Medical catheter based on high-biocompatibility polyurethane material and preparation method thereof

Abstract

The invention discloses a medical catheter based on a high-biocompatibility polyurethane material and a preparation method of the medical catheter. The medical catheter comprises a catheter-shaped base body and a modification layer wrapping the outer portion of the catheter-shaped base body, and the catheter-shaped base body comprises modified polyurethane and an auxiliary additive. Modified polyurethane with antibacterial performance and hydrophilic performance is prepared through design, a catheter-shaped matrix is further prepared through fusion and extrusion, after plasma activation and swelling adsorption treatment are conducted on a catheter material, the catheter material is soaked in a modification solution and subjected to ultraviolet curing, and the antibacterial performance of the catheter is improved. According to the medical catheter based on the high-biocompatibility polyurethane material, not only are the antibacterial performance and the biocompatibility of the medical catheter greatly improved, but also the mechanical performance of the medical catheter is remarkably improved.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of polyurethane material processing, in particular to a medical catheter based on high biocompatibility polyurethane material and a preparation method thereof. BACKGROUND

[0002] With the rapid development of interventional medicine, minimally invasive surgery and in-vivo delivery system, flexible medical catheter materials are required to have higher biocompatibility, mechanical flexibility and long-term service stability. Polyurethane materials (PU) are widely used in medical tubes such as disposable urinary catheters, vascular catheters, drainage tubes and nerve catheters due to their adjustable physical properties, excellent mechanical strength, good flexibility and certain biocompatibility.

[0003] At present, flexible polyurethane catheters usually adopt a thermoplastic polyurethane structure constructed by reacting polyether glycol or polyester glycol as a soft segment with diisocyanate and a chain extender. To improve the biological safety and tissue adaptability, the traditional enhancement method is to modify by coating a hydrophilic coating or adding an antibacterial monomer. Although these modification methods can improve the antibacterial performance and biocompatibility of PU catheters to some extent, they still face a series of challenges in long-term use.

[0004] In the prior art, although the commonly used modification methods can improve the antibacterial performance and biocompatibility of flexible polyurethane materials, in the long-term use process, the flexible polyurethane materials prepared by physical blending or the flexible polyurethane materials coated with a hydrophilic coating on the surface have the problems of poor bonding force and insufficient long-term stability.

[0005] In addition, part of the modifiers are easy to migrate or release, increasing the risk of toxicity or inducing drug resistance, and the conventional polyurethane surface is relatively hydrophobic, easy to adsorb blood proteins and bacteria, thereby causing risks such as immune response, thrombosis or biofilm pollution. The flexible polyurethane material on the tissue contact interface may also cause patient discomfort due to problems such as a relatively rough and hard surface. SUMMARY

[0006] The purpose of the present application is to provide a medical catheter based on high biocompatibility polyurethane material and a preparation method and application thereof, which solves the technical problem that the antibacterial performance and biocompatibility of polyurethane materials in the prior art need to be further improved.

[0007] The purpose of the present application can be achieved by the following technical solutions:

[0008] The first aspect of the present application provides a medical catheter based on high biocompatibility polyurethane material, which comprises a catheter-shaped base and a modification layer coated on the outside of the catheter-shaped base, the catheter-shaped base comprises the following components by weight parts: 60-80 parts of modified polyurethane and 10-15 parts of auxiliary additives.

[0009] The modification forming method of the modification layer comprises:

[0010] A1, plasma treating the conduit-shaped substrate to obtain an activated conduit-shaped substrate.

[0011] A2, dipping the activated conduit-shaped substrate in a benzophenone solution to obtain a flexible polyurethane conduit precursor through a first post-treatment.

[0012] The preparation reaction principle of the flexible polyurethane conduit precursor is mainly as follows: during the reaction, the activated conduit-shaped substrate can be slightly chain segment swollen in acetone to increase the chain spacing, and the benzophenone molecules diffuse into the conduit surface layer and are adsorbed on the polar groups such as surface active hydroxyl groups to obtain the flexible polyurethane conduit precursor with introduced photoinitiator.

[0013] A3, dipping the flexible polyurethane conduit precursor in a modification liquid, dipping for 1-2 min, taking out and irradiating under ultraviolet light for 1-3 min to obtain the medical conduit.

[0014] The preparation reaction principle of the medical conduit is mainly as follows: during the reaction, under the irradiation of the ultraviolet lamp, the lithium phenyl-2,4,6-trimethylbenzoyl phosphinate in the modification liquid is cracked to generate free radicals, which attack the carbon-carbon unsaturated double bond on the intermediate I in the modification liquid, gradually chain growth and crosslinking, and form a hydrogel network on the surface of the flexible polyurethane conduit precursor, and the benzophenone absorbs ultraviolet light to extract hydrogen from the flexible polyurethane conduit precursor to form free radicals, which provide reaction sites for the growth of the hydrogel network on the surface of the flexible polyurethane conduit precursor to obtain the medical conduit.

[0015] The preparation method of the conduit-shaped substrate comprises: placing the modified polyurethane and auxiliary additives in a twin-screw extruder, melt extruding, injecting into a mold, and solidifying to obtain the conduit-shaped substrate.

[0016] Further, in step A2, the dipping ratio of the dipping operation is 1:30-35, and the benzophenone solution is a 5-8wt% benzophenone acetone solution.

