A medicine sealing plug and a preparation method thereof

Abstract

The present application relates to a kind of medicine sealing plug and its preparation method, its sealing plug includes core body, self-sealing body and sealing body, the lower end of core body forms the plug neck of big cone shape from top to bottom, the center of plug neck forms the cone hole of big cone shape from top to bottom;The components of core body include brominated butyl rubber, white carbon black, dicumyl peroxide, zinc oxide, stearic acid, amino silane coupling agent;Self-sealing body is conical to be embedded in cone hole, the components of self-sealing body include brominated butyl rubber, white carbon black, polyisobutylene, sulfur, TBBS, zinc oxide, stearic acid;Sealing body is conical sleeve to be set on plug neck, the components of sealing body include fluorine rubber, white carbon black, perfluoropolyether plasticizer, bisphenol AF, BPP, heat stabilizer;Core body, self-sealing body and sealing body are formed by moulding vulcanization.

Description

Technical Field

[0001] This invention relates to the field of polymer rubber product preparation technology, specifically to a pharmaceutical sealing plug and its preparation method. Background Technology

[0002] Pharmaceutical sealing plugs are used to ensure the airtightness, safety, and ease of use of pharmaceutical packaging. Common pharmaceutical sealing plugs include flat plugs, plungers, and conical plugs. Different types of sealing plugs are suitable for different scenarios. Among them, conical plugs are widely used due to their easy insertion and removal and their ability to flexibly adapt to medicine bottles of different diameters.

[0003] Currently, conical stoppers are commonly used for sealing multi-dose external medication vials. Patients remove the medication by pulling off the stopper and then pouring or drawing it with a syringe. While convenient, this method exposes the medication to air frequently, increasing the risk of contamination. Furthermore, there are areas for improvement in current conical stoppers. The seal relies on an interference fit between the conical surface and the inner wall of the bottle opening. If the hardness is too high, the insertion and removal resistance is too great, making operation difficult; the poor elasticity of the rubber is also detrimental to sealing, and long-term use can lead to aging and cracking. If the hardness is too low, the stopper is prone to collapse during insertion and removal, making it difficult to insert and remove, and it cannot provide sufficient radial support for elasticity, also posing a risk of seal failure. Summary of the Invention

[0004] The purpose of this invention is to provide a pharmaceutical sealing plug that improves upon the existing sealing plugs' difficulty in balancing hardness and elasticity, and the problem of pharmaceutical liquid being easily exposed to air.

[0005] To achieve the above objectives, the present invention adopts the following technical solution:

[0006] A pharmaceutical sealing plug, comprising:

[0007] The core has a cone-shaped neck formed at its lower end, wider at the top and narrower at the bottom, with a cone-shaped hole formed at the center of the neck; the core comprises, by weight, 100 parts of brominated butyl rubber, 30-40 parts of silica, 1.5-2 parts of dicumyl peroxide, 5-6 parts of zinc oxide, 0.9-1.1 parts of stearic acid, and 0.4-0.6 parts of aminosilane coupling agent;

[0008] The self-sealing body is cone-shaped and embedded in the cone hole. The self-sealing body comprises, by weight, 100 parts of brominated butyl rubber, 15-18 parts of silica, 8-10 parts of polyisobutylene, 0.6-0.8 parts of sulfur, 0.3-0.5 parts of TBBS, 3-4 parts of zinc oxide, and 0.8-1 parts of stearic acid.

[0009] A sealing body, wherein the sealing body is in the shape of a conical sleeve to be fitted onto the neck of the plug, the sealing body comprising, by weight, 100 parts of fluororubber, 5 to 8 parts of silica, 25 to 30 parts of perfluoropolyether plasticizer, 1.5 to 2 parts of bisphenol AF, 0.5 to 0.8 parts of BPP, and 0.3 to 0.5 parts of heat stabilizer;

[0010] The core, self-sealing body, and sealing body are molded and vulcanized.

[0011] Further, the core comprises, by weight, 100 parts of brominated butyl rubber, 35 parts of silica, 1.8 parts of dicumyl peroxide, 5.5 parts of zinc oxide, 1 part of stearic acid, and 0.5 parts of aminosilane coupling agent; the self-sealing body comprises, by weight, 100 parts of brominated butyl rubber, 16.5 parts of silica, 9 parts of polyisobutylene, 0.7 parts of sulfur, 0.4 parts of TBBS, 3.5 parts of zinc oxide, and 0.9 parts of stearic acid; the sealing body comprises, by weight, 100 parts of fluororubber, 6 parts of silica, 28 parts of perfluoropolyether plasticizer, 1.7 parts of bisphenol AF, 0.6 parts of BPP, and 0.4 parts of heat stabilizer.

[0012] Furthermore, the Mooney viscosity of the fluororubber is ≤60.

[0013] Furthermore, the upper end of the core is formed with a concave recess, and a puncture platform is formed in the center of the recess. The puncture platform is provided with a guide needle hole, which penetrates the core.

[0014] This invention also provides a method for preparing a pharmaceutical sealing plug, which includes the following steps:

[0015] S1. Prepare the core, self-sealing body, and sealing body;

[0016] S2. The self-sealing body is embedded in the conical hole to form a hybrid body, and then the surface of the hybrid body is polished to a roughness > 1 μm, and after descaling, the surface of the hybrid body is plasma treated.

[0017] S3. Place the sealing body onto the plug neck, then place it in the mold, and mold and vulcanize it at 175-180°C and 18-20MPa for 10-11 minutes; after vulcanization, cool it to below 60°C and demold.

[0018] S4. Place the demolded composite rubber in a vacuum environment at 110-130℃ for 2-3 hours to de-dry, and then allow it to cool naturally to room temperature.

[0019] Furthermore, S1 includes the following steps:

[0020] Preparation of core compound: Add brominated butyl rubber to a closed kneader and knead at room temperature for 5 minutes until softened; add silica, zinc oxide and stearic acid and knead at 70-75℃ for 6 minutes; finally add dicumyl peroxide and knead at 70-80℃ for 4 minutes, then discharge the rubber, press it into shape, and let it mature at room temperature for 24 hours.

