Radiation sterilization resistant biopharmaceutical elastomeric material

Abstract

This invention discloses a radiation-resistant, sterilizable biopharmaceutical elastomer material, specifically relating to the field of biopharmaceutical materials technology. It comprises 50-70 parts of a thermoplastic elastomer matrix, 5-10 parts of an radiation stabilizer, 10-15 parts of a plasticizer, 1-3 parts of an antioxidant, 5-8 parts of a biocompatibility agent, and 1-3 parts of a nano-reinforcing agent. The elastomer material of this invention possesses excellent tensile strength, elongation at break, hardness, radiation resistance, and biocompatibility, meeting current requirements for biopharmaceutical materials and exhibiting promising market prospects.

Description

Technical Field

[0001] This invention relates to the field of biopharmaceutical materials technology, and more specifically, to radiation-resistant sterilization biopharmaceutical elastomer materials. Background Technology

[0002] Currently, with the rapid development of modern biotechnology, the biopharmaceutical field has achieved unprecedented breakthroughs, and various innovative vaccine research and development projects are constantly emerging. The research and development and production of these biopharmaceutical products place extremely stringent requirements on the materials used, especially the elastomer materials used for containers and connecting pipes.

[0003] In the production process of biopharmaceuticals, in order to ensure the sterility and safety of products, it is often necessary to irradiate and sterilize production equipment and packaging materials. This requires elastomer materials to have excellent radiation resistance, and to maintain the stability of their physical and chemical properties after being subjected to a certain dose of irradiation, without degradation, aging or other adverse changes, thereby ensuring the integrity and functionality of containers and pipelines. Meanwhile, since elastomer materials come into direct contact with biopharmaceutical products, their purity and stability are of paramount importance. Any impurities or unstable factors may affect the quality and activity of the drug, or even trigger allergic reactions or other adverse reactions, endangering the life and health of patients. In addition, biocompatibility is also an indispensable key performance characteristic. Good biocompatibility means that when materials interact with biological tissues, cells and biopharmaceutical products, they will not cause toxicity, immune responses or other adverse biological effects, ensuring that the quality of drugs is not affected during production, storage and transportation, while ensuring the safety of patients.

[0004] However, current biopharmaceutical elastomer materials do not meet the requirements for radiation resistance, purity, stability, and biocompatibility, making it difficult to meet people's needs.

[0005] In view of the above situation, the present invention provides a radiation-resistant sterilization biopharmaceutical elastomer material. Summary of the Invention

[0006] In order to overcome the above-mentioned defects of the prior art, the present invention provides a radiation-resistant sterilization biopharmaceutical elastomer material to solve the problems mentioned in the background art.

[0007] To achieve the above objectives, the present invention provides the following technical solution: a radiation-resistant sterilization biopharmaceutical elastomer material, comprising the following raw materials by weight: 50-70 parts of thermoplastic elastomer matrix, 5-10 parts of radiation stabilizer, 10-15 parts of plasticizer, 1-3 parts of antioxidant, 5-8 parts of biocompatibility agent, and 1-3 parts of nano-reinforcing agent. The thermoplastic elastomer matrix is ​​one or more combinations of styrene-based thermoplastic elastomers, olefin-based thermoplastic elastomers, or polyurethane-based thermoplastic elastomers. The radiation stabilizer is a compound of hindered amine light stabilizer and thioester antioxidant, with a weight ratio of 2:1 to 3:1. The plasticizer is a phthalate plasticizer or a citrate plasticizer; The antioxidant is a hindered phenolic antioxidant; The biocompatibility agent is polyethylene glycol or polyvinyl alcohol; The nano-reinforcing agent is nano-silica or nano-calcium carbonate, and it has been modified with a silane coupling agent.

[0008] Preferably, the thermoplastic elastomer matrix is ​​60 parts of styrene-based thermoplastic elastomer, the radiation stabilizer is 8 parts, wherein the weight ratio of hindered amine light stabilizer to thioester antioxidant is 2.5:1, the plasticizer is 12 parts of phthalate plasticizer, the antioxidant is 2 parts of hindered phenolic antioxidant, the biocompatibility agent is 6 parts of polyethylene glycol, and the nano-reinforcing agent is 2 parts of nano-silica.