[0017] Further, the first post-treatment comprises: after the reaction is completed, the product conduit is washed with isopropyl alcohol for 2-3 times, transferred to an oven with a temperature of 30-40℃, and dried for 4-6h to obtain the flexible polyurethane conduit precursor.

[0018] Further, the temperatures of the eight temperature sections of the twin-screw extruder from the feeding port to the discharging port are 160℃, 160℃, 170℃, 170℃, 190℃, 190℃, 210℃, and 210℃ in sequence, the main machine speed of the twin-screw extruder is 50-80rpm, and the pressure is 100-150bar.

[0019] In step A3, the impregnation ratio of the impregnation operation is 1:30-35, and the wavelength of the ultraviolet light is set to 380-400 nm.

[0020] Further, the auxiliary additive can be composed of a plasticizer, a lubricant and an antioxidant in a mass ratio of 3:1:1. The plasticizer can be one or more of dioctyl phthalate, diisononyl phthalate and dibutyl sebacate. The lubricant can be one or more of oleic acid, fatty acid amide and oleic acid amide. The antioxidant can be one or more of 4,4'-thiobis(6-tert-butyl-3-methylphenol), bis(2,4-di-tert-butylphenyl) pentaerythritol diphosphite and 2,6-di-tert-butyl-4-methylphenol.

[0021] Further, the preparation method of the modified polyurethane comprises the following steps:

[0022] B1, N-methyldiethanolamine, polycarbonate diol, polycaprolactone diol, N,N-dimethylformamide and stannous octoate are placed in a reaction kettle protected by nitrogen atmosphere and stirred, the reaction kettle is heated to 90-100℃, and stirred for 15-30 min, and then a calculated amount of L-lysine diisocyanate is added, and the reaction is carried out for 4-6 h to obtain a prepolymer solution;

[0023] B2, the prepolymer solution and L-arginine are placed in a reaction kettle protected by nitrogen atmosphere and stirred, the reaction kettle is heated to 45-55℃, and the reaction is carried out for 2-4 h, and then acetic acid is added, and the reaction is carried out for 20-30 min, and then the modified polyurethane is obtained through a second post-treatment.

[0024] The preparation reaction formula of the modified polyurethane is:

[0025]

[0026] In the formula:

[0027] The preparation reaction principle of the modified polyurethane is mainly:

[0028] In the reaction process, under the conditions of heating and catalyst, the terminal hydroxyl groups of N-methyldiethanolamine, polycarbonate diol and polycaprolactone diol and the isocyanate groups of L-lysine diisocyanate undergo nucleophilic addition reaction, by controlling the excess of L-lysine diisocyanate, the prepolymer terminated by isocyanate is obtained, the prepolymer in the prepolymer solution further undergoes nucleophilic addition reaction with L-arginine to chain-extend the prepolymer, and further under the action of acetic acid, the nitrogen atom of N-methyldiethanolamine undergoes acid-base neutralization reaction to form tertiary amine acetate, and the modified polyurethane is obtained.

[0029] Further, in step B1, the amount of N-methyldiethanolamine, polycarbonate diol, polycaprolactone diol, N,N-dimethylformamide and stannous octoate is 1-2 g: 4-6 g: 2-4 g: 80-120 mL: 0.5-1 g.

[0030] Further, in step B1, the amount of L-lysine diisocyanate is 0.55-0.60 times the total molar amount of hydroxyl groups of N-methyldiethanolamine, polycarbonate diol and polycaprolactone diol.

[0031] Further, in step B2, the amount of the prepolymer solution, L-arginine and acetic acid is 30-40 mL: 1-2 g: 0.5-1 g.

[0032] Further, the second post-treatment comprises: after the reaction is completed, the reaction system is cooled to room temperature, the reaction solution is added to 100-150 mL of anhydrous ether for precipitation, suction filtration, the filter cake is washed with ethanol for 2-3 times, and then transferred to an oven with a temperature of 50-60°C for drying until the weight is constant, to obtain the modified polyurethane.

[0033] Further, in step A1, the preparation method of the activated conduit-shaped matrix comprises: adding the conduit-shaped matrix into a plasma treatment instrument, and performing plasma treatment for 3-5 min in an atmospheric environment to obtain the activated conduit-shaped matrix.

[0034] The preparation reaction principle of the activated conduit-shaped matrix mainly comprises:

[0035] During the reaction, high-energy particles in the plasma treatment instrument bombard the surface of the conduit-shaped matrix, so that chain segment rupture and free radical sites are generated, part of the free radicals react with O2, H2O, O3 and the like in the atmosphere to generate polar groups such as hydroxyl, carboxyl and carbonyl, and the surface becomes rough, which is beneficial to the subsequent combination with the modification solution, so as to obtain the activated conduit-shaped matrix containing free radicals and having polar functional groups on the surface.

[0036] Further, the power of the plasma treatment instrument is 18-20 W.

[0037] Further, in step A3, the preparation method of the modification solution comprises the following steps:

[0038] C1, polysialic acid and buffer are placed in a reaction kettle and stirred, the reaction kettle is cooled to 0-5°C, white peony acid anhydride is added, sodium hydroxide solution is added, the pH value is adjusted to 9-11, and the reaction is kept for 20-24 h, and then the intermediate I is obtained through the third post-treatment.

