergistic effect of the two coatings, making it less likely to be washed away and lose its effectiveness by blood flow, with good lubrication and less likely to damage the patient's urethra, and has a local inhibitory effect on the inflammation of the patient's urethral stricture.

[0020] 2. The controlled-release balloon catheter of the present invention can accurately reach the urethral stricture site through guide wire. After inflation, the balloon can fit tightly against the stricture site. The main body of the catheter is made of biocompatible polyetheretherketone material, and the balloon is made of biodegradable polylactic acid-glycolic acid copolymer, which reduces irritation to urethral tissue and foreign body reaction, and reduces the risk of complications.

[0021] 3. The drug-loaded microcapsule complex coating of the present invention encapsulates the active pharmaceutical ingredients, such as anti-fibrotic drugs and anti-inflammatory drugs, into microcapsules. The microcapsules are obtained by co-coordinating carboxymethyl chitosan and terephthalic acid with iron ions. Terephthalic acid acts as a rigid ligand, forming a porous network of metal-organic framework with iron ions. Then, the carboxyl groups cross-link with carboxymethyl chitosan to form an organic-inorganic hybrid capsule wall, which improves the mechanical stress that the microcapsules can withstand in the urethra. Combined with the nanogel structure, it enhances the sustained-release function of the active pharmaceutical ingredients.

[0022] 4. The quaternary ammonium salt modified silica coating of the present invention is obtained by treating the surface of the coating with 3-mercaptopropyltrimethoxysilane to produce abundant thiol groups, resulting in thiol silica powder. The chloride ions in 2-chloroethanethiol undergo a substitution reaction with N,N-dimethyl-n-octylamine to obtain a thiol quaternary ammonium salt containing thiol groups. The thiol silica powder and the thiol quaternary ammonium salt undergo an oxidation reaction to generate a quaternary ammonium salt modified silica coating linked by disulfide bonds. The disulfide bonds are pH-responsive; urethral inflammatory bacteria produce acidic metabolites locally in the urethra, lowering the local pH and causing some disulfide bonds to break, promoting the precise release of the quaternary ammonium salt. This allows the quaternary ammonium salt to pre-treat urethral inflammation before the drug capsule takes effect, improving efficacy. The role of silica is to increase the strength of the coating and provide a smooth surface, reducing friction in the controlled-release balloon catheter and preventing patient discomfort and exacerbation of inflammation.

[0023] 5. The controlled-release balloon catheter of this invention utilizes the synergistic effect of two coatings. The inner layer of drug-loaded microcapsule complex coating has a certain swelling effect, easily absorbing water and swelling in the urethra. The radial pressure generated by the swelling stretches the outer layer, increasing the gaps between silica particles and fully exposing disulfide bonds. Fully exposed disulfide bonds are more likely to come into contact with acidic metabolites and reducing agents at the site of urethral inflammation, improving the disulfide bond breaking efficiency and accelerating the release of quaternary ammonium salts. The synergistic effect of the two coatings can prevent the active drug ingredients from being washed away by the bloodstream, thus preventing the loss of active ingredients. Detailed Implementation

[0024] The technical solutions of the present invention will be clearly and completely described below with reference to the embodiments of the present invention. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative effort are within the scope of protection of the present invention.

[0025] Example 1: A method for preparing a controlled-release balloon catheter for the treatment of urethral stricture, comprising the following steps: S1: Add 5.5g of therapeutic drug, 300mL of acetonitrile, and 300mL of acetone to a reaction vessel and stir for 20min at 20℃ and 500r / min to form the organic phase; add 30g of carboxymethyl chitosan and 1.5L of deionized water to the reaction vessel and stir for 20min at 20℃ and 500r / min to form the aqueous phase. Then, pour the organic phase into the aqueous phase at a 1:1 mass ratio and homogenize at 4000r / min for 3min to obtain a homogeneous emulsion; add 70mL of the homogeneous emulsion and 20g of... Terephthalic acid and 12g of ferric chloride were added to a reaction vessel and stirred for 20 min at 20℃ and 500 r / min. Then, a mixture of 0.2g of sodium hexadecyl sulfate and 20mL of 60wt% ethanol solution was added and stirred for 24 h at 120℃ and 500 r / min. After centrifugation at 10000-12000 r / min for 3-5 min, the mixture was filtered. The precipitate was washed 2-3 times with deionized water and anhydrous ethanol and dried under vacuum at 60-70℃ for 1-2 h to obtain the drug-loaded microcapsule complex coating.