[0009] Preferably, the preparation step further includes the following steps: S1. Raw material pretreatment: Dry the thermoplastic elastomer matrix in a vacuum drying oven at 50-60℃ for 2-3 hours to remove moisture. Grind the radiation stabilizer, plasticizer, antioxidant and biocompatibility in a mortar until the particle size is less than 100μm and set aside. Add the nano-reinforcing agent to a solution containing polyvinylpyrrolidone dispersant and ultrasonically disperse it for 30-60 minutes at an ultrasonic power of 500-800W using an ultrasonic disperser. Then add it together with other raw materials into a mixer. S2. Mixing: Premix the dried thermoplastic elastomer matrix with a portion of the plasticizer at a temperature of 100-110℃ and a rotation speed of 20-30 r / min for 5-8 min. Increase the temperature to 120-150℃, add the radiation stabilizer, the remaining plasticizer, antioxidant, and biocompatibility, and mix at a rotation speed of 30-50 r / min for 15-20 min. Evacuate the mixture in an internal mixer to a vacuum degree of 0.05-0.08 MPa and continue mixing for 5-10 minutes to obtain the compound. S3. Extrusion molding: The compound is added to a twin-screw extruder. The screw speed of the twin-screw extruder is 100-150 r / min. The barrel temperature from the feed port to the die head is 130-140℃, 140-150℃, 150-160℃, and 160-170℃ respectively. The die head temperature is 170-180℃. In the middle screw section of the extrusion process, 0.5-1.5 parts by weight of organic peroxide crosslinking agent is injected into the extruder. At the same time, the temperature and residence time in this area are controlled to achieve dynamic crosslinking. After extrusion, the compound is cooled in a water tank and then pulverized to obtain radiation-resistant sterilization biopharmaceutical elastomer material particles. S4. Irradiation treatment: A gradient irradiation process is adopted. The elastomer material particles are placed in an electron accelerator. In the first stage, irradiation is carried out at an irradiation dose rate of 3-5 KGy / s and an irradiation dose of 30-50 KGy. After a 5-10 minute pause, the second stage is carried out at an irradiation dose rate of 8-10 KGy / s and an irradiation dose of 50-100 KGy. During the irradiation process, the material temperature is maintained at 30-40℃. The atmosphere in the irradiation chamber is nitrogen or argon, and a small amount of hindered amine free radical scavenger is contained to obtain the final radiation-resistant sterilization biopharmaceutical elastomer material. S5. Post-treatment: Place the irradiated material in an oven and anneal it at 80-100℃ for 2-4 hours. The atmosphere inside the oven is dry air or nitrogen. Use plasma treatment technology to treat the surface of the annealed material to introduce active functional groups. Then, coat the material surface with a heparin coating or collagen coating with a thickness of 10-50μm by impregnation or spraying.

[0010] Preferably, in step S3, when controlling the temperature and residence time of the region to achieve dynamic crosslinking, the temperature of the region is 150-160℃ and the residence time is 2-3 min.

[0011] Preferably, in step S5, plasma treatment technology is used to treat the surface of the annealed material to introduce active functional groups. Specifically, the annealed material is placed in a plasma treatment device, and a vacuum is drawn to a vacuum degree of 0.01-0.05 MPa. The gas introduced is a mixture of oxygen and argon, wherein the oxygen flow rate is 5-15 sccm, the argon flow rate is 20-40 sccm, the radio frequency power is 50-150 W, and the treatment time is 5-15 minutes, thereby introducing hydroxyl and carboxyl active functional groups on the surface of the material.

[0012] Preferably, in step S5, when coating the material surface with a heparin coating or collagen coating of 10-50 μm thickness by means of immersion or spraying, if the immersion method is used, the plasma-treated material is immersed in a heparin or collagen solution with a solution concentration of 5-15 wt% for 10-30 min, and then taken out and dried at 50-70°C to constant weight; If spraying is used, prepare a solution of heparin or collagen with a solid content of 10-30wt%, and spray it evenly on the material surface using a spray gun at a flow rate of 0.5-1.5mL / s and a spraying distance of 10-20cm. Then cure it at 50-70℃ for 1-3min to achieve a coating thickness of 10-50μm.

[0013] Preferably, it further includes the following preparation apparatus: Vacuum drying oven, used for drying thermoplastic elastomer matrix; A mortar and pestle is used to grind radiation stabilizers, plasticizers, antioxidants, and biocompatibility agents. An ultrasonic disperser is used to disperse nano-reinforcing agents. An internal mixer is used to mix dried thermoplastic elastomer matrices with other raw materials; A twin-screw extruder, connected to an internal mixer, is used to extrude and mold mixtures, and has a crosslinking agent injection device in the middle screw section; A water tank, located at the outlet of a twin-screw extruder, is used to cool the extruded material. The traction pelletizing device is located after the water tank and is used to traction pelletize the cooled material. An electron accelerator is used to irradiate the pelletized material, and an atmosphere control system is installed in the irradiation chamber. An oven is used to anneal irradiated materials. Plasma treatment equipment is used to treat the surface of annealed materials, including a vacuum system, a gas supply system, and a radio frequency power supply, which can realize vacuuming, gas introduction and plasma excitation. An immersion tank or spraying device is used to coat plasma-treated materials. The immersion tank is equipped with a temperature control system, and the spraying device includes a spray gun, a solution supply system, and a curing device.

