Puncture-resistant medical rubber plug and preparation method thereof

Abstract

The invention relates to the technical field of medical materials, in particular to a puncture-resistant medical rubber plug and a preparation method thereof. The puncture-resistant medical rubber plug comprises the following components in parts by mass: 100 phr of a rubber base material; a modified filler; antibacterial load particles: 3 to 8 phr of Ag (at) SiO2 / CMCS load particles; 3 to 6 phr of medicinal grade liquid polyethylene glycol; 0.8 to 1.2 phr of a hindered phenol antioxidant; 0.5 to 0.8 phr of a thioester antioxidant; 1.5 to 3 phr of a peroxide cross-linking agent; and a metal deactivator: 0.3 to 0.5 phr of N-salicylanilide. The comprehensive performance of the rubber plug is remarkably improved through nanofiller modification, supported antibacterial agent design and cross-linking system optimization.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of medical materials, and particularly relates to a puncture-resistant medical rubber plug and a preparation method thereof. BACKGROUND

[0002] As a core sealing component of drug packaging, the medical rubber plug needs to meet multiple requirements such as high sealing property, puncture resistance, aging resistance, biological safety and the like. Traditional medical rubber plugs are mainly prepared from butyl rubber (such as brominated butyl rubber BIIR and chlorinated butyl rubber CIIR) as a main material by adding fillers, vulcanizing agents and a small amount of additives. However, the existing technical solutions still have the following key defects, which are difficult to meet the stringent requirements of high-end medical packaging: 1. Insufficient antibacterial performance and safety risks The antibacterial function of traditional medical rubber plugs usually relies on the addition of small-molecule organic antibacterial agents (such as quaternary ammonium salts and nipagin esters). Although such substances can inhibit the growth of microorganisms in the short term, they are prone to gradually precipitate due to solvent extraction or molecular chain migration, resulting in a short antibacterial time (usually < 3 months). In addition, some antibacterial agents (such as chlorine-containing disinfectant residues) may dissolve harmful ions, pollute the drug or cause irritant reactions, which do not meet the safety requirements of medical-grade "absolute harmlessness".

[0003] 2. Defects in mechanical properties (puncture resistance) and anti-pulverization In traditional formulations, fillers are mostly ordinary inorganic particles, which have weak interfacial bonding with the rubber matrix and are prone to agglomerate and fall off under puncture stress, resulting in the appearance of chipping on the surface of the rubber plug. At the same time, ordinary fillers have limited binding ability to molecular chains, and the rubber is prone to tear due to crack propagation during repeated puncture or long-term use, affecting the sealing property and clinical use safety.

[0004] 3. Poor medium resistance and aging resistance When the medical rubber plug is in contact with ethanol (such as disinfectant alcohol) and physiological saline (containing NaCl) for a long time, the rubber molecular chain is prone to breakage due to solvent swelling or ion catalytic oxidation, resulting in volume expansion, tensile strength decrease (swelling rate > 20%), and even surface cracking, pulverization, and ultimately loss of sealing function. The polysulfide bonds generated by the traditional sulfur vulcanization system are more prone to oxidation and hydrolysis, accelerating the aging process.

[0005] 4. Insufficient verification of biological compatibility and safety Some technical solutions use non-pharmaceutical-grade additives to reduce costs, resulting in the presence of harmful impurities such as heavy metals (such as Pb and Cd) and polycyclic aromatic hydrocarbons (PAHs). In addition, the biological compatibility (such as cytotoxicity and sensitization) of the antibacterial agent has not been strictly verified, which may cause adverse reactions in the human body, and it is difficult to meet the medical-grade standards of ISO 10993, USP Class VI and the like.

[0006] In summary, existing technologies have significant shortcomings in terms of long-lasting antibacterial properties, puncture resistance, anti-powdering properties, resistance to media aging, and absolute safety. There is an urgent need to develop a method for preparing medical rubber stoppers that balances performance and safety. Summary of the Invention

[0007] To address the problems of short antibacterial duration, insufficient mechanical properties, poor resistance to aging media, and inadequate biosafety verification in existing technologies, this invention provides a puncture-resistant medical rubber stopper and its preparation method. Through modification with nanofillers, design of supported antibacterial agents, and optimization of the crosslinking system, the comprehensive performance of the rubber stopper is significantly improved.

[0008] Specifically, a puncture-resistant medical rubber stopper, by weight, comprises the following components: Rubber substrate: Pharmaceutical grade brominated butyl rubber or chlorinated butyl rubber 100 phr; Modified fillers: modified nano silica 8-12 phr, modified nano zinc oxide 3-5 phr, modified pharmaceutical grade kaolin 5-10 phr; Antibacterial loaded particles: Ag@SiO2 / CMCS loaded particles 3-8 phr, Pharmaceutical-grade liquid polyethylene glycol 3-6 phr; Hindered phenolic antioxidant 0.8-1.2 phr; Thioester antioxidant 0.5-0.8 phr; Peroxide crosslinking agent 1.5-3 phr; Metal passivating agent: N-salicylic acid aniline 0.3-0.5 phr; The preparation method of the Ag@SiO2 / CMCS supported particles is as follows: The particles have a pore size of 5-10 nm and a specific surface area of ​​800-1200 m². 2 / g of mesoporous silica was mixed with 0.05-0.1mol / L silver nitrate solution, with a dry weight ratio of mesoporous silica to silver nitrate of 5-10:1. Ammonia was added to adjust the pH to 8-9, and then 1-1.5 times the amount of silver ions as ascorbic acid reducing agent was added. The mixture was stirred at 60℃ for 2-4h. After centrifugation and washing, the particles were dispersed in a 2-3% acetic acid solution. Chitosan carboxymethylated product with a degree of deacetylation ≥90% was added, with the amount of chitosan carboxymethylated product grafted to 5-10% of the mass of mesoporous silica. After stirring for 2-3h, the mixture was dried to obtain Ag@SiO2 / CMCS supported particles.

[0009] This invention further discloses the preparation process of the above-mentioned puncture-resistant medical rubber stopper, including the following steps: Step (1): Take pharmaceutical grade brominated butyl rubber (BIIR) or chlorinated butyl rubber (CIIR) as the base material, and vacuum dry it at 50-60℃ for 2-4 hours to reduce the moisture content to ≤0.1% (mass fraction). Step (2): Mix nano-silica, nano-zinc oxide, pharmaceutical-grade kaolin with silane coupling agent, and then modify the mixture to obtain a surface-hydroxylated filler. Step (3): Preparation of antibacterial loaded particles: Mesoporous silica with a pore size of 5-10 nm is mixed with 0.05-0.1 mol / L silver nitrate solution, with a dry weight ratio of 5-10:1 between mesoporous silica and silver nitrate. Ammonia is added to adjust the pH to 8-9, and then 1-1.5 times the amount of silver ions as ascorbic acid reducing agent is added. The mixture is stirred at 60°C for 2-4 h. After centrifugation and washing, the particles are dispersed in a 2-3% acetic acid solution. Chitosan carboxymethylated product (CMCS) is added, with the amount of chitosan carboxymethylated product grafted to 5-10% of the mass of MSNs. After stirring for 2-3 h, the mixture is dried to obtain Ag@SiO2 / CMCS loaded particles. Step (4): Mix the dried substrate with the following components in parts by weight: Modified fillers: nano-silica 8-12 phr, nano-zinc oxide 3-5 phr, kaolin 5-10 phr. Antibacterial loaded particles Ag@SiO2 / CMCS 3-8phr, Pharmaceutical grade liquid polyethylene glycol PEG-400 3-6 phr Hindered phenolic antioxidant 1010 0.8-1.2 phr Thioester antioxidant DLTP 0.5-0.8 phr Metal passivating agent N-salicylic acid aniline (NSA) 0.3-0.5 phr; Mixing in a mixer; Step (5): Cool the internal mixer to 75-85℃, add 1.5-3 phr of peroxide crosslinking agent di-tert-butyl peroxide (DTBP), mix for 3-5 min to obtain the compound; Step (6): Place the compounded rubber in a mold and vulcanize to form the initial product; Step (7): The initial product is steam-treated for secondary sulfurization to remove residual low-molecular-weight substances; Step (8): Clean the surface with deionized water and vacuum dry it to reduce the moisture content to ≤0.5% (mass fraction) to obtain puncture-resistant medical rubber stoppers.

[0010] Preferably, in step (1), when the substrate is brominated butyl rubber (BIIR), its bromine content by mass percentage is 1.8-2.2%; when the substrate is chlorinated butyl rubber (CIIR), its chlorine content by mass percentage is 1.3-1.6%. The choice of brominated or chlorinated butyl rubber ensures the gas barrier properties and aging resistance of the rubber stopper.

[0011] In step (2), the modification of the filler with silane coupling agent is a routine operation. It can be achieved by mixing nano-silica, nano-zinc oxide, pharmaceutical-grade kaolin with silane coupling agent, adding the mixture to an 80-95% (v / v) ethanol aqueous solution, ball milling for 30-60 min, unloading, and drying. The appropriate addition of silane coupling agent enhances the interfacial bonding force between the filler and the rubber matrix through chemical bonding, avoiding filler agglomeration and detachment.

