CN115252914B

CN115252914B - Network interpenetrating drug controlled release super-smooth coating catheter

Info

Publication number: CN115252914B
Application number: CN202211204388.8A
Authority: CN
Inventors: 张海军; 支树迪; 袁坤山
Original assignee: Shandong Branden Medical Devices Co Ltd
Current assignee: Shandong Branden Medical Devices Co Ltd
Priority date: 2022-09-30
Filing date: 2022-09-30
Publication date: 2022-11-29
Anticipated expiration: 2042-09-30
Also published as: CN115252914A

Abstract

The invention relates to a network interpenetrating drug controlled-release ultra-smooth coating catheter, belonging to the field of medical instruments. Comprises a methyl vinyl silicone rubber conduit and a coating; the coating consists of a bottom layer and a top layer, the bottom layer contains double-layer drug-loaded particles, and the outer layer of the particles is poly-N- (beta-phenylacrylamide oxyethyl) pyrrolidone which has a temperature-responsive controlled release effect; the drug-loaded coating and the silicon rubber form a network interpenetrating structure under the action of a coupling agent; the top layer is a polyvinylpyrrolidone hydrophilic coating, and is combined with the drug-loaded coating in various ways such as chemical bonds, hydrogen bonds and the like. The catheter coating has the characteristics of firmness and controllable release, and has an excellent anticoagulation effect.

Description

Network interpenetrating drug controlled release super-smooth coating catheter

Technical Field

The invention relates to the technical field of medical instruments, in particular to a network interpenetrating drug controlled-release ultra-smooth coating catheter.

Background

Cardiovascular diseases and cancers are two diseases threatening the health of people at present, and high-end interventional medical instruments are main instruments and means for diagnosing and treating various diseases. Catheters are widely used clinically as common interventional instruments. In the process of intervention, use and retention of the medical catheter, bacteria and plasma protein can be adsorbed on the surface of the catheter, so that local thrombus is caused, and the health of a patient is seriously harmed. Therefore, the preparation of the anticoagulant medical catheter has extremely important significance.

The surface wettability modification of the material can not only keep the physical and mechanical properties of the material, but also endow the material surface with the necessary ultra-smooth property, and is one of the common modification methods. At present, the more consistent view is: hydrophilic materials have better biocompatibility than hydrophobic materials. The reason is that the hydrophobic surface is easy to cause the conformational change of the protein, the low surface energy coating formed by the super-hydrophobic polymer cannot prevent the nonspecific adsorption of the protein on the surface, and the hydrophilic surface is favorable for the adjustment and maintenance of the free conformation of the protein.

Patent CN104740690.A discloses a marine organism medicine carrying nanometer antibacterial super-smooth coating, the coating is through the method of dip-coating silane coupling agent, produce covalent bond connection between marine organism medicine carrying coating and substrate, then through the dip-coating method, obtain the hydrophilic coating in top layer, the hydrophilic coating on the surface layer does not show the valence bond connection with medicine carrying coating in the text, and the slow release effect of its medicine carrying granule only relies on the degradation of medicine carrying granule, can't control release rate according to the demand, in addition silicon rubber is as most common medical catheter material, its molecular weight is generally great, surface molecular arrangement is inseparable, stable, chemical group and unsaturated bond hardly provide enough sites for the bonding reaction of coating, consequently simple coupling agent activation hardly guarantees the firmness of coating.

On one hand, the invention provides enough reaction sites for the bottom coating through swelling, on the other hand, the invention provides a drug-loaded coating with temperature response, which contains double-layer drug-loaded microspheres, wherein the molecular functional groups of the outer layer of the microspheres are the same as the functional groups of the main components of the drug-loaded coating and the super-smooth coating, and the drug-loaded microspheres change conformation under a certain temperature condition to directly release the outermost drug; the inner layer is a slow-release balloon, and can slowly degrade and release the drug wrapped by the inner layer, so that the effective time of the coating is prolonged.

Disclosure of Invention

Aiming at the defects in the prior art, the invention provides a network interpenetrating drug controlled-release ultra-smooth coating catheter, which can be used for preparing a coating interpenetrating with a methyl vinyl silicone rubber network and has an anti-infection and anticoagulation multifunctional catheter coating.