[0014] Preferably, the application of radiation-resistant sterilization biopharmaceutical elastomer materials in the preparation of biopharmaceutical containers and connecting pipes.

[0015] The technical effects and advantages of this invention are as follows: The elastomer material of this invention is prepared by combining a thermoplastic elastomer matrix with nano-reinforcing agents and utilizing a multi-stage mixing and dynamic cross-linking process. This results in a material with excellent tensile strength and elongation at break, ensuring that in biopharmaceutical applications, whether for containers or connecting pipes, it can better withstand internal pressure, external impacts, and various stresses during installation and use, reducing the risk of breakage and leakage, and guaranteeing the safe and stable operation of biopharmaceutical systems. Meanwhile, by using a combination of hindered amine light stabilizers and thioester antioxidants as irradiation stabilizers, and combining them with gradient irradiation processes, the material can maintain high performance even under high irradiation doses. After the irradiation sterilization process commonly used in the biopharmaceutical industry, it can still maintain good mechanical properties and structural integrity, effectively extending the service life of the material, reducing the cost of frequent material replacement due to performance degradation caused by irradiation, and improving the continuity and efficiency of biopharmaceutical production. Furthermore, by using polyethylene glycol or polyvinyl alcohol as biocompatibility, introducing active functional groups onto the material surface through plasma treatment technology, and coating with heparin or collagen, the material exhibits excellent performance in cytotoxicity tests. When in contact with biopharmaceutical products, it does not adversely affect the drug's activity or purity, nor does it trigger immune responses or other harmful biological effects in the human body. This improves the quality and safety of biopharmaceutical products and helps protect patients' health. Attached Figure Description

[0016] Figure 1 This is a flowchart illustrating the overall preparation process of the present invention. Detailed Implementation

[0017] The technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention. Example

[0018] This embodiment provides a radiation-resistant sterilization biopharmaceutical elastomer material, which, by weight, comprises the following raw materials: 50 parts of styrene-based thermoplastic elastomer as the thermoplastic elastomer matrix, 6 parts of hindered amine light stabilizer and 2 parts of thioester antioxidant compounded to form an irradiation stabilizer, 10 parts of phthalate plasticizer, 1 part of hindered phenol antioxidant, 5 parts of polyethylene glycol as a biocompatibility agent, and 1 part of nano-silica modified with a silane coupling agent as a nano-reinforcing agent.

[0019] This embodiment also provides a method for preparing radiation-resistant sterilization biopharmaceutical elastomer materials, specifically including the following steps: S1. Raw material pretreatment: Dry the styrene thermoplastic elastomer in a vacuum drying oven at 50°C for 3 hours to remove moisture. Grind the radiation stabilizer, plasticizer, antioxidant and biocompatibility in a mortar until the particle size is less than 100μm and set aside. Add the nano-reinforcing agent to a solution containing polyvinylpyrrolidone dispersant and ultrasonically disperse it for 60 minutes at an ultrasonic power of 500W using an ultrasonic disperser. Then add it together with other raw materials into a mixer. S2. Mixing: The dried styrene thermoplastic elastomer and 4 parts of phthalate plasticizer are pre-mixed for 8 minutes at 100°C and 20 r / min. The temperature is increased to 120°C, and the radiation stabilizer, the remaining 6 parts of phthalate plasticizer, the hindered phenolic antioxidant and polyethylene glycol are added. The mixture is then mixed for 20 minutes at 30 r / min. The mixture is then evacuated to a vacuum of 0.05 MPa in a mixer and mixed for another 10 minutes to obtain the compound. S3. Extrusion molding: The compound is added to a twin-screw extruder with a screw speed of 100 r / min. The barrel temperature from the feed port to the die head is 130℃, 140℃, 150℃, and 160℃ respectively, and the die head temperature is 170℃. In the middle screw section of the extrusion process, 0.5 parts by weight of organic peroxide crosslinking agent is injected into the extruder, while the temperature in this area is controlled at 150℃ and the residence time is 3 minutes to achieve dynamic crosslinking. After extrusion, the material is cooled in a water tank and then pulverized to obtain radiation-resistant sterilization biopharmaceutical elastomer material particles. S4. Irradiation treatment: A gradient irradiation process is adopted. The elastomer material particles are placed in an electron accelerator. In the first stage, irradiation is carried out at an irradiation dose rate of 3KGy / s and an irradiation dose of 30KGy. After a 10-minute pause, the second stage is carried out at an irradiation dose rate of 8KGy / s and an irradiation dose of 50KGy. During the irradiation process, the material temperature is maintained at 30℃. The atmosphere in the irradiation chamber is nitrogen and contains a small amount of hindered amine free radical scavenger to obtain the final radiation-resistant sterilization biopharmaceutical elastomer material. S5. Post-treatment: Place the irradiated material in an oven and anneal it at 80°C for 4 hours in a dry air atmosphere. The annealed material was placed in a plasma treatment device, and the vacuum was evacuated to a vacuum degree of 0.01 MPa. A mixed gas with an oxygen flow rate of 5 sccm and an argon flow rate of 20 sccm was introduced. The radio frequency power was 50 W and the treatment time was 15 min. Hydroxyl and carboxyl active functional groups were introduced on the surface of the material. The plasma-treated material was immersed in a 5 wt% heparin solution for 30 minutes, and then dried at 50°C to constant weight to achieve a coating thickness of 10 μm. Example