[0026] A porous network of metal-organic framework is formed by coordinating the carboxyl groups of carboxymethyl chitosan and terephthalic acid with iron ions. Then, the carboxyl groups are cross-linked with carboxymethyl chitosan to form an organic-inorganic hybrid capsule wall. The core of the capsule is the active pharmaceutical ingredient paclitaxel, thus obtaining a drug-loaded microcapsule complex coating.

[0027] S2: Add 10g of silica powder, 12mL of 3-mercaptopropyltrimethoxysilane, 50mL of anhydrous ethanol and 400mL of deionized water to a reaction vessel, adjust the pH value to 3 with hydrochloric acid solution, stir for 24h at 20℃ and 500r / min, filter, wash the precipitate twice with deionized water and anhydrous ethanol, and dry under vacuum at 60℃ for 1h to obtain mercaptosilica powder.

[0028] Silica powder is combined with silane bonds generated by the hydrolysis of 3-mercaptopropyltrimethoxysilane to obtain mercaptosilica powder with mercapto groups.

[0029] S3: Add 30g of 2-chloroethanethiol, 50g of N,N-dimethyl-n-octylamine, and 100mL of acetonitrile to a reaction vessel, stir for 6h at 20℃ and 500r / min, filter, wash the precipitate twice with deionized water and anhydrous ethanol, and vacuum dry at 60℃ for 1h to remove acetonitrile, obtaining mercapto-quaternary ammonium salt; add 20g of mercapto-silica powder, 22g of mercapto-quaternary ammonium salt, 50mL of dimethyl sulfoxide, and 500mL of deionized water to a reaction vessel, stir for 4h at 20℃ and 500r / min, filter, wash the precipitate twice with deionized water and anhydrous ethanol, and vacuum dry at 60℃ for 1h to obtain quaternary ammonium salt modified silica coating.

[0030] S4: Add 800g of polylactic acid-glycolic acid copolymer and 1L of dichloromethane to a reaction vessel and stir for 30min at 20℃ and 500r / min to obtain a polylactic acid-glycolic acid copolymer solution. Using nanoimprinting technology, coat the polylactic acid-glycolic acid copolymer solution onto a template, dry at 20℃ for 24h and cure at 60℃ for 12h to obtain a 2.0×20mm microporous balloon.

[0031] S5: The drug-loaded microcapsule complex coating is sprayed onto the capsule at a flow rate of 0.1 mL / min for 0.5 min. After spraying, the capsule is removed and dried at 30℃ and 60% relative humidity for 30 min. After the drug-loaded microcapsule complex coating is sprayed and dried, solvents such as acetonitrile evaporate and are removed, and the therapeutic drug recrystallizes. Then, the quaternary ammonium salt modified silica coating is sprayed onto the capsule a second time at a flow rate of 0.1 mL / min for 0.5 min. The capsule is removed and dried under the same conditions for 30 min to obtain the controlled-release drug capsule.

[0032] S6: The controlled-release balloon and the inflation chamber of the polyether ether ketone catheter are sealed together by heat sealing to obtain a controlled-release balloon catheter for the treatment of urethral stricture.

