CN111053952A

CN111053952A - Preparation method of catheter

Info

Publication number: CN111053952A
Application number: CN201911235849.6A
Authority: CN
Inventors: 戴冬伟; 邢孟秋; 吴军; 叶海雁; 刘抗; 郭瀛军
Original assignee: Huzhou Siman Biomaterial Co ltd
Current assignee: Huzhou Siman Biomaterial Co ltd
Priority date: 2019-12-05
Filing date: 2019-12-05
Publication date: 2020-04-24

Abstract

The invention discloses a preparation method of a catheter, which comprises the step of soaking a catheter head of the catheter in a dopamine solution, wherein the dopamine solution is a tris buffer solution of dopamine, the concentration of the dopamine solution is 0.5-5 mg/ml, and the pH value is 8-9. The catheter prepared by the method of the invention has obviously improved hydrophilic lubrication effect, obviously reduced friction on the surface of the catheter and greatly improved blood compatibility of the catheter.

Description

Preparation method of catheter

Technical Field

The invention relates to the field of medical catheters, in particular to a preparation method of a catheter with a hydrophilic coating.

Background

The medical catheter is made of PVC, polyurethane, silicon rubber, latex and the like. The surface lubricity of the catheter has been found to be important during clinical use. The high surface lubricity can reduce the damage of the catheter to various tissues and organs in the using process, relieve the pain of patients, reduce virus infection and reduce the adhesion of fibrin, platelets and walls of the catheter. In order to meet the requirements of clinical application, the surface of the material needs to be modified to improve the lubricity. For biomedical materials, the hydrophilicity/hydrophobicity of the material surface is the primary factor affecting the lubricity and protein adsorption of the material surface. Clinical studies show that hydrophilic materials have better lubricity and biocompatibility than hydrophobic materials. And the adhesion strength of the hydrophilic surface to the protein is lower, which is beneficial to the adjustment and maintenance of the original free conformation of the protein. Therefore, the development of hydrophilic modification of the surface of the medical catheter is necessary.

The hydrophilic lubricating coating is an effective means for hydrophilic modification of the catheter, for example, a polymer film forming material containing a large amount of pyrrolidone groups, ethylene oxide groups, carboxyl groups and amide groups is used as the coating to improve the hydrophilicity of the catheter. However, the catheter has poor lubricating properties and coating stability, and the hydrophilic coating is easily peeled off.

The appearance of bionic technology similar to marine mussel foot gland secretion mussel foot silk adhesive protein (Mfp-5) presented by oxidative polymerization products of dopamine attracts extensive attention to the modification of the super-strong adhesive property of the surface of a solid material. Dopamine undergoes self-polymerization in a weakly alkaline aqueous solution to form a Polydopamine (PDA) layer that adheres to the surface of almost any material. The surface of the film formed by polydopamine contains a large number of active functional groups, a series of reactions can occur, and potential secondary reactions based on PDA are realized for further realizing the super-hydrophilicity of the surface.

Disclosure of Invention

The application provides a preparation method of a catheter, which comprises the step of soaking a tube head of the catheter in a dopamine solution, wherein the dopamine solution is a trihydroxymethyl aminomethane (tris) buffer solution of dopamine, the concentration of the dopamine solution is 0.5-5 mg/ml, and the pH value is 8-9.

Further, the tube head of the catheter is soaked in the dopamine solution for 15-25 hours. Less than 15h, the polydopamine layer is too thin, and a compact film layer is not formed on the surface of the catheter; the thickness of the polydopamine layer gradually increases along with the increase of time; after more than 25 hours, the thickness of the polydopamine layer tends to be stable and basically constant.

Further, the method comprises the step of immersing the catheter soaked by the dopamine solution in a hydrophilic polymer solution, wherein the hydrophilic polymer does not comprise polydopamine. Dopamine is subjected to self-polymerization in an aqueous solution, a polydopamine layer with extremely strong adhesion capacity is generated on the surface of the catheter, and the polydopamine layer can play a role in adhering the catheter and the hydrophilic coating.