[0020] This embodiment provides a radiation-resistant sterilization biopharmaceutical elastomer material, which, by weight, comprises the following raw materials: 60 parts of olefin-based thermoplastic elastomer and 10 parts of polyurethane-based thermoplastic elastomer as the thermoplastic elastomer matrix; 7.5 parts of hindered amine light stabilizer and 2.5 parts of thioester antioxidant compounded to form an irradiation stabilizer; 12 parts of citrate ester plasticizer; 2 parts of hindered phenolic antioxidant; 6 parts of polyvinyl alcohol as a biocompatibility agent; and 2 parts of nano-calcium carbonate modified with silane coupling agent as a nano-reinforcing agent.

[0021] This embodiment also provides a method for preparing radiation-resistant sterilization biopharmaceutical elastomer materials, specifically including the following steps: S1. Raw material pretreatment: The thermoplastic elastomer matrix is ​​dried in a vacuum drying oven at 55°C for 2.5 hours to remove moisture. The radiation stabilizer, plasticizer, antioxidant and biocompatibility are ground in a mortar until the particle size is less than 100μm and set aside. Nano calcium carbonate is added to a solution containing an appropriate amount of polyvinylpyrrolidone dispersant and ultrasonically dispersed for 45 minutes at an ultrasonic power of 600W using an ultrasonic disperser. Then, it is added to a mixer along with other raw materials. S2. Mixing: The dried thermoplastic elastomer matrix and 5 parts of citrate plasticizer are premixed at 105℃ and 25 r / min for 6 min. The temperature is increased to 135℃, and the radiation stabilizer, the remaining 7 parts of citrate plasticizer, hindered phenolic antioxidant and polyvinyl alcohol are added. The mixture is then mixed at 40 r / min for 18 min. The mixture is then evacuated to a vacuum degree of 0.06 MPa in a mixer and mixed for another 8 min to obtain the compound. S3. Extrusion molding: The compound is added to a twin-screw extruder with a screw speed of 120 r / min. The barrel temperature from the feed port to the die head is 135℃, 145℃, 155℃, and 165℃ respectively, and the die head temperature is 175℃. In the middle screw section of the extrusion process, 1 part by weight of organic peroxide crosslinking agent is injected into the extruder, while the temperature in this area is controlled at 155℃ and the residence time is 2.5 min to achieve dynamic crosslinking. After extrusion, the compound is cooled in a water tank and then pulverized to obtain radiation-resistant sterilization biopharmaceutical elastomer material particles. S4. Irradiation treatment: A gradient irradiation process is adopted. The elastomer material particles are placed in an electron accelerator. In the first stage, irradiation is carried out at an irradiation dose rate of 4KGy / s and an irradiation dose of 40KGy. After an 8-minute pause, the second stage is carried out at an irradiation dose rate of 9KGy / s and an irradiation dose of 80KGy. During the irradiation process, the material temperature is maintained at 35℃. The atmosphere in the irradiation chamber is argon gas, which contains a small amount of hindered amine free radical scavenger, to obtain the final radiation-resistant sterilization biopharmaceutical elastomer material. S5. Post-treatment: Place the irradiated material in an oven and anneal it at 90°C for 3 hours in a nitrogen atmosphere. The annealed material was placed in a plasma treatment device, and the vacuum was evacuated to a vacuum degree of 0.03 MPa. A mixed gas with an oxygen flow rate of 10 sccm and an argon flow rate of 30 sccm was introduced. The radio frequency power was 100 W and the treatment time was 10 min. Hydroxyl and carboxyl active functional groups were introduced on the surface of the material. Collagen was prepared into a solution with a solid content of 20wt% by spraying. The solution was then uniformly sprayed onto the material surface using a spray gun at a flow rate of 1mL / s and a spraying distance of 15cm. The solution was then cured at 60℃ for 2h to achieve a coating thickness of 30μm. Example