[0012] Preferably, in step (3), the mesoporous silica (MSNs) has a pore size of 5-10 nm and a specific surface area of ​​800-1200 m². 2 / g. The high specific surface area and controllable pore size of mesoporous silica provide ideal conditions for the loading and sustained release of antibacterial agents.

[0013] Preferably, in step (3), the degree of deacetylation of the chitosan carboxymethylated product (CMCS) is ≥90%. CMCS with a high degree of deacetylation has a strong positive charge density, which can fix silver ions in the mesopores through electrostatic adsorption, thereby reducing the loss of antibacterial agents.

[0014] Preferably, in step (4), the mixing speed is 50-60 rpm, the mixing temperature is 80-100℃, and the mixing time is 15-20 min. The optimization of the mixing parameters ensures the uniform dispersion of each component in the rubber matrix and avoids local aggregation.

[0015] Preferably, in step (5), the amount of the peroxide crosslinking agent DTBP is 1.5-3 phr. The appropriate addition of the peroxide crosslinking agent forms a stable crosslinking network through free radical reaction, which improves the mechanical properties and aging resistance of the rubber stopper.

[0016] Preferably, in step (6), the vulcanization temperature is 150-160℃ and the time is 8-10 min. Optimization of vulcanization parameters ensures that the crosslinking reaction is fully carried out, while avoiding performance degradation caused by excessive crosslinking.

[0017] Preferably, in step (7), the secondary vulcanization process involves secondary vulcanization at 100°C and a steam pressure of 0.2-0.3 MPa for 2 hours. This secondary vulcanization process further removes residual low-molecular-weight substances, reduces the risk of leaching from the rubber stopper, and improves biocompatibility.

[0018] Preferably, in step (8), the drying temperature is ≤60℃ and the time is 2-3 hours. Low-temperature drying conditions avoid oxidative degradation of the rubber stopper at high temperatures, ensuring the long-term stability of the product.

[0019] The main preparation mechanism of this scheme is as follows: First, pharmaceutical-grade brominated butyl rubber or chlorinated butyl rubber is selected as the base material according to step (1), and vacuum dried at 50-60℃ for 2-4 hours to reduce the moisture content to ≤0.1% (mass fraction). This process ensures that the dryness of the base material meets the requirements and avoids the problem of bubbles caused by residual moisture during subsequent mixing. The selection of the base material is particularly important. When brominated butyl rubber is used, its bromine content should be controlled at 1.8-2.2% (mass fraction), while when chlorinated butyl rubber is used, its chlorine content should be controlled at 1.3-1.6% (mass fraction). The gas barrier properties and aging resistance of brominated or chlorinated butyl rubber are the basis for ensuring the long-term stability of the rubber stopper.

[0020] Next, following step (2), nano-silica, nano-zinc oxide, pharmaceutical-grade kaolin, and silane coupling agent KH-560 are mixed, with KH-560 accounting for 1-2% of the total filler mass. The role of silane coupling agent KH-560 is to firmly connect the filler to the rubber matrix through chemical bonding, avoiding the agglomeration and detachment of traditional fillers due to weak interfacial bonding. Specifically, after uniformly mixing the filler and KH-560 in a high-speed mixer, the mixture is placed in an 80°C oven for 1 hour to complete the surface modification of the filler. The modified filler surface forms a hydroxylated structure, which can react with the active groups in the rubber matrix, further enhancing the interfacial bonding.

[0021] Subsequently, antibacterial loaded particles were prepared according to step (3). First, mesoporous silica was mixed with 0.05-0.1 mol / L silver nitrate solution, and ammonia was added to adjust the pH to 8-9. Then, ascorbic acid reducing agent with a mass of 1-1.5 times the amount of silver ions was added, and the mixture was stirred at 60°C for 2-4 hours. During this process, ascorbic acid, as a reducing agent, reduced silver ions to metallic silver and loaded them into the pores of the mesoporous silica. After the reaction was completed, silver-loaded mesoporous silica particles were obtained by centrifugation and washed with deionized water until neutral. The washed particles were dispersed in a 2-3% acetic acid solution, and chitosan carboxymethylated product with a degree of deacetylation ≥90% was added. The amount of chitosan carboxymethylated product grafted was 5-10% of the mass of MSNs. After stirring for 2 hours, the mixture was dried to obtain Ag@SiO2 / CMCS loaded particles. Chitosan carboxymethylated products fix silver ions in mesopores through electrostatic adsorption and chemical bonding, thereby achieving stable loading and long-lasting sustained-release function of antibacterial agents.

[0022] In step (4), the dried substrate is mixed with modified filler, antibacterial loaded particles, pharmaceutical-grade liquid polyethylene glycol PEG-400, hindered phenolic antioxidant 1010, thioester antioxidant DLTP, and metal passivator N-salicylic acid aniline in parts by mass. The specific proportions are as follows: the modified filler includes 8-12 phr of nano-silica, 3-5 phr of nano-zinc oxide, and 5-10 phr of kaolin; antibacterial loaded particles Ag@SiO2 / CMCS 3-8 phr; PEG-400 3-6 phr; antioxidant 1010 0.8-1.2 phr; antioxidant DLTP 0.5-0.8 phr; and metal passivator NSA 0.3-0.5 phr. The above components are mixed in an internal mixer at 80-100°C and 50-60 rpm for 15-20 minutes. During the mixing process, each component is uniformly dispersed in the rubber matrix, avoiding localized aggregation. Optimization of mixing temperature and time ensures sufficient bonding between the filler and the rubber matrix, while preventing material degradation caused by excessively high temperatures.

[0023] In step (5), after cooling the internal mixer to 75-85℃, add the peroxide crosslinking agent di-tert-butyl peroxide (DTBP) at a dosage of 1.5-3 phr. The peroxide crosslinking agent forms a stable crosslinking network in the rubber matrix through free radical reaction, improving the mechanical properties and aging resistance of the rubber stopper. After mixing for 3-5 minutes, the compound is obtained. During the mixing process, temperature and time must be strictly controlled to ensure the uniform distribution of the crosslinking agent and the fullness of the reaction.

[0024] In step (6), the compounded rubber is placed in a mold and vulcanized at 150-160℃ and 10-15MPa pressure for 8-10 minutes to form a preliminary product. During vulcanization, the free radicals generated by the decomposition of the crosslinking agent initiate crosslinking reactions between rubber molecular chains, forming a three-dimensional network structure. The optimization of vulcanization temperature and time ensures that the crosslinking reaction proceeds fully, while avoiding performance degradation caused by excessive crosslinking.

[0025] In step (7), the initial product is vulcanized a second time for 2 hours at 100℃ and 0.2-0.3MPa steam pressure. The second vulcanization process further removes residual low-molecular-weight substances, reduces the risk of leaching from the rubber stopper, and improves biocompatibility. The temperature and time of the second vulcanization are precisely controlled to ensure the complete vulcanization of low-molecular-weight substances while avoiding damage to the rubber matrix from high temperatures.

[0026] Finally, in step (8), the surface of the initial product is washed with deionized water to remove any possible residual impurities, and then vacuum dried at ≤60℃ for 2-3 hours to reduce the moisture content to ≤0.5% (mass fraction), thus obtaining the puncture-resistant medical rubber stopper. The low-temperature drying conditions prevent the rubber stopper from oxidizing and degrading at high temperatures, ensuring the long-term stability of the product.

[0027] The present invention also discloses the application of the above-mentioned puncture-resistant medical rubber stopper, which is used in the field of pharmaceutical packaging such as injection bottles and lyophilized powder injection bottles.

[0028] Compared with the prior art, the present invention has the following advantages: 1. This invention significantly improves the mechanical properties and anti-powdering properties of rubber stoppers by modifying fillers with silane coupling agents and combining them with a reasonable ratio of nanofillers, thus solving the problems of easy shedding and tearing of traditional rubber stoppers; by using mesoporous silica as an antibacterial agent carrier and grafting silver ions onto chitosan carboxymethylated products, stable loading and long-term sustained release of antibacterial agents are achieved, solving the problems of easy precipitation and short antibacterial time of traditional antibacterial agents.

[0029] 2. This invention significantly improves the resistance to aging in media by optimizing the crosslinking system and the secondary vulcanization process, solving the problem of easy swelling and aging of traditional rubber stoppers in media such as ethanol and saline. By strictly selecting pharmaceutical-grade excipients, the absolute safety of the rubber stoppers is ensured, meeting the requirements of pharmaceutical-grade standards such as ISO 10993 and USP Class VI, thus solving the problem of insufficient biosafety verification in traditional technologies. Detailed Implementation

[0030] The technical solutions of the present invention will be clearly and completely described below with reference to the embodiments of the present invention. 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 of ordinary skill in the art without creative effort are within the scope of protection of the present invention.

[0031] In the following examples and comparative examples: Nano silica: D 50 The particle size is 50 nm; Nano zinc oxide: D 50 The particle size is 50 nm; Pharmaceutical grade kaolin: D 90 ≤1μm.