[0039] The preparation reaction formula of the intermediate I is:

[0040]

[0041] The reaction principle of the preparation of the intermediate I is mainly as follows:

[0042] During the reaction, a large number of hydroxyl groups in the polysialic acid molecule are ionized into oxygen negative ions under the condition of pH = 9-12, the nucleophilicity is enhanced, the anhydride ring of the angelica acid anhydride is an electron-deficient carbon structure, and is easily attacked by the oxygen negative ions in the polysialic acid molecule to open the ring to generate a new ester bond, and at the same time, the acid anhydride is hydrolyzed to generate methacrylic acid in the reaction, and the sodium hydroxide can neutralize the acid to maintain the reaction pH and control the reaction temperature to be 0-5 DEG C, so that the occurrence of side reactions can be reduced, and the intermediate I is finally obtained.

[0043] C2, the intermediate I and the buffer are placed in a reaction kettle and stirred, the lithium phenyl-2, 4, 6-trimethylbenzoyl phosphinic acid is added and uniformly mixed to obtain a modified liquid.

[0044] Further, in step C1, the use amount ratio of the polysialic acid, the buffer and the angelica acid anhydride is 2-4 g: 20-40 mL: 4-6 mL.

[0045] Further, in step C1, the buffer is a phosphate buffer.

[0046] Further, in step C1, the sodium hydroxide solution is a 50-70 wt% sodium hydroxide aqueous solution.

[0047] Further, the third post-treatment comprises: after the reaction is completed, the reaction system is cooled to room temperature, the reaction liquid is added into 200-250 mL of anhydrous ethanol to precipitate a precipitate, the filter cake is dispersed with deionized water, and then transferred to a freeze dryer with a temperature of-60 DEG C for freeze drying for 6-10 h to obtain the intermediate I.

[0048] Further, in step C2, the use amount ratio of the intermediate I, the buffer and the lithium phenyl-2, 4, 6-trimethylbenzoyl phosphinic acid is 4-6 g: 40-60 mL: 0.4-0.6 g.

[0049] Further, in step C2, the buffer is a phosphate buffer.

[0050] The second aspect of the application further provides a preparation method of the medical catheter based on the high biocompatibility polyurethane material: the modified polyurethane and auxiliary additives are placed in a double-screw extruder, melt-extruded, injected into a mold, solidified, and coated with a modification layer to obtain the medical catheter.

[0051] Compared with the prior art, the application has at least the following beneficial effects:

[0052] 1. The invention is to prepare a block copolymer modified polyurethane with N-methyldiethanolamine, polycarbonate diol and polycaprolactone diol as soft segments, and L-lysine diisocyanate and L-arginine as hard segments. The flexible N-methyldiethanolamine, polycaprolactone and polycarbonate segments provide excellent tensile properties and toughness, while the urethane hard segment formed by lysine diisocyanate provides good structural support to the polymer. L-arginine and triazine chain extender introduce multiple hydrogen bonds and microcrystalline regions, further enhancing the toughness of the material. The overall strength and flexibility of the flexible polyurethane-based medical catheter are balanced, and the mechanical properties are enhanced.

[0053] 2. In the preparation of modified polyurethane, chain extender L-arginine is added, which contains guanidino structure in its molecular structure. The outer membrane of bacteria is rich in negatively charged phospholipid head, lipopolysaccharide and peptidoglycan. Guanidino can be combined with the bacterial membrane through high-strength electrostatic adsorption, causing membrane structure disorder, membrane potential collapse and content leakage, and further leading to bacterial death. N-methyldiethanolamine generates tertiary amine acetate with antibacterial properties under the action of acetic acid. Both substances are embedded in polyurethane through chemical bonding to avoid the inactivation of antibacterial properties caused by migration during use, improve the antibacterial properties and durability of flexible polyurethane materials, and the invention also uses aliphatic structure lysine diisocyanate to avoid the potential cytotoxicity of aromatic isocyanate, and introduces natural amino acid L-arginine and triazine chain extender to improve the biocompatibility of flexible polyurethane materials.

[0054] 3. The invention is to prepare an intermediate I by esterification reaction, and mix it with a photoinitiator to prepare a modified liquid. The catheter-shaped substrate is treated by plasma to introduce free radical reaction sites and polar functional groups on the catheter-shaped substrate. Diphenyl ketone is used to swell the activated catheter-shaped substrate. Under the initiation of ultraviolet light, intermediate I in the modified liquid is bonded to the surface of the activated catheter-shaped substrate through free radical polymerization reaction to form a firm hydrogel layer, which can prevent proteins or bacteria from directly contacting the substrate, reduce bacterial adhesion and inhibit biofilm formation, improve the antibacterial properties and hydrophilic properties of flexible polyurethane materials. The main body of the modified liquid is polysialic acid, which is derived from amino acid and has non-toxic degradation products, improving the biocompatibility of flexible polyurethane materials. In practical application, the hydrogel layer can disperse external force impact, reduce microcracks, reduce surface lubrication and friction and wear, and improve the mechanical properties of flexible polyurethane materials. DETAILED DESCRIPTION

[0055] The technical solutions of the present application will be clearly and completely described below in combination with the embodiments. Apparently, the described embodiments are only some of the embodiments of the present application, rather than all the embodiments. Based on the embodiments in the present application, all other embodiments obtained by those skilled in the art without creative efforts belong to the scope of protection of the present application.