[0033] Example 2: A method for preparing a controlled-release balloon catheter for the treatment of urethral stricture, comprising the following steps: S1: Add 5.5g of therapeutic drug, 350mL of acetonitrile, and 350mL of acetone to a reaction vessel and stir for 25min at 22.5℃ and 550r / min to form the organic phase. Add 35g of carboxymethyl chitosan and 1.75L of deionized water to the reaction vessel and stir for 25min at 22.5℃ and 550r / min to form the aqueous phase. Then, pour the organic phase into the aqueous phase at a 1:1 mass ratio and homogenize for 3.5min at 4100r / min to obtain a homogeneous emulsion. Add 75mL of the homogeneous emulsion, 25g of terephthalic acid, and 13.5g of ferric chloride to the reaction vessel and stir for 25min at 22.5℃ and 550r / min. Then, add 0.3g of sodium hexadecyl sulfate and 25mL of... A mixture of 65wt% ethanol solution was stirred at 125℃ and 550r / min for 25h, centrifuged at 10000-12000r / min for 3-5min, filtered, and the precipitate was washed 2-3 times with deionized water and anhydrous ethanol and dried under vacuum at 60-70℃ for 1-2h to obtain the drug-loaded microcapsule complex coating.

[0034] S2: Add 11g of silica powder, 13mL of 3-mercaptopropyltrimethoxysilane, 50-60mL of anhydrous ethanol and 400-500mL of deionized water to a reaction vessel, adjust the pH value to 3-4 with hydrochloric acid solution, stir for 25h at 22.5℃ and 550r / min, filter, wash the precipitate twice with deionized water and anhydrous ethanol, and dry under vacuum at 65℃ for 1.5h to obtain mercaptosilica powder.

[0035] S3: Add 40g of 2-chloroethanethiol, 55g of N,N-dimethyl-n-octylamine, and 110mL of acetonitrile to a reaction vessel, stir at 22.5℃ and 550r / min for 6.5h, filter, wash the precipitate twice with deionized water and anhydrous ethanol, and dry under vacuum at 65℃ for 1.5h to remove acetonitrile, obtaining mercapto-quaternary ammonium salt; add 25g of mercapto-silica powder, 23g of mercapto-quaternary ammonium salt, 50-60mL of dimethyl sulfoxide, and 550mL of deionized water to a reaction vessel, stir at 22.5℃ and 550r / min for 4.5h, filter, wash the precipitate twice with deionized water and anhydrous ethanol, and dry under vacuum at 65℃ for 1.5h, obtaining quaternary ammonium salt modified silica coating.

[0036] S4: Add 850g of polylactic acid-glycolic acid copolymer and 1.5L of dichloromethane to a reactor and stir for 35min at 22.5℃ and 550r / min to obtain a polylactic acid-glycolic acid copolymer solution. Using nanoimprinting technology, coat the polylactic acid-glycolic acid copolymer solution onto a template and dry at 22.5℃ for 25h and cure at 65℃ for 13h to obtain a 2.0×20mm microporous balloon.

[0037] S5: Spray the drug-loaded microcapsule complex coating onto the capsule at a flow rate of 0.15 mL / min for 0.75 min. After spraying, remove the capsule and dry it at 35°C and 65% relative humidity for 35 min. Then, spray the capsule a second time with the quaternary ammonium salt modified silica coating at a flow rate of 0.15 mL / min for 0.75 min. Remove the capsule and dry it under the same conditions for 35 min to obtain the controlled-release drug capsule.

[0038] S6: The controlled-release balloon and the inflation chamber of the polyether ether ketone catheter are sealed together by heat sealing to obtain a controlled-release balloon catheter for the treatment of urethral stricture.

[0039] Example 3: A method for preparing a controlled-release balloon catheter for the treatment of urethral stricture, comprising the following steps: S1: Add 5.5g of therapeutic drug, 350mL of acetonitrile, and 350mL of acetone to a reaction vessel and stir for 25min at 22.5℃ and 550r / min to form the organic phase. Add 35g of carboxymethyl chitosan and 1.75L of deionized water to the reaction vessel and stir for 25min at 22.5℃ and 550r / min to form the aqueous phase. Then, pour the organic phase into the aqueous phase at a 1:1 mass ratio and homogenize for 3.5min at 4200r / min to obtain a homogeneous emulsion. Add 75mL of the homogeneous emulsion, 25g of terephthalic acid, and 13.5g of ferric chloride to the reaction vessel and stir for 25min at 22.5℃ and 550r / min. Then, add 0.3g of sodium hexadecyl sulfate and 25mL of... A mixture of 65wt% ethanol solution was stirred at 125℃ and 550r / min for 25h, centrifuged at 10000-12000r / min for 3-5min, filtered, and the precipitate was washed 2-3 times with deionized water and anhydrous ethanol and dried under vacuum at 60-70℃ for 1-2h to obtain the drug-loaded microcapsule complex coating.