In order to achieve the purpose, the technical scheme adopted by the invention for solving the technical problems is as follows:

a network interpenetration drug controlled release ultra-smooth coating catheter is mainly characterized by comprising a methyl vinyl silicone rubber main body and a surface coating; the surface coating is composed of a bottom layer and a top layer, the bottom layer is a polyvinylpyrrolidone drug-loaded coating which contains poly-N- (beta-phenylacrylamide oxyethyl) pyrrolidone and polylactic acid microsphere-glycolic acid double-layer drug-loaded particles, wherein the poly-N- (beta-phenylacrylamide oxyethyl) pyrrolidone is an outer layer and has a temperature-responsive controlled-release effect, the poly-N- (beta-phenylacrylamide oxyethyl) pyrrolidone is insoluble in water at the temperature of a human body, the temperature is reduced, the solubility of the poly-N- (beta-phenylacrylamide oxyethyl) pyrrolidone is increased, and internal drugs are released; the drug-loaded coating and the methyl vinyl silicone rubber form a network interpenetrating structure under the action of a coupling agent; the top layer is a polyvinylpyrrolidone super-smooth coating, and is combined with the drug-loaded coating in various ways such as chemical bonds, hydrogen bonds and the like;

the preparation method comprises the following steps:

(1) Dissolving N- (beta-phenylacrylamide oxyethyl) pyrrolidone monomer, molecular weight regulator and photoinitiator in absolute ethyl alcohol according to a certain proportion, introducing inert gas to fully remove oxygen in the system, performing visible light initiated polymerization reaction under the gas, introducing air after 6h +/-1 h, stopping the reaction, and obtaining poly (N- (beta-phenylacrylamide oxyethyl) pyrrolidone;

(2) Dissolving an anticoagulant and polylactic acid-glycolic acid in butanone solution to obtain inner layer solution, wherein the mass ratio of the anticoagulant to the butanone solution in the inner layer solution is (0.5-1): 1000, and the mass ratio of the polylactic acid-glycolic acid to the butanone solution is (1-5): 1000; dissolving anticoagulant drug and poly-N- (beta-phenyl acrylamide oxyethyl) pyrrolidone in ethanol solution to obtain outer layer solution, wherein the mass ratio of the anticoagulant drug, the poly-N- (beta-phenyl acrylamide oxyethyl) pyrrolidone and the ethanol solution in the outer layer solution is 3 (30-100) to 1000; respectively filling the inner layer solution and the outer layer solution into corresponding injectors, and preparing temperature-responsive double-layer drug-loaded particles by a coaxial electrostatic spinning method;

(3) Catheter extrusion and activation: adding a certain amount of hydrogen-containing silicone oil and a platinum catalyst into methyl vinyl silicone rubber, uniformly mixing, processing and forming to obtain a guide pipe, then carrying out plasma treatment on the guide pipe, placing the guide pipe into an alcohol solution, soaking for a period of time for swelling, and finally transferring the guide pipe into a coupling agent solution for activation treatment;

(4) Preparing a drug-loaded coating: adding the double-layer drug-loaded particles into a polyvinylpyrrolidone solution containing a coupling agent with a certain concentration, quickly and uniformly stirring, then immersing the activated catheter into the drug-loaded coating solution for 30s, taking out at a constant speed, and drying to obtain a drug-loaded coating capable of controlling drug release; the drug-loaded coating and the methyl vinyl silicone rubber form a network interpenetrating structure and are connected together through a coupling agent by chemical bonds;

(5) Preparing an ultra-smooth coating: preparing 5-10 wt% polyvinylpyrrolidone alcohol/ketone solution, wherein the mass ratio of polyvinylpyrrolidone to coupling agent in the solution is 50; and coating the hydrophilic super-smooth coating on the surface of the drug-loaded coating by a dip coating process, and drying at 90-150 ℃ to obtain the network interpenetrating drug-loaded super-smooth coating catheter.

Further, the molar ratio of the N- (beta-phenylacrylamide oxyethyl) pyrrolidone monomer to the molecular weight regulator to the photoinitiator in the step (1) is (500-700): 1.

Further, in the step (1), the molecular weight regulator is dithiobenzyl benzoate or dithio-isobutyronitrile-p-fluorobenzoate, and the photoinitiator is benzoyl peroxide or diphenyl (2,4,6-trimethylbenzoyl) phosphine oxide.

Further, the polylactic acid-glycolic acid copolymer in the step (2) has a relative molecular weight of 5000-10000.

Further, the anticoagulant in the step (2) is one or more of heparin, warfarin, aspirin, dessiculine, bivalirudin, argatroban and rivaroxaban.

Further, the content of the hydrogen-containing silicone oil in the step (3) is not more than 1.2%.

Further, the alcoholic solution in the step (3) is one or more of ethanol, isopropanol and propanol solution.

Further, the coupling agent in the step (3) is silicate ester or/and silane coupling agent.

Preferably, the silicate in the step (3) is tetraethoxysilane, and the silane coupling agent is an epoxy silane coupling agent.

Further, the mass ratio of the double-layer medicine-carrying particles to the polyvinylpyrrolidone in the step (4) is (1.

Furthermore, the relative molecular weight of the polyvinylpyrrolidone in the step (4) is 4-36 ten thousand, and the coupling agent is isocyanate.

Preferably, the polyvinylpyrrolidone in step (4) has a relative molecular weight of 5 to 16 ten thousand.

Further, the polyvinylpyrrolidone in the step (5) has a relative molecular weight of 16 to 36 ten thousand; the coupling agent is isocyanate.