Further, the hydrophilic polymer is selected from the group consisting of poly 2- (methacryloxy) ethyl- (trimethyl amino) ethyl phosphate (polyMPC), or a product of polymerization of 2- (methacryloxy) ethyl-2- (trimethyl amino) ethyl phosphate (MPC) monomer with one or more of Stearyl Methacrylate (SMA) monomer, hydroxypropyl methacrylate (HPMA) monomer, trimethoxy silyl propyl methacrylate (TSMA) monomer, n-Butyl Methacrylate (BMA) monomer, alkyl methacrylate monomer. Wherein the polymer of MPC and BMA is poly (2-methacryloxyphosphorylcholine-co-butyl methacrylate) (PMB).

Further, the catheter is immersed in the hydrophilic polymer solution for 15 to 30 hours. Less than 15 hours, a dense hydrophilic polymer layer has not yet formed on the catheter surface; after more than 30 hours, the thickness of the hydrophilic polymer layer tends to be stable without substantially increasing.

Further, the preparation of the hydrophilic polymer solution includes the steps of polymerization, purification, and formulation.

Further, the polymerization reaction step comprises the steps of initiating the monomer by using an initiator, adding a chain transfer agent, introducing inert gas into a first solvent for degassing treatment to generate polymerization reaction, adding a precipitator for precipitation, and finally performing vacuum drying to obtain the hydrophilic polymer.

In the polymerization reaction step for preparing the hydrophilic polymer solution, an initiator is selected from Azobisisobutyronitrile (AIBN) or peroxybenzamide (BPO), a chain transfer agent is selected from trithiocarbonate or α -acetic acid dithiobenzyl ester, a first solvent is selected from methanol or ethanol, an inert gas is nitrogen or argon, wherein the mass ratio of the initiator to the MPC is 1: 100-1: 150, the mass ratio of the chain transfer agent to the MPC is 1: 10-1: 20, the mass ratio of the first solvent to the MPC is 2: 1-5: 1, the polymerization reaction temperature is 40-60 ℃, the polymerization reaction time is 10-20 hours, the degassing treatment time is 10-30 minutes, and a precipitating agent is acetone or diethyl ether, wherein the trithiocarbonate is 2- (dodecyl trithiocarbonate) -2-methylpropionic acid.

Further, the purification step comprises the steps of dissolving the hydrophilic polymer subjected to vacuum drying in the previous step in a first solvent, introducing nitrogen for degassing treatment for 15-40 minutes, adding n-butylamine, reacting at 50-60 ℃ for 30-50 minutes, adding acetone after the reaction is finished, and drying the purified hydrophilic polymer after vacuum drying.

Further, the step of preparing comprises dissolving the purified hydrophilic polymer and a crosslinking agent in a second solvent, wherein the crosslinking agent is 1-ethyl- (3-dimethylaminopropyl) carbonyldiimine hydrochloride (EDC & HCl) and N-hydroxysuccinimide (NHS), the mass ratio of EDC & HCl to NHS is 1.5: 1-2: 1, and the second solvent is selected from double distilled water or triple distilled water.

Further, the catheter soaked in the dopamine solution is soaked in the hydrophilic polymer solution for 15-30 hours, then is washed by double distilled water, and finally is cured to obtain the catheter.

The blood compatibility of the catheter modified by the hydrophilic coating is greatly improved

Drawings

The following description will explain embodiments of the present invention in further detail with reference to the accompanying drawings.

FIG. 1 is a graph showing the change in surface contact angle of the catheters of examples 1-3 when immersed in distilled water for various periods of time.

Detailed Description

The following description of the embodiments of the present invention is provided for illustrative purposes, and other advantages and effects of the present invention will become apparent to those skilled in the art from the present disclosure. While the invention will be described in connection with the preferred embodiments, there is no intent to limit its features to those embodiments. On the contrary, the invention is described in connection with the embodiments for the purpose of covering alternatives or modifications that may be extended based on the claims of the present invention. In the following description, numerous specific details are set forth in order to provide a thorough understanding of the present invention. The invention may be practiced without these particulars. Moreover, some of the specific details have been left out of the description in order to avoid obscuring or obscuring the focus of the present invention.