[0040] S2: Add 12g of silica powder, 14mL of 3-mercaptopropyltrimethoxysilane, 50-60mL of anhydrous ethanol and 400-500mL of deionized water to a reaction vessel, adjust the pH value to 3-4 with hydrochloric acid solution, stir for 26h at 25℃ and 600r / min, filter, wash the precipitate three times with deionized water and anhydrous ethanol, and dry under vacuum at 70℃ for 2h to obtain mercaptosilica powder.

[0041] S3: Add 50g of 2-chloroethanethiol, 60g of N,N-dimethyl-n-octylamine, and 120mL of acetonitrile to a reaction vessel, stir for 7h at 25℃ and 600r / min, filter, wash the precipitate three times with deionized water and anhydrous ethanol, and vacuum dry at 70℃ for 2h to remove acetonitrile, obtaining mercapto-quaternary ammonium salt; add 30g of mercapto-silica powder, 24g of mercapto-quaternary ammonium salt, 50-60mL of dimethyl sulfoxide, and 600mL of deionized water to a reaction vessel, stir for 5h at 25℃ and 600r / min, filter, wash the precipitate three times with deionized water and anhydrous ethanol, and vacuum dry at 70℃ for 2h to obtain quaternary ammonium salt modified silica coating.

[0042] S4: Add 900g of polylactic acid-glycolic acid copolymer and 2L of dichloromethane to a reactor and stir for 40min at 25℃ and 600r / min to obtain a polylactic acid-glycolic acid copolymer solution. Using nanoimprinting technology, coat the polylactic acid-glycolic acid copolymer solution onto a template, dry at 25℃ for 26h and cure at 70℃ for 14h to obtain a 2.0×20mm microporous balloon.

[0043] S5: Spray the drug-loaded microcapsule complex coating onto the capsule at a flow rate of 0.2 mL / min for 1 min. After spraying, remove the capsule and dry it at 40℃ and 70% relative humidity for 40 min. Then, spray the capsule a second time with quaternary ammonium salt modified silica coating at a flow rate of 0.2 mL / min for 1 min. Remove the capsule and dry it under the same conditions for 40 min to obtain the controlled-release drug capsule.

[0044] S6: The controlled-release balloon and the inflation chamber of the polyether ether ketone catheter are sealed together by heat sealing to obtain a controlled-release balloon catheter for the treatment of urethral stricture.

[0045] In the examples and comparative examples: the therapeutic drugs include, but are not limited to, antifibrotic drugs and anti-inflammatory drugs, and may also be a combination of multiple drugs.

[0046] Antifibrotic drugs include, but are not limited to, one or more of rapamycin, mitomycin C, and paclitaxel.

[0047] Anti-inflammatory drugs include, but are not limited to, one or more of levofloxacin, dexamethasone, and prednisone.

[0048] Comparative Example 1: Based on Example 3, terephthalic acid in step S1 was omitted, while the remaining steps remained unchanged, resulting in a controlled-release balloon catheter for the treatment of urethral stricture.

[0049] Comparative Example 2: Based on Example 3, the quaternary ammonium salt modified silica coating in step S4 was replaced with mercapto silica powder in step S3, while the other steps remained unchanged, resulting in a controlled-release balloon catheter for the treatment of urethral stricture.

[0050] Comparative Example 3: Based on Example 3, the mercapto quaternary ammonium salt in step S4 was replaced with dimethyl dioctadecyl ammonium chloride, while the other steps remained unchanged, resulting in a controlled-release balloon catheter for the treatment of urethral stricture.