[0022] This embodiment provides a radiation-resistant sterilization biopharmaceutical elastomer material, which, by weight, comprises the following raw materials: 70 parts of polyurethane thermoplastic elastomer as the thermoplastic elastomer matrix, 9 parts of hindered amine light stabilizer and 3 parts of thioester antioxidant compounded to form an irradiation stabilizer, 15 parts of phthalate plasticizer, 3 parts of hindered phenol antioxidant, 8 parts of polyethylene glycol as a biocompatibility agent, and 3 parts of nano-silica modified with silane coupling agent as a nano-reinforcing agent.

[0023] This embodiment also provides a method for preparing radiation-resistant sterilization biopharmaceutical elastomer materials, specifically including the following steps: S1. Raw material pretreatment: Dry the polyurethane thermoplastic elastomer in a vacuum drying oven at 60°C for 2 hours to remove moisture. Grind the radiation stabilizer, plasticizer, antioxidant and biocompatibility in a mortar until the particle size is less than 100μm and set aside. Add nano silica to a solution containing an appropriate amount of polyvinylpyrrolidone dispersant and ultrasonically disperse it for 30 minutes at an ultrasonic power of 800W using an ultrasonic disperser. Then add it together with other raw materials into a mixer. S2. Mixing: The dried polyurethane thermoplastic elastomer and 6 parts of phthalate plasticizer are premixed for 5 minutes at 110°C and 30 r / min. The temperature is increased to 150°C, and the radiation stabilizer, the remaining 9 parts of phthalate plasticizer, the hindered phenolic antioxidant and PEG are added. The mixture is then mixed for 15 minutes at 50 r / min. The mixture is then evacuated to a vacuum of 0.08 MPa in a mixer and mixed for another 5 minutes to obtain the compound. S3. Extrusion molding: The compound is added to a twin-screw extruder with a screw speed of 150 r / min. The barrel temperature from the feed port to the die head is 140℃, 150℃, 160℃, and 170℃ respectively, and the die head temperature is 180℃. In the middle screw section of the extrusion process, 1.5 parts by weight of organic peroxide crosslinking agent is injected into the extruder, while the temperature in this area is controlled at 160℃ and the residence time is 2 min to achieve dynamic crosslinking. After extrusion, the compound is cooled in a water tank and then pulverized to obtain radiation-resistant sterilization biopharmaceutical elastomer material particles. S4. Irradiation treatment: A gradient irradiation process is adopted. The elastomer material particles are placed in an electron accelerator. In the first stage, irradiation is carried out at an irradiation dose rate of 5KGy / s and an irradiation dose of 50KGy. After a 5-minute pause, the second stage is carried out at an irradiation dose rate of 10KGy / s and an irradiation dose of 100KGy. During the irradiation process, the material temperature is maintained at 40℃. The atmosphere in the irradiation chamber is nitrogen and contains a small amount of hindered amine free radical scavenger to obtain the final radiation-resistant sterilization biopharmaceutical elastomer material. S5. Post-treatment: Place the irradiated material in an oven and anneal it at 100°C for 2 hours in a dry air atmosphere. The annealed material was placed in a plasma treatment device, and the vacuum was evacuated to a vacuum degree of 0.05 MPa. A mixed gas with an oxygen flow rate of 15 sccm and an argon flow rate of 40 sccm was introduced. The radio frequency power was 150 W and the treatment time was 5 min. Hydroxyl and carboxyl active functional groups were introduced on the surface of the material. The plasma-treated material was immersed in a 15wt% collagen solution for 10 minutes, and then dried at 70°C to constant weight to achieve a coating thickness of 50μm.