The preparation method of the catheter mainly comprises the following steps:

1) preparing a dopamine solution, and adjusting the pH value of the solution.

The concentration of the tris buffer solution in the step is 0.01-1 mol/l, the concentration of the tris buffer solution of dopamine is 0.5-5 mg/ml, hydrochloric acid is adopted to adjust the dopamine solution, and the pH value of the dopamine solution is 8-9.

2) And (3) soaking the tube head of the catheter in a dopamine solution for 15-25 hours, and cleaning and airing.

3) And (3) preparing a hydrophilic polymer.

The method comprises the steps of using azobisisobutyronitrile or benzoperoxide amide as an initiator initiating monomer, adding a chain transfer agent trithiocarbonate or α -acetic acid dithiobenzyl ester into one or more monomers selected from MPC, SMA, HPMA, TSMA, BMA and alkyl methacrylate, introducing inert gas nitrogen or argon into methanol or ethanol as a solvent for degassing treatment for 10-30 minutes, reacting at the temperature of 40-60 ℃ for 10-20 hours, adding acetone or diethyl ether as a precipitating agent for precipitation, and performing vacuum drying to obtain the hydrophilic polymer, wherein the mass ratio of the initiator to the MPC is 1: 100-1: 150, the mass ratio of the chain transfer agent to the MPC is 1: 10-1: 20, and the mass ratio of a first solvent to the MPC is 2: 1-5: 1.

4) And (4) purifying the hydrophilic polymer.

Dissolving the hydrophilic polymer subjected to vacuum drying in a first solvent, introducing nitrogen, degassing for 15-40 minutes, adding n-butylamine, reacting at 50-60 ℃ for 30-50 minutes, adding acetone after the reaction is finished, and drying the purified hydrophilic polymer after vacuum drying.

5) And (4) preparing a hydrophilic polymer solution.

Dissolving the purified hydrophilic polymer and a cross-linking agent in double distilled water or triple distilled water, wherein the cross-linking agent is EDC & HCl and NHS, and the mass ratio of EDC & HCl to NHS is 1.5: 1-2: 1.

6) The catheter soaked in the dopamine solution is soaked in the hydrophilic polymer solution for 15-30 hours, then is washed by double distilled water, and finally is cured to obtain the catheter.

The performance test items and methods are as follows:

1. contact angle testing of catheter surfaces

And (3) carrying out water contact angle test on the surface of the catheter sample by a contact angle measuring instrument. Dropping a drop of water on the surface of a sample by using a hydrostatic dropping method, measuring the angle by using a three-point method, measuring for three times in each group of experiments, taking an average value, namely the size of the contact angle, and analyzing the quality of the hydrophilicity of the surface of the material according to the contact angle. The smaller the angle, the better the wettability of the liquid on the solid surface.

2. Catheter surface continuous water contact angle test

The catheter sample manufactured by the preparation method is soaked in distilled water at 37 ℃ for different days (1d, 2d, 3d, 4d, 5d, 6d, 7d and 8d), the soaking solution is replaced every 24 hours, and the change condition of the contact angle of the surface of the sample is observed.

3. Catheter lubricity test

Coating the coating on half of the length of the catheter, not coating the coating on the other half of the length of the catheter, vertically fixing one end of the catheter on a lower clamp of a stretcher, clamping a self-made sliding block on the surface of the catheter, rotatably screwing the sliding block on the catheter and applying fixed pressure to the catheter, enabling an interlayer in the sliding block to bear a certain volume of deionized water and continuously infiltrating the catheter, clamping the sliding block by using an upper clamp connected with a mechanical sensor in the stretcher, pulling the sliding block to the upper part of the catheter from the lower part of the catheter at a fixed speed, reflecting the friction force on the two surfaces of the catheter by the stress change of the sensor, and reflecting the hydrophilic lubricity of the catheter by the difference of numerical values of the friction force. And recording the friction values corresponding to the central positions of the surfaces of the two parts, obtaining the reduction amplitude of the friction of the hydrophilic surface, and recording the reduction amplitude as fp-r, wherein the larger the fp-r value is, the better the lubricity is.