The invention has the beneficial effects that:

1. a network interpenetrating structure is generated between the coating and the methyl vinyl silicone rubber, so that the firmness and uniformity of the coating are improved, and in addition, the silicate is subjected to chemical reaction, so that more reaction sites are provided, and the firmness of the coating is improved;

2. the poly-N- (beta-phenyl acrylamide oxygen ethyl) pyrrolidone has temperature responsiveness, changes the environmental temperature, can adjust the molecular conformation and achieves the purpose of controlling and releasing the drug;

3. the drug-loaded coating at the bottom layer contains double drug-loaded particles, on one hand, the slow release effect can be achieved, on the other hand, the outer shell of the particles is the same as the main component of the coating, and can be connected with the coating network through a covalent bond, so that the drug-loaded amount is increased, and the responsive release of the outer drug is realized;

4. the polyvinylpyrrolidone not only has hydrophilic and super-slippery performance, but also has good protein adsorption resistance, thereby inhibiting the formation of a biofilm and reducing the occurrence probability of thrombus;

5. the main components of the drug-loaded coating at the bottom layer and the super-smooth coating at the top layer are homopolymerized polyvinylpyrrolidone, and the drug-loaded coating and the super-smooth coating can be connected together in various ways such as physics and chemistry, so that the firmness of the coating is increased, and the integration of the coating is realized.

Drawings

FIG. 1 is a schematic view of a coated catheter;

FIG. 2 shows the results of a thrombogenesis test;

FIG. 3 is an SEM image of platelet adhesion of example 1, comparative example 3 and uncoated catheter;

wherein 1 a catheter body; 2. a bottom coating; 3. a top coating layer; 1.1 A silica gel macromolecule; 2.1 Polyvinylpyrrolidone macromolecules; 2.2 Double-layer drug-loaded particles.

Detailed Description

Reference standard

GB/T16886.4-2003 section 4 for the biological evaluation of medical devices: selecting a catheter to be evaluated in a blood interaction test;

YY/T1536-2017 standard test model for evaluating the surface sliding performance of the non-intravascular catheter.

The chemical reagent sources are purchased from a traditional Chinese medicine chemical reagent net or an avastin chemical reagent net without special instructions, and the anticoagulant drugs are purchased from the common market.

1.N- (beta-phenylacrylamide oxyethyl) pyrrolidone synthesis method:

33 g dry N-hydroxyethyl pyrrolidone, 31 g triethylamine were dissolved in 65mL anhydrous chloroform, followed by ice bath, followed by slow dropwise addition of 95mL of 3mol/L beta-phenyl acryloyl chloride in chloroform, and the reaction was stirred at 0 + -2 deg.C for 12 h. Then rotary steaming is carried out, and 5% Na is used in turn ₂ CO ₃ The aqueous solution, saturated NaCl aqueous solution and distilled water are washed until the solution is neutral. The resulting solution was extracted with anhydrous MgSO ₄ Drying for 24h, then distilling under reduced pressure to obtain N- (beta-phenylacrylamide oxyethyl) pyrrolidone. The reaction equation is as follows:

。

2. preparation method of network interpenetrating drug controlled-release super-smooth coating catheter

(1) Dissolving N- (beta-phenylacrylamide oxyethyl) pyrrolidone monomer, a molecular weight regulator and a photoinitiator in absolute ethyl alcohol according to a certain proportion, introducing inert gas to fully remove oxygen in the system, performing visible light initiated polymerization reaction under the gas, introducing air after 6h +/-1 h, and stopping the reaction to obtain poly-N- (beta-phenylacrylamide oxyethyl) pyrrolidone;

(2) Dissolving an anticoagulant drug and polylactic acid-glycolic acid in butanone solution to obtain inner layer solution, wherein the anticoagulant drug: the mass ratio of the butanone solution is (0.5-1) 1000, polylactic acid-glycolic acid: the mass ratio of the butanone solution is (1-5) to 1000; dissolving anticoagulant drug and poly-N- (beta-phenyl acrylamide oxyethyl) pyrrolidone in ethanol solution to obtain outer layer solution, wherein the mass ratio of the anticoagulant drug, the poly-N- (beta-phenyl acrylamide oxyethyl) pyrrolidone and the ethanol solution in the outer layer solution is 3 (30-100) to 1000; respectively filling the inner layer solution and the outer layer solution into corresponding injectors, and preparing temperature-responsive double-layer drug-loaded particles by a coaxial electrostatic spinning method;

(4) Preparing a drug-loaded coating: adding the double-layer drug-loaded particles into a polyvinylpyrrolidone solution containing a coupling agent with a certain concentration, quickly and uniformly stirring, then immersing the activated catheter into the drug-loaded coating solution for 30s, taking out the catheter at a uniform speed, and drying to obtain a drug-loaded coating capable of controlling the release of the drug; the drug-loaded coating and the methyl vinyl silicone rubber form a network interpenetrating structure and are connected together by a coupling agent through chemical bonds; the reaction equation of polyvinylpyrrolidone and poly-N- (beta-phenylacrylamide oxyethyl) pyrrolidone is as follows:

；

(5) Preparing an ultra-smooth coating: preparing 5-10 wt% of polyvinylpyrrolidone ketol or/and ketone solution, wherein the mass ratio of polyvinylpyrrolidone to coupling agent in the solution is 50; coating the hydrophilic ultra-smooth coating on the surface of the drug-loaded coating through a dip coating process, and drying at 90-150 ℃ to obtain the network interpenetrating drug-loaded ultra-smooth coating catheter, wherein the reaction equation of polyvinylpyrrolidone hydrolysis and heating curing is as follows:

。

example 1

The relative molecular weight of the polylactic acid-glycolic acid copolymer is 5000, and the relative molecular weight of the polyvinylpyrrolidone of the ultra-smooth coating and the drug-loaded coating is 36 ten thousand.

1. Preparation of poly-N- (beta-phenylacrylamide-oxyethyl) pyrrolidone

(1) Dissolving N- (beta-phenylacrylamide oxyethyl) pyrrolidone in absolute ethyl alcohol, using benzyl dithiobenzoate as a molecular weight regulator, using diphenyl (2,4,6-trimethylbenzoyl) phosphine oxide as a photoinitiator, N- (beta-phenylacrylamide oxyethyl) pyrrolidone, benzyl dithiobenzoate, diphenyl (2,4,6-trimethylbenzoyl) phosphine oxide =700, 0.2 to fully remove oxygen in the system, irradiating for 6h by using visible light, then introducing air, and stopping the reaction, wherein the reaction equation is as follows:

the value of n is about 800.

2. Preparation of double-layer drug-loaded microspheres

A. Preparation of two drug-loaded solutions

(1) Preparation of inner layer solution: dissolving deshellidine and a polylactic acid-glycolic acid copolymer in a butanone solution, wherein the mass ratio of the deshellidine to the butanone is 0.7 to 1000, and the mass ratio of the polylactic acid-glycolic acid copolymer to the butanone is 1;

(2) Preparing an outer layer solution: dissolving heparin and poly-N- (beta-phenylacrylamide oxyethyl) pyrrolidone in an ethanol solution, wherein the mass ratio of the heparin to the poly-N- (beta-phenylacrylamide oxyethyl) pyrrolidone is 3;

B. preparation of drug-loaded microspheres

The inner layer solution and the outer layer solution were filled into the respective syringes. Setting the injection voltage to be 13kV, the liquid supply speed of the inner layer electrospray precursor to be 0.15 mL/h, the liquid supply speed of the shell layer electrospray precursor to be 0.3 mL/h, the distance between the receiver and the needle head to be 13cm, the temperature to be 25 +/-3 ℃, and the relative humidity to be 40 +/-5%, and obtaining the medicine-carrying particles.

3. Preparation of network interpenetrating drug controlled-release ultra-smooth coating catheter

(1) Mixing methyl vinyl silicone rubber according to the mass ratio of the methyl vinyl silicone rubber to the hydrogen-containing silicone oil to the platinum vulcanizing agent of 100;

(2) Treating the catheter by plasma for 5min, and then soaking the catheter in a mixed solution of ethanol and isopropanol (the volume ratio is 1:1) for 5h for swelling;

(3) Transferring the swollen conduit to a mixed solution of tetraethoxysilane and KH560 for activation treatment;

(4) Preparing a drug-loaded coating solution: taking the double-drug-loaded particles prepared by the electrostatic spinning process, then adding the double-layer drug-loaded particles into a mixed solution of butanone and ethanol of polyvinylpyrrolidone, and uniformly stirring, wherein the mass fraction of the polyvinylpyrrolidone is 5wt%, and the concentration of the drug-loaded microspheres is 5 wt%;

(5) Heating the activated catheter in a drying oven at 110 ℃ for 10min, then immersing the catheter in the drug-loaded coating solution for 30s, taking out the catheter at a constant speed, and drying the catheter at 80 ℃ to obtain a drug-loaded coating capable of controlling drug release; the drug-loaded coating and the methyl vinyl silicone rubber form a network interpenetrating structure and are connected together by a coupling agent through chemical bonds;

(6) Preparing an ultra-smooth coating: preparing an ultra-smooth coating solution by taking a mixed solution of butanone and ethanol as a solvent and diphenylmethane diisocyanate as a coupling agent, wherein the mass ratio of polyvinylpyrrolidone to diphenylmethane diisocyanate to the solvent is 50; and (3) immersing the catheter prepared in the step (5) in the super-smooth solution for 30s, then taking out at a constant speed, and drying at 120 ℃ to obtain the network interpenetrating drug-loaded super-smooth coated catheter.

Example 2

The preparation method is basically the same as that of example 1, except that:

the polylactic acid-glycolic acid copolymer has a relative molecular weight of 8000, the polyvinyl pyrrolidone used for the medicine-carrying coating has a relative molecular weight of 5 ten thousand, and the polyvinyl pyrrolidone used for the ultra-smooth coating has a relative molecular weight of 36 ten thousand.