[0032] Example 1 A method for preparing a puncture-resistant medical rubber stopper includes the following steps: Step (1) Take brominated butyl rubber with a pharmaceutical grade chlorine mass ratio of 2.0% as the base material and vacuum dry it at 55℃ for 3 hours to make the moisture content ≤0.1% (actual measurement 0.08%). Step (2) Mix nano silica, nano zinc oxide, pharmaceutical grade kaolin with silane coupling agent KH-560, wherein nano silica is 10 phr, nano zinc oxide is 4 phr, kaolin is 8 phr, and the amount of KH-560 is 1.5% of the total mass of the filler. After modification treatment, surface hydroxylated filler is obtained. Step (3) Preparation of antibacterial loaded particles: 8 nm pore size, 1000 m² specific surface area... 2 / g of mesoporous silica was mixed with 0.08mol / L silver nitrate solution at a dry weight ratio of 8:1. Ammonia was added to adjust the pH to 8.5, and then 1.2 times the amount of silver ions as ascorbic acid reducing agent was added. The mixture was stirred at 60℃ for 3h. After centrifugation and washing, the particles were dispersed in 2% acetic acid solution. Chitosan carboxymethylated product with a degree of deacetylation ≥90% was added, and the amount of chitosan carboxymethylated product grafted was 7% of the mass of mesoporous silica. After stirring for 2h, the mixture was dried to obtain Ag@SiO2 / CMCS supported particles. Step (4) Mix the dried substrate with the following components in parts by weight: The modified filler component obtained in step (2) Ag@SiO2 / CMCS supported particles 5 phr Pharmaceutical grade liquid polyethylene glycol PEG-400 4phr Hindered phenolic antioxidant 1010 1.0 phr Thioester antioxidant DLTP 0.6 phr Metal passivating agent N-salicylic acid aniline 0.4 phr; Mix in an internal mixer at 90°C and 55 rpm for 18 minutes; Step (5) Cool the internal mixer to 80°C, add 2.0 phr of peroxide crosslinking agent di-tert-butyl peroxide, and mix for 4 min to obtain the compound; Step (6) Place the compounded rubber in a mold and vulcanize it at 155°C and 12MPa pressure for 9 minutes to form the initial product; Step (7) The initial product is vulcanized for 2 hours at 100℃ and 0.25MPa steam pressure to remove residual low molecular weight substances; Step (8) Clean the surface with deionized water and vacuum dry at 55°C for 2.5 hours to make the moisture content ≤0.5% (actual measurement 0.4%), thus obtaining the puncture-resistant medical rubber stopper.

[0033] Example 2 A method for preparing a puncture-resistant medical rubber stopper includes the following steps: Step (1) Take chlorinated butyl rubber with a chlorine mass ratio of 1.45% as the base material and vacuum dry it at 58℃ for 2.5h to make the moisture content ≤0.1% (actual measurement 0.06%). Step (2) Mix nano silica, nano zinc oxide, pharmaceutical grade kaolin with silane coupling agent KH-560, wherein nano silica is 9 phr, nano zinc oxide is 3.5 phr, kaolin is 6 phr, and the amount of KH-560 is 1.8% of the total mass of the filler. After modification treatment, surface hydroxylated filler is obtained. Step (3) Preparation of antibacterial loaded particles: 6 nm pore size, 900 m² specific surface area... 2 / g of mesoporous silica was mixed with 0.06mol / L silver nitrate solution, with a dry weight ratio of silica to silver nitrate of 6:1. Ammonia was added to adjust the pH to 8.2, and then 1.2 times the amount of silver ions as ascorbic acid reducing agent was added. The mixture was stirred at 60℃ for 2.5h. After centrifugation and washing, the particles were dispersed in 2.5% acetic acid solution. Chitosan carboxymethylated product with a degree of deacetylation ≥90% was added, with the grafting amount of chitosan carboxymethylated product being 8% of the mass of mesoporous silica. After stirring for 2.5h, the mixture was dried to obtain Ag@SiO2 / CMCS supported particles. Step (4) Mix the dried substrate with the following components in parts by weight: The modified filler component obtained in step (2) Ag@SiO2 / CMCS supported particles 4phr Pharmaceutical grade liquid polyethylene glycol PEG-400 3.5 phr Hindered phenolic antioxidant 1010 0.9 phr Thioester antioxidant DLTP 0.55 phr Metal passivating agent N-salicylic acid aniline 0.35 phr; Mix in an internal mixer at 85°C and 52 rpm for 16 minutes; Step (5) Cool the internal mixer to 78°C, add 1.8 phr of peroxide crosslinking agent di-tert-butyl peroxide, and mix for 3.5 min to obtain the compound; Step (6) Place the compounded rubber in a mold and vulcanize it at 152°C and 11MPa pressure for 8.5 minutes to form the initial product; Step (7) The initial product is vulcanized for 2 hours at 100℃ and 0.25MPa steam pressure to remove residual low molecular weight substances; Step (8) Clean the surface with deionized water and vacuum dry at 55°C for 2.5 hours to make the moisture content ≤0.5% (actual measurement 0.3%), thus obtaining the puncture-resistant medical rubber stopper.

[0034] Example 3 A method for preparing a puncture-resistant medical rubber stopper includes the following steps: Step (1) Take brominated butyl rubber with a pharmaceutical grade chlorine mass ratio of 2.1% as the base material and vacuum dry it at 52℃ for 3.5h to make the moisture content ≤0.1% (actual measurement 0.09%). Step (2) Mix nano silica, nano zinc oxide, pharmaceutical grade kaolin with silane coupling agent KH-560, wherein nano silica is 11 phr, nano zinc oxide is 4.5 phr, kaolin is 9 phr, and the amount of KH-560 is 2.0% of the total mass of the filler. After modification treatment, surface hydroxylated filler is obtained. Step (3) Preparation of antibacterial loaded particles: 9 nm pore size, 1100 m² specific surface area... 2 / g of mesoporous silica was mixed with 0.09mol / L silver nitrate solution, with a dry weight ratio of mesoporous silica to silver nitrate of 10:1. Ammonia was added to adjust the pH to 8.8, and then 1.5 times the amount of silver ions as ascorbic acid reducing agent was added. The mixture was stirred at 60℃ for 3.5h. After centrifugation and washing, the particles were dispersed in 3% acetic acid solution. Chitosan carboxymethylated product with a degree of deacetylation ≥90% was added, with the grafting amount of chitosan carboxymethylated product being 9% of the mass of mesoporous silica. After stirring for 2-3h, the mixture was dried to obtain Ag@SiO2 / CMCS supported particles. Step (4) Mix the dried substrate with the following components in parts by weight: The modified filler component obtained in step (2) Ag@SiO2 / CMCS supported particles 7phr Pharmaceutical grade liquid polyethylene glycol PEG-400 5phr Hindered phenolic antioxidant 1010 1.1 phr Thioester antioxidant DLTP 0.7 phr Metal passivating agent N-salicylic acid aniline 0.45 phr; Mix in an internal mixer at 95°C and 58 rpm for 19 minutes; Step (5) Cool the internal mixer to 82°C, add 2.5 phr of peroxide crosslinking agent di-tert-butyl peroxide, and mix for 4.5 min to obtain the compound; Step (6) Place the compounded rubber in a mold and vulcanize it at 158°C and 14MPa pressure for 9.5 minutes to form the initial product; Step (7) The initial product is vulcanized for 2 hours at 100℃ and 0.25MPa steam pressure to remove residual low molecular weight substances; Step (8) Clean the surface with deionized water and vacuum dry at 55°C for 2.5 hours to make the moisture content ≤0.5% (actual measurement 0.42%), thus obtaining the puncture-resistant medical rubber stopper.

[0035] Example 4 A method for preparing a puncture-resistant medical rubber stopper includes the following steps: Step (1) Take chlorinated butyl rubber with a pharmaceutical grade chlorine content of 1.6% as the base material and vacuum dry it at 60℃ for 2 hours to make the moisture content ≤0.1% (actual measurement 0.05%). Step (2) Mix nano silica, nano zinc oxide, pharmaceutical grade kaolin and silane coupling agent KH-560, wherein nano silica is 8.5 phr, nano zinc oxide is 5 phr, kaolin is 10 phr, and the amount of KH-560 is 1.0% of the total mass of the filler. After modification treatment, surface hydroxylated filler is obtained. Step (3) Preparation of antibacterial loaded particles: Particles with a pore size of 5 nm and a specific surface area of ​​850 m² are prepared. 2 / g of mesoporous silica was mixed with 0.10mol / L silver nitrate solution at a dry weight ratio of 8:1. Ammonia was added to adjust the pH to 8.0, and then ascorbic acid reducing agent with an amount equal to the amount of silver ions was added. The mixture was stirred at 60℃ for 2h. After centrifugation and washing, the particles were dispersed in 2.5% acetic acid solution. Chitosan carboxymethylated product with a degree of deacetylation ≥90% was added, and the amount of chitosan carboxymethylated product grafted was 6% of the mass of mesoporous silica. After stirring for 2-3h, the mixture was dried to obtain Ag@SiO2 / CMCS supported particles. Step (4) Mix the dried substrate with the following components in parts by weight: The modified filler component obtained in step (2) Ag@SiO2 / CMCS supported particles 3phr Pharmaceutical grade liquid polyethylene glycol PEG-400 3.0 phr Hindered phenolic antioxidant 1010 0.85 phr Thioester antioxidant DLTP 0.5 phr Metal passivating agent N-salicylic acid aniline 0.3 phr; Mix in an internal mixer at 80°C and 50 rpm for 15 minutes; Step (5) Cool the internal mixer to 75°C, add 1.5 phr of peroxide crosslinking agent di-tert-butyl peroxide, and mix for 3 min to obtain the compound; Step (6) Place the compounded rubber in a mold and vulcanize it at 150°C and 10MPa pressure for 8 minutes to form the initial product; Step (7) The initial product is vulcanized again at 100℃ and 0.2MPa steam pressure for 2 hours to remove residual low molecular weight substances; Step (8) Clean the surface with deionized water and vacuum dry at 55°C for 2.5 hours to make the moisture content ≤0.5% (actual measurement 0.35%), thus obtaining the puncture-resistant medical rubber stopper.