[0056] The polycarbonate diol used in the present application is purchased from Baishu (Shanghai) Biomedical Technology Co., Ltd., has a molecular weight of 332.39086, and has a product alias of polycarbonate diol, and a product grade of superior product;

[0057] The polycaprolactone diol used in the present application is purchased from Shandong Jinshengtai Chemical Co., Ltd., has a model of JST, a part number of 13520, and a molecular weight of 1000;

[0058] The polysialic acid used in the present application is purchased from Zhongke Hongji Biological Technology Co., Ltd., has a model of 2024081900131;

[0059] The phosphate buffer used in the present application is purchased from Shenzhen Dotpoint Biological Technology Co., Ltd., has a product name of phosphate buffer (pH 7.2 dry powder), a part number of GF1011, and a brand of

[0060] Example 1

[0061] The present embodiment provides a preparation method of modified polyurethane, comprising the following steps:

[0062] Step I, preparation of prepolymer solution

[0063] Take N-methyldiethanolamine 10 g, polycarbonate diol 40 g, polycaprolactone diol 20 g, N,N-dimethylformamide 800 mL and stannous octoate 5 g, and place them in a reaction kettle protected by nitrogen atmosphere for stirring. The reaction kettle is heated to 90 DEG C, and kept stirring for 15 min. L-lysine diisocyanate is added at 0.55 times the total molar amount of the hydroxyl groups of N-methyldiethanolamine, polycarbonate diol and polycaprolactone diol, and kept reacting for 4 h to obtain a prepolymer solution.

[0064] Step II, preparation of modified polyurethane

[0065] Take the prepolymer solution 300 mL and L-arginine 10 g, and place them in a reaction kettle protected by nitrogen atmosphere for stirring. The reaction kettle is heated to 45 DEG C, and kept reacting for 2 h. Acetic acid 5 g is added, and kept reacting for 20 min. After the reaction is completed, the reaction system is cooled to room temperature. The reaction liquid is added into 1000 mL of anhydrous ether for precipitation. Filtration is performed, the filter cake is washed with ethanol for 2 times, and then transferred to an oven with a temperature of 50 DEG C for drying until the weight is constant to obtain the modified polyurethane.

[0066] Example 2

[0067] The embodiment provides a preparation method of modified polyurethane, and comprises the following steps:

[0068] Step I, preparation of prepolymer solution

[0069] The N-methyldiethanolamine 15 g, polycarbonate diol 50 g, polycaprolactone diol 30 g, N,N-dimethylformamide 1000 mL and stannous octoate 7 g are placed in a reaction kettle protected by a nitrogen atmosphere and stirred, the reaction kettle is heated to 95 DEG C, and then stirred for 20 min, L-lysine diisocyanate is added at 0.58 times of the total molar amount of the hydroxyl groups of the N-methyldiethanolamine, polycarbonate diol and polycaprolactone diol, and then the reaction is kept for 5 h to obtain a prepolymer solution.

[0070] Step II, preparation of modified polyurethane

[0071] The prepolymer solution 350 mL and L-arginine 15 g are placed in a reaction kettle protected by a nitrogen atmosphere and stirred, the reaction kettle is heated to 50 DEG C, and then the reaction is kept for 3 h, acetic acid 7 g is added, and then the reaction is kept for 25 min, after the reaction is completed, the reaction system is cooled to room temperature, the reaction solution is added into 1250 mL of anhydrous ether for precipitation, filtration is performed, the filter cake is washed with ethanol for 3 times, and then the filter cake is transferred to an oven with a temperature of 55 DEG C for drying until the weight is constant, so as to obtain the modified polyurethane.

[0072] Example 3

[0073] The embodiment provides a preparation method of modified polyurethane, and comprises the following steps:

[0074] Step I, preparation of prepolymer solution

[0075] The N-methyldiethanolamine 20 g, polycarbonate diol 60 g, polycaprolactone diol 40 g, N,N-dimethylformamide 1200 mL and stannous octoate 10 g are placed in a reaction kettle protected by a nitrogen atmosphere and stirred, the reaction kettle is heated to 100 DEG C, and then stirred for 30 min, L-lysine diisocyanate is added at 0.60 times of the total molar amount of the hydroxyl groups of the N-methyldiethanolamine, polycarbonate diol and polycaprolactone diol, and then the reaction is kept for 6 h to obtain a prepolymer solution.

[0076] Step II, preparation of modified polyurethane

[0077] The prepolymer solution 400 mL and L-arginine 20 g are placed in a reaction kettle protected by a nitrogen atmosphere and stirred, the reaction kettle is heated to 55 DEG C, and then the reaction is kept for 4 h, acetic acid 10 g is added, and then the reaction is kept for 30 min, after the reaction is completed, the reaction system is cooled to room temperature, the reaction solution is added into 1500 mL of anhydrous ether for precipitation, filtration is performed, the filter cake is washed with ethanol for 3 times, and then the filter cake is transferred to an oven with a temperature of 60 DEG C for drying until the weight is constant, so as to obtain the modified polyurethane.