1. Preparation of double-layer drug-loaded microspheres

A. Preparation of two drug-loaded solutions

(1) Preparation of inner layer solution: dissolving warfarin, rivaroxaban and a polylactic acid-glycolic acid copolymer in a butanone solution, wherein the mass ratio of warfarin to rivaroxaban to butanone is 1;

(2) Preparing an outer layer solution: dissolving cefamycin and poly-N- (beta-phenylacrylamide oxyethyl) pyrrolidone in an ethanol solution, wherein the mass ratio of the cefamycin to the poly-N- (beta-phenylacrylamide oxyethyl) pyrrolidone is 3.

N- (beta-phenylacrylamide oxyethyl) pyrrolidone in the synthesis of poly N- (beta-phenylacrylamide oxyethyl) pyrrolidone, isobutyronitrile dithiop-fluorobenzoate, diphenyl (2,4,6-trimethylbenzoyl) phosphine oxide =500, reaction time is 5h, and N value is about 400.

(1) The mass ratio of the methyl vinyl silicone rubber to the hydrogen-containing silicone oil to the platinum vulcanizing agent is 100, and the swelling solution is propanol;

(2) Preparing a drug-loaded coating solution: taking the double drug-loaded particles prepared by the electrostatic spinning process, then adding the double drug-loaded particles into a mixed solution of butanone and ethanol of polyvinylpyrrolidone, and uniformly stirring, wherein the mass ratio of polyvinylpyrrolidone to solvent is 5wt%, and the concentration of drug-loaded microspheres is 1wt%.

Example 3

The relative molecular weight of the polylactic acid-glycolic acid copolymer is 10000, the relative molecular weight of polyvinylpyrrolidone used for the drug-loaded coating is 4 ten thousand, and the relative molecular weight of polyvinylpyrrolidone used for the ultra-smooth coating is 16 ten thousand.

1. Preparation of poly-N- (beta-phenylacrylamide-oxyethyl) pyrrolidone

(1) Dissolving N- (beta-phenylacrylamide oxyethyl) pyrrolidone in absolute ethyl alcohol, using benzyl dithiobenzoate as a molecular weight regulator and benzoyl peroxide as a photoinitiator, wherein N- (beta-phenylacrylamide oxyethyl) pyrrolidone, benzyl dithiobenzoate and benzoyl peroxide in the system are fully removed, visible light is used for irradiation for 7h, then air is introduced, the reaction is stopped, and the value of N is about 1000.

2. Preparation of double-layer drug-loaded microspheres

A. Preparing two drug-loaded solutions:

(1) Preparation of inner layer solution: dissolving desiccanidine and polylactic acid-glycolic acid copolymer in butanone solution, wherein the mass ratio of the desiccanidine to the butanone is 0.5;

(2) Preparing an outer layer solution: dissolving aspirin, argatroban and poly-N- (beta-phenylacrylamide oxyethyl) pyrrolidone in an ethanol solution, wherein the mass ratio of the argatroban to the poly-N- (beta-phenylacrylamide oxyethyl) pyrrolidone is 3;

B. preparation of drug-loaded microspheres

The inner layer solution and the outer layer solution were filled into the respective syringes. Setting the injection voltage to be 13kV, the liquid supply speed of the inner layer electrospray precursor to be 0.15 mL/h, the liquid supply speed of the shell layer electrospray precursor to be 0.3 mL/h, the distance between the receiver and the needle head to be 13cm, the temperature to be 25 +/-3 ℃, and the relative humidity to be 40 +/-5% to obtain the drug-loaded particles.

(1) Mixing methyl vinyl silicone rubber according to the mass ratio of the methyl vinyl silicone rubber to the hydrogen-containing silicone oil to the platinum vulcanizing agent of 100.5;

(2) Performing plasma treatment on the catheter for 5min, and then soaking the catheter in an isopropanol solution for 5h for swelling;

(3) Transferring the swollen catheter to a mixed solution of tetraethoxysilane and KH570 for activation treatment;

(4) Preparing a drug-loaded coating solution: taking the double-drug-loaded particles prepared by the electrostatic spinning process, then adding the double-layer drug-loaded particles into a mixed solution of butanone and ethanol of polyvinylpyrrolidone, and uniformly stirring, wherein the mass ratio of the polyvinylpyrrolidone to the solvent is 5wt%, and the concentration of the drug-loaded microspheres is 5 wt%;

(5) Immersing the activated catheter in the drug-loaded coating solution for 30s, taking out at a constant speed, and drying at 80 ℃ to obtain a drug-loaded coating capable of controlling drug release; the drug-loaded coating and the methyl vinyl silicone rubber form a network interpenetrating structure and are connected together by a coupling agent through chemical bonds;

(6) Preparing an ultra-smooth coating: uniformly mixing ethanol serving as a solvent, toluene diisocyanate serving as a coupling agent according to the mass ratio of polyvinylpyrrolidone to toluene diisocyanate to the solvent of 50; and (3) immersing the catheter prepared in the step (5) in the super-smooth coating solution for 30s, taking out at a constant speed, and drying at 100 ℃ to obtain the network interpenetrating drug-loaded super-smooth coating catheter.