[0036] Example 5 A method for preparing a puncture-resistant medical rubber stopper includes the following steps: Step (1) Take brominated butyl rubber with a pharmaceutical grade chlorine mass ratio of 1.8% as the base material and vacuum dry it at 50℃ for 4 hours to make the moisture content ≤0.1% (actual measurement 0.10%). Step (2) Mix nano silica, nano zinc oxide, pharmaceutical grade kaolin with silane coupling agent KH-560, wherein nano silica is 12 phr, nano zinc oxide is 3 phr, kaolin is 5 phr, and the amount of KH-560 is 1.2% of the total mass of the filler. After modification treatment, surface hydroxylated filler is obtained. Step (3) Preparation of antibacterial loaded particles: Particles with a pore size of 10 nm and a specific surface area of ​​1200 m² are prepared. 2 / g of mesoporous silica was mixed with 0.05mol / L silver nitrate solution, with a dry weight ratio of mesoporous silica to silver nitrate of 8:1. Ammonia was added to adjust the pH to 9.0, and then 1.3 times the amount of silver ions as ascorbic acid reducing agent was added. The mixture was stirred at 60℃ for 4h. After centrifugation and washing, the particles were dispersed in a 2-3% acetic acid solution. Chitosan carboxymethylated product with a degree of deacetylation ≥90% was added, with the amount of chitosan carboxymethylated product grafted to 10% of the mass of mesoporous silica. After stirring for 2-3h, the mixture was dried to obtain Ag@SiO2 / CMCS supported particles. Step (4) Mix the dried substrate with the following components in parts by weight: The modified filler component obtained in step (2) Ag@SiO2 / CMCS supported particles 8phr Pharmaceutical grade liquid polyethylene glycol PEG-400 6phr Hindered phenolic antioxidant 1010 1.2 phr Thioester antioxidant DLTP 0.8 phr Metal passivating agent N-salicylic acid aniline 0.5 phr; Mix in an internal mixer at 100°C and 60 rpm for 20 minutes; Step (5) Cool the internal mixer to 85°C, add 3.0 phr of peroxide crosslinking agent di-tert-butyl peroxide (DTBP), and mix for 5 min to obtain the compound; Step (6) Place the compounded rubber in a mold and vulcanize it at 160°C and 15MPa pressure for 10 minutes to form the initial product; Step (7) The initial product is vulcanized for 2 hours at 100℃ and 0.3MPa steam pressure to remove residual low molecular weight substances; Step (8) Clean the surface with deionized water and vacuum dry at 60°C for 3 hours to make the moisture content ≤0.5% (actual measurement 0.48%), thus obtaining the puncture-resistant medical rubber stopper.

[0037] Comparative Example 1 A method for preparing a puncture-resistant medical rubber stopper includes the following steps: Step (1) Take brominated butyl rubber with a pharmaceutical grade chlorine mass ratio of 2.5% as the base material and vacuum dry it at 55℃ for 3 hours to make the moisture content ≤0.1% (actual measurement 0.08%). Step (2) Mix nano silica, nano zinc oxide, pharmaceutical grade kaolin with silane coupling agent KH-560, wherein nano silica is 10 phr, nano zinc oxide is 4 phr, kaolin is 8 phr, and the amount of KH-560 is 1.5% of the total mass of the filler. After modification treatment, surface hydroxylated filler is obtained. Step (3) Preparation of antibacterial loaded particles: 8 nm pore size, 1000 m² specific surface area... 2 / g of mesoporous silica was mixed with 0.08mol / L silver nitrate solution at a dry weight ratio of 8:1. Ammonia was added to adjust the pH to 8.5, and then 1.2 times the amount of silver ions as ascorbic acid reducing agent was added. The mixture was stirred at 60℃ for 3h. After centrifugation and washing, the particles were dispersed in 2% acetic acid solution. Chitosan carboxymethylated product with a degree of deacetylation ≥90% was added, and the amount of chitosan carboxymethylated product grafted was 7% of the mass of mesoporous silica. After stirring for 2h, the mixture was dried to obtain Ag@SiO2 / CMCS supported particles. Step (4) Mix the dried substrate with the following components in parts by weight: The modified filler component obtained in step (2) Ag@SiO2 / CMCS supported particles 5 phr Pharmaceutical grade liquid polyethylene glycol PEG-400 4phr Hindered phenolic antioxidant 1010 1.0 phr Thioester antioxidant DLTP 0.6 phr Metal passivating agent N-salicylic acid aniline 0.4 phr; Mix in an internal mixer at 90°C and 55 rpm for 18 minutes; Step (5) Cool the internal mixer to 80°C, add 2.0 phr of peroxide crosslinking agent di-tert-butyl peroxide, and mix for 4 min to obtain the compound; Step (6) Place the compounded rubber in a mold and vulcanize it at 155°C and 12MPa pressure for 9 minutes to form the initial product; Step (7) The initial product is vulcanized for 2 hours at 100℃ and 0.25MPa steam pressure to remove residual low molecular weight substances; Step (8) Clean the surface with deionized water and vacuum dry at 55°C for 2.5 hours to make the moisture content ≤0.5% (actual measurement 0.4%), thus obtaining the puncture-resistant medical rubber stopper.

[0038] Comparative Example 2 A method for preparing a puncture-resistant medical rubber stopper includes the following steps: Step (1) Take brominated butyl rubber with a pharmaceutical grade chlorine mass ratio of 2.0% as the base material and vacuum dry it at 55℃ for 3 hours to make the moisture content ≤0.1% (actual measurement 0.08%). Step (2) Mix nano silica, nano zinc oxide, pharmaceutical grade kaolin with silane coupling agent KH-560, wherein nano silica is 15 phr, nano zinc oxide is 4 phr, kaolin is 8 phr, and the amount of KH-560 is 1.5% of the total mass of the filler. After modification treatment, surface hydroxylated filler is obtained. Step (3) Preparation of antibacterial loaded particles: 8 nm pore size, 1000 m² specific surface area... 2 / g of mesoporous silica was mixed with 0.08mol / L silver nitrate solution at a dry weight ratio of 8:1. Ammonia was added to adjust the pH to 8.5, and then 1.2 times the amount of silver ions as ascorbic acid reducing agent was added. The mixture was stirred at 60℃ for 3h. After centrifugation and washing, the particles were dispersed in 2% acetic acid solution. Chitosan carboxymethylated product with a degree of deacetylation ≥90% was added, and the amount of chitosan carboxymethylated product grafted was 7% of the mass of mesoporous silica. After stirring for 2h, the mixture was dried to obtain Ag@SiO2 / CMCS supported particles. Step (4) Mix the dried substrate with the following components in parts by weight: The modified filler component obtained in step (2) Ag@SiO2 / CMCS supported particles 5 phr Pharmaceutical grade liquid polyethylene glycol PEG-400 4phr Hindered phenolic antioxidant 1010 1.0 phr Thioester antioxidant DLTP 0.6 phr Metal passivating agent N-salicylic acid aniline 0.4 phr; Mix in an internal mixer at 90°C and 55 rpm for 18 minutes; Step (5) Cool the internal mixer to 80°C, add 2.0 phr of peroxide crosslinking agent di-tert-butyl peroxide, and mix for 4 min to obtain the compound; Step (6) Place the compounded rubber in a mold and vulcanize it at 155°C and 12MPa pressure for 9 minutes to form the initial product; Step (7) The initial product is vulcanized for 2 hours at 100℃ and 0.25MPa steam pressure to remove residual low molecular weight substances; Step (8) Clean the surface with deionized water and vacuum dry at 55°C for 2.5 hours to make the moisture content ≤0.5% (actual measurement 0.4%), thus obtaining the puncture-resistant medical rubber stopper.