[0051] The performance of the controlled-release balloon catheters obtained in Examples 1-3 and Comparative Examples 1-3 was tested, and the results are shown in Table 1: Evaluation of the potential cytotoxicity of drug-loaded microcapsule complex coatings and quaternary ammonium salt modified silica coatings to L-929 mammalian fibroblasts. In vitro cytotoxicity test GB / T 16886.5-2017, sample preparation and reference materials GB / T16886.12-2017.

[0052] The two coatings were extracted separately in MEM medium containing 10% FBS and incubated at 37℃, 5% CO2, and 60 rpm for 24 h to obtain the corresponding extracts. The sampling ratio was 0.2 g: 1 mL. Cells grown to the logarithmic growth phase were digested with 0.25% trypsin (containing EDTA). After digestion, the cell suspension was centrifuged (1000 rpm, 5 min), the supernatant was discarded, and the cells were resuspended in MEM medium. Cells were counted to obtain 1×10⁶ cells. 5 Cell suspension per mL. 100 μL of cell suspension was seeded into each well of a 96-well plate and cultured in a cell culture incubator (37℃, 5% CO2, >90% humidity). Cell morphology was observed under a microscope. After 24 h of culture, the 96-well plates were removed, and cell morphology was observed under a microscope. The liquid was then removed, and 50 T (final concentration 1 mg / mL) was added to each well. The plates were then incubated in a CO2 incubator. After 2 h, the supernatant was removed, and 100 μL of isopropanol was added to each well to dissolve the crystals. The absorbance (OD value) at 570 nm was measured using a microplate reader. Each set of data was measured 6 times, and cell viability was calculated. Higher cell viability indicated lower in vitro cytotoxicity. The blank group represented cell viability without either of the two coatings. The results are shown in Table 1.

[0053] The hydrophilicity of the balloon catheter samples was tested using a contact angle meter manufactured by DataPhysicsOCA (Germany). The contact angle of the coating was measured using the droplet method; a lower contact angle indicates better hydrophilicity. The frictional properties of the catheter surface were determined according to the method in YY / T1536-2017 "Standard Test Model for Evaluating the Sliding Performance of Non-Intravascular Catheters". Frictional force was measured before and after immersion of the balloon catheter in artificial urine for 30 days, with 200 tests conducted and the frictional force (N) recorded. The results are shown in Table 2.

[0054] Table 1 Results of Cytotoxicity Experiment

[0055] Table 2 Performance Test Table for Controlled-Release Drug Balloon Catheters

[0056] As can be seen from Tables 1 and 2, the cell activity of the controlled-release balloon catheters obtained in Examples 1-3 is significantly better than that of Comparative Examples 1-3 and is greater than 80%, which meets the national standards. The contact angle and friction before and after immersion of the controlled-release balloon catheter of the present invention are significantly lower than those of the comparative examples, indicating that the controlled-release balloon catheter prepared by the present invention is safe and non-toxic, has strong hydrophilicity and low friction, and is not likely to cause damage to the patient's urethra.

[0057] In Comparative Example 1, the removal of terephthalic acid reduced the mechanical strength of the microcapsules. The metal-organic framework formed by terephthalic acid and iron ions is the core supporting structure of the microcapsule wall. Without it, the microcapsules rely solely on carboxymethyl chitosan cross-linking, which significantly reduces their ability to resist urethral mechanical stress. They are prone to rupture during balloon dilation or urethral friction, leading to sudden drug release, weakened sustained-release function, and loosened capsule wall structure. Paclitaxel is more easily washed away by blood flow, resulting in insufficient local effective concentration and decreased efficacy.

[0058] In Comparative Example 2, the quaternary ammonium salt modified silica coating was replaced with mercapto silica powder, which lost its pH-responsive antibacterial function. In the original scheme, the disulfide bonds broke and released quaternary ammonium salt in the acidic environment of urethral inflammation, thus inhibiting bacterial infection in advance. After the replacement, the coating only had the lubricity of mercapto silica and no active antibacterial ability. It could not block the deterioration of inflammation. The outer coating failed to work synergistically, and the swelling of the inner microcapsules could not promote the release of antibacterial components from the outer layer, leading to uncontrolled inflammation. This may aggravate urethral mucosal damage and weaken the antiproliferative effect of paclitaxel. The outer layer lacked the hydrophobic antibacterial layer of quaternary ammonium salt, and the inner microcapsules were more easily exposed to the blood flow environment, accelerating drug loss.