[0021] Preparation of self-sealing compound: Add brominated butyl rubber to a closed kneader and knead at room temperature for 5 minutes until softened; add polyisobutylene in two batches, 3 minutes apart, and knead at 60-65°C; add silica, zinc oxide, and stearic acid, and knead at 70-75°C for 6 minutes; finally add sulfur and TBBS, and knead at below 80°C for 4 minutes, then discharge the compound, press it into shape, and let it mature at room temperature for 30 hours.

[0022] Preparation of sealing compound: Add fluororubber to a closed kneader and knead at room temperature for 5 minutes until softened; add perfluoropolyether plasticizer in 2-3 batches, with 3-minute intervals, and knead at 60-65℃; add 5-8 parts of silica and 0.3-0.5 parts of pharmaceutical-grade fluororubber heat stabilizer, and knead at 70-75℃ for 6 minutes; finally add 1.5-2 parts of bisphenol AF, 0.5-0.8 parts of BPP, and 1-1.2 parts of aminosilane coupling agent, and knead at below 80℃ for 4 minutes, then extrude the compound, press it into shape, and let it mature at room temperature for 24 hours.

[0023] Furthermore, in S2, the parameters for plasma treatment are controlled as follows: power 300-500W, treatment time 45-60 seconds, and distance 5-8mm.

[0024] Furthermore, before the sealing body is fitted onto the neck in step S3, a silane coupling agent is coated on the surface of the mixture, with the coating thickness controlled at 0.5–1 μm; after coating, it is dried at 80–100°C for 10–15 minutes.

[0025] Furthermore, before vulcanization in S3, the temperature is increased to 50-65°C at a rate of 5°C / min, and then increased to 175-180°C at a rate of 2-3°C / min.

[0026] Furthermore, after vulcanization, the temperature is reduced to below 60°C at a cooling rate of 3–4°C / minute.

[0027] By adopting the above technical solution, the present invention has the following advantages compared with the prior art:

[0028] 1. This application, by setting a self-sealing body, allows the conical stopper to draw out the drug solution through the syringe without insertion or removal when liquid needs to be taken out, and then the self-sealing body seals the needle hole, reducing the probability of the drug coming into contact with the external environment; when used as a transfer bottle, the conical stopper can be removed to achieve rapid replenishment or transfer of the drug solution, which is especially suitable for short-term, high-frequency use of multiple doses of drug solution, as well as for use in laboratories;

[0029] 2. This application utilizes the taper of the plug neck to increase the interlayer bonding force between the core and the sealing body from a physical perspective, making it less likely for delamination to occur between the core and the sealing body during long-term insertion and removal. Setting the hole for installing the self-sealing body as a tapered hole also increases the interlayer bonding force from a physical perspective, so that when the syringe is used to puncture and extract the drug, the resistance of the needle will not act on the sealing body through the self-sealing body, thus avoiding delamination between the self-sealing body and the sealing body caused by long-term repeated stress.

[0030] 3. This application uses the same base rubber material for both the core and the self-sealing body, and obtains rubber bodies with different elasticities by optimizing only from the perspective of formula optimization. This not only reduces the types of raw materials, but also makes the interlayer bonding force after vulcanization of the two more compact than that of dissimilar rubber materials, making them less prone to peeling. At the same time, it simplifies the molding and vulcanization conditions, making the vulcanization parameters and time of the three components similar, so that molding and vulcanization can be successful in one go.

[0031] 4. This application utilizes the excellent chemical inertness of fluororubber to prevent molecular migration or precipitation that could contaminate the drug. At the same time, through formulation improvement, the defects of poor elasticity and poor bonding with other rubbers of fluororubber are optimized. Meanwhile, the formulation and process of the core and self-sealing body are optimized so that the core balances hardness and elasticity, improving tear resistance while ensuring elastic support and preventing collapse during insertion and removal. The self-sealing body has moderate hardness, which is neither too soft to cause needle sticking, and has good elastic deformation ability, enhancing the self-sealing effect in the cone hole. Attached Figure Description

[0032] Figure 1 This is a schematic diagram of the sealing plug described in this invention.

[0033] Explanation of reference numerals in the attached figures:

[0034] 100. Core; 110. Neck; 120. Conical hole; 130. Recess; 140. Puncture platform; 150. Guide needle hole; 200. Self-sealing body; 300. Sealing body; 310. Molding indentation. Detailed Implementation

[0035] The technical solution of the present invention is illustrated below through specific examples. It should be understood that the one or more method steps mentioned in the present invention do not preclude the existence of other method steps before or after the combined steps, or the insertion of other method steps between these explicitly mentioned steps; it should also be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the present invention. Furthermore, unless otherwise stated, the numbering of each method step is merely a convenient tool for identifying each method step, and not for limiting the order of the method steps or defining the scope of the present invention. Changes or adjustments to their relative relationships, without substantially altering the technical content, are also considered to fall within the scope of the present invention.

[0036] To better understand the above technical solutions, exemplary embodiments of the present invention are described in more detail below. While exemplary embodiments of the present invention are shown, it should be understood that the present invention can be implemented in various forms and should not be limited to the embodiments set forth herein. Rather, these embodiments are provided to enable a more thorough understanding of the present invention and to fully convey the scope of the invention to those skilled in the art.

[0037] The test materials used in this invention are all common commercial products and can be purchased on the market. Example

[0038] Please refer to Figure 1 As shown, this embodiment discloses a drug sealing plug, which includes a core 100, a self-sealing body 200 and a sealing body 300.

[0039] Structurally: Core 100 refers to the rubber matrix that bears the main support function and is used to bear the insertion and extraction force and the radial force required to maintain the radial seal. Specifically, the lower end of Core 100 forms a cone-shaped neck 110 that is larger at the top and smaller at the bottom. The cone shape is adapted to different bottlenecks. The center of Neck 110 forms a cone-shaped hole 120 that is larger at the top and smaller at the bottom for installing Self-Sealing Body 200. Self-Sealing Body 200 is a rubber part with elastic recovery properties, used to achieve self-sealing of the needle hole after needle puncture to prevent leakage. It is cone-shaped to be embedded in the cone-shaped hole 120. Sealing Body 300 is cone-shaped to be sleeved on Neck 110, forming a covering of Neck 110 and Self-Sealing Body 200. Finally, Core 100, Self-Sealing Body 200 and Sealing Body 300 are molded and vulcanized into an integral structure.