4. Plasma platelet adhesion test on catheter surfaces

Placing a catheter sample on clean filter paper at 25 ℃, dropwise adding 20 microliters of fresh platelet-rich plasma by using a micro-sampler, contacting the catheter with a membrane and keeping the catheter for 30min, then carefully cleaning the surface of the catheter by using PBS (pH 7.2) buffer solution to remove blood platelets which are not firmly adsorbed, immersing the catheter in 1% glutaraldehyde fixing solution for 30min, then cleaning the surface of the membrane for a plurality of times by using triple distilled water, and then sequentially immersing and washing the surface of the catheter by using ethanol/water gradient solutions with the concentrations (volume fractions) of 30%, 40%, 50%, 60%, 70%, 80%, 90% and 100% to dehydrate the blood platelets on the surface, and respectively immersing and washing the surface of the catheter for 10-20 min. After naturally drying in the air, the sample is placed in a dryer and kept to be tested.

The raw material sources of the embodiment of the invention are as follows:

tris (hydroxymethyl) aminomethane: purchased from national drug group chemical agents, ltd;

dopamine: purchased from Sigma;

trithiocarbonate: 2- (dodecyl trithiocarbonate) -2-methylpropionic acid, available from alatin;

AIBN: azobisisobutyronitrile, available from national pharmaceutical group chemical agents, ltd;

n-butylamine: purchased from alatin;

EDC. HCl: 1-ethyl- (3-dimethylaminopropyl) carbonyldiimine hydrochloride from alatin;

NHS: n-hydroxysuccinimide from alatin;

BPO: peroxidated benzamide, available from alatin;

BMA: n-butyl methacrylate, available from alatin.

Example 1

1) Preparing a dopamine solution, adjusting the pH of the solution:

0.3028g of Tris (hydroxymethyl) aminomethane (Tris) was weighed out and dissolved in 250ml of deionized water, and stirred to be completely dissolved, followed by dropwise addition of dilute hydrochloric acid to the Tris solution to adjust its pH to 8.5 to obtain a Tris-HCl buffer. 1.25g of dopamine was added to Tris-HCl buffer to prepare a 5mg/mL dopamine solution.

2) And (3) soaking the tube head of the catheter in the prepared dopamine solution, standing for 18 hours at room temperature, cleaning with double distilled water, and drying in the air.

3) Preparation of hydrophilic polymer:

0.59g of MPC, 42.8mg of trithiocarbonate, 4.8mg of AIBN were dissolved in 2.2ml of methanol, the solution was degassed with nitrogen for 20 minutes, and reacted at 60 ℃ for 18 hours. After precipitation by addition of acetone, the precipitated product is dried under vacuum.

4) Purification of hydrophilic polymers:

and (3) dissolving the polyMPC dried in the previous step in methanol, introducing nitrogen to perform degassing treatment for 20 minutes, adding n-butylamine to react for 30 minutes to change the reaction liquid from yellow to nearly colorless, adding acetone again to precipitate after the reaction is finished, pouring out the supernatant, and then putting the mixture into vacuum to be dried to obtain a dried and purified polyMPC product.

5) Preparation of hydrophilic polymer solution:

0.3g of purified polyMPC, 34mg of EDC. HCl and 21mg of NHS were dissolved in 10ml of double distilled water.

6) The dopamine treated tip was soaked in this solution for 24 hours. Washing the pipe head treated by the above steps with double distilled water, and then drying.

Example 2

1) Preparing a dopamine solution, adjusting the pH of the solution:

0.6056g of Tris (hydroxymethyl) aminomethane (Tris) was weighed out and dissolved in 250ml of deionized water, and stirred to be completely dissolved, followed by dropwise addition of dilute hydrochloric acid to the Tris solution to adjust its pH to 8.5 to obtain a Tris-HCl buffer. 0.75g of dopamine was added to Tris-HCl buffer to prepare a 2.5mg/mL dopamine solution.