[0059] In Comparative Example 3, the mercapto quaternary ammonium salt was replaced with dimethyl dioctadecyl ammonium chloride, resulting in the loss of precise pH-responsive release. Dimethyl dioctadecyl ammonium chloride cannot be linked to silica via disulfide bonds and can only be physically adsorbed onto the coating surface. It is rapidly released in the early stages of balloon implantation and cannot target the acidic environment of urethral inflammation, leading to premature depletion of antibacterial components and decreased coating stability. The physically adsorbed quaternary ammonium salt is prone to detachment during spraying, folding, or implantation, reducing coating lubricity and antibacterial durability. It may even increase the risk of urethral friction damage due to particle detachment. The synergistic swelling mechanism fails. When the inner microcapsule absorbs water and swells, the outer layer cannot expand the gap through disulfide bond breakage, which not only limits the release of quaternary ammonium salt but also weakens the sustained-release permeation efficiency of the inner layer drug.

[0060] Although embodiments of the invention have been shown and described, it will be understood by those skilled in the art that various changes, modifications, substitutions and variations can be made to these embodiments without departing from the principles and spirit of the invention.

Claims

1. A method for preparing a controlled-release balloon catheter for the treatment of urethral stricture, the method comprising: A controlled-release drug-eluting balloon and a polyetheretherketone (PEEK) catheter are sealed together using a heat-sealing process to obtain a controlled-release drug-eluting balloon catheter for the treatment of urethral stricture. The controlled-release drug-eluting balloon is characterized by being prepared through the following steps: Step 1: Using the coordination assembly method, carboxymethyl chitosan, terephthalic acid and ferric chloride are self-assembled into microcapsules to encapsulate antifibrotic drugs and anti-inflammatory drugs, thus obtaining drug-loaded microcapsule complex coatings. Step 2: Treat the product with 3-mercaptopropyltrimethoxysilane to obtain mercaptosilica powder; 2-chloroethanethiol reacts with N,N-dimethyl-n-octylamine to obtain mercaptoquaternary ammonium salt, which is then oxidized with the mercaptosilica powder to obtain quaternary ammonium salt modified silica coating. Step 3: Using nanoimprinting technology, a polylactic acid-glycolic acid copolymer solution is coated onto a template to obtain a capsule with micropores. The capsule is then sprayed with a drug-loaded microcapsule complex coating and a quaternary ammonium salt modified silica coating to obtain a controlled-release drug capsule.

2. The method for preparing a controlled-release drug-eluting balloon catheter for the treatment of urethral stricture according to claim 1, characterized in that, The specific preparation steps of the drug-loaded microcapsule complex coating are as follows: Add the therapeutic drug, acetonitrile, and acetone to a reaction vessel at a ratio of 5-6g:5-6g:300-400mL:300-400mL, and stir at 20-25℃ and 500-600 rpm for 20-30 minutes to form the organic phase. Add carboxymethyl chitosan and deionized water to the reaction vessel at a ratio of 30-40g:1.5-2L, and stir at 20-25℃ and 500-600 rpm for 20-30 minutes to form the aqueous phase. Then, pour the organic phase into the aqueous phase at a 1:1 mass ratio and stir at 4000-4200 rpm until homogenized. The mixture was stirred for 3-4 minutes to obtain a homogeneous emulsion. The homogeneous emulsion, terephthalic acid, and ferric chloride were added to a reaction vessel and stirred at 20-25℃ and 500-600 rpm for 20-30 minutes. Then, a mixed solution of sodium hexadecyl sulfate and 60-70 wt% ethanol was added and stirred at 120-130℃ and 500-600 rpm for 24-26 hours. The mixture was centrifuged at 10000-12000 rpm for 3-5 minutes, filtered, and the precipitate was washed 2-3 times with deionized water and anhydrous ethanol. The mixture was then vacuum dried at 60-70℃ for 1-2 hours to obtain the drug-loaded microcapsule complex coating.