Example 4

The preparation method is basically the same as that of example 1, except that:

(1) Preparing a drug-loaded coating solution: the concentration of the drug-loaded microspheres is 10 wt%;

(2) In the preparation of the super-smooth coating, the mass fraction of polyvinylpyrrolidone is 10wt, and the mass ratio of polyvinylpyrrolidone to diphenylmethane diisocyanate is 50.

Comparative example 1

The preparation method is basically the same as that of example 1, except that: the silica gel catheter is not subjected to swelling and activation treatment.

Comparative example 2

The preparation method is basically the same as that of example 2, except that:

in the preparation of the network interpenetrating drug controlled-release ultra-smooth coating catheter, the catheter after swelling is transferred into KH550 for activation treatment.

Comparative example 3

Essentially the same as example 1, except that the double layer drug loaded microspheres were not loaded with drug.

Comparative example 4

The method is basically the same as that in example 1, except that the outer layer of the double-layer drug-loaded microsphere is polyvinylpyrrolidone with the relative molecular weight of 20 ten thousand.

Detection and results

1. Thrombogenesis test and results

The catheter samples prepared in examples 1 to 4 and comparative examples 1 to 4, and the catheter sample without coating (control group) were each cut to 1cm, immersed in sterile water for injection at 33 ℃ for 3min, then placed in a 96-well plate, 100. Mu.l of fresh platelet plasma PRP was added to the sample, incubated at 37 ℃ for 1 hour, aspirated plasma, and washed with PBS. Adding 1wt% Triton-X PBS solution to the sample, incubating at 37 deg.C for 1 hr, mixing the supernatant with lactate dehydrogenase working solution, and measuring absorbance at 490 nm. The experimental result shows (figure 1), 1) the samples of the embodiment and the comparative example have obvious anticoagulation effect, and the samples of the comparative example have poor anticoagulation capability; 2) In the comparative example 3, the drug-loaded particles are not loaded with drugs, and only the surface of the catheter is adhered by virtue of the ultra-smooth effect, so that the absorbance is high; 3) It can be seen from comparison of examples 1, 2 and 4 that the higher the drug content, the more significant the anticoagulation effect.

2. Platelet adhesion test and results

Mixing fresh blood with 0.109mol/L sodium citrate solution 10%, preparing anticoagulated blood, placing anticoagulated blood in a centrifuge, centrifuging at 800r/min for 15min, and collecting upper layer blood platelet-rich plasma for platelet adhesion experiment. A catheter of 1cm in length each of example 1, comparative example 3 and the uncoated catheter was placed in sterile water for injection at 33 ℃ for 3min, taken out, placed in platelet-rich plasma and incubated at 37 ℃ for 1h, taken out and washed three times with PBS buffer, and then the catheter piece was fixed and crosslinked in 2.5% by mass glutaraldehyde aqueous solution for 30min, then washed with PBS buffer, and then placed in 40%, 50%, 60%, 70%, 80%, 90%, 100% (v/v) by mass in order to be dehydrated in stages, and then dried at room temperature. And performing SEM observation after gold plating on the surface to obtain the adhesion condition of the blood platelets on the surface of the sample, as shown in figure 2. In the figure, (1) the uncoated catheter surface has a large number of adherent platelets, and most of the platelets are in an activated state; (2) Comparative example 3 the number of surface-adherent platelets was general and most of the platelets were in an activated state; (3) The number of platelets adhered to the surface of the catheter in the embodiment 1 is small, and most of the platelets are in an unactivated state, which shows that the drug-loaded catheter can inhibit the adhesion and activation of the platelets, so that blood is prevented from coagulating on the surface of the catheter, and an antithrombotic effect is achieved.

3. Drug release test

55cm 3 catheters prepared in example 1 are taken and immersed in 20mL sterile water for injection respectively for sealing, the water bath temperature of the experimental group 1 is set to be 37 ℃, the water bath temperature of the experimental group 2 is set to be 33 ℃, the water bath temperature of the experimental group 3 is set to be 29 ℃, the water bath is carried out, and the standard heparin curve is measured by an ultraviolet spectrophotometer method to obtain the heparin content in 1min, 30min, 60min, 120min and 240min of three groups of solutions, as shown in Table 1:

TABLE 1 heparin release assay results

As can be seen from Table 1, a decrease in temperature is effective in increasing the rate of drug release.