[0078] Example 4

[0079] The present example provides a method for preparing a modified liquid, comprising the following steps:

[0080] Step ①, preparation of intermediate I

[0081] Take: polysialic acid 20 g and phosphate buffer 200 mL in the reaction kettle stirring, the reaction kettle to 0 ℃, add white peony acid anhydride 40 mL, add 50 wt% sodium hydroxide solution, adjust pH = 9, incubation reaction 20 h, after the reaction is completed, the reaction system is reduced to room temperature, the reaction liquid is added to 2000 mL of anhydrous ethanol to precipitate the precipitate, suction filtration, filter cake to deionized water dispersion, transfer to the temperature of-60 ℃ freeze dryer kind, freeze drying 6 h, to get intermediate I.

[0082] Step ②, preparation of modified liquid

[0083] Take: intermediate I 40 g and buffer 400 mL in the reaction kettle stirring, add phenyl-2, 4, 6-trimethyl benzoyl hypophosphorous acid lithium 4 g, mixed evenly, to get modified liquid.

[0084] Example 5

[0085] The present example provides a method for preparing a modified liquid, comprising the following steps:

[0086] Step ①, preparation of intermediate I

[0087] Take: polysialic acid 30 g and phosphate buffer 300 mL in the reaction kettle stirring, the reaction kettle to 2 ℃, add white peony acid anhydride 50 mL, add 60 wt% sodium hydroxide solution, adjust pH = 10, incubation reaction 22 h, after the reaction is completed, the reaction system is reduced to room temperature, the reaction liquid is added to 2250 mL of anhydrous ethanol to precipitate the precipitate, suction filtration, filter cake to deionized water dispersion, transfer to the temperature of-60 ℃ freeze dryer kind, freeze drying 8 h, to get intermediate I.

[0088] Step ②, preparation of modified liquid

[0089] Take: intermediate I 50 g and buffer 500 mL in the reaction kettle stirring, add phenyl-2, 4, 6-trimethyl benzoyl hypophosphorous acid lithium 5 g, mixed evenly, to get modified liquid.

[0090] Example 6

[0091] The present example provides a method for preparing a modified liquid, comprising the following steps:

[0092] Step ①, preparation of intermediate I

[0093] Take: polysialic acid 40 g and phosphate buffer 400 mL in the reaction kettle stirring, the reaction kettle cooling to 5 ℃, add white xanthotoxol 60 mL, add 70 wt % sodium hydroxide aqueous solution, adjust pH = 11, incubation reaction 24 h, after the reaction is completed, the reaction system is reduced to room temperature, the reaction liquid is added to 2500 mL of anhydrous ethanol to precipitate the precipitate, suction filtration, filter cake with deionized water dispersion, transfer to the temperature of-60 ℃ freeze dryer kind, freeze drying 10 h, get intermediate I.

[0094] Step 2, preparation of modified liquid

[0095] Take: intermediate I 60 g and buffer 600 mL in the reaction kettle stirring, add lithium phenyl-2,4,6-trimethylbenzoyl phosphinic acid 6 g, mixed evenly, get modified liquid.

[0096] Example 7

[0097] The present embodiment provides a preparation method of medical catheter based on high biocompatibility polyurethane material, comprising the following steps:

[0098] Step (1), preparation of catheter-shaped matrix

[0099] The diisononyl phthalate, oleic acid and 2,6-di-tert-butyl-4-methyl phenol are mixed uniformly according to the mass ratio of 3:1:1 to obtain an auxiliary additive, which is ready for use;

[0100] According to the weight part, 60 parts of the modified polyurethane prepared in example 1 and 10 parts of auxiliary additive are placed in a twin screw extruder, melt extruded, injected into a mold, room temperature curing, to obtain a catheter-shaped matrix;

[0101] The eight temperature zones of the twin screw extruder from the feeding port to the discharge port are 160℃, 160℃, 170℃, 170℃, 190℃, 190℃, 210℃, 210℃, respectively. The main machine speed of the twin screw extruder is 50 rpm, and the pressure is 100 bar.

[0102] Step (2), preparation of activated catheter-shaped matrix

[0103] The catheter-shaped matrix is added to the plasma treatment instrument, and the power of the plasma treatment instrument is set to 18 W under atmospheric atmosphere. The plasma treatment is carried out for 3 min to obtain an activated catheter-shaped matrix.

[0104] Step (3), preparation of flexible polyurethane catheter precursor

[0105] The activated catheter-shaped matrix is immersed in a 5 wt% benzophenone acetone solution with an immersion ratio of 1:30. After the reaction is completed, the product catheter is washed with isopropyl alcohol for 2 times, and then transferred to an oven with a temperature of 30℃ for drying for 4 h to obtain a flexible polyurethane catheter precursor.

[0106] Step (4), preparation of flexible polyurethane material

[0107] The flexible polyurethane catheter precursor was immersed in the modified liquid prepared in Example 4 for 1 min at an immersion ratio of 1:30, and then taken out and irradiated under ultraviolet light for 1 min. The wavelength of the ultraviolet light was set to 380 nm. Thus, the medical catheter was obtained.

[0108] Example 8

[0109] The present example provides a method for preparing a medical catheter based on a high biocompatibility polyurethane material, which comprises the following steps:

[0110] Step (1), preparation of a catheter-shaped substrate

[0111] The diisononyl phthalate, oleic acid and 2,6-di-tert-butyl-4-methylphenol were mixed uniformly at a mass ratio of 3:1:1 to obtain an auxiliary additive, which was used as needed.