[0040] In terms of composition, the core 100 uses a brominated butyl rubber and silica reinforcement system, specifically comprising, by weight, 100 parts brominated butyl rubber, 30-40 parts silica, 1.5-2 parts dicumyl peroxide, 5-6 parts zinc oxide, 0.9-1.1 parts stearic acid, and 0.4-0.6 parts aminosilane coupling agent; the self-sealing body 200 uses a polyisobutylene-modified brominated butyl rubber formulation, specifically comprising, by weight, 100 parts brominated butyl rubber, 15-1... The sealant 300 is made of a perfluoropolyether plasticized fluororubber system, specifically including 100 parts by weight of fluororubber, 5 to 8 parts by weight of fumed silica, 25 to 30 parts by weight of perfluoropolyether plasticizer, 1.5 to 2 parts by weight of bisphenol AF, 0.5 to 0.8 parts by weight of BPP, and 0.3 to 0.5 parts by weight of heat stabilizer.

[0041] Therefore, by setting up a self-sealing body 200, when liquid needs to be taken out, the conical stopper can be used to draw out the liquid through the syringe without insertion or removal, and then the self-sealing body 300 seals the needle hole, reducing the probability of the drug coming into contact with the external environment; when used as a transfer bottle, the conical stopper can be removed to achieve rapid replenishment or transfer of liquid, which is especially suitable for short-term, high-frequency use of multiple doses of liquid, as well as for use in laboratories.

[0042] This application utilizes the taper of the neck 110 to physically increase the interlayer bonding force between the core 100 and the sealing body 300, making it less likely for delamination to occur between the core 100 and the sealing body 300 during long-term insertion and removal. Setting the hole for installing the self-sealing body 200 as a tapered hole 120 also physically increases the interlayer bonding force, ensuring that when the syringe is used to puncture and extract the drug, the resistance of the needle will not act on the sealing body 300 through the self-sealing body 200, thus avoiding delamination between the self-sealing body 200 and the sealing body 300 caused by long-term repeated stress.

[0043] This application uses the same base rubber material for both the core 100 and the self-sealing body 200, and obtains rubber bodies with different elasticities only from the perspective of formula optimization. This not only reduces the types of raw materials, but also makes the interlayer bonding force of the two after vulcanization more compact than that of dissimilar rubber materials, making them less prone to peeling. At the same time, it simplifies the molding and vulcanization conditions, making the vulcanization parameters and time of the three components similar, so that molding and vulcanization can be successful in one go.

[0044] This application utilizes the excellent chemical inertness of fluororubber to prevent molecular migration or precipitation that could contaminate the drug. At the same time, through formulation improvements, the defects of poor elasticity and poor bonding with other rubbers of fluororubber are optimized. Meanwhile, the formulation and process of the core 100 and the self-sealing body 200 are optimized, so that the core 100 balances hardness and elasticity, improving tear resistance while ensuring elastic support and preventing collapse during insertion and removal. The self-sealing body 200 has moderate hardness, which is neither too soft to cause pin seizing, and has good elastic deformation ability, enhancing the self-sealing effect within the conical hole 120.

[0045] This invention preferably uses a Mooney viscosity of less than or equal to 60 for the fluororubber, ensuring that the sealing body 300 material achieves suitable flowability and crosslinking density during vulcanization. This guarantees that the fluororubber can fully fill the mold cavity during compression molding, avoiding molding defects caused by excessive viscosity. It also ensures that the elastic modulus of the sealing body 300 after vulcanization is within a reasonable range, allowing it to generate sufficient radial elastic deformation to achieve an interference fit when fitted with the neck 110. Furthermore, it improves the fatigue resistance of the fluororubber, delaying stress relaxation caused by repeated deformation, thereby enhancing the structural stability of the sealing body 300 during long-term use.

[0046] Furthermore, this application forms a recessed portion 130 at the upper end of the core 100, with a puncture platform 140 formed at the center of the recessed portion 130. The puncture platform 140 is provided with a guide needle hole 150, which penetrates the core 100. In this way, by providing a recessed area at the upper end of the core 100, the needle puncture stroke is reduced; by providing a raised puncture platform 140 and a guide needle hole 150 at the center of the recessed portion 130, the needle can be guided to accurately puncture the guide needle hole 150, reducing the difficulty of long-stroke punctures.

[0047] In addition, during molding, this application sets several molding rings on the mold with the guide pin hole 150 as the center. The molding rings are 0.5 to 1 mm high and 1 to 2 mm wide, forming corresponding molding indentations 310 on the sealing body 300. This improves the local reinforcement structure that resists needle puncture and prevents the separation of the sealing body and self-sealing body interface around the guide pin hole 150 caused by long-term needle puncture.

[0048] Furthermore, the present invention also provides a method for preparing a pharmaceutical sealing plug, which includes the following steps:

[0049] S1. Prepare the core, self-sealing body, and sealing body;

[0050] S2. The self-sealing body is embedded in the conical hole to form a mixture, and then the surface of the mixture is polished to a roughness Ra > 1 μm, and the surface of the mixture is plasma treated after descaling.

[0051] S3. Place the sealing body onto the plug neck, then place it in the mold, and mold and vulcanize it at 175-180°C and 18-20MPa for 10-11 minutes; after vulcanization, cool it to below 60°C and demold.

[0052] S4. Place the demolded composite rubber in a vacuum environment at 110-130℃ for 2-3 hours to de-dry, and then allow it to cool naturally to room temperature.