4. Drug responsive release test

The temperature responsiveness of the double drug-loaded microspheres in example 1 is further examined by adopting an intermittent temperature control mode, namely 3 parts of 1cm catheter in example 1 are placed in a test tube, 5ml of sterile injection aqueous solution is added at the same time, the catheter is completely immersed and placed in a constant-temperature oscillator at 37 ℃, and the catheter is taken out after the balance is carried out for 1 hour; 5ml of sterile injection aqueous solution is still added to each group, and the temperature of the solution is kept at 29 plus or minus 2 ℃ in the experimental group 1, 33 plus or minus 2 ℃ in the experimental group 2 and 37 plus or minus 2 ℃ in the control group. After release for 1h, the sterile aqueous solution for injection is returned to a temperature of 37. + -. 2 ℃. After 1h, the experimental group is changed into normal saline, and the respective set temperature is kept; the control group was replaced with sterile water for injection, and this was repeated 3 times. Sampling every hour, and measuring the heparin content by adopting an ultraviolet spectrophotometer method. It can be seen that 1) during the time period when saline is exchanged, the amount of drug released is: experiment group 1 > experiment group 2 > control group; 2) In the time period of replacing sterile water for injection, the drug release amount of the experimental group is obviously reduced;

TABLE 2 drug-responsive Release results

This is due to:

1) The poly N- (beta-phenyl acrylamide oxyethyl) pyrrolidone has high molecular thermal responsiveness, is dehydrated and is insoluble in water when the temperature is higher than the cloud point temperature, and is quickly hydrated when the temperature is lower than the cloud point temperature, the shell of the outer layer of the drug-loaded microsphere is opened, and the drug of the outer layer is released;

2) The dehydration process of the poly-N- (beta-phenylacrylamide oxyethyl) pyrrolidone is reversible, and the poly-N- (beta-phenylacrylamide oxyethyl) pyrrolidone and the polyvinylpyrrolidone in the coating have chemical bonds and hydrogen bonds, so that the molecular loss and large-range displacement can be greatly reduced, therefore, under the condition of sterile water for injection at 37 +/-2 ℃, the poly-N- (beta-phenylacrylamide oxyethyl) pyrrolidone is recovered to be dehydrated, the shell of the drug-loaded particles is recovered to be closed, and the drug release is reduced. Therefore, the experiment proves that the poly-N- (beta-phenylacrylamide oxyethyl) pyrrolidone has good temperature responsiveness and the response is reversible, so that a stimulation factor can be selected according to the requirement clinically to regulate and control the drug release.

5. Coating coefficient of friction and firmness test

The conduit clip is installed in a clip slot of a clamping system. The distance between the two sliding clamping blocks is adjusted to be 40cm, and then the clamping pieces are fastened to ensure that the catheter clamping pieces are kept in good fit. One end of the test conduit passes through the two conduit clamping sheets from bottom to top, and the upper clamp of the tester clamps the head end of the conduit. The rest part of the conduit is inserted into a cylinder filled with water at 37 + -1 deg.C, and naturally suspended and soaked for 1min. The positions of the two sliding clamping blocks in the sliding groove are adjusted to enable the guide pipe to be positioned at the midpoint, the clamping force is 3N, and the lifting speed is 200 mm/min. The tester was started to pass the wetted part of the catheter 15cm through the silicone sheet and the force versus displacement curve was recorded. Taking the average force value of the pipe body soaking section of the catheter on the curve as the friction force.

The firmness after 30 times of rubbing test was calculated as follows:

firmness = U2/U1

Wherein, U1 is the friction coefficient average value of the first 5 times, U2 is the friction coefficient average value of the last 5 times, and the ratio of the two can be used for judging the coating firmness compared with 1. A ratio closer to 1 indicates a stronger coating;

TABLE 3 coating Friction coefficient and firmness test results

It can be seen that the friction coefficients of example 1 and comparative example 1 are 0.010 and 0.011, respectively, and both samples exhibit super-lubricity, because the surfaces of the samples are coated with hydrophilic polyvinylpyrrolidone, and a water film is formed after the samples are fully soaked, so that the friction resistance is reduced.

On the other hand, the coating firmness of example 1 is clearly better than that of comparative example 1. Compared with the comparative example 1, the reason is that in the example 1, the methyl ethyl silicone rubber is subjected to soaking swelling and coupling agent activation treatment, the coupling agent enters the inside of the network of the shallow methyl vinyl silicone rubber through the infiltration effect, and forms chemical crosslinking with molecules in the methyl vinyl silicone rubber, so that firm and active grafting sites are provided for the grafting and curing of polyvinylpyrrolidone; the coupling agent in the comparative example exists in the coating, active sites are formed only with partial positions of the surface of the catheter after dip coating, the site density is lower than that of example 1, and the active sites exist only on the surface of silica gel, so that the coating firmness is lower than that of example 1.

While particular embodiments of the present invention have been described above, it will be understood by those skilled in the art that this is by way of illustration only, and that the scope of the invention is defined by the appended claims. Various changes or modifications to these embodiments may be made by those skilled in the art without departing from the spirit and scope of the invention, and these changes and modifications are within the scope of the invention.