[0112] The modified polyurethane prepared in Example 2 and the auxiliary additive were weighed at 70 parts by weight and 12 parts by weight, respectively, and then placed in a twin-screw extruder for melt extrusion. The product was injected into a mold and cured at room temperature to obtain a catheter-shaped substrate with a tube diameter of about 4 Fr.

[0113] The eight temperature zones of the twin-screw extruder from the feeding port to the discharging port were set to 160°C, 160°C, 170°C, 170°C, 190°C, 190°C, 210°C and 210°C, respectively. The main motor speed of the twin-screw extruder was 65 rpm, and the pressure was 125 bar.

[0114] Step (2), preparation of an activated catheter-shaped substrate

[0115] The catheter-shaped substrate was added to a plasma treatment instrument. Under an atmospheric atmosphere, the power of the plasma treatment instrument was set to 19 W, and the plasma treatment was performed for 4 min to obtain an activated catheter-shaped substrate.

[0116] Step (3), preparation of a flexible polyurethane catheter precursor

[0117] The activated catheter-shaped substrate was immersed in a 6 wt% benzophenone acetone solution at an immersion ratio of 1:32. After the reaction was completed, the product catheter was washed with isopropyl alcohol for 3 times, and then transferred to an oven with a temperature of 35°C for drying for 5 h to obtain a flexible polyurethane catheter precursor.

[0118] Step (4), preparation of flexible polyurethane material

[0119] The flexible polyurethane conduit precursor was prepared by immersing the modified liquid prepared in Example 5 for 2 min at an immersion ratio of 1:32, and then irradiating it under ultraviolet light for 2 min, with the wavelength of the ultraviolet light set to 390 nm.

[0120] Example 9

[0121] The present example provides a method for preparing a medical conduit based on a highly biocompatible polyurethane material, which comprises the following steps:

[0122] Step (1), preparation of a conduit-shaped substrate

[0123] The auxiliary additive was prepared by uniformly mixing diisononyl phthalate, oleic acid, and 2,6-di-tert-butyl-4-methylphenol at a mass ratio of 3:1:1.

[0124] The modified polyurethane prepared in Example 3 and the auxiliary additive were weighed at 80 parts and 15 parts, respectively, and then placed in a twin-screw extruder for melt extrusion, injection into a mold, and room temperature curing to obtain a conduit-shaped substrate with a tube diameter of about 4 Fr.

[0125] The eight temperature zones of the twin-screw extruder from the feeding port to the discharging port were set to 160°C, 160°C, 170°C, 170°C, 190°C, 190°C, 210°C, and 210°C, respectively, the main motor speed of the twin-screw extruder was 80 rpm, and the pressure was 150 bar.

[0126] Step (2), preparation of an activated conduit-shaped substrate

[0127] The conduit-shaped substrate was placed in a plasma treatment instrument, and plasma treatment was performed for 5 min under atmospheric conditions with the power of the plasma treatment instrument set to 20 W to obtain an activated conduit-shaped substrate.

[0128] Step (3), preparation of a flexible polyurethane conduit precursor

[0129] The activated conduit-shaped substrate was immersed in a 8 wt% benzophenone acetone solution at an immersion ratio of 1:35, and after the reaction was completed, the product conduit was washed with isopropyl alcohol for 3 times and then transferred to an oven with a temperature of 40°C for drying for 6 h to obtain a flexible polyurethane conduit precursor.

[0130] Step (4), preparation of a flexible polyurethane material

[0131] The flexible polyurethane conduit precursor was prepared by immersing the modified liquid prepared in Example 6 for 2 min at an immersion ratio of 1:35, and then irradiating it under ultraviolet light for 3 min, with the wavelength of the ultraviolet light set to 400 nm.

[0132] Comparative Example 1

[0133] The difference between the present comparative example and Example 9 is that N-methyldiethanolamine is not added in the preparation of the prepolymer solution in Step I.

[0134] Comparative Example 2

[0135] The difference between the present comparative example and Example 9 is that L-arginine is not added in the preparation of the modified polyurethane in Step II.

[0136] Comparative Example 3

[0137] The difference between the present comparative example and Example 9 is that the modified solution is not used in the preparation of the flexible polyurethane material in Step (4).

[0138] Performance test:

[0139] The tensile strength and elongation at break of the medical catheter prepared in Examples 7-9 and Comparative Examples 1-3 were tested according to the standard HG / T 5070-2016 “Thermoplastic Polyurethane (TPU) Film”.

[0140] The water contact angle of the medical catheter prepared in Examples 7-9 and Comparative Examples 1-3 was tested according to the standard HY / T 266-2018 “Test Contact Angle Method for Surface Hydrophilicity of Hollow Fiber Ultrafiltration Membrane under External Pressure”.

[0141] The antibacterial performance of the medical catheter prepared in Examples 7-9 and Comparative Examples 1-3 against Staphylococcus aureus was tested according to the standard T / CADBM 35-2021 “Antibacterial Functional Finishing Materials for Hospitals”.

