Hydrophilic Medical Catheters

Abstract

This invention disclosed medical catheters with surface hydrophilic coatings. Said catheters were grafted with a thin layer of zwitterions, which forms lubricious water layer when contacted with human body liquids or other water solutions, to lower the surface friction and mechanical damage to human body. One benefit of the present invention is due to the excellent biocompatibility and tight bonding between modification material and catheter substrate, the modification will stably stay on the substrate during usage, to avoid the potential side effects caused by lubricants. This modification can be applied to multiple material surfaces, including but not limited to silicone rubber, polyurethane, rubber, polyetheretherketone, polyethylene, polypropylene, polyvinyl chloride, nylon, ABS (Acylonitrile Butadiene Styrene), and polycarbonate.

Claims

1. Catheters comprising surface hydrophilic coatings, wherein said catheters have been grafted with at least one zwitterionic polymer, said at least one zwitterionic polymer which forms a lubricious water film and reduces surface friction when introduced to a liquid environment.

2. The catheters of claim 1, where the cationic groups of the zwitterionic polymers are quaternary ammonium, quaternary phosphonium, pyridinium, or imidazolium.

3. The catheters of claim 1, where anion groups of the zwitterionic polymers are sulfonate, carboxylic, or phosphate.

4. The catheters of claim 1, where the zwitterionic polymer is sulfobetaine, carboxybetiane, or phosphorylcholine.

5. The catheters of claim 1, where the substrate materials include silicone rubber, polyurethane, rubber, polyetheretherketone, polyethylene, polypropylene, polyvinyl chloride, nylon, ABS, polycarbonate.

6. The catheters of claim 1, where the method of surface grafting is atomic transfer, ultraviolet, thermal, or redox free radical polymerization.

Description

EXAMPLES

Example 1 Hydrophilic Catheters by ATRP Method

[0031] Step 1: 100 gram of N,N-dimethylaminoethyl methacrylate was dissolved into 1000 ml of glacial acetic acid. 40 gram of ethenesulfonyl chloride was slowly added into the solution, which was then stirred at room temperature for 24 hours. The precipitate was collected, washed in anhydrous ethanol twice, and then ground into powder after drying.

[0032] Step 2: Polyurethane catheters were first treated with chlorine plasma, and then added into 100 ml of 1:1 (v:v) methanol aqueous solution, which contained of 10 mM of CuCl.sub.2, 20 mM of N,N,N′, N′, N″-pentamethyldiethylenetriamine, and 10% (w/v) of the product from Step 1. After sealing, samples and solution were purged with nitrogen for 15 minutes and then heated to 60° C. After 3 hours, the catheters were taken out, first washed with the mixture of methanol and water, then washed with saline and water, and dried in air.

Example 2: Hydrophilic Catheters by UV Free Radical Polymerization

[0033] Step 1:100 gram of N,N-dimethylaminoethyl methacrylate was dissolved into 1000 ml of acetonitrile. Then 80 gram of 1,4-butanesultone and 300 mg of 1,3-dinitrobenzene were slowly added to the solution, which was refluxed at room temperature for 24 hours. The precipitate was collected, washed twice in acetonitrile, and dried at room temperature.

[0034] Step 2: Silicone catheters were washed and cleaned, then immersed in 100 ml of 0.1M benzophenone in ethanol for 60 minutes. After drying in air, samples were put in 100 ml of 10% (w/v) solution of the product from Step 1 in water, which was then purged with nitrogen for 15 minutes and reacted in UV rotation reactor for 6 hours. Catheters were then taken out, rinsed with saline and water, and dried in air.

Example 3: Hydrophilic Catheters by Heat Free Radical Polymerization

[0035] Step 1: 100 gram of N,N-dimethylarninoethyl methacrylate was dissolved into 600 ml of anhydrous acetone. 55 gram of β-propiolactone was slowly added into the solution and then reacted under nitrogen at 15° C. for 6 hours. The precipitate was collected, washed with anhydrous acetone twice, dried, and then ground into powder.

[0036] Step 2: Natural rubber catheters were first immersed into 100 ml of 1% (w/v) azobisisobutyronitrile in ethanol for 60 minutes, dried in air, and then put into 100 ml of 10% (w/v) solution of product from Step 1 and 1 mM of FeCl.sub.2. After purging with nitrogen for 15 minutes, the solution was heated to 80 ° C. and reacted for 3 hours. Then the catheters were taken out, washed with saline and water, and dried.

Example 4: Hydrophilic Catheters by Redox Free Radical Polymerization

[0037] Step 1: 100 gram of N,N-dimethylaminoethyl methacrylate was added into 400 ml of anhydrous acetone, and 75 gram of 1,3-propanesultone was dissolved into 100 ml of anhydrous acetone. The two solutions were slowly mixed together, stirred at room temperature for 4 hours, and left at room temperature for 7 days. Then the precipitate was collected, washed with anhydrous acetone and dried.

[0038] Step 2: PVC catheters were immersed in 100 ml of 1% (w/v) tent-butyl hydroperoxide in methanol for 60 minutes, dried in aft, and then put into 100 ml of 10% (w/v) solution of the product from Step 1 and 1 mg/ml of diammonium cerium(IV) nitrate in water. After purging with nitrogen for 15 minutes, the solution was heated to 60° C. and reacted for 3 hours. Then the catheters were taken out, washed with saline and water, and dried.

Example 5 Physical Testing of Hydrophilic Catheters

[0039] The catheters prepared in Example 1 to 4 were cleaned and dried, and the measurement found no change in size or appearance. Catheters' surface were smooth without defects, and the labels and marks on the catheter surface were clear and complete.

[0040] According to EN 1618:1997 “Catheters other than intravascular catheters—Test methods for common properties” Appendix B or ISO 10555-1:2013 “Intravascular catheters—Sterile and single-use catheters—Part 1: General requirements” Appendix B, the physical properties of the coated catheters were tested, and the uncoated catheters with the same size were used as control samples. There was no difference in the physical tensile properties between the samples before and after coating.

Example 6: The Measurement of Surface Friction Coefficient

[0041] To measure the surface friction coefficient of control and modified catheters, ASTM standard D1894-14 “Standard Test Method for Static and Kinetic Coefficients of Friction of Plastic Film and Sheeting” was referenced with modification. Specifically, the catheters prepared in Examples 1 to 4 were placed in parallel in a friction tester containing normal saline. The two ends of the catheter were fixed horizontally at the bottom of the container and a slider with a mass of 200 grams was placed on the catheters. The slider was pulled to determine the wet friction coefficient. The tester's measurement range was 0 to 5 N and the test accuracy was not less than 0.2%. When the mold moved at a speed of 100 mm/min, the dynamic friction coefficient was measured. It has been measured that the coefficient of friction of the catheter without a surface hydrophilic coating was between 0.5 and 1, and the friction coefficient of the hydrophilic catheter prepared according to the present invention was less than 0.05, which indicates that the friction coefficient of the hydrophilic is reduced by more than an order of magnitude.

Example 7 The Coating on the Internal Surface

[0042] Catheters prepared in Examples 3 to 4 were cut into half and the internal surface was exposed. The internal and external surfaces were measured with an Attenuated Total Reflectance-Infrared Spectroscope (ATR-IR). The coatings on internal surface and external surfaces were confirmed by the coating material fingerprint regions.

Example 8 The Stability of the Hydrophilic Coating on Catheters

[0043] According to Chinese GB/T 14233.1-2008 “ Test methods for infusion, transfusion, injection equipment for medical use—Part 1: Chemical analysis methods”, the catheters prepared in Example 1 to 4 were soaked in 37 degrees of purification water for 72 hours by the ratio of 0.2 g/ml and purified water was used as the control sample. 50 ml of solution was taken respectively for evaporation. Compared with the control samples\, the weight gain from the testing solutions after evaporation didn't exceed 5 mg, which proved those the hydrophilic coatings were stable without peeling-off.

Example 9 The Stability of the Coating on Hydrophilic Catheters in Artificial Gastric and Artificial Intestinal Fluids

[0044] Artificial gastric and artificial intestinal fluids were prepared according to the Chinese Pharmacopoeia 2020 edition. Six catheters from Example 1 to 4, respectively, were soaked in 37° C. artificial gastric or artificial intestinal fluid for 30 days. After removal, catheters' coefficients of friction were tested according to the method used in Example 6. It has been found that the friction coefficients didn't change after soaking.

Example 10 The Stability of the Coating on Hydrophilic Catheters in Artificial Urine

[0045] Six catheters prepared according to Example 1 to 4, respectively, were soaked in 37° C. artificial urine in accordance with ISO 20696:2018 “Sterile urethral catheters for single use” for 30 days. After removal, catheters' coefficients of friction were tested according to the method used in Example 6. It has been found that the friction coefficients didn't change after soaking.

Example 11 Aging Stability of Hydrophilic Catheters

[0046] According to Chinese YY/T 0681.1-2018 “Test methods for sterile medical device package—Part 1: Test guide for accelerated aging”, catheters prepared in Example 1 to 4 were stored at 55° C. for 80 days, and then the physical properties and surface friction properties of the catheter were tested according to the methods used in Example 5 and Example 6. Their physical properties and surface friction properties of the catheters before and after the aging test were measured without difference.

Example 12 Sterilization of Hydrophilic Catheters

[0047] The catheters prepared in Example 1 to 4 were sterilized in the ethylene oxide sterilization cabinet at 55° C., 60% humidity, 1.0 g/L ethylene oxide for four hours. After degassing, microbial testing was preformed and no microbe were detected on the surface of the catheter. catheters' coefficients of friction were tested according to the method used in Example 6. It has been found that the friction coefficients didn't change after sterilization.

Example 13 Biocompatibility of Hydrophilic Catheters

[0048] Catheters made in Examples 1 to 4 were tested for in vitro cytotoxicity (ISO 10993-5:2009 Biological evaluation of medical devices—Part 5: Tests for in vitro cytotoxicity), irritation, and skin sensitization (ISO 10993-10:2010 Biological evaluation of medical devices—Part 10: Tests for irritation and skin sensitization). In brief, in vitro cytotoxicity is based on MTT method, according to the quantitative determination criteria of the survival rate of the cultured cells (L929 mouse fibroblasts). It has been found that 100% extract of the test samples did not have cytotoxic reactions. The irritation test was carried out by intradermal reaction test method. The results showed that the final scores of the polar and non-polar extracted liquid intradermal reactions (rabbits) of the test samples were less than 1.0 and there was no skin irritation. The skin sensitization test was based on the maximum dosage method, and the skin response level in the provocation stage of all animals (guinea pigs) was 0. So no polar and non-polar extracts of the test samples were observed to cause animal sensitization. The above test results proved that the hydrophilic catheters have good biocompatibility.

[0049] The above examples only showed preferred embodiments of the present invention. It should be noted that for those of ordinary skill in the art, without departing from the technical principles of the present invention, improvements and modifications can be made. These improvements and modifications should also be regarded as the scope of protection of the present invention.