Claims

1. A network interpenetration drug controlled release super-smooth coating catheter is mainly characterized by comprising a methyl vinyl silicone rubber main body and a surface coating; the surface coating comprises a bottom layer and a top layer, wherein the bottom layer is a polyvinylpyrrolidone drug-loaded coating and contains double-layer drug-loaded particles, and the outer layer of the drug-loaded particles is poly-N- (beta-phenyl acrylamide oxyethyl) pyrrolidone which has a temperature-responsive controlled release effect; the drug-loaded coating and the methyl vinyl silicone rubber form a network interpenetrating structure under the action of a coupling agent; the top layer is a polyvinylpyrrolidone super-smooth coating, and is combined with the drug-loaded coating in various ways such as chemical bonds, hydrogen bonds and the like;

the preparation method comprises the following steps:

(1) Dissolving N- (beta-phenylacrylamide oxyethyl) pyrrolidone monomer, a molecular weight regulator and a photoinitiator in absolute ethyl alcohol according to a certain proportion, introducing inert gas to fully remove oxygen in a system, performing visible light initiated polymerization reaction under the gas, introducing air after 6h +/-1 h, and stopping the reaction to obtain poly-N- (beta-phenylacrylamide oxyethyl) pyrrolidone, wherein the molecular formula is as follows:

wherein n is selected from an integer within 400-1000;

(2) Dissolving an anticoagulant drug and polylactic acid-glycolic acid in butanone solution to obtain inner layer solution, wherein the anticoagulant drug in the inner layer solution: the mass ratio of the butanone solution is (0.5-1) 1000, polylactic acid-glycolic acid: the mass ratio of the butanone solution is (1-5) to 1000; dissolving anticoagulant drug and poly-N- (beta-phenyl acrylamide oxyethyl) pyrrolidone in ethanol solution to obtain outer layer solution, wherein the mass ratio of the anticoagulant drug, the poly-N- (beta-phenyl acrylamide oxyethyl) pyrrolidone and the ethanol solution in the outer layer solution is 3 (30-100) to 1000; respectively filling the inner layer solution and the outer layer solution into corresponding injectors, and preparing temperature-responsive double-layer drug-loaded particles by a coaxial electrostatic spinning method;

(4) Preparing a drug-loaded coating: adding the double-layer drug-loaded particles into a polyvinylpyrrolidone solution containing a coupling agent with a certain concentration, quickly and uniformly stirring, then immersing the activated catheter into the drug-loaded coating solution for 30s, and taking out and drying at a uniform speed to obtain a drug-loaded coating capable of controlling the release of the drug; the drug-loaded coating and the methyl vinyl silicone rubber form a network interpenetrating structure and are connected together through a coupling agent by chemical bonds;

(5) Preparing an ultra-smooth coating: preparing 5-10 wt% polyvinylpyrrolidone alcohol or/and ketone solution, wherein the mass ratio of polyvinylpyrrolidone to coupling agent in the solution is 50; and coating the super-smooth coating on the surface of the drug-loaded coating by a dip coating process, and heating and curing to obtain the network interpenetrating drug controlled release super-smooth coating catheter.

2. The catheter with the super-smooth coating for the drug controlled release and the drug interpenetrating network, according to claim 1, wherein the molar ratio of N- (beta-phenylacrylamide oxyethyl) pyrrolidone monomer to molecular weight regulator to photoinitiator in step (1) is (500-700) to 1.0.2.

3. The catheter with the ultra-smooth coating for the controlled release of the drugs interpenetrated by the network of claim 1, wherein the polylactic acid-glycolic acid copolymer in the step (2) has a relative molecular weight of 5000 to 10000.

4. The catheter of claim 1, wherein said anticoagulant in step (2) is one or more of heparin, warfarin, aspirin, dessicatin, bivalirudin, argatroban, and rivaroxaban.

5. The catheter with the interpenetrating network drug controlled release and ultra-smooth coating of claim 1, wherein the hydrogen-containing silicone oil content in step (3) is not more than 1.2%.

6. The catheter with the ultra-smooth coating for the interpenetrated drug controlled release of the network according to claim 1, wherein the alcoholic solution in step (3) is one or more of ethanol, isopropanol and propanol solution.

7. The catheter with the ultra-smooth coating for the interpenetrated drug controlled release of the network in claim 1, wherein the coupling agent in the step (3) is silicate ester or/and silane coupling agent.

8. The catheter with the ultra-smooth coating for the interpenetrated drug controlled release of the network in claim 1, wherein the polyvinylpyrrolidone in the step (4) has a relative molecular weight of 4 to 36 ten thousand; the coupling agent is isocyanate.

9. The catheter with the ultra-smooth coating for the controlled release of drugs interpenetrating with networks according to claim 1, wherein, in the step (5), the relative molecular weight of the polyvinylpyrrolidone is 16 to 36 ten thousand; the coupling agent is isocyanate.