[0142] The biocompatibility of the medical catheter prepared in Examples 7-9 and Comparative Examples 1-3 was tested according to the standard GB / T 16886.5-2017 “Biological Evaluation of Medical Devices Part 5: In Vitro Cytotoxicity Test”, and the specific data are shown in Table 1.

[0143] Table 1-Performance test data table of each sample

[0144]

[0145]

[0146] Data analysis:

[0147] Comparative analysis of the data in Table 1 above shows that the medical catheter prepared by the present application has a tensile strength of 45.3 MPa, an elongation at break of 428.7%, a water contact angle of 31°, an antibacterial property of 99.5%, an antibacterial durability of 98.7%, and a cell survival rate of 92.6%;

[0148] It can be found from the table data of comparative example 9 and comparative example 1 that the tensile strength, elongation at break, water contact angle, antibacterial property and antibacterial durability of the medical catheter of comparative example 1 are significantly reduced, which shows that the block copolymer type modified polyurethane is prepared by taking N-methyldiethanolamine, polycarbonate diol and polycaprolactone diol as soft segments and L-lysine diisocyanate and L-arginine as hard segments, the flexible N-methyldiethanolamine, polycaprolactone and polycarbonate segments provide excellent tensile property and toughness, the urethane hard segment formed by L-lysine diisocyanate endows the polymer with good structural support, L-arginine and the triazine type chain extender introduce multi-point hydrogen bonds and microcrystalline regions, which further enhance the toughness of the material, so that the medical catheter based on the flexible polyurethane material achieves a good balance between strength and flexibility as a whole, the mechanical property is enhanced, N-methyldiethanolamine generates tertiary amine acetate with antibacterial property under the action of acetic acid, both substances are embedded in the polyurethane through chemical bonding, which avoids the inactivation of the antibacterial property caused by migration during use, improves the antibacterial property and antibacterial durability of the flexible polyurethane material, and the two hydroxyl groups of N-methyldiethanolamine can participate in the chain growth reaction of polyurethane to increase the polarity of the segment and improve the water affinity of the flexible polyurethane;

[0149] It can be found from the table data of comparative example 9 and comparative example 2 that the tensile strength, elongation at break, water contact angle, antibacterial property, antibacterial durability and cell survival rate of the medical catheter of comparative example 2 are significantly reduced, which shows that the block copolymer type modified polyurethane is prepared by taking N-methyldiethanolamine, polycarbonate diol and polycaprolactone diol as soft segments and L-lysine diisocyanate and L-arginine as hard segments, the flexible N-methyldiethanolamine, polycaprolactone and polycarbonate segments provide excellent tensile property and toughness, the urethane hard segment formed by L-lysine diisocyanate endows the polymer with good structural support, L-arginine and the triazine type chain extender introduce multi-point hydrogen bonds and microcrystalline regions, which further enhance the toughness of the material, so that the flexible polyurethane material achieves a good balance between strength and flexibility as a whole, the mechanical property is enhanced, in the preparation of the modified polyurethane, the chain extender L-arginine is added, which contains guanidino structure in the molecular structure, the bacterial outer membrane is rich in negatively charged phospholipid head, lipopolysaccharide and peptidoglycan, the guanidino group can combine the bacterial membrane through high-strength electrostatic adsorption, causing the membrane structure to be disordered, the membrane potential to collapse and the contents to leak, and then leading to the death of bacteria, N-methyldiethanolamine generates tertiary amine acetate with antibacterial property under the action of acetic acid, both substances are embedded in the polyurethane through chemical bonding, which avoids the inactivation of the antibacterial property caused by migration during use, improves the antibacterial property and antibacterial durability of the flexible polyurethane material, the present application also uses aliphatic structure lysine diisocyanate, which avoids the potential cytotoxicity of aromatic isocyanate, and introduces natural amino acid L-arginine and triazine type chain extender, which improves the biocompatibility of the flexible polyurethane material;

[0150] It is found from the table data of comparative example 9 and comparative example 3 that the tensile strength, elongation at break, water contact angle, antibacterial property, antibacterial durability and cell survival rate of the medical catheter of comparative example 3 are all significantly decreased, which shows that the intermediate I is prepared by esterification reaction in the application, and is mixed uniformly with the photoinitiator to prepare a modified liquid, the catheter-shaped substrate is treated by plasma, the free radical reaction sites and polar functional groups are introduced on the catheter-shaped substrate, the activated catheter-shaped substrate is swollen by benzophenone, under the initiation of ultraviolet light, the intermediate I in the modified liquid is bonded to the surface of the activated catheter-shaped substrate by free radical polymerization reaction to form a firm hydrogel layer, which hinders the direct contact of proteins or bacteria with the substrate, can reduce bacterial adhesion and inhibit biofilm formation, improve the antibacterial property and hydrophilic property of the flexible polyurethane material, the main body of the modified liquid is polysialic acid which is derived from amino acid, the degradation product is non-toxic, the biocompatibility of the flexible polyurethane material is improved, in actual application, the hydrogel layer can disperse external force impact, reduce microcracks, surface lubrication reduces friction and wear, and the mechanical property of the flexible polyurethane material is improved.