[0053] This application grinds the surface roughness to Ra > 1 μm to form a micro-mechanical interlocking structure on the surface of the mixture. Combined with plasma treatment, the CH and CC bonds on the rubber surface are broken to generate active groups such as hydroxyl (-OH) and carboxyl (-COOH). These groups can form hydrogen bonds or chemical bonds with the molecular chains of another layer of rubber, so that the interlayer bonding forms a chemical crosslink.

[0054] This application employs medium-temperature vulcanization at 175–180℃ combined with high pressure of 18–20 MPa. This avoids thermal decomposition of fluororubber while ensuring full cross-linking of the interfaces of each component. Cooling temperature is controlled to prevent demolding stress deformation. At the vulcanization temperature, the holding pressure is maintained for 10–11 minutes, which is 20%–30% longer than single-layer vulcanization, ensuring that molecules have sufficient time to cross the interlayer interfaces and form a uniform transition layer.

[0055] This application promotes further cross-linking of incompletely reacted molecules between layers through vacuum devolatilization, while releasing residual volatile substances (such as hydrolysis products of coupling agents), thus avoiding the weakening of binding force due to material migration in the later stage.

[0056] Furthermore, S1 includes the following steps:

[0057] Preparation of core compound: Add brominated butyl rubber to a closed kneader and knead at room temperature for 5 minutes until softened; add silica, zinc oxide and stearic acid and knead at 70-75℃ for 6 minutes; finally add dicumyl peroxide and knead at 70-80℃ for 4 minutes, then discharge the rubber, press it into shape, and let it mature at room temperature for 24 hours.

[0058] Preparation of self-sealing compound: Add brominated butyl rubber to a closed kneader and knead at room temperature for 5 minutes until softened; add polyisobutylene in two batches, 3 minutes apart, and knead at 60-65°C; add silica, zinc oxide, and stearic acid, and knead at 70-75°C for 6 minutes; finally add sulfur and TBBS, and knead at below 80°C for 4 minutes, then discharge the compound, press it into shape, and let it mature at room temperature for 30 hours.

[0059] Preparation of sealing compound: Add fluororubber to a closed kneader and knead at room temperature for 5 minutes until softened; add perfluoropolyether plasticizer in 2-3 batches, with 3-minute intervals, and knead at 60-65°C; add 5-8 parts of silica and 0.3-0.5 parts of pharmaceutical-grade fluororubber heat stabilizer, and knead at 70-75°C for 6 minutes; finally add 1.5-2 parts of bisphenol AF, 0.5-0.8 parts of BPP, and 1-1.2 parts of aminosilane coupling agent, and knead at below 80°C for 4 minutes, then discharge the compound, press it into shape, and let it mature at room temperature for 24 hours.

[0060] Following the above process, using 100 parts by weight of brominated butyl rubber as the base material, the core compound is manufactured according to the parameters in Table 1. The brominated butyl rubber is BBK232 (pharmaceutical grade, bromine content 2.0–2.5%), the silica is fumed silica (specific surface area 200±20 m² / g, pharmaceutical grade), the dicumyl peroxide (DCP) (40% purity, silica as carrier, pharmaceutical grade), the zinc oxide is active zinc oxide (particle size 50–100 nm, purity ≥99.7%, pharmaceutical grade), the stearic acid is pharmaceutical grade stearic acid (purity ≥99%, iodine value ≤1.0, heavy metals ≤10 ppm), and the aminosilane coupling agent is KH-550 (γ-aminopropyltriethoxysilane, purity ≥98%, pharmaceutical grade).

[0061]

[0062] Among them, brominated butyl rubber has good aging resistance and deformation stability. At the same time, it is easy to work in synergy with the reinforcing system and flexibly adjust the range of rigidity. Therefore, this application uses it as the base material for the core and self-sealing body.

[0063] Dicumyl peroxide decomposes at high temperatures (vulcanization temperature 160–180 °C) to generate active free radicals. These free radicals can attack the CH bonds in the brominated butyl rubber molecular chain, causing adjacent molecular chains to form C-C covalent cross-linking bonds. Simultaneously, its decomposition products are easily volatilized, resulting in low residual risk. Therefore, this application uses it as a cross-linking agent for brominated butyl rubber.

[0064] Zinc oxide, as an activator in the vulcanization system, is used to improve vulcanization efficiency and crosslinking quality. Specifically, zinc oxide lowers the decomposition temperature of dicumyl peroxide and makes the free radical generation rate more gradual, avoiding excessive local free radicals that could lead to uneven crosslinking. As an alkaline substance, it neutralizes the trace acidic byproducts of dicumyl peroxide, preventing acidic substances from attacking the C-Br bonds of brominated butyl rubber, which could lead to molecular chain breakage or crosslinking bond degradation, thus affecting core strength.

[0065] The long carbon chain of stearic acid (C 17 H 35 - It can insert itself between the molecular chains of brominated butyl rubber, weakening the intermolecular forces and improving molecular chain fluidity. This promotes uniform dispersion of silica and reduces agglomeration. While a high silica ratio increases rigidity, it can also lead to rubber embrittlement. The long carbon chains of stearic acid can form a flexible buffer between rubber joints, allowing the core to maintain toughness while meeting hardness requirements. Its low surface energy reduces demolding resistance, minimizing burrs and chipped edges during demolding. Furthermore, stearic acid is a synergist for zinc oxide; the two can form a soluble zinc soap (zinc stearate), solving the problem of uneven zinc oxide dispersion in rubber.

[0066] Aminosilane coupling agents can modify silica by utilizing their amino groups (-NH2, polar) to undergo a dehydration condensation reaction with the hydroxyl groups (-OH) on the silica surface, forming stable Si-O-Si covalent bonds. Furthermore, their long-chain alkoxy groups (-OCH3, non-polar) replace the polar hydroxyl groups on the silica surface, changing the silica surface from strongly polar to weakly polar, thus reducing agglomeration. The non-polar ends of the coupling agent can physically entangle with the main chain of brominated butyl rubber, reducing the amount of silica required while improving processing fluidity and avoiding embrittlement caused by high-filler silica, all while meeting the same rigidity requirements.

[0067] Additionally, when zinc oxide is used in conjunction with an aminosilane coupling agent, zinc oxide can further reduce the surface energy of silica, making it easier for the coupling agent to be adsorbed onto the silica surface.

[0068] The above samples were molded and vulcanized at 178℃ and 19MPa for 8 minutes. After vulcanization, they were cooled to below 60℃ and demolded, and mechanical tests were performed. The test results are shown in Table 2.

[0069]

[0070] The hardness measurement method is as follows: place the sample and hardness tester in an environment of 23±2℃ and 50±5% relative humidity for at least 24 hours; place the sample stably on a rigid test platform to ensure that the sample is completely in contact with the platform surface without warping; align the hardness tester indenter vertically with the sample surface, slowly apply pressure to fully press the indenter into the sample, maintain the pressure for 3 seconds, and then read the reading.

[0071] The method for measuring tear strength is as follows: Place the sample and testing instrument in an environment of 23±2℃ and 50±5% relative humidity for at least 24 hours; clamp the sample: fix both ends of the sample in the upper and lower clamps of the tensile testing machine, ensuring that the sample axis is consistent with the direction of tensile force, and stretch the sample at a speed of (500±50) mm / min until the sample is completely torn (the fracture location must be within the working section; if the fracture occurs at the clamp, the data is invalid and the test must be repeated), record the maximum tensile force value during the tearing process, and calculate the tear strength based on the maximum tensile force value.

[0072] The test method for hardness change after sterilization at 121℃ is as follows: The sample is placed at a constant temperature and humidity of 23±2℃ and 50±5% for ≥24 hours; the initial hardness is tested and recorded; the sample is placed in a high-pressure steam sterilizer at a sterilization temperature of (121±1)℃, an absolute pressure of 0.105MPa, and a sterilization time of 20 minutes; after sterilization, the pressure is naturally reduced to atmospheric pressure, and the sample is taken out and cooled at room temperature for 30 minutes; after constant cooling, it is placed in an environment of 23±1)℃ and 50±5% relative humidity for 24 hours, and the hardness after sterilization is tested. The average value of multiple tests is taken as the hardness after sterilization, and the change value is calculated.

[0073] Comparing the test results of samples 1-1, 2-1 and 3-1, it can be seen that sample 2-1 achieved a balance between hardness and tear strength.

[0074] Comparing the test results of sample 2-1 and sample 4-1, it can be seen that after removing the aminosilane coupling agent, the local rigidity is high due to the agglomeration phenomenon. At the same time, the stress concentration caused by the agglomeration of silica leads to a significant decrease in tear resistance, that is, the hardness is high but uneven.

[0075] Comparing the tests of samples 2-1 and 5-1, it is evident that when the zinc oxide content is low, the decomposition rate of the vulcanizing agent decreases, the required vulcanization time becomes longer, the vulcanization is too slow, and the amount of free radicals generated is insufficient, leading to a decrease in crosslinking density. The core hardness is only 44-46 degrees, which cannot meet the rigid support requirements, making it prone to deformation during insertion and extraction, and the tear strength also decreases to 20. Comparing the tests of samples 2-1 and 6-1, when the zinc oxide content is high, stearic acid cannot completely react with it to form zinc stearate. The unreacted zinc oxide, due to its strong polarity and high density, easily forms agglomerates in the rubber. At the same time, because the local concentration of zinc oxide is too high, the decomposition rate of DCP around the free zinc oxide agglomerates is abnormally accelerated, resulting in excessively high local crosslinking density in the core, manifesting as local hardness and brittleness. In other areas, due to insufficient zinc oxide, the crosslinking density is low, the hardness is low, the overall hardness fluctuates greatly, and the tear strength also decreases significantly.

[0076] Following the above process, using 100 parts by weight of brominated butyl rubber as the base material, manufacture the self-sealing compound according to the parameters in Table 3. The brominated butyl rubber is BBK232 (pharmaceutical grade, bromine content 2.0-2.5%), the silica is fumed silica (specific surface area 200±20m² / g, pharmaceutical grade), the polyisobutylene is pharmaceutical grade polyisobutylene (PIB1300, number average molecular weight 1200-1400, purity ≥99.5%), the sulfur is insoluble sulfur IS-60 (content 60%, carrier is silica, high temperature stable, pharmaceutical grade), the accelerator N-tert-butyl-2-benzothiazole sulfenamide (purity ≥98%, heavy metals ≤10ppm, pharmaceutical grade), the zinc oxide is active zinc oxide (particle size 50-100nm, purity ≥99.7%, pharmaceutical grade), and the stearic acid is pharmaceutical grade stearic acid (purity ≥99%, iodine value ≤1.0, heavy metals ≤10ppm).

[0077]

[0078] Polyisobutylene, a saturated linear polymer with a flexible molecular chain and no double bonds, significantly improves the resilience of brominated butyl rubber when blended with it, allowing the needle hole to close quickly after puncture. Simultaneously, polyisobutylene acts as both a plasticizer and a lubricant, reducing the Mooney viscosity of the compound and enabling the self-sealing body to precisely fill the fine structure of the mold while preventing interlayer bubbles during core bonding. Furthermore, polyisobutylene is chemically inert, stable against acids, alkalis, organic solvents, and active pharmaceutical ingredients, posing no risk of dissolution. Its saturated structure also contributes to its excellent aging resistance; after sterilization at 121°C, its elasticity decay is minimal, ensuring long-term stable self-sealing performance.

[0079] Sulfur reacts with the molecular chains of brominated butyl rubber to form polysulfide crosslinks with moderate bond energy (approximately 272 kJ / mol), ensuring both the tear resistance of the self-sealing compound and sufficient elasticity, thus preventing puncture cracking caused by hardness and brittleness.

[0080] TBBS acts as a post-curing accelerator, preventing premature vulcanization. Its good dispersibility ensures a uniform distribution of crosslinking density, reducing overall hardness fluctuations in the self-sealing body and preventing self-sealing failure caused by localized hardness / brittleness or softness / elasticity. It produces few byproducts after vulcanization, which are easily volatilized, eliminating the risk of chemical contamination.

[0081] The above samples were molded and vulcanized at 178℃ and 19MPa for 8 minutes. After vulcanization, they were cooled to below 60℃ and demolded, and mechanical tests were performed. The test results are shown in Table 4.

[0082]

[0083] Resilience Test: Referring to GB / T1681-2009, place the sample in an environment of 23±2℃ and 50±5% relative humidity for at least 24 hours; fix the sample in the center of the testing machine base, ensuring that the impact direction of the pendulum is perpendicular to the sample axis; raise the pendulum to 90°, release the pendulum, and let it freely impact the upper surface of the sample; record the maximum rebound angle after the pendulum impact, and calculate the resilience based on the angle; test the same sample 3 times, with an interval of ≥1 minute between each test. Take the arithmetic mean of the 3 test results.

[0084] Compression set: Referring to GB / T7759.1-2015, the specimen was placed in an environment of 23±2℃ and 50±5% relative humidity for at least 24 hours, and the initial thickness d0 was measured (measured at 3 different points and the average value was taken). The specimen was placed in a metal confinement device and compressed to 75% of the original thickness (i.e., compression rate 25%) through the confinement device, ensuring that the specimen was compressed evenly and without displacement. The specimen, along with the confinement device, was placed in an oven at 70±1℃ and kept at a constant temperature for 22 hours. The specimen and confinement device were removed and cooled at room temperature for 30 minutes before the confinement device was removed. The specimen was then placed at room temperature for another 24 hours, and the recovered thickness (d1) of the specimen was measured at the initial thickness measurement point. The deformation rate was calculated.

[0085] Self-sealing performance test: Place the sample in an environment of 23±2℃ and 50±5% relative humidity for ≥24 hours; install the sample on the fixture to simulate the actual sealing state (self-sealing body on top, liquid medicine on the bottom), and use purified water as the liquid medicine; insert a 1.2mm needle vertically through the self-sealing body at a speed of (100±10)mm / min, maintain a puncture depth of 5mm, hold for 3 seconds, and then pull out the needle at the same speed; start timing the moment the needle is pulled out, observe the pinhole with a magnifying glass (10x), and record the time (accurate to 0.1 seconds) until the pinhole is completely closed (no liquid medicine seepage, no obvious pores); after the pinhole is closed, invert the sample and container as a whole by 180° and keep it for 30 minutes to observe whether there is any liquid medicine leakage (such as dripping, wetting the sample surface), and record the results; repeat the test 3 times for each sample, with a puncture point spacing of ≥5mm to avoid the influence of adjacent pinholes.

[0086] Oxygen permeability test: Refer to GB-T1038-2000, place the sample in an environment of 23±2℃ and 50±5% relative humidity, and keep it at constant temperature and humidity for ≥24 hours; fix the sample between the sealing gaskets of the test chamber, ensuring that the sample and the gaskets are completely in contact, without wrinkles or gaps, and perform vacuuming and gas filling: first, vacuum the low-pressure side to ≤10Pa and maintain it for 30 minutes; then fill the high-pressure side with pure oxygen and maintain the pressure at 0.1±0.005MPa; after starting the equipment, oxygen begins to diffuse through the sample. After 2 to 4 hours, when the oxygen concentration on the low-pressure side stabilizes, start recording data continuously and measure continuously for ≥3 hours.

[0087] Comparing the test structures of samples 1-2, 2-2, and 3-2, it can be seen that sample 2-2 achieved the best resilience, while the excess sulfur in sample 3-2 slightly affected the elasticity; sample 2-2 had the most stable compression set, while sample 3-2's compression set increased slightly due to the increased crosslinking density; sample 2-2 had the fastest self-sealing speed, while samples 2-2 and 2-3 had slightly slower self-sealing speeds but still met the usage requirements; sample 2-3 had the best airtightness; and sample 2-2 had the best sterilization resistance with almost no change in hardness.

[0088] Comparing the test results of sample 2-2 and sample 4-2, it can be seen that the core and the self-sealing body have different requirements for the optimal ratio of zinc oxide and stearic acid due to different functional needs. The core needs more zinc oxide to assist silica in reinforcement, while the self-sealing body needs higher elasticity. When zinc oxide is excessive, the vulcanization rate is too fast, the proportion of polysulfide bonds decreases, and the crosslinking is too dense, resulting in a significant decrease in resilience and self-sealing properties.

[0089] Following the above process, using 100 parts by weight of fluororubber as the base material, the sealing compound is manufactured according to the parameters in Table 5. The fluororubber is FKM2602 (vinylidene fluoride-hexafluoropropylene copolymer, fluorine content 66%–68%, pharmaceutical grade), the perfluoropolyether plasticizer is PFPE1500 (number average molecular weight 1400–1600, viscosity 200–300 mPa・s / 25℃, pharmaceutical grade), the bisphenol AF is pharmaceutical grade AF (purity ≥99%, moisture ≤0.1%), and the BPP is pharmaceutical grade (benzyltriphenylphosphine chloride, purity ≥98%, moisture ≤0.2%).

[0090]

[0091] Fluororubber, as the core matrix of the sealant, can withstand strong acids, strong alkalis, organic solvents (such as ethanol and acetone) and various pharmaceutical solutions (including highly corrosive chemotherapy drugs and biological agents), without swelling or degradation; it can withstand high temperatures of 150℃ for a long time, and its performance decreases by ≤3% after sterilization at 121℃; its molecular chains are dense, and its oxygen permeability is ≤3cm³ / (m²・24h), which can effectively block gas penetration and prevent the pharmaceutical solution from oxidizing and deteriorating.

[0092] By adding silica, the tear resistance and tensile strength of the pure rubber are improved, ensuring that the seal is resistant to insertion and removal and is not damaged.

[0093] Perfluoropolyether plasticizers are plasticizers for fluororubber, exhibiting excellent compatibility with fluororubber (due to their similar fluorinated structure). They can insert into the molecular chains to weaken the forces, reduce Mooney viscosity, and allow the rubber compound to easily fill the mold. Simultaneously, they improve resilience, ensuring a tight fit between the sealant and the contact surface.

[0094] Bisphenol AF reacts with active sites (such as -CH2-) on the molecular chain of fluororubber to form COC crosslinking bonds (bond energy 358kJ / mol), building a stable crosslinking network and improving the strength and deformation resistance of the seal. BPP is used to reduce the vulcanization temperature of bisphenol AF, shorten the vulcanization time, and at the same time ensure uniform crosslinking density, avoid local hard and brittle or soft and elastic, and ensure the overall performance of the seal is consistent.

[0095] The heat stabilizer is selected from fluorine-containing or fluorine-resistant stabilizers. In this application, lanthanum oxide is selected to inhibit thermo-oxidative aging: capture free radicals generated during high-temperature processing or sterilization of fluororubber, avoid molecular chain breakage and avoid degradation of vulcanization bonds. After sterilization at 121℃ for 10 times, the hardness of the sealant changes little and the tear resistance decreases little.

[0096] The above samples were molded and vulcanized at 178℃ and 19MPa for 8 minutes; after vulcanization, they were cooled to below 60℃ and demolded, and mechanical tests were performed. The test results are shown in Table 6.

[0097]

[0098] Comparing the test structures of samples 1-3, 2-3 and 3-3, it can be seen that there is no significant difference in the mechanical properties of each sample, but sample 2 has the best sterilization stability and the best long-term stability.

[0099] In a more preferred embodiment of this application, in S2, the plasma treatment parameters are controlled as follows: power 300-500W, treatment time 45-60 seconds, and distance 5-8mm. Before placing the sealing body onto the neck in S3, a silane coupling agent is coated on the surface of the mixture, with the coating thickness controlled at 0.5-1μm; after coating, it is dried at 80-100°C for 10-15 minutes. Before vulcanization in S3, the temperature is increased to 50-65°C at a rate of 5°C / min, and then increased to 175-180°C at a rate of 2-3°C / min. After vulcanization, the temperature is reduced to below 60°C at a rate of 3-4°C / min.

[0100] Following the above method, unvulcanized samples were prepared according to Sample 2-1, Sample 2-2, and Sample 2-3, and assembled to form a composite sample.

[0101] Composite Sample 1: After assembling the mixture, the surface was polished and then the sealing body was assembled. It was directly molded and vulcanized at 178℃ and 19MPa for 8 minutes. After vulcanization, it was cooled to below 60℃ at a heating rate of 5℃ / minute and then demolded.

[0102] Combination Sample 2: After assembling the mixture, the surface was polished, and then plasma was treated with a power of 400W for 50 seconds at a distance of 6mm. The sealed body was then assembled and molded and vulcanized at 178℃ and 19MPa for 8 minutes. After vulcanization, the mixture was cooled to below 60℃ at a heating rate of 5℃ / minute before demolding.

[0103] Composite Sample 3: After assembling the mixture, the surface was polished and then plasma treated with a power of 400W for 50 seconds at a distance of 6mm. Then, a silane coupling agent was coated on the surface of the mixture with a coating thickness of 0.8μm. After coating, the mixture was dried at 90℃ for 12 minutes, and then the sealing body was assembled. It was then molded and vulcanized at 178℃ and 19MPa for 8 minutes. After vulcanization, the mixture was cooled to below 60℃ at a heating rate of 5℃ / min before demolding.

[0104] Combined sample 4: After assembling the mixture, the surface is polished, and then plasma treatment is performed at a power of 400W for 50 seconds at a distance of 6mm. The sealed body is then assembled, and the temperature is increased to 50-65℃ at a rate of 5℃ / minute, then increased to 175-180℃ at a rate of 2-3℃ / minute, and finally cooled to below 60℃ at a rate of 5℃ / minute for demolding.

[0105] Combined sample 5: After assembling the core and the self-sealing body, the surface was polished and then plasma treated with a power of 400W for 50 seconds at a distance of 6mm. Then the sealing body was assembled and directly molded and vulcanized at 178℃ and 19MPa for 8 minutes. After vulcanization, it was cooled to below 60℃ at a heating rate of 5℃ / minute for demolding.

[0106] Peeling tests were conducted on combined samples 1-5 respectively: the large end diameter of the plug neck of the combined sample was 20 mm, the small end diameter was 16 mm, and the height was 17 mm; the thickness of the sealing body was 2 mm; the large end diameter of the self-sealing body was 15 mm, the small end diameter was 14 mm, and the height was 3.5 mm. The vulcanized complete sealing body was cut in half to form a pair of samples. Then, the initial peeling opening was circumferentially cut at the root of the plug neck, separating only one separation opening between the core and the sealing body without damaging the single-layer body, for clamping by the fixture. One of the samples in each pair was placed in a constant temperature and humidity environment of 23±2℃ and 50±5% relative humidity for ≥24 hours. Peeling was performed using a tensile testing machine at a tensile speed of 50 mm / min, with the tensile force direction parallel to the interface direction. The tensile force-displacement curve was recorded in real time to capture the maximum force value during the peeling process. During the process, the state of the peeling interface was observed to see whether it was interface separation or single-layer body fracture. The interlayer peel strength (σ) is calculated as σ=F / b, where F is the maximum tensile force (N) and b is the effective width of the specimen, i.e. the average half-circumference of the neck. The result is the arithmetic mean of ≥3 effective specimens, accurate to 0.1N / mm, and the test results are shown in Table 7.

[0107]

[0108] Two of each sample were sterilized three times at 121℃, and then placed in a constant temperature and humidity environment of 23±2℃ and 50±5% for ≥24 hours. The above peeling test was repeated to obtain the test results in Table 8.

[0109]

[0110] After three sterilization cycles, the peel strength did not change significantly, indicating high thermal stability.

[0111] In the description of this specification, the references to terms such as "one embodiment," "some embodiments," "example," "specific example," or "some examples," etc., indicate that a specific feature, structure, material, or characteristic described in connection with that embodiment or example is included in at least one embodiment or example of the invention. The illustrative expressions of the above terms in this specification should not be construed as necessarily referring to the same embodiment or example. Furthermore, the specific features, structures, materials, or characteristics described may be combined in any suitable manner in one or more embodiments or examples. In addition, those skilled in the art can combine and integrate the different embodiments or examples described in this specification.