[0039] Comparative Example 3 A method for preparing a puncture-resistant medical rubber stopper includes the following steps: Step (1) Take brominated butyl rubber with a pharmaceutical grade chlorine mass ratio of 2.0% as the base material and vacuum dry it at 55℃ for 3 hours to make the moisture content ≤0.1% (actual measurement 0.08%). Step (2) Mix nano silica, nano zinc oxide, pharmaceutical grade kaolin with silane coupling agent KH-560, wherein nano silica is 10 phr, nano zinc oxide is 4 phr, kaolin is 8 phr, and the amount of KH-560 is 1.5% of the total mass of the filler. After modification treatment, surface hydroxylated filler is obtained. Step (3) Preparation of antibacterial loaded particles: Particles with a pore size of 15 nm and a specific surface area of ​​1000 m² are prepared. 2 / g of mesoporous silica was mixed with 0.08mol / L silver nitrate solution at a dry weight ratio of 8:1. Ammonia was added to adjust the pH to 8.5, and then 1.2 times the amount of silver ions as ascorbic acid reducing agent was added. The mixture was stirred at 60℃ for 3h. After centrifugation and washing, the particles were dispersed in 2% acetic acid solution. Chitosan carboxymethylated product with a degree of deacetylation ≥90% was added, and the amount of chitosan carboxymethylated product grafted was 15% of the mass of mesoporous silica. After stirring for 2h, the mixture was dried to obtain Ag@SiO2 / CMCS supported particles. Step (4) Mix the dried substrate with the following components in parts by weight: The modified filler component obtained in step (2) Ag@SiO2 / CMCS supported particles 5 phr Pharmaceutical grade liquid polyethylene glycol PEG-400 4phr Hindered phenolic antioxidant 1010 1.0 phr Thioester antioxidant DLTP 0.6 phr Metal passivating agent N-salicylic acid aniline 0.4 phr; Mix in an internal mixer at 90°C and 55 rpm for 18 minutes; Step (5) Cool the internal mixer to 80°C, add 2.0 phr of peroxide crosslinking agent di-tert-butyl peroxide, and mix for 4 min to obtain the compound; Step (6) Place the compounded rubber in a mold and vulcanize it at 155°C and 12MPa pressure for 9 minutes to form the initial product; Step (7) The initial product is vulcanized for 2 hours at 100℃ and 0.25MPa steam pressure to remove residual low molecular weight substances; Step (8) Clean the surface with deionized water and vacuum dry at 55°C for 2.5 hours to make the moisture content ≤0.5% (actual measurement 0.4%), thus obtaining the puncture-resistant medical rubber stopper.

[0040] Comparative Example 4 A method for preparing a puncture-resistant medical rubber stopper includes the following steps: Step (1) Take brominated butyl rubber with a pharmaceutical grade chlorine mass ratio of 2.0% as the base material and vacuum dry it at 55℃ for 3 hours to make the moisture content ≤0.1% (actual measurement 0.08%). Step (2) Mix nano silica, nano zinc oxide, pharmaceutical grade kaolin with silane coupling agent KH-560, wherein nano silica is 10 phr, nano zinc oxide is 4 phr, kaolin is 8 phr, and the amount of KH-560 is 1.5% of the total mass of the filler. After modification treatment, surface hydroxylated filler is obtained. Step (3) Preparation of antibacterial loaded particles: 8 nm pore size, 1000 m² specific surface area... 2 / g of mesoporous silica was mixed with 0.08mol / L silver nitrate solution at a dry weight ratio of 8:1. Ammonia was added to adjust the pH to 8.5, and then 1.2 times the amount of silver ions as ascorbic acid reducing agent was added. The mixture was stirred at 60℃ for 3h. After centrifugation and washing, the particles were dispersed in 2% acetic acid solution. Chitosan carboxymethylated product with a degree of deacetylation ≥90% was added, and the amount of chitosan carboxymethylated product grafted was 7% of the mass of mesoporous silica. After stirring for 2h, the mixture was dried to obtain Ag@SiO2 / CMCS supported particles. Step (4) Mix the dried substrate with the following components in parts by weight: The modified filler component obtained in step (2) Ag@SiO2 / CMCS supported particles 5 phr Pharmaceutical grade liquid polyethylene glycol PEG-400 8phr Hindered phenolic antioxidant 1010 0.3 phr Thioester antioxidant DLTP 0.6 phr Metal passivating agent N-salicylic acid aniline 0.4 phr; Mix in an internal mixer at 90°C and 55 rpm for 18 minutes; Step (5) Cool the internal mixer to 80°C, add 2.0 phr of peroxide crosslinking agent di-tert-butyl peroxide, and mix for 4 min to obtain the compound; Step (6) Place the compounded rubber in a mold and vulcanize it at 155°C and 12MPa pressure for 9 minutes to form the initial product; Step (7) The initial product is vulcanized for 2 hours at 100℃ and 0.25MPa steam pressure to remove residual low molecular weight substances; Step (8) Clean the surface with deionized water and vacuum dry at 55°C for 2.5 hours to make the moisture content ≤0.5% (actual measurement 0.4%), thus obtaining the puncture-resistant medical rubber stopper.

[0041] Comparative Example 5 A method for preparing a puncture-resistant medical rubber stopper includes the following steps: Step (1) Take brominated butyl rubber with a pharmaceutical grade chlorine mass ratio of 2.0% as the base material and vacuum dry it at 55℃ for 3 hours to make the moisture content ≤0.1% (actual measurement 0.08%). Step (2) Mix nano silica, nano zinc oxide, pharmaceutical grade kaolin with silane coupling agent KH-560, wherein nano silica is 10 phr, nano zinc oxide is 4 phr, kaolin is 8 phr, and the amount of KH-560 is 1.5% of the total mass of the filler. After modification treatment, surface hydroxylated filler is obtained. Step (3) Preparation of antibacterial loaded particles: 8 nm pore size, 1000 m² specific surface area... 2 / g of mesoporous silica was mixed with 0.08mol / L silver nitrate solution at a dry weight ratio of 8:1. Ammonia was added to adjust the pH to 8.5, and then 1.2 times the amount of silver ions as ascorbic acid reducing agent was added. The mixture was stirred at 60℃ for 3h. After centrifugation and washing, the particles were dispersed in 2% acetic acid solution. Chitosan carboxymethylated product with a degree of deacetylation ≥90% was added, and the amount of chitosan carboxymethylated product grafted was 7% of the mass of mesoporous silica. After stirring for 2h, the mixture was dried to obtain Ag@SiO2 / CMCS supported particles. Step (4) Mix the dried substrate with the following components in parts by weight: The modified filler component obtained in step (2) Ag@SiO2 / CMCS supported particles 5 phr Pharmaceutical grade liquid polyethylene glycol PEG-400 4phr Hindered phenolic antioxidant 1010 1.0 phr Thioester antioxidant DLTP 0.6 phr Metal passivating agent N-salicylic acid aniline 0.4 phr; Mix in an internal mixer at 120°C and 70 rpm for 25 minutes; Step (5) Cool the internal mixer to 80°C, add 2.0 phr of peroxide crosslinking agent di-tert-butyl peroxide, and mix for 4 min to obtain the compound; Step (6) Place the compounded rubber in a mold and vulcanize it at 155°C and 12MPa pressure for 9 minutes to form the initial product; Step (7) The initial product is vulcanized for 2 hours at 100℃ and 0.25MPa steam pressure to remove residual low molecular weight substances; Step (8) Clean the surface with deionized water and vacuum dry at 55°C for 2.5 hours to make the moisture content ≤0.5% (actual measurement 0.4%), thus obtaining the puncture-resistant medical rubber stopper.

[0042] Comparative Example 6 A method for preparing a puncture-resistant medical rubber stopper includes the following steps: Step (1) Take brominated butyl rubber with a pharmaceutical grade chlorine mass ratio of 2.0% as the base material and vacuum dry it at 55℃ for 3 hours to make the moisture content ≤0.1% (actual measurement 0.08%). Step (2) Mix nano silica, nano zinc oxide, pharmaceutical grade kaolin with silane coupling agent KH-560, wherein nano silica is 10 phr, nano zinc oxide is 4 phr, kaolin is 8 phr, and the amount of KH-560 is 1.5% of the total mass of the filler. After modification treatment, surface hydroxylated filler is obtained. Step (3) Preparation of antibacterial loaded particles: 8 nm pore size, 1000 m² specific surface area... 2 / g of mesoporous silica was mixed with 0.08mol / L silver nitrate solution at a dry weight ratio of 8:1. Ammonia was added to adjust the pH to 8.5, and then 1.2 times the amount of silver ions as ascorbic acid reducing agent was added. The mixture was stirred at 60℃ for 3h. After centrifugation and washing, the particles were dispersed in 2% acetic acid solution. Chitosan carboxymethylated product with a degree of deacetylation ≥90% was added, and the amount of chitosan carboxymethylated product grafted was 7% of the mass of mesoporous silica. After stirring for 2h, the mixture was dried to obtain Ag@SiO2 / CMCS supported particles. Step (4) Mix the dried substrate with the following components in parts by weight: The modified filler component obtained in step (2) Ag@SiO2 / CMCS supported particles 5 phr Pharmaceutical grade liquid polyethylene glycol PEG-400 4phr Hindered phenolic antioxidant 1010 1.0 phr Thioester antioxidant DLTP 0.6 phr Metal passivating agent N-salicylic acid aniline 0.4 phr; Mix in an internal mixer at 90°C and 55 rpm for 18 minutes; Step (5) Cool the internal mixer to 90°C, add 0.8 phr of peroxide crosslinking agent di-tert-butyl peroxide, and mix for 1 min to obtain the compound; Step (6) Place the compounded rubber in a mold and vulcanize it at 155°C and 12MPa pressure for 9 minutes to form the initial product; Step (7) The initial product is vulcanized for 2 hours at 100℃ and 0.25MPa steam pressure to remove residual low molecular weight substances; Step (8) Clean the surface with deionized water and vacuum dry at 55°C for 2.5 hours to make the moisture content ≤0.5% (actual measurement 0.4%), thus obtaining the puncture-resistant medical rubber stopper.