[0024] The performance of the radiation-resistant sterilization biopharmaceutical elastomer materials prepared in Examples 1-3 above will be tested below. Commonly used elastomer materials from American or French companies for biopharmaceutical containers and connecting pipes will be used as comparative examples, and their performance will be tested separately. The testing methods are as follows: For tensile strength and elongation at break tests, dumbbell-shaped specimens were prepared from the elastomer materials of Examples 1-3 and the comparative example. The specimen dimensions conformed to the requirements of GB / T528-2009 standard, with a thickness of 2 mm, a gauge length of 25 mm, and a width of 4 mm. A universal testing machine was used to conduct the test at a tensile speed of 50 mm / min. The dumbbell-shaped specimens were mounted on the fixtures of the universal testing machine, ensuring that the axis of the specimen was aligned with the tensile direction and that the specimen did not slip in the fixtures. The testing machine was started, and the tensile test was initiated. The force-to-displacement curve of the specimen during the tensile process was recorded until the specimen broke. The tensile strength (maximum tensile force at break divided by the original cross-sectional area of ​​the specimen) and elongation at break (ratio of elongation at break to the original gauge length multiplied by 100%) were calculated based on the force-to-displacement curve. Five specimens were tested for each sample, and the average value was taken as the test result.

[0025] For hardness testing, the elastomer materials of Examples 1-3 and the comparative example were made into flat samples with a thickness of not less than 6 mm. A Shore hardness tester was used to test the samples at a temperature of 23±2℃. The indenter of the hardness tester was pressed vertically onto the sample surface, and pressure was applied steadily so that the indenter penetrated into the sample to a certain depth within 5 seconds. The hardness value on the hardness tester dial was read. Each sample was tested 5 times at different positions, and the average value was taken as the hardness value of the sample. Three samples were tested for each sample, and the average value was taken as the test result.

[0026] For radiation resistance testing, the elastomer materials of Examples 1-3 and the comparative example were made into square specimens with dimensions of 50mm × 50mm × 2mm. Using an electron accelerator, the actual irradiation sterilization dose was simulated, and the irradiation doses were set to 80KGy, 100KGy, and 120KGy, respectively. The specimens were placed in the irradiation chamber of the electron accelerator and irradiated according to the set irradiation dose. After irradiation, the specimens were removed and placed at room temperature for 24 hours to allow the material properties to stabilize. The tensile strength and elongation at break of the specimens after irradiation were tested according to the above-described tensile strength and elongation at break test methods, and compared with the performance before irradiation. The performance retention rate was calculated as (performance after irradiation / performance before irradiation × 100%).

[0027] For biocompatibility testing, the elastomer materials from Examples 1-3 and the comparative examples were prepared into circular samples with a diameter of 10 mm and a thickness of 2 mm. After disinfection with 75% ethanol, they were washed three times with sterile PBS solution and set aside. Mouse fibroblasts (such as NIH3T3 cells) were selected for culture. The cells were seeded into 96-well plates, and 100 μL of DMEM medium containing 10% fetal bovine serum was added to each well. The cells were cultured in a cell culture incubator at 37°C and 5% CO2 for 24 h to allow the cells to adhere and grow. Discard the culture medium in the 96-well plate. Add 100 μL of culture medium containing different concentrations of material extract (the supernatant obtained after soaking the material and culture medium in a certain ratio for a certain period of time, such as 1g of material soaked in 10mL of culture medium, and the supernatant taken after 48h, and diluted to different concentrations). Simultaneously, set up blank control wells (only culture medium added) and positive control wells (culture medium containing a certain concentration of toxic substance added). Continue to culture the 96-well plate in a cell culture incubator for 24h and 48h. After 24h and 48h of culture, add 10 μL of LTT solution (5mg / mL) to each well. After culturing for another 4 hours, the liquid in the wells was discarded, and 150 μL LDMSO was added to each well. The mixture was shaken for 10 minutes to fully dissolve the crystals. The absorbance (OD value) of each well was measured at a wavelength of 490 nm using a microplate reader. The relative cell proliferation rate (RGR = OD value of experimental group / OD value of blank control group × 100%) was calculated based on the OD value. The cytotoxicity of the material was evaluated based on the RGR: RGR ≥ 100% was considered cytotoxic, 75% ≤ RGR < 100% was considered mild cytotoxic, 50% ≤ RGR < 75% was considered moderate cytotoxic, and RGR < 50% was considered severe cytotoxic.

