Oral liquid coated rubber plug and preparation method thereof

Abstract

The invention belongs to the technical field of medical materials, and particularly relates to an oral liquid film-covered rubber plug and a preparation method thereof.The oral liquid film-covered rubber plug is characterized in that vulcanized halogenated butyl rubber serves as a base material piece, a functional film is bonded to the surface of the base material piece through a hot-pressