Thermoplastic polyurethane for medical catheter and preparation method thereof

Abstract

The invention relates to thermoplastic polyurethane for a medical catheter and a preparation method of the thermoplastic polyurethane, and belongs to the technical field of high polymer materials. The polyurethane is formed by carrying out copolymerization and chain extension on a modified polyol monomer, polycarbonate diol and hexamethylene diisocyanate, the modified polyol monomer is a chain compound formed by carrying out quaternization reaction on bromoalkane and N-methyldiethanolamine and carrying out ring opening on ethylene glycol diglycidyl ether and a quaternary ammonium product; the modified polyol monomer introduces a short-chain ether bond and quaternary ammonium structure alternately arranged chain segment into a polymeric chain, the surface wettability of the polyurethane material is effectively improved through a polarity-charge synergistic effect, side-chain hydroxyl forms micro-crosslinking, swelling of the polyether chain segment is relieved, the structural stability and shape maintaining capacity of a conduit are improved, and the service life of the conduit is prolonged. The clinical risk caused by catheter deformation is reduced.

Description

Technical Field

[0001] The present invention relates to the technical field of polymer materials, and specifically, to a thermoplastic polyurethane for medical catheters and a preparation method thereof. Background Art

[0002] Due to its excellent elasticity, wear resistance and biocompatibility, thermoplastic polyurethane is widely used in the manufacture of medical catheters (such as infusion tubes and indwelling catheters). However, traditional polyurethane catheters have insufficient wettability. When the surface of a catheter with poor wettability contacts blood vessels or tissues, the friction force increases significantly, and doctors need to apply greater thrust to complete intubation, which easily leads to catheter position deviation or penetration of the blood vessel wall, increasing the difficulty of catheter implantation and the surgical risk.

[0003] In the prior art, the technical means to improve the wettability of medical catheters mainly include the outer coating method and the inner modification method. Among them, the outer coating method is to attach a highly wettable coating to the surface of the catheter. This method can effectively improve the wettability of the catheter. However, the bonding performance between the coating and the polyurethane catheter matrix is insufficient, and it is greatly affected by the process. The residual peeling coating poses a great risk to the safety of the body. The inner modification method is to modify the wettability of polyurethane, such as introducing an organosilicon block modification. Although it can reduce the friction coefficient of polyurethane, its compatibility with polyurethane segments is poor, resulting in uneven lubrication, and the overall wettability improvement is not significant. Moreover, it is easy to introduce inhomogeneous phases between polymer chains, deteriorating the anti-deformation ability of the catheter, and irreversible deformation is likely to occur during use, affecting the structural stability of the catheter. Another example is to introduce a hydrophilic polyether chain modification. Although the hydrophilicity of the ether chain can improve the surface wettability, after absorbing water, the soft segment swells, resulting in an increase in the catheter diameter or a contraction in length, affecting the matching with blood vessels or tissues, and even causing local compression or leakage risks. Summary of the Invention

[0004] In order to solve the technical problems mentioned in the background art, the purpose of the present invention is to provide a thermoplastic polyurethane for medical catheters and a preparation method thereof.

[0005] The purpose of the present invention can be achieved by the following technical solutions:

[0006] A thermoplastic polyurethane for medical catheters is copolymerized and chain-extended from a modified polyol monomer, a polycarbonate diol and hexamethylene diisocyanate;

[0007] Among them, the preparation method of the modified polyol monomer includes the following steps:

[0008] Step 1: Mix N-methyldiethanolamine, bromoalkane and dioxane, introduce nitrogen until a stable gas flow escapes, heat up to 90 - 100 °C, stir and reflux for 6 - 8 h. After the reaction ends, distill off dioxane under reduced pressure. The substrate is redissolved in water, and the aqueous phase is centrifuged and dried to obtain an intermediate;

[0009] Furthermore, the feeding ratio of N-methyldiethanolamine, alkyl bromide, and dioxane is 10 mmol: 12 - 15 mmol: 35 - 45 mL. The alkyl bromide undergoes a quaternization reaction with N-methyldiethanolamine. The specific reaction route is as follows:

[0010]

[0011] Furthermore, the alkyl chain length of the alkyl bromide is C5 - C10. By regulating the steric hindrance of the alcoholic hydroxyl groups of the modified polyol monomer through the alkyl chain length, the reactivity of the modified polyol monomer is further regulated, thereby regulating the micro-crosslinked state of the polymerization.

[0012] Step 2: Mix the intermediate, ethylene glycol diglycidyl ether, and dimethyl sulfoxide, introduce dry nitrogen until a stable gas flow escapes, raise the temperature to 115 - 130 °C, and stir and react for 2.5 - 3 h. After the reaction, remove dimethyl sulfoxide by rotary evaporation under reduced pressure to obtain the modified polyol monomer;

[0013] Furthermore, the feeding ratio of the intermediate, ethylene glycol diglycidyl ether, and dimethyl sulfoxide is 10 mmol: 10 mmol: 20 - 30 mL. The quaternary ammonium structure of the intermediate autocatalyzes the ring-opening of the terminal hydroxyl groups in its molecule with ethylene glycol diglycidyl ether to form a chain-like compound. The specific reaction route is as follows:

[0014]

[0015] A preparation method of a thermoplastic polyurethane for medical catheters is as follows:

[0016] Prepolymerization: Mix and dissolve the modified polyol monomer and dimethylformamide, add polycarbonate diol, introduce dry nitrogen until a stable gas flow escapes, raise the temperature to 75 - 85 °C, and add hexamethylene diisocyanate and stir and react for 3.5 - 4 h to obtain a prepolymer;

[0017] Chain extension: Add 1,4-butanediol to the prepolymer, raise the temperature to 120 - 130 °C, stir and react for 1.5 - 2 h, then reduce the pressure to 5 kPa, control the temperature at 90 - 100 °C and continue to react for 2 - 3 h. After cooling, discharge to obtain the thermoplastic polyurethane for medical catheters.

[0018] Furthermore, during the synthesis of the prepolymer, the molar ratio of the total hydroxyl groups to the isocyanate groups is 1: 1.15 - 1.22.

[0019] Furthermore, during the synthesis of the prepolymer, the molar ratio of the hydroxyl groups of the polycarbonate diol to the modified polyol monomer is 1: 0.13 - 0.18.

[0020] Furthermore, the dosage of 1,4-butanediol is 8.5 - 10.2 wt% of the prepolymer.

[0021] Advantages of the present invention:

[0022] Based on the thermoplastic polyurethane synthesis process, the present invention introduces a modified polyol monomer for copolymerization, enabling good surface wettability and structural stability of the polyurethane material, while endowing it with certain antibacterial properties and high biological safety; the modified polyol monomer is formed by the quaternization reaction of alkyl bromide and N-methyldiethanolamine, and then the ring-opening reaction of ethylene glycol diglycidyl ether and the quaternary ammonium product to form a chain compound; compared with the existing polyurethane materials containing polyether segments, the modified polyol monomer introduces short-chain ether bonds and quaternary ammonium structures arranged alternately into the polymer chain. Among them, the ether segment has a high polarity match with water molecules, and the quaternary ammonium structure carries a positive charge and forms an electrostatic interaction with water molecules. The alternating structure effectively improves the surface wettability of the polyurethane material through the synergistic effect of polarity-charge. It can be seen from the surface wettability test data that the surface energy of the polyurethane material of the present invention is relatively high. After being infiltrated with physiological saline for 30 s, the surface contact angle decreases significantly, showing excellent wettability. When applied to medical catheters, it is easy to quickly infiltrate and reduce the intubation difficulty; different from the existing polyether-based polyurethanes, the short-chain polyether segments are formed by the ring-opening of epoxy, and active hydroxyl groups are introduced on the side chains. By adjusting the alkyl chain length of the alkyl bromide, different steric hindrances are regulated, so that the side-chain hydroxyl groups form micro-crosslinks, reducing the swelling of the polyether segments and improving the structural stability of the catheter. At the same time, the micro-crosslinking characteristics endow the polyurethane material with good anti-deformation ability and reduce the clinical risk caused by catheter deformation; in addition, the modified polyol monomer introduces a quaternary ammonium structure and is anchored through the micro-crosslinking characteristics, providing a stable antibacterial effect. At the same time, the quaternary ammonium structure forms a self-catalytic effect in the synthesis process, eliminating the need to introduce additional catalysts and having high biological safety. Specific embodiments

[0023] The following will describe clearly and completely the technical solutions in the embodiments of the present invention in conjunction with the embodiments of the present invention. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative efforts shall fall within the protection scope of the present invention.

[0024] Example 1, preparation of thermoplastic polyurethane for medical catheters, and the specific implementation process is as follows:

[0025] I. Preparation of modified polyol monomer

[0026] Step 1: Mix N-methyldiethanolamine, 1-bromopentane and dioxane, introduce nitrogen until a stable gas flow escapes, heat up to 90 °C, and stir and reflux for 6 h. Among them, the feeding ratio of N-methyldiethanolamine, bromoalkane and dioxane is 10 mmol: 13 mmol: 40 mL. After the reaction, distill off dioxane under reduced pressure, redissolve the substrate in water, centrifuge to separate the aqueous phase and dry it to obtain an intermediate.

[0027] Step 2: Mix the intermediate, ethylene glycol diglycidyl ether and dimethyl sulfoxide, introduce dry nitrogen until a stable gas flow escapes, heat up to 115 °C and stir for 2.5 h. Among them, the feeding ratio of the intermediate, ethylene glycol diglycidyl ether and dimethyl sulfoxide is 10 mmol: 10 mmol: 20 mL. After the reaction, rotary evaporate and remove dimethyl sulfoxide under reduced pressure to obtain a modified polyol monomer.

[0028] II. Preparation of thermoplastic polyurethane

[0029] Prepolymerization: Charge polycarbonate diol (model: BENEBiOL TM NL1030DB) and the modified polyol monomer according to a hydroxyl molar ratio of 1:0.15, and then take hexamethylene diisocyanate according to a molar ratio of total hydroxyl to isocyanate group of 1:1.15; first add dimethylformamide to the modified polyol monomer until it is completely dissolved, then add polycarbonate diol and mix, introduce dry nitrogen until a stable gas flow escapes, heat up to 75 °C, add hexamethylene diisocyanate and stir for 3.5 h to obtain a prepolymer.

[0030] Chain extension: Add 8.5 wt% of 1,4-butanediol to the prepolymer, heat up to 120 °C and stir for 1.5 h, then reduce the pressure to 5 kPa, control the temperature at 90 °C and continue to react for 2 h, and discharge after cooling to obtain thermoplastic polyurethane for medical catheters.

[0031] Example 2, the preparation of thermoplastic polyurethane for medical catheters, the specific implementation process is as follows:

[0032] I. Preparation of modified polyol monomer

[0033] Step 1: Mix N-methyldiethanolamine, 1-bromopentane and dioxane, introduce nitrogen until a stable gas flow escapes, heat up to 90 °C, and stir and reflux for 6.5 h. Among them, the feeding ratio of N-methyldiethanolamine, bromoalkane and dioxane is 10 mmol: 12 mmol: 35 mL. After the reaction, distill off dioxane under reduced pressure, redissolve the substrate in water, centrifuge to separate the aqueous phase and dry it to obtain an intermediate.

[0034] Step 2: Take the intermediate, ethylene glycol diglycidyl ether and dimethyl sulfoxide, mix them, introduce dry nitrogen until a stable gas flow escapes, raise the temperature to 120 °C and stir for reaction for 2.5 h. Among them, the feeding ratio of the intermediate, ethylene glycol diglycidyl ether and dimethyl sulfoxide is 10 mmol: 10 mmol: 25 mL. After the reaction, dimethyl sulfoxide is removed by rotary evaporation under reduced pressure to obtain the modified polyol monomer.

[0035] II. Preparation of thermoplastic polyurethane

[0036] Prepolymerization: Charge polycarbonate diol (model: BENEBiOL TM NL1030DB) and the modified polyol monomer according to the molar ratio of hydroxyl groups of 1:0.13, and then take hexamethylene diisocyanate according to the molar ratio of total hydroxyl groups to isocyanate groups of 1:1.17; first add dimethylformamide to the modified polyol monomer until it is completely dissolved, then add polycarbonate diol and mix, introduce dry nitrogen until a stable gas flow escapes, raise the temperature to 75 °C, add hexamethylene diisocyanate and stir for reaction for 3.5 h to obtain the prepolymer.

[0037] Chain extension: Add 9.2 wt% of 1,4-butanediol to the prepolymer, raise the temperature to 120 °C and stir for reaction for 1.6 h, then reduce the pressure to 5 kPa, control the temperature at 100 °C and continue the reaction for 2 h, and discharge after cooling to obtain the thermoplastic polyurethane for medical catheters.

[0038] Example 3, preparation of thermoplastic polyurethane for medical catheters, the specific implementation process is as follows:

[0039] I. Preparation of modified polyol monomer

[0040] Step 1: Take N-methyldiethanolamine, 1-bromodecane and dioxane, mix them, introduce nitrogen until a stable gas flow escapes, raise the temperature to 95 °C, and stir and reflux for reaction for 8 h. Among them, the feeding ratio of N-methyldiethanolamine, bromoalkane and dioxane is 10 mmol: 14 mmol: 40 mL. After the reaction, dioxane is removed by distillation under reduced pressure, the substrate is redissolved in water, and the aqueous phase is centrifuged and dried to obtain the intermediate.

[0041] Step 2: Take the intermediate, ethylene glycol diglycidyl ether and dimethyl sulfoxide, mix them, introduce dry nitrogen until a stable gas flow escapes, raise the temperature to 130 °C and stir for reaction for 2.8 h. Among them, the feeding ratio of the intermediate, ethylene glycol diglycidyl ether and dimethyl sulfoxide is 10 mmol: 10 mmol: 30 mL. After the reaction, dimethyl sulfoxide is removed by rotary evaporation under reduced pressure to obtain the modified polyol monomer.

[0042] II. Preparation of thermoplastic polyurethane

[0043] Prepolymerization: Charge polycarbonate diol (model: BENEBiOL TMThe polycarbonate diol (model: BENEBiOL

[0044] Chain extension: Add 9.5 wt% of 1,4-butanediol to the prepolymer, heat up to 130 °C and stir for 2 h. Then reduce the pressure to 5 kPa, control the temperature at 100 °C and continue the reaction for 2.8 h. After cooling, discharge the material to obtain the thermoplastic polyurethane for medical catheters.

[0045] Example 4. Preparation of thermoplastic polyurethane for medical catheters. The specific implementation process is as follows:

[0046] I. Preparation of modified polyol monomer

[0047] Step 1: Take N-methyldiethanolamine, 1-bromopentane and dioxane and mix them. Pass nitrogen until a stable gas flow escapes, heat up to 100 °C, and stir and reflux for 7.5 h. Among them, the feeding ratio of N-methyldiethanolamine, bromoalkane and dioxane is 10 mmol: 15 mmol: 45 mL. After the reaction, distill off dioxane under reduced pressure. The substrate is redissolved in water, and the aqueous phase is centrifuged and dried to obtain an intermediate.

[0048] Step 2: Take the intermediate, ethylene glycol diglycidyl ether and dimethyl sulfoxide and mix them. Pass dry nitrogen until a stable gas flow escapes, heat up to 130 °C and stir for 3 h. Among them, the feeding ratio of the intermediate, ethylene glycol diglycidyl ether and dimethyl sulfoxide is 10 mmol: 10 mmol: 30 mL. After the reaction, distill off dimethyl sulfoxide by rotary evaporation under reduced pressure to obtain the modified polyol monomer.

[0049] II. Preparation of thermoplastic polyurethane

[0050] Prepolymerization: Mix the polycarbonate diol (model: BENEBiOL TM NL1030DB) and the modified polyol monomer according to a hydroxyl molar ratio of 1:0.17, and then take hexamethylene diisocyanate according to a molar ratio of total hydroxyl groups to isocyanate groups of 1:1.22. First, add dimethylformamide to the modified polyol monomer until it is completely dissolved, then add the polycarbonate diol and mix. Pass dry nitrogen until a stable gas flow escapes, heat up to 85 °C, add hexamethylene diisocyanate and stir and react for 4 h to obtain a prepolymer.

[0051] Chain extension: 1,4-butanediol accounting for 10.2 wt% of the prepolymer was added thereto, and the temperature was raised to 130 °C for stirring reaction for 1.8 h. Then, the pressure was reduced to 5 kPa, and the temperature was controlled at 100 °C for continuous reaction for 3 h. After cooling, the product was discharged to obtain the thermoplastic polyurethane for medical catheter.

[0052] Comparative Example 1: Referring to the implementation process of Example 4, the modified polyol monomer was replaced with polycarbonate diol in equal amount according to the hydroxyl content, and bismuth isooctanoate accounting for 0.8‰ of the reaction raw materials was added during the prepolymerization process, and the rest of the implementation process was exactly the same.

[0053] Comparative Example 2: Referring to the implementation process of Example 4, the modified polyol monomer was replaced with polyether polyol (model: N-6300) in equal amount according to the hydroxyl content, and bismuth isooctanoate accounting for 0.8‰ of the reaction raw materials was added during the prepolymerization process, and the rest of the implementation process was exactly the same.

[0054] Comparative Example 3: Referring to the implementation process of Example 4, the polycarbonate diol was replaced with polyether diol (model: N210) in equal amount according to the hydroxyl content, and the modified polyol monomer was replaced with polyether polyol (model: N-6300) in equal amount according to the hydroxyl content. Bismuth isooctanoate accounting for 0.8‰ of the reaction raw materials was added during the prepolymerization process, and the rest of the implementation process was exactly the same.

[0055] The thermoplastic polyurethane prepared as above was hot-pressed into samples. Among them, 0.01 wt% of sodium heparin was added to the hot-pressing raw materials of the comparative examples, and the following tests were carried out:

[0056] Surface wettability test: Referring to GB / T 30693-2014, the contact angle of normal saline was detected by the sessile drop method, and the surface energy was detected by the Owens-Wendt method; referring to the ASTM D7334-08 standard, the rising height of normal saline along the catheter surface was detected by the vertical hanging method; the specific test data are shown in Table 1:

[0057] Table 1

[0058]

[0059] It can be seen from the test results in Table 1 that the thermoplastic polyurethane material prepared in the examples has a relatively high surface energy, a low initial water contact angle, and a significant decrease in the contact angle after 30 s of soaking, and the wicking height is significantly better than that of the comparative examples, showing excellent wettability, which is beneficial to the implantation of the catheter.

[0060] Immersion structure stability test: According to the ISO 62-2008 standard, using normal saline as the immersion liquid, soaking at 37 °C for 7 days, and using a laser micrometer to detect the change rates of the length and thickness of the sample; the specific test data are shown in Table 2:

[0061] Table 2

[0062]

[0063] As can be seen from the test results in Table 2, the thermoplastic polyurethane prepared in the examples has good dimensional stability during soaking, which is beneficial to maintaining the structural stability after the catheter is implanted.

[0064] Mechanical structure stability test: The cyclic bending test was carried out with reference to the ASTM D790-17 standard, the bending angle was 180°, the number of bending times was 100 times, and the recovery angle and permanent deformation rate were detected; the compression permanent deformation test was carried out with reference to the ASTM D395-18 standard, the compression amount was 10%, and the cycle was 24 h; the dynamic scanning was carried out at 0-100 °C with reference to the ISO 6721-1:2019 standard to detect the storage modulus; the specific test results are shown in Table 3:

[0065] Table 3

[0066]

[0067]

[0068] As can be seen from the test results in Table 3, the thermoplastic polyurethane prepared in the examples exhibits low modulus and high elasticity, has good shape retention ability, and is beneficial to the implantation operation of the catheter and its stability after implantation.

[0069] Biological performance test: The antibacterial test was carried out with reference to the ISO 22196-2011 standard, and the test bacterial strains were Staphylococcus aureus (ATCC 6538) and Escherichia coli (ATCC 8739); with reference to the ISO 10993-5:2009 standard, the MTT method was used to detect the cell survival rate; the hemolysis rate detection was carried out with reference to the ASTM F756-17 standard; the specific test results are shown in Table 4:

[0070] Table 4

[0071]

[0072] As can be seen from the test results in Table 4, the thermoplastic polyurethane prepared in the examples has certain antibacterial properties. Compared with the externally added antibacterial materials, the antibacterial activity is relatively low, the cell survival rate is high, and the hemolysis rate is extremely low, showing high biological safety.

[0073] In the description of the specification, the descriptions referring to terms such as "one embodiment", "example", "specific example", etc. mean that the specific features, structures, materials or characteristics described in connection with the embodiment or example are included in at least one embodiment or example of the present invention. In this specification, the schematic representations of the above terms do not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials or characteristics described can be combined in a suitable manner in any one or more embodiments or examples.

[0074] The above content is only an example and illustration of the present invention. Those skilled in the art of this technology can make various modifications or supplements to the described specific embodiments, or use similar methods for substitution. As long as they do not deviate from the invention or exceed the scope defined by this claim book, they shall fall within the protection scope of the present invention.

Claims

1. A thermoplastic polyurethane for medical catheters, characterized in that, It is copolymerized and chain-extended from a modified polyol monomer, a polycarbonate diol and hexamethylene diisocyanate; The said modified polyol monomer is prepared by the following steps: Step 1: Mix N-methyldiethanolamine, bromoalkane and dioxane, introduce nitrogen until a stable gas flow escapes, heat up to 90 - 100 °C, and stir and reflux for 6 - 8 h to prepare an intermediate; Step 2: Mix the intermediate, ethylene glycol diglycidyl ether and dimethyl sulfoxide, introduce dry nitrogen until a stable gas flow escapes, heat up to 115 - 130 °C and stir and react for 2.5 - 3 h to prepare the modified polyol monomer.

2. The thermoplastic polyurethane for a medical catheter according to claim 1, wherein, The feeding ratio of N-methyldiethanolamine, bromoalkane and dioxane is 10 mmol: 12 - 15 mmol: 35 - 45 mL.

3. The thermoplastic polyurethane for a medical catheter according to claim 2, wherein The alkyl chain length of the bromoalkane is C5 - C10.

4. The thermoplastic polyurethane for medical catheters according to claim 2, wherein The feeding ratio of the intermediate, ethylene glycol diglycidyl ether and dimethyl sulfoxide is 10 mmol: 10 mmol: 20 - 30 mL.

5. The preparation method of a thermoplastic polyurethane for a medical catheter according to claim 4, characterized in that, Specifically, it includes: Pre-polymerization: Mix the modified polyol monomer and dimethylformamide, add the polycarbonate diol and mix, introduce dry nitrogen until a stable gas flow escapes, heat up to 75 - 85 °C, add hexamethylene diisocyanate and stir and react for 3.5 - 4 h to obtain a prepolymer; Chain extension: Add 1,4-butanediol to the prepolymer, heat up to 120 - 130 °C and stir and react for 1.5 - 2 h, then reduce the pressure to 5 kPa, control the temperature at 90 - 100 °C and continue to react for 2 - 3 h, cool and discharge to obtain the thermoplastic polyurethane for medical catheters.

6. The preparation method of a thermoplastic polyurethane for a medical catheter according to claim 5, characterized in that, During the synthesis of the prepolymer, the molar ratio of the total hydroxyl groups to the isocyanate groups is 1:1.15 - 1.

22.

7. The preparation method of a thermoplastic polyurethane for a medical catheter according to claim 5, characterized in that, During the synthesis of the prepolymer, the molar ratio of the hydroxyl groups of the polycarbonate diol to the modified polyol monomer is 1:0.13 - 0.

18.

8. The preparation method of a thermoplastic polyurethane for a medical catheter according to claim 5, characterized in that, The dosage of 1,4-butanediol is 8.5 - 10.2 wt% of the prepolymer.

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