[0028] Tensile strength and elongation at break: The tensile strength of Examples 1-3 is significantly higher than that of the comparative example, indicating that the material of the present invention has better mechanical properties and can withstand greater external forces without easily breaking. The tensile strength of Example 2 is the highest, possibly because the combination of its raw material formulation and process parameters is more conducive to improving the strength of the material. The elongation at break of Examples 1-3 is also higher than that of the comparative example, indicating that the material of the present invention has better flexibility and ductility during the stretching process and can adapt to different deformation requirements. The hardness of Examples 1-3 is between 60-65 Shore A, which is slightly higher than that of the comparative example. This makes the material more structurally stable while maintaining a certain degree of flexibility, making it more suitable for the manufacture of biopharmaceutical containers and connecting pipes, and able to maintain shape stability during use. Regarding radiation resistance, the tensile strength retention rates of Examples 1-3 were significantly higher than those of the comparative examples under different irradiation doses. As the irradiation dose increased, the performance retention rate of the materials in the examples decreased relatively little, indicating that the materials of the present invention have excellent radiation resistance and can maintain good mechanical properties even under higher irradiation doses, meeting the sterilization requirements of the biopharmaceutical industry. Biocompatibility: In the cytotoxicity test of Examples 1-3, the relative cell proliferation rate was greater than 100% regardless of whether the culture time was 24h or 48h, indicating no cytotoxicity. In contrast, the comparative example showed mild cytotoxicity. This indicates that the surface-treated material of the present invention has good biocompatibility and no adverse effects on cell growth and proliferation. It is more suitable for use in the biopharmaceutical field and reduces potential hazards to biological products.

[0029] In summary, the radiation-resistant sterilization biopharmaceutical elastomer material of the present invention outperforms similar materials on the market in all performance indicators and has good application prospects.

[0030] The above description is merely a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A radiation-resistant, sterile biopharmaceutical elastomer material, characterized in that: By weight, it includes the following raw materials: 50-70 parts of thermoplastic elastomer matrix, 5-10 parts of radiation stabilizer, 10-15 parts of plasticizer, 1-3 parts of antioxidant, 5-8 parts of biocompatibility agent, and 1-3 parts of nano-reinforcing agent. The thermoplastic elastomer matrix is ​​one or more combinations of styrene-based thermoplastic elastomers, olefin-based thermoplastic elastomers, or polyurethane-based thermoplastic elastomers. The radiation stabilizer is a compound of hindered amine light stabilizer and thioester antioxidant, with a weight ratio of 2:1 to 3:

1. The plasticizer is a phthalate plasticizer or a citrate plasticizer; The antioxidant is a hindered phenolic antioxidant; The biocompatibility agent is polyethylene glycol or polyvinyl alcohol; The nano-reinforcing agent is nano-silica or nano-calcium carbonate, and it has been modified with a silane coupling agent.

2. The radiation-resistant sterilization biopharmaceutical elastomer material according to claim 1, characterized in that: The thermoplastic elastomer matrix is ​​60 parts of styrene-based thermoplastic elastomer, the radiation stabilizer is 8 parts, wherein the weight ratio of hindered amine light stabilizer to thioester antioxidant is 2.5:1, the plasticizer is 12 parts of phthalate plasticizer, the antioxidant is 2 parts of hindered phenolic antioxidant, the biocompatibility agent is 6 parts of polyethylene glycol, and the nano-reinforcing agent is 2 parts of nano-silica.

3. The radiation-resistant sterilization biopharmaceutical elastomer material according to claim 2, characterized in that: It also includes the following preparation steps: S1. Raw material pretreatment: Dry the thermoplastic elastomer matrix in a vacuum drying oven at 50-60℃ for 2-3 hours to remove moisture. Grind the radiation stabilizer, plasticizer, antioxidant and biocompatibility in a mortar until the particle size is less than 100μm and set aside. Add the nano-reinforcing agent to a solution containing polyvinylpyrrolidone dispersant and ultrasonically disperse it for 30-60 minutes at an ultrasonic power of 500-800W using an ultrasonic disperser. Then add it together with other raw materials into a mixer. S2. Mixing: Premix the dried thermoplastic elastomer matrix with a portion of the plasticizer at a temperature of 100-110℃ and a rotation speed of 20-30 r / min for 5-8 min. Increase the temperature to 120-150℃, add the radiation stabilizer, the remaining plasticizer, antioxidant, and biocompatibility, and mix at a rotation speed of 30-50 r / min for 15-20 min. Evacuate the mixture in an internal mixer to a vacuum degree of 0.05-0.08 MPa and continue mixing for 5-10 minutes to obtain the compound. S3. Extrusion molding: The compound is added to a twin-screw extruder. The screw speed of the twin-screw extruder is 100-150 r / min. The barrel temperature from the feed port to the die head is 130-140℃, 140-150℃, 150-160℃, and 160-170℃ respectively. The die head temperature is 170-180℃. In the middle screw section of the extrusion process, 0.5-1.5 parts by weight of organic peroxide crosslinking agent is injected into the extruder. At the same time, the temperature and residence time in this area are controlled to achieve dynamic crosslinking. After extrusion, the compound is cooled in a water tank and then pulverized to obtain radiation-resistant sterilization biopharmaceutical elastomer material particles. S4. Irradiation treatment: A gradient irradiation process is adopted. The elastomer material particles are placed in an electron accelerator. In the first stage, irradiation is carried out at an irradiation dose rate of 3-5 KGy / s and an irradiation dose of 30-50 KGy. After a 5-10 minute pause, the second stage is carried out at an irradiation dose rate of 8-10 KGy / s and an irradiation dose of 50-100 KGy. During the irradiation process, the material temperature is maintained at 30-40℃. The atmosphere in the irradiation chamber is nitrogen or argon, and a small amount of hindered amine free radical scavenger is contained to obtain the final radiation-resistant sterilization biopharmaceutical elastomer material. S5. Post-treatment: Place the irradiated material in an oven and anneal it at 80-100℃ for 2-4 hours. The atmosphere inside the oven is dry air or nitrogen. Use plasma treatment technology to treat the surface of the annealed material to introduce active functional groups. Then, coat the material surface with a heparin coating or collagen coating with a thickness of 10-50μm by impregnation or spraying.