[0151] The above disclosed preferred embodiments of the application are only used to help explain the application. The preferred embodiments do not describe all the details, nor limit the application to the specific implementation. Obviously, according to the content of the specification, many modifications and changes can be made. The specification selects and specifically describes these embodiments in order to better explain the principles and practical applications of the application, so that those skilled in the art can well understand and utilize the application. The application is limited only by the claims and their full scope and equivalents.

Claims

1. Medical catheter based on a highly biocompatible polyurethane material, characterized in that, The medical catheter comprises a catheter-shaped base and a modification layer coated outside the catheter-shaped base, wherein the catheter-shaped base comprises the following components by weight parts: 60-80 parts of modified polyurethane and 10-15 parts of auxiliary additives. The modification forming method of the modification layer comprises: A1, plasma treatment of the catheter-shaped base to obtain an activated catheter-shaped base; A2, dipping the activated catheter-shaped base in a benzophenone solution to obtain a flexible polyurethane catheter precursor through first post-treatment; A3, dipping the flexible polyurethane catheter precursor in a modification liquid for 1-2 min, taking it out and irradiating it under ultraviolet light for 1-3 min to obtain the medical catheter; The preparation method of the catheter-shaped base comprises: placing the modified polyurethane and the auxiliary additives in a twin-screw extruder, melt extruding, injecting into a mold, and solidifying to obtain the catheter-shaped base.

2. Medical catheter based on a highly biocompatible polyurethane material according to claim 1, characterized in that, In step A2, the dipping ratio of the dipping operation is 1:30-35, and the benzophenone solution is a 5-8wt% benzophenone acetone solution; in step A3, the dipping ratio of the dipping operation is 1:30-35, and the wavelength of the ultraviolet light is set to 380-400nm.

3. The medical catheter based on a highly biocompatible polyurethane material according to claim 1, characterized in that, The preparation method of the modified polyurethane comprises the following steps: B1, placing N-methyldiethanolamine, polycarbonate diol, polycaprolactone diol, N,N-dimethylformamide and stannous octoate in a reaction kettle protected by nitrogen atmosphere and stirring, heating the reaction kettle to 90-100℃, and keeping the temperature and stirring for 15-30 min, adding a calculated amount of L-lysine diisocyanate, keeping the temperature and reacting for 4-6 h to obtain a prepolymer solution; B2, placing the prepolymer solution and L-arginine in a reaction kettle protected by nitrogen atmosphere and stirring, heating the reaction kettle to 45-55℃, keeping the temperature and reacting for 2-4 h, adding acetic acid, keeping the temperature and reacting for 20-30 min, and obtaining the modified polyurethane through second post-treatment.

4. Medical catheter based on a highly biocompatible polyurethane material according to claim 3, characterized in that, In step B1, the amount ratio of the N-methyldiethanolamine, polycarbonate diol, polycaprolactone diol, N,N-dimethylformamide and stannous octoate is 1-2g:4-6g:2-4g:80-120mL:0.5-1g, and the addition amount of L-lysine diisocyanate is 0.55-0.60 times of the total molar amount of the hydroxyl groups of the N-methyldiethanolamine, polycarbonate diol and polycaprolactone diol.

5. The medical catheter based on a highly biocompatible polyurethane material according to claim 3, characterized in that, In step B2, the amount ratio of the prepolymer solution, L-arginine and acetic acid is 30-40mL:1-2g:0.5-1g.

6. The medical catheter based on a highly biocompatible polyurethane material according to claim 1, characterized in that, In step A1, the preparation method of the activated catheter-shaped base comprises: adding the catheter-shaped base into a plasma treatment instrument, and performing plasma treatment for 3-5 min in an atmospheric environment to obtain the activated catheter-shaped base.

7. Medical catheter based on a highly biocompatible polyurethane material according to claim 6, characterized in that, The power of the plasma treatment instrument is 18-20W.

8. The medical catheter based on a highly biocompatible polyurethane material according to claim 1, characterized in that, In step A3, the preparation method of the modification liquid comprises the following steps: C1, placing polysialic acid and buffer in a reaction kettle and stirring, cooling the reaction kettle to 0-5℃, adding angelica acid anhydride, adding sodium hydroxide solution, adjusting the pH value to 9-11, keeping the temperature and reacting for 20-24 h, and obtaining intermediate I through third post-treatment; C2, the intermediate I and buffer are placed in a reaction kettle for stirring, lithium phenyl-2, 4, 6-trimethylbenzoyl phosphinate is added, mixed uniformly, and the modified liquid is obtained through a fourth post-treatment.

9. Medical catheter based on a highly biocompatible polyurethane material according to claim 8, characterized in that, In step C1, the poly sialic acid, buffer and angelica lactone are used in a ratio of 2-4 g: 20-40 mL: 4-6 mL, the buffer is a phosphate buffer, and the sodium hydroxide solution is a 50-70 wt% sodium hydroxide aqueous solution; in step C2, the intermediate I, buffer and lithium phenyl-2, 4, 6-trimethylbenzoyl phosphinate are used in a ratio of 4-6 g: 40-60 mL: 0.4-0.6 g, and the buffer is a phosphate buffer.

10. Process for the production of medical catheters based on highly biocompatible polyurethane materials according to any one of claims 1 to 9, characterized in that, Comprise: The modified polyurethane and auxiliary additives are placed in a twin-screw extruder, melt-extruded, injected into a mold, solidified, and coated with a modification layer to obtain the medical catheter.

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