3. The method for preparing a controlled-release balloon catheter for the treatment of urethral stricture according to claim 2, characterized in that, The ratio of the homogeneous emulsion, terephthalic acid, ferric chloride, sodium hexadecyl sulfate, and ethanol solution is 70-80 mL: 20-30 g: 12-15 g: 0.2-0.4 g: 20-30 mL.

4. The method for preparing a controlled-release balloon catheter for the treatment of urethral stricture according to claim 1, characterized in that, The specific preparation steps for the mercapto-silica powder are as follows: Add silica powder, 3-mercaptopropyltrimethoxysilane, anhydrous ethanol and deionized water to a reaction vessel in a ratio of 10-12 g: 12-14 mL: 50-60 mL: 400-500 mL. Adjust the pH to 3-4 with hydrochloric acid solution. Stir at 20-25℃ and 500-600 r / min for 24-26 h. Filter, wash, and vacuum dry to obtain mercaptosilica powder.

5. A method for preparing a controlled-release balloon catheter for the treatment of urethral stricture according to claim 1, characterized in that, The specific preparation steps of the quaternary ammonium salt modified silica coating are as follows: Mercaptosilica powder, mercaptoquaternary ammonium salt, dimethyl sulfoxide and deionized water are added to a reaction vessel and stirred at 20-25℃ and 500-600 r / min for 4-5 h. The mixture is then filtered, washed, and vacuum dried to obtain a quaternary ammonium salt modified silica coating.

6. A method for preparing a controlled-release drug-eluting balloon catheter for the treatment of urethral stricture according to claim 5, characterized in that, The ratio of mercapto silica powder, mercapto quaternary ammonium salt, acetonitrile, dimethyl sulfoxide and deionized water is 20-30g: 22-24g: 50-60mL: 500-600mL.

7. A method for preparing a controlled-release balloon catheter for the treatment of urethral stricture according to claim 1, characterized in that, The specific preparation steps for the thiol quaternary ammonium salt are as follows: 2-Chloroethanethiol, N,N-dimethyl-n-octylamine, and acetonitrile were added to a reaction vessel at a ratio of 30-50 g: 50-60 g: 100-120 mL. The mixture was stirred at 20-25 °C and 500-600 r / min for 6-7 h. After filtration, washing, and vacuum drying, mercapto-quaternary ammonium salt was obtained.

8. A method for preparing a controlled-release balloon catheter for the treatment of urethral stricture according to claim 1, characterized in that, The specific preparation steps of the controlled-release drug-eluting balloon are as follows: The drug-loaded microcapsule complex coating was sprayed onto the capsules at a flow rate of 0.1-0.2 mL / min for 0.5-1 min. After spraying, the capsules were removed and dried at 30-40℃ and 60-70% relative humidity for 30-40 min. Then, the quaternary ammonium salt modified silica coating was sprayed onto the capsules a second time at a flow rate of 0.1-0.2 mL / min for 0.5-1 min. The capsules were removed and dried under the same conditions for 30-40 min. After folding, tube filling, sterilization, and packaging, the controlled-release drug capsules were obtained.

9. A method for preparing a controlled-release balloon catheter for the treatment of urethral stricture according to claim 8, characterized in that, The specific preparation steps of the balloon are as follows: Polylactic acid-glycolic acid copolymer and dichloromethane were added to a reaction vessel at a ratio of 800-900g:1-2L. The mixture was stirred at 20-25℃ and 500-600r / min for 30-40min to obtain a polylactic acid-glycolic acid copolymer solution. The polylactic acid-glycolic acid copolymer solution was coated onto a template using nanoimprinting technology. The template was dried at 20-25℃ for 24-26h and cured at 60-70℃ for 12-14h to obtain a 2.0×20mm microporous balloon.

10. A controlled-release balloon catheter for the treatment of urethral stricture, characterized in that, It is prepared by the preparation method described in any one of claims 1-9.

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