[0112] Although embodiments of the present invention have been shown and described above, it is understood that the above embodiments are exemplary and should not be construed as limiting the present invention. Those skilled in the art can make changes, modifications, substitutions and variations to the above embodiments within the scope of the present invention.

Claims

1. A method for preparing a pharmaceutical sealing plug, characterized in that, Includes the following steps: S1. Preparation of the core, self-sealing body, and sealing body; The lower end of the core forms a cone-shaped neck that is wider at the top and narrower at the bottom, and the center of the neck forms a cone-shaped hole that is wider at the top and narrower at the bottom; the core comprises, by weight, 100 parts of brominated butyl rubber, 30-40 parts of silica, 1.5-2 parts of dicumyl peroxide, 5-6 parts of zinc oxide, 0.9-1.1 parts of stearic acid, and 0.4-0.6 parts of aminosilane coupling agent; The self-sealing body is cone-shaped and comprises, by weight, 100 parts of brominated butyl rubber, 15-18 parts of silica, 8-10 parts of polyisobutylene, 0.6-0.8 parts of sulfur, 0.3-0.5 parts of TBBS, 3-4 parts of zinc oxide, and 0.8-1 parts of stearic acid. The sealing body is in the shape of a conical sleeve, and the sealing body comprises, by weight, 100 parts of fluororubber, 5-8 parts of silica, 25-30 parts of perfluoropolyether plasticizer, 1.5-2 parts of bisphenol AF, 0.5-0.8 parts of BPP, and 0.3-0.5 parts of heat stabilizer. S2. The self-sealing body is embedded in the conical hole to form a hybrid body, and then the surface of the hybrid body is polished to a roughness Ra > 1 μm, and after descaling, the surface of the hybrid body is plasma treated; S3. Place the sealing body onto the plug neck, then place it in the mold, and mold and vulcanize it at 175-180°C and 18-20MPa for 10-11 minutes; after vulcanization, cool it to below 60°C and demold. S4. Place the demolded composite rubber in a vacuum environment at 110-130℃ for 2-3 hours to de-dry, and then allow it to cool naturally to room temperature.

2. The method for preparing a pharmaceutical sealing plug as described in claim 1, characterized in that, S1 includes the following steps: Preparation of core compound: Add brominated butyl rubber to a closed kneader and knead at room temperature for 5 minutes until softened; add silica, zinc oxide and stearic acid and knead at 70-75℃ for 6 minutes; finally add dicumyl peroxide and knead at 70-80℃ for 4 minutes, then discharge the rubber, press it into shape, and let it mature at room temperature for 24 hours. Preparation of self-sealing compound: Add brominated butyl rubber to a closed kneader and knead at room temperature for 5 minutes until softened; add polyisobutylene in two batches, 3 minutes apart, and knead at 60-65℃; add silica, zinc oxide, and stearic acid, and knead at 70-75℃ for 6 minutes; finally add sulfur and TBBS, and knead at below 80℃ for 4 minutes, then discharge the compound, press it into shape, and let it mature at room temperature for 30 hours. Preparation of sealing compound: Add fluororubber to a closed kneader and knead at room temperature for 5 minutes until softened; add perfluoropolyether plasticizer in 2-3 batches, with 3-minute intervals, and knead at 60-65°C; add 5-8 parts of silica and 0.3-0.5 parts of pharmaceutical-grade fluororubber heat stabilizer, and knead at 70-75°C for 6 minutes; finally add 1.5-2 parts of bisphenol AF, 0.5-0.8 parts of BPP, and 1-1.2 parts of aminosilane coupling agent, and knead at below 80°C for 4 minutes, then discharge the compound, press it into shape, and let it mature at room temperature for 24 hours.

3. The method for preparing the pharmaceutical sealing plug as described in claim 1, characterized in that: In S2, the parameters for plasma treatment are controlled as follows: power 300-500W, treatment time 45-60 seconds, and distance 5-8mm.

4. The method for preparing a pharmaceutical sealing plug as described in claim 1, characterized in that: Before the sealing body is fitted onto the neck in step S3, a silane coupling agent is coated on the surface of the mixture, with the coating thickness controlled at 0.5–1 μm; after coating, it is dried at 80–100°C for 10–15 minutes.

5. The method for preparing a pharmaceutical sealing plug as described in claim 1, characterized in that: Before vulcanization in S3, the temperature is increased to 50-65°C at a rate of 5°C / min, and then increased to 175-180°C at a rate of 2-3°C / min.

6. The method for preparing a pharmaceutical sealing plug as described in claim 1, characterized in that: After vulcanization, the temperature is reduced to below 60°C at a rate of 3–4°C / minute.

7. A pharmaceutical sealing plug, characterized in that: Prepared using the preparation method described in any one of claims 1-6.

8. The pharmaceutical sealing plug as described in claim 7, characterized in that: The core comprises, by weight, 100 parts of brominated butyl rubber, 35 parts of silica, 1.8 parts of dicumyl peroxide, 5.5 parts of zinc oxide, 1 part of stearic acid, and 0.5 parts of aminosilane coupling agent; the self-sealing body comprises, by weight, 100 parts of brominated butyl rubber, 16.5 parts of silica, 9 parts of polyisobutylene, 0.7 parts of sulfur, 0.4 parts of TBBS, 3.5 parts of zinc oxide, and 0.9 parts of stearic acid; the sealing body comprises, by weight, 100 parts of fluororubber, 6 parts of silica, 28 parts of perfluoropolyether plasticizer, 1.7 parts of bisphenol A (BFA), 0.6 parts of BPP, and 0.4 parts of heat stabilizer.

9. The pharmaceutical sealing plug as described in claim 7, characterized in that: The Mooney viscosity of the fluororubber is ≤60.

10. The pharmaceutical sealing plug as described in claim 7, characterized in that: The upper end of the core forms a concave recess, and the center of the recess forms a puncture platform. The puncture platform is provided with a guide needle hole, which penetrates the core.

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