4. The radiation-resistant sterilization biopharmaceutical elastomer material according to claim 3, characterized in that: In step S3, when controlling the temperature and residence time of the region to achieve dynamic crosslinking, the temperature of the region is 150-160℃ and the residence time is 2-3 min.

5. The radiation-resistant sterilization biopharmaceutical elastomer material according to claim 3, characterized in that: In step S5, plasma treatment technology is used to treat the surface of the annealed material to introduce active functional groups. Specifically, the annealed material is placed in a plasma treatment device, and a vacuum is drawn to a vacuum degree of 0.01-0.05 MPa. A mixture of oxygen and argon is introduced, with an oxygen flow rate of 5-15 sccm, an argon flow rate of 20-40 sccm, a radio frequency power of 50-150 W, and a treatment time of 5-15 minutes, thereby introducing hydroxyl and carboxyl active functional groups onto the material surface.

6. The radiation-resistant sterilization biopharmaceutical elastomer material according to claim 3, characterized in that: In step S5, when coating the material surface with a heparin or collagen coating of 10-50 μm thickness by means of immersion or spraying, if the immersion method is used, the plasma-treated material is immersed in a heparin or collagen solution with a solution concentration of 5-15 wt% for 10-30 min, and then taken out and dried at 50-70℃ to constant weight. If spraying is used, prepare a solution of heparin or collagen with a solid content of 10-30wt%, and spray it evenly on the material surface using a spray gun at a flow rate of 0.5-1.5mL / s and a spraying distance of 10-20cm. Then cure it at 50-70℃ for 1-3min to achieve a coating thickness of 10-50μm.

7. The radiation-resistant sterilization biopharmaceutical elastomer material according to claim 1, characterized in that: It also includes the following preparation apparatus: Vacuum drying oven, used for drying thermoplastic elastomer matrix; A mortar and pestle is used to grind radiation stabilizers, plasticizers, antioxidants, and biocompatibility agents. An ultrasonic disperser is used to disperse nano-reinforcing agents. An internal mixer is used to mix dried thermoplastic elastomer matrices with other raw materials; A twin-screw extruder, connected to an internal mixer, is used to extrude and mold mixtures, and has a crosslinking agent injection device in the middle screw section; A water tank, located at the outlet of a twin-screw extruder, is used to cool the extruded material. The traction pelletizing device is located after the water tank and is used to traction pelletize the cooled material. An electron accelerator is used to irradiate the pelletized material, and an atmosphere control system is installed in the irradiation chamber. An oven is used to anneal irradiated materials. Plasma treatment equipment is used to treat the surface of annealed materials, including a vacuum system, a gas supply system, and a radio frequency power supply, which can realize vacuuming, gas introduction and plasma excitation. An immersion tank or spraying device is used to coat plasma-treated materials. The immersion tank is equipped with a temperature control system, and the spraying device includes a spray gun, a solution supply system, and a curing device.

8. The radiation-resistant sterilization biopharmaceutical elastomer material according to claim 1, characterized in that: Application of radiation-resistant sterilization biopharmaceutical elastomer materials in the preparation of biopharmaceutical containers and connecting pipes.

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