2) The tip of the catheter was immersed in the prepared dopamine solution and allowed to stand at room temperature for 20 hours. Then washing with triple distilled water and drying in the air.

3) Preparation of hydrophilic polymer:

0.59g of MPC, 29.5mg of trithiocarbonate, 3.93mg of BPO were dissolved in 2.95ml of ethanol, the solution was degassed with nitrogen for 40 minutes, and reacted at 50 ℃ for 18 hours. After precipitation by addition of acetone, the precipitated product is dried under vacuum.

4) Purification of hydrophilic polymers:

and (3) dissolving the polyMPC dried in the previous step in ethanol, introducing nitrogen to perform degassing treatment for 30 minutes, adding n-butylamine to react for 45 minutes to change the reaction liquid from yellow to nearly colorless, adding acetone again to precipitate after the reaction is finished, pouring out the supernatant, and then putting the mixture into vacuum to be dried to obtain a dried and purified polyMPC product.

5) Preparation of hydrophilic polymer solution:

0.3g of polyMPC prepared as described above, 42mg of EDC. HCl, 21mg of NHS were dissolved in 10ml of triple distilled water.

6) The dopamine treated tip was soaked in this solution for 28 hours. Washing the pipe head treated by the above steps with double distilled water, and then drying.

Example 3

1) Preparing a dopamine solution, adjusting the pH of the solution:

2) The tip of the catheter was immersed in the prepared dopamine solution and allowed to stand at room temperature for 18 hours. Then the mixture is washed by double distilled water and dried in the air.

3) Preparation of hydrophilic polymer:

0.59g of MPC, 0.28g of BMA, 42.8mg of trithiocarbonate and 4.8mg of AIBN were dissolved in 2.2ml of methanol, the solution was degassed with nitrogen for 20 minutes, and reacted at 60 ℃ for 18 hours. After precipitation by addition of acetone, the precipitated product is dried under vacuum.

4) Purification of hydrophilic polymers:

and (3) dissolving the PMB dried in the last step in methanol, introducing nitrogen to perform degassing treatment for 20 minutes, adding n-butylamine to react for 30 minutes to change the reaction liquid from yellow to nearly colorless, adding acetone again to precipitate after the reaction is finished, pouring out the supernatant, and then putting into vacuum to be dried to obtain a dried and purified PMB product.

5) Preparation of hydrophilic polymer solution:

0.3g of the purified PMB, 42mg of EDC. HCl and 21mg of NHS were dissolved in 10ml of double distilled water.

The performance test results for the catheters prepared according to the above examples are shown in table 1 and fig. 1:

table 1 results of performance testing

1. Contact Angle testing

The results of this test show that the catheter, which was not coated with a hydrophilic coating, had a water contact angle of 97.6 ° ± 2 °, whereas the catheter, which was coated with a hydrophilic coating, had a water contact angle of 23.1 ° ± 2 ° to 33.1 ° ± 3 °. The water contact angle of the catheter surface coated with the hydrophilic coating of the present invention was significantly reduced compared to the catheter not coated with the coating of the present invention, indicating that the coating of the present invention has a hydrophilic lubricating effect.

2. Continuous water contact Angle test

The test results are shown in fig. 1, and fig. 1 shows that the catheter sample manufactured by the preparation method of the present application is soaked in distilled water at 37 ℃ for different times, the surface contact angle is not greatly changed, and the surface contact angle is always smaller than that of the catheter without the coating.

3. Catheter lubricity test

The test result shows that the friction force reduction amplitude of the surface of the catheter prepared by the method is remarkably increased, and the lubricating property is better.

4. Catheter surface platelet adhesion test

The test results showed that the catheter surface without the hydrophilic coating adhered a greater number of blood platelets, 135000/mm, than the catheter surface coated with the hydrophilic coating of the present invention²The number of the blood platelets adhered to the surface of the catheter prepared by the method is obviously reduced, which shows that the blood compatibility of the catheter modified by the hydrophilic coating is greatly improved.