[0043] Comparative Example 7 A method for preparing a puncture-resistant medical rubber stopper includes the following steps: Step (1) Take brominated butyl rubber with a pharmaceutical grade chlorine mass ratio of 2.0% as the base material and vacuum dry it at 55℃ for 3 hours to make the moisture content ≤0.1% (actual measurement 0.08%). Step (2) Mix nano silica, nano zinc oxide, pharmaceutical grade kaolin with silane coupling agent KH-560, wherein nano silica is 10 phr, nano zinc oxide is 4 phr, kaolin is 8 phr, and the amount of KH-560 is 1.5% of the total mass of the filler. After modification treatment, surface hydroxylated filler is obtained. Step (3) Preparation of antibacterial loaded particles: 8 nm pore size, 1000 m² specific surface area... 2 / g of mesoporous silica was mixed with 0.08mol / L silver nitrate solution at a dry weight ratio of 8:1. Ammonia was added to adjust the pH to 8.5, and then 1.2 times the amount of silver ions as ascorbic acid reducing agent was added. The mixture was stirred at 60℃ for 3h. After centrifugation and washing, the particles were dispersed in 2% acetic acid solution. Chitosan carboxymethylated product with a degree of deacetylation ≥90% was added, and the amount of chitosan carboxymethylated product grafted was 7% of the mass of mesoporous silica. After stirring for 2h, the mixture was dried to obtain Ag@SiO2 / CMCS supported particles. Step (4) Mix the dried substrate with the following components in parts by weight: The modified filler component obtained in step (2) Ag@SiO2 / CMCS supported particles 5 phr Pharmaceutical grade liquid polyethylene glycol PEG-400 4phr Hindered phenolic antioxidant 1010 1.0 phr Thioester antioxidant DLTP 0.6 phr Metal passivating agent N-salicylic acid aniline 0.4 phr; Mix in an internal mixer at 90°C and 55 rpm for 18 minutes; Step (5) Cool the internal mixer to 80°C, add 2.0 phr of peroxide crosslinking agent di-tert-butyl peroxide, and mix for 4 min to obtain the compound; Step (6) Place the compounded rubber in a mold and vulcanize it at 140°C and 8MPa pressure for 6 minutes to form the initial product; Step (7) The initial product is vulcanized for 2 hours at 100℃ and 0.25MPa steam pressure to remove residual low molecular weight substances; Step (8) Clean the surface with deionized water and vacuum dry at 55°C for 2.5 hours to make the moisture content ≤0.5% (actual measurement 0.4%), thus obtaining the puncture-resistant medical rubber stopper.

[0044] Comparative Example 8 A method for preparing a puncture-resistant medical rubber stopper includes the following steps: Step (1) Take brominated butyl rubber with a pharmaceutical grade chlorine mass ratio of 2.0% as the base material and vacuum dry it at 55℃ for 3 hours to make the moisture content ≤0.1% (actual measurement 0.08%). Step (2) Mix nano silica, nano zinc oxide, pharmaceutical grade kaolin with silane coupling agent KH-560, wherein nano silica is 10 phr, nano zinc oxide is 4 phr, kaolin is 8 phr, and the amount of KH-560 is 1.5% of the total mass of the filler. After modification treatment, surface hydroxylated filler is obtained. Step (3) Preparation of antibacterial loaded particles: 8 nm pore size, 1000 m² specific surface area... 2 / g of mesoporous silica was mixed with 0.08mol / L silver nitrate solution at a dry weight ratio of 8:1. Ammonia was added to adjust the pH to 8.5, and then 1.2 times the amount of silver ions as ascorbic acid reducing agent was added. The mixture was stirred at 60℃ for 3h. After centrifugation and washing, the particles were dispersed in 2% acetic acid solution. Chitosan carboxymethylated product with a degree of deacetylation ≥90% was added, and the amount of chitosan carboxymethylated product grafted was 7% of the mass of mesoporous silica. After stirring for 2h, the mixture was dried to obtain Ag@SiO2 / CMCS supported particles. Step (4) Mix the dried substrate with the following components in parts by weight: The modified filler component obtained in step (2) Ag@SiO2 / CMCS supported particles 5 phr Pharmaceutical grade liquid polyethylene glycol PEG-400 4phr Hindered phenolic antioxidant 1010 1.0 phr Thioester antioxidant DLTP 0.6 phr Metal passivating agent N-salicylic acid aniline 0.4 phr; Mix in an internal mixer at 90°C and 55 rpm for 18 minutes; Step (5) Cool the internal mixer to 80°C, add 2.0 phr of peroxide crosslinking agent di-tert-butyl peroxide, and mix for 4 min to obtain the compound; Step (6) Place the compounded rubber in a mold and vulcanize it at 155°C and 12MPa pressure for 9 minutes to form the initial product; Step (7) The initial product is vulcanized for 2 hours at 120℃ and 0.4MPa steam pressure to remove residual low molecular weight substances; Step (8) Clean the surface with deionized water and vacuum dry at 55°C for 2.5 hours to make the moisture content ≤0.5% (actual measurement 0.4%), thus obtaining the puncture-resistant medical rubber stopper.

[0045] Comparative Example 9 A method for preparing a puncture-resistant medical rubber stopper includes the following steps: Step (1) Take brominated butyl rubber with a pharmaceutical grade chlorine mass ratio of 2.0% as the base material and vacuum dry it at 55℃ for 3 hours to make the moisture content ≤0.1% (actual measurement 0.08%). Step (2) Mix nano silica, nano zinc oxide, pharmaceutical grade kaolin with silane coupling agent KH-560, wherein nano silica is 10 phr, nano zinc oxide is 4 phr, kaolin is 8 phr, and the amount of KH-560 is 1.5% of the total mass of the filler. After modification treatment, surface hydroxylated filler is obtained. Step (3) Preparation of antibacterial loaded particles: 8 nm pore size, 1000 m² specific surface area... 2 / g of mesoporous silica was mixed with 0.08mol / L silver nitrate solution at a dry weight ratio of 8:1. Ammonia was added to adjust the pH to 8.5, and then 1.2 times the amount of silver ions as ascorbic acid reducing agent was added. The mixture was stirred at 60℃ for 3h. After centrifugation and washing, the particles were dispersed in 2% acetic acid solution. Chitosan carboxymethylated product with a degree of deacetylation ≥90% was added, and the amount of chitosan carboxymethylated product grafted was 7% of the mass of mesoporous silica. After stirring for 2h, the mixture was dried to obtain Ag@SiO2 / CMCS supported particles. Step (4) Mix the dried substrate with the following components in parts by weight: The modified filler component obtained in step (2) Ag@SiO2 / CMCS supported particles 5 phr Pharmaceutical grade liquid polyethylene glycol PEG-400 4phr Hindered phenolic antioxidant 1010 1.0 phr Thioester antioxidant DLTP 0.6 phr Metal passivating agent N-salicylic acid aniline 0.4 phr; Mix in an internal mixer at 90°C and 55 rpm for 18 minutes; Step (5) Cool the internal mixer to 80°C, add 2.0 phr of peroxide crosslinking agent di-tert-butyl peroxide, and mix for 4 min to obtain the compound; Step (6) Place the compounded rubber in a mold and vulcanize it at 155°C and 12MPa pressure for 9 minutes to form the initial product; Step (7) The initial product is vulcanized for 2 hours at 100℃ and 0.25MPa steam pressure to remove residual low molecular weight substances; Step (8) Clean the surface with deionized water and vacuum dry at 70°C for 4 hours to make the water content 1.0%, thus obtaining the puncture-resistant medical rubber stopper.

[0046] Comparative Example 10 A method for preparing a puncture-resistant medical rubber stopper includes the following steps: Step (1) Take chlorinated butyl rubber with a pharmaceutical grade chlorine content of 1.0% as the base material, and vacuum dry it at 40℃ for 1 hour to make the moisture content 0.5%; Step (2) Mix nano silica, nano zinc oxide, pharmaceutical grade kaolin with silane coupling agent KH-560, wherein nano silica is 10 phr, nano zinc oxide is 4 phr, kaolin is 8 phr, and the amount of KH-560 is 1.5% of the total mass of the filler. After modification treatment, surface hydroxylated filler is obtained. Step (3) Preparation of antibacterial loaded particles: 8 nm pore size, 1000 m² specific surface area... 2 / g of mesoporous silica was mixed with 0.01mol / L silver nitrate solution at a dry weight ratio of 8:1. Ammonia was added to adjust the pH to 8.5, and then 1.2 times the amount of silver ions as ascorbic acid reducing agent was added. The mixture was stirred at 60℃ for 3h. After centrifugation and washing, the particles were dispersed in 2% acetic acid solution. Chitosan carboxymethylated product with a degree of deacetylation ≥90% was added. The amount of chitosan carboxymethylated product grafted was 7% of the mass of mesoporous silica. After stirring for 2h, the mixture was dried to obtain Ag@SiO2 / CMCS supported particles. Step (4) Mix the dried substrate with the following components in parts by weight: The modified filler component obtained in step (2) Ag@SiO2 / CMCS supported particles 1phr Pharmaceutical grade liquid polyethylene glycol PEG-400 4phr Hindered phenolic antioxidant 1010 1.0 phr Thioester antioxidant DLTP 0.6 phr Metal passivating agent N-salicylic acid aniline 0.4 phr; Mix in an internal mixer at 90°C and 55 rpm for 10 minutes; Step (5) Cool the internal mixer to 80°C, add 5.0 phr of peroxide crosslinking agent di-tert-butyl peroxide, and mix for 4 min to obtain the compound; Step (6) Place the compounded rubber in a mold and vulcanize it at 170°C and 12MPa pressure for 15 minutes to form the initial product; Step (7) The initial product is vulcanized for 2 hours at 100℃ and 0.25MPa steam pressure to remove residual low molecular weight substances; Step (8) Clean the surface with deionized water and vacuum dry at 55°C for 2.5 hours to make the moisture content ≤0.5% (actual measurement 0.4%), thus obtaining the puncture-resistant medical rubber stopper.

[0047] Comparative Example 11 A method for preparing a puncture-resistant medical rubber stopper includes the following steps: Step (1) Take brominated butyl rubber with a pharmaceutical grade chlorine mass ratio of 2.0% as the base material and vacuum dry it at 55℃ for 3 hours to make the moisture content ≤0.1% (actual measurement 0.08%). Step (2) Mix nano silica, nano zinc oxide, pharmaceutical grade kaolin with silane coupling agent KH-560, wherein nano silica is 10 phr, nano zinc oxide is 4 phr, kaolin is 8 phr, and the amount of KH-560 is 1.5% of the total mass of the filler. After modification treatment, surface hydroxylated filler is obtained. Step (3) Preparation of antibacterial loaded particles: 8 nm pore size, 1000 m² specific surface area... 2 / g of mesoporous silica was mixed with 0.08mol / L silver nitrate solution at a dry weight ratio of 8:1. Ammonia was added to adjust the pH to 8.5, and then 1.2 times the amount of silver ions as ascorbic acid reducing agent was added. The mixture was stirred at 60℃ for 3h. After centrifugation and washing, the particles were dispersed in 2% acetic acid solution. Chitosan carboxymethylated product with a degree of deacetylation ≥90% was added, and the amount of chitosan carboxymethylated product grafted was 7% of the mass of mesoporous silica. After stirring for 2h, the mixture was dried to obtain Ag@SiO2 / CMCS supported particles. Step (4) Mix the dried substrate with the following components in parts by weight: The modified filler component obtained in step (2) Ag@SiO2 / CMCS supported particles 5 phr Pharmaceutical grade liquid polyethylene glycol PEG-400 4phr Hindered phenolic antioxidant 1010 1.0 phr Thioester antioxidant DLTP 0.6 phr Metal passivating agent N-salicylic acid aniline 0.4 phr; Mix in an internal mixer at 90°C and 55 rpm for 18 minutes; Step (5) Cool the internal mixer to 80°C, add 2.0 phr of peroxide crosslinking agent di-tert-butyl peroxide, and mix for 4 min to obtain the compound; Step (6) Place the compounded rubber in a mold and vulcanize it at 155°C and 12MPa pressure for 9 minutes to form the initial product; Step (7) Clean the surface with deionized water and vacuum dry at 55°C for 2.5 hours to make the moisture content ≤0.5% (actual measurement 0.4%), thus obtaining the puncture-resistant medical rubber stopper.

[0048] Comparative Example 12 A method for preparing a puncture-resistant medical rubber stopper includes the following steps: Step (1) Take brominated butyl rubber with a pharmaceutical grade chlorine mass ratio of 2.0% as the base material and vacuum dry it at 55℃ for 3 hours to make the moisture content ≤0.1% (actual measurement 0.08%). Step (2) Preparation of antibacterial loaded particles: 8 nm pore size, 1000 m² specific surface area... 2 / g of mesoporous silica was mixed with 0.08mol / L silver nitrate solution at a dry weight ratio of 8:1. Ammonia was added to adjust the pH to 8.5, and then 1.2 times the amount of silver ions as ascorbic acid reducing agent was added. The mixture was stirred at 60℃ for 3h. After centrifugation and washing, the particles were dispersed in 2% acetic acid solution. Chitosan carboxymethylated product with a degree of deacetylation ≥90% was added, and the amount of chitosan carboxymethylated product grafted was 7% of the mass of mesoporous silica. After stirring for 2h, the mixture was dried to obtain Ag@SiO2 / CMCS supported particles. Step (3) Mix the dried substrate with the following components in parts by weight: Nano silica 10 phr, nano zinc oxide 4 phr, kaolin 8 phr Ag@SiO2 / CMCS supported particles 5 phr Pharmaceutical grade liquid polyethylene glycol PEG-400 4phr Hindered phenolic antioxidant 1010 1.0 phr Thioester antioxidant DLTP 0.6 phr Metal passivating agent N-salicylic acid aniline 0.4 phr; Mix in an internal mixer at 90°C and 55 rpm for 18 minutes; Step (4) Cool the internal mixer to 80°C, add 2.0 phr of peroxide crosslinking agent di-tert-butyl peroxide, and mix for 4 min to obtain the compound; Step (5) Place the compounded rubber in a mold and vulcanize it at 155°C and 12MPa pressure for 9 minutes to form the initial product; Step (6) The initial product is vulcanized for 2 hours at 100℃ and 0.25MPa steam pressure to remove residual low molecular weight substances; Step (7) Clean the surface with deionized water and vacuum dry at 55°C for 2.5 hours to make the moisture content ≤0.5% (actual measurement 0.4%), thus obtaining the puncture-resistant medical rubber stopper.

[0049] Comparative Example 13 A method for preparing a puncture-resistant medical rubber stopper includes the following steps: Step (1) Take brominated butyl rubber with a pharmaceutical grade chlorine mass ratio of 2.0% as the base material and vacuum dry it at 55℃ for 3 hours to make the moisture content ≤0.1% (actual measurement 0.08%). Step (2) Mix nano silica, nano zinc oxide, pharmaceutical grade kaolin with silane coupling agent KH-560, wherein nano silica is 10 phr, nano zinc oxide is 4 phr, kaolin is 8 phr, and the amount of KH-560 is 1.5% of the total mass of the filler. After modification treatment, surface hydroxylated filler is obtained. Step (3) Mix the dried substrate with the following components in parts by weight: The modified filler component obtained in step (2) 5 phr of nano silver particles Pharmaceutical grade liquid polyethylene glycol PEG-400 4phr Hindered phenolic antioxidant 1010 1.0 phr Thioester antioxidant DLTP 0.6 phr Metal passivating agent N-salicylic acid aniline 0.4 phr; Mix in an internal mixer at 90°C and 55 rpm for 18 minutes; Step (4) Cool the internal mixer to 80°C, add 2.0 phr of peroxide crosslinking agent di-tert-butyl peroxide, and mix for 4 min to obtain the compound; Step (5) Place the compounded rubber in a mold and vulcanize it at 155°C and 12MPa pressure for 9 minutes to form the initial product; Step (6) The initial product is vulcanized for 2 hours at 100℃ and 0.25MPa steam pressure to remove residual low molecular weight substances; Step (7) Clean the surface with deionized water and vacuum dry at 55°C for 2.5 hours to make the moisture content ≤0.5% (actual measurement 0.4%), thus obtaining the puncture-resistant medical rubber stopper.

[0050] Performance testing: Table 1 shows the test standards or methods for comparing the performance of the finished products in the examples and comparative examples.

[0051] Table 1. Performance Comparison Test Standards or Methods between Examples and Comparative Examples

[0052] The performance test results are shown in Table 2.

[0053] Table 2. Performance comparison test results of the examples and comparative examples.

[0054] Examples 1-5 of this invention significantly outperform traditional methods in key indicators such as puncture chip removal, tensile strength, antibacterial aging effect, and aging resistance. The fundamental reason lies in the synergistic optimization of each component and process: First, brominated butyl rubber or chlorinated butyl rubber is selected as the substrate. By forming stable covalent bonds with the rubber molecular chain through halogen atoms (Br / Cl), both gas barrier performance and aging resistance are improved. Second, the silane coupling agent KH-560 modifies the surface of nano-silica, zinc oxide, and kaolin. Through hydroxylation reaction, active sites are formed on the filler surface, forming chemical bonds with the polar groups of the rubber matrix. This significantly improves the interfacial bonding force between the filler and the matrix, avoiding the agglomeration and detachment of traditional fillers due to weak interfacial bonding. The puncture chip removal in these examples is only 6-9 particles / puncture, far lower than the 16-30 particles / puncture in the comparative example. Third, the antibacterial loading particles use mesoporous silica as a carrier, whose high specific surface area and controllable pore size provide stable loading sites for silver ions. Chitosan carboxymethylated products fix silver ions within the mesopores through electrostatic adsorption and chemical bonding, reducing initial silver ion dissolution (migration <0.5 mg / L) and extending the antibacterial effect through the sustained-release effect of the mesopores. The initial antibacterial zone diameter is 20-26 mm, and it remains 17-22 mm after 72 hours of hot air aging. Furthermore, the peroxide crosslinking agent DTBP undergoes a free radical crosslinking reaction with the rubber molecular chains at 75-85℃, forming a uniform three-dimensional network structure and improving the material's tear resistance. The secondary vulcanization process further removes residual low-molecular-weight substances, reducing the risk of dissolution and ensuring a total extract content <1.3 mg / stopper. Simultaneously, steam pressure promotes the densification of the crosslinked network, ultimately resulting in a high tensile strength retention rate in this embodiment.

[0055] Analysis of the reasons for the inferior performance of comparative examples compared to Example 1: Comparative examples 1-13 are generally inferior to the example in performance. The core problem is that the key components or process parameters deviate from the optimal range, resulting in the synergistic failure of various performance indicators. Halogen imbalance in the substrate (Comparative Examples 1 and 10): In Comparative Example 1, the BIIR bromine content was too high, resulting in an excessively high C-Br bond density in the rubber molecular chain. This made it prone to oxidative breakage during hot air aging, and the tensile strength retention rate was only 75%. In Comparative Example 10, the CIIR chlorine content was too low, resulting in an insufficient number of C-Cl bonds, reduced gas barrier performance, high swelling rate, and weakened interfacial bonding between the substrate and the filler. The number of chips dropped during puncture was 24-28 per puncture.

[0056] Excessive filler modifier (Comparative Examples 2 and 12): In Comparative Example 2, the amount of KH-560 was too high, resulting in excessive hydroxylation of the filler surface. This caused the nanoparticles to agglomerate due to hydrogen bonding between hydroxyl groups, with 22 particles falling off per puncture. In Comparative Example 12, no filler was modified, and the filler and rubber matrix were only bonded through physical adsorption, resulting in extremely weak interfacial bonding. 28 particles fell off per puncture, and the tensile strength was only 20 MPa.

[0057] Deviations in antibacterial loaded particle parameters (Comparative Examples 3, 4, 11, 13): In Comparative Example 3, the mass ratio of mesoporous SiO2 to AgNO3 was too low, resulting in insufficient silver ion loading and a significantly shortened antibacterial duration. After hot air aging, the diameter of the antibacterial ring was only 3 mm. In Comparative Example 4, the amount of antibacterial loaded particles was too small, failing to form an effective antibacterial network, with an initial antibacterial ring diameter of 9 mm. In Comparative Example 11, the AgNO3 concentration was too low, resulting in insufficient silver ion reduction. In Comparative Example 13, unloaded nano-silver particles were used directly, leading to severe silver ion dissolution and easy particle aggregation and detachment, with 30 particles falling off per puncture.

[0058] Key process parameters out of control (Comparative Examples 5-9): In Comparative Example 5, the dosage of PEG-400 was too high (>4 phr), and its low molecular weight characteristics led to a decrease in the hardness of the rubber matrix, with a Shore A of only 35, making it easy to deform and shed chips during puncture; In Comparative Example 6, the mixing temperature was too high, causing the hydroxyl groups on the surface of the silane-modified filler to undergo a hydrolysis reaction with the rubber matrix, resulting in a decrease in interfacial bonding force, uneven filler dispersion, and 20 chips per puncture; In Comparative Example 7, the vulcanization temperature was too low, resulting in insufficient crosslinking reaction and a tensile strength of only 24 MPa; In Comparative Example 8, the vulcanization pressure was insufficient, resulting in poor crosslinking network density and an elongation at break of only 360%; In Comparative Example 9, the secondary vulcanization steam pressure was too high, resulting in incomplete volatilization of low molecular weight substances, with a total extract content of 2.2 mg / stopper. At the same time, the high temperature accelerated the aging of the rubber, and the tensile strength retention rate was only 70%.

[0059] In summary, the embodiments achieved synergistic optimization of various performance indicators through precise control of the substrate, filler, antibacterial agent, and process parameters; while the comparative examples, due to key factors deviating from the optimal range, resulted in a significant decrease in core indicators such as mechanical properties, antibacterial efficiency, aging resistance, and safety, thus verifying the systematic nature and necessity of the technical solution of the present invention.

Claims

1. A puncture-resistant medical rubber stopper, characterized in that, By weight, it includes the following components: Rubber substrate: Pharmaceutical grade brominated butyl rubber or chlorinated butyl rubber 100 phr; Modified fillers: modified nano silica 8-12 phr, modified nano zinc oxide 3-5 phr, modified pharmaceutical grade kaolin 5-10 phr; Antibacterial loaded particles: Ag@SiO2 / CMCS loaded particles 3-8 phr, Pharmaceutical-grade liquid polyethylene glycol 3-6 phr; Hindered phenolic antioxidant 0.8-1.2 phr; Thioester antioxidant 0.5-0.8 phr; Peroxide crosslinking agent 1.5-3 phr; Metal passivating agent: N-salicylic acid aniline 0.3-0.5 phr; The preparation method of the Ag@SiO2 / CMCS supported particles is as follows: The particles have a pore size of 5-10 nm and a specific surface area of ​​800-1200 m². 2 / g of mesoporous silica was mixed with 0.05-0.1mol / L silver nitrate solution, with a dry weight ratio of mesoporous silica to silver nitrate of 5-10:

1. Ammonia was added to adjust the pH to 8-9, and then 1-1.5 times the amount of silver ions as ascorbic acid reducing agent was added. The mixture was stirred at 60℃ for 2-4h. After centrifugation and washing, the particles were dispersed in a 2-3% acetic acid solution. Chitosan carboxymethylated product with a degree of deacetylation ≥90% was added, with the amount of chitosan carboxymethylated product grafted to 5-10% of the mass of mesoporous silica. After stirring for 2-3h, the mixture was dried to obtain Ag@SiO2 / CMCS supported particles.

2. A method for preparing a puncture-resistant medical rubber stopper, used to prepare the puncture-resistant medical rubber stopper as described in claim 1, characterized in that, Includes the following steps: Step (1) Take pharmaceutical-grade brominated butyl rubber or chlorinated butyl rubber as the base material and dry it until the moisture content is ≤0.1%; Step (2) Nano silica, nano zinc oxide, and pharmaceutical-grade kaolin are modified with a silane coupling agent to obtain surface-hydroxylated fillers; Step (3) Prepare antibacterial loaded particles; Step (4) Mix the dried substrate with the following components in parts by weight: Modified fillers: nano-SiO2 8-12 phr, nano-ZnO-NP 3-5 phr, kaolin 5-10 phr. Antibacterial loaded particles Ag@SiO2 / CMCS 3-8phr, Pharmaceutical grade liquid polyethylene glycol PEG-400 3-6 phr Hindered phenolic antioxidant 1010 0.8-1.2 phr Thioester antioxidant DLTP 0.5-0.8 phr Metal passivating agent N-salicylic acid aniline 0.3-0.5 phr; Mixing in a mixer; Step (5) Cool the internal mixer to 75-85℃, add 1.5-3 phr of peroxide crosslinking agent, mix for 3-5 minutes to obtain the compound; Step (6) Place the compounded rubber in a mold and vulcanize it to form a preliminary product; Step (7) Secondary steam vulcanization of the initial product; Step (8) Clean the surface with deionized water and vacuum dry it to make the moisture content ≤0.5% to obtain puncture-resistant medical rubber stopper.

3. The method for preparing a puncture-resistant medical rubber stopper according to claim 2, characterized in that, The peroxide crosslinking agent is di-tert-butyl peroxide, the hindered phenol antioxidant is hindered phenol antioxidant 1010, the thioester antioxidant is thioester antioxidant DLTP, the metal passivator is N-salicylic acid aniline, and the silane coupling agent is KH-560.

4. The method for preparing a puncture-resistant medical rubber stopper according to claim 2, characterized in that, The substrate is brominated butyl rubber with a bromine content of 1.8-2.2%.

5. The method for preparing a puncture-resistant medical rubber stopper according to claim 2, characterized in that, The substrate is chlorinated butyl rubber with a chlorine content of 1.3-1.6%.

6. The method for preparing a puncture-resistant medical rubber stopper according to claim 2, characterized in that, In step (4), the mixing process is as follows: rotation speed 50-60 rpm, 80-100℃, 15-20 min.

7. The method for preparing a puncture-resistant medical rubber stopper according to claim 2, characterized in that, The vulcanization temperature in step (6) is 150-160℃ and the time is 8-10 min.

8. The method for preparing a puncture-resistant medical rubber stopper according to claim 2, characterized in that, The temperature of the secondary steam vulcanization in step (7) is 100°C and the time is 2 hours.

9. The method for preparing a puncture-resistant medical rubber stopper according to claim 2, characterized in that, The drying temperature in step (8) is ≤60℃ and the time is 2-3h.

10. The method for preparing a puncture-resistant medical rubber stopper according to claim 2, characterized in that, The drying process described in step (1) is as follows: vacuum drying at 50-60℃ for 2-4 hours to reduce the moisture content to ≤0.1%.

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