In summary, the above-mentioned embodiments are provided only for illustrating the principles and effects of the present invention, and not for limiting the present invention. Any person skilled in the art can modify or change the above-mentioned embodiments without departing from the spirit and scope of the present invention. Accordingly, it is intended that all equivalent modifications or changes which can be made by those skilled in the art without departing from the spirit and technical spirit of the present invention be covered by the claims of the present invention.

Claims

1. The preparation method of the catheter is characterized by comprising the step of soaking a tube head of the catheter in a dopamine solution, wherein the dopamine solution is a tris buffer solution of dopamine, the concentration of the dopamine solution is 0.5-5 mg/ml, and the pH value is 8-9.

2. The method for preparing a catheter according to claim 1, wherein the tube head of the catheter is soaked in the dopamine solution for 15 to 25 hours.

3. The method of preparing a catheter according to claim 1 or 2, further comprising dipping the catheter soaked in the dopamine solution in a solution of a hydrophilic polymer, the hydrophilic polymer not comprising polydopamine.

4. The method of claim 3, wherein the hydrophilic polymer is selected from the group consisting of poly 2- (methacryloyloxy) ethyl- (trimethylamino) ethyl phosphate, and a product of polymerization of 2- (methacryloyloxy) ethyl-2- (trimethylamino) ethyl phosphate monomer with one or more of octadecyl methacrylate monomer, hydroxypropyl methacrylate monomer, trimethoxysilylpropyl methacrylate monomer, n-butyl methacrylate monomer, and alkyl methacrylate monomer.

5. The method of claim 4, wherein the catheter is immersed in the hydrophilic polymer solution for 15 to 30 hours.

6. The method of claim 4, wherein the preparing of the hydrophilic polymer solution comprises the steps of polymerization, purification, and formulation.

7. The catheter preparation method according to claim 6, wherein the polymerization reaction comprises the steps of initiating the monomer by using an initiator, adding a chain transfer agent, introducing an inert gas into a first solvent for degassing treatment, polymerizing, adding a precipitator for precipitation, and performing vacuum drying to obtain the hydrophilic polymer, wherein the initiator is selected from azobisisobutyronitrile or benzoperoxide amide, the chain transfer agent is selected from trithiocarbonate or α -acetic acid dithiobenzyl ester, the first solvent is selected from methanol or ethanol, the inert gas is nitrogen or argon, the mass ratio of the initiator to the chain transfer agent to 2- (methacryloyloxy) ethyl-2- (trimethylamino) ethyl phosphate is 1: 100-1: 150, 1: 10-1: 20, and 2: 1-5: 1, the polymerization reaction temperature is 40-60 ℃, the polymerization reaction degassing time is 10-20 hours, the treatment time is 10-30 minutes, and the precipitator is acetone or ethyl ether.

8. The method for preparing a catheter according to claim 7, wherein the purifying step comprises dissolving the hydrophilic polymer dried under vacuum in a first solvent, introducing nitrogen gas, degassing for 15 to 40 minutes, adding n-butylamine, reacting at 50 to 60 ℃ for 30 to 50 minutes, adding acetone after the reaction is completed, vacuum-drying, and drying the purified hydrophilic polymer.

9. The method of preparing a catheter according to claim 8, wherein the step of formulating comprises dissolving the purified hydrophilic polymer and a crosslinking agent in a second solvent, wherein the crosslinking agent is 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride and N-hydroxysuccinimide, wherein the mass ratio of 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride to N-hydroxysuccinimide is 1.5:1 to 2:1, and the second solvent is selected from double distilled water or triple distilled water.

10. The method of manufacturing a catheter according to any one of claims 6 to 10, wherein the catheter soaked in the dopamine solution is immersed in the hydrophilic polymer solution for 15 to 30 hours, then washed with double distilled water, and finally subjected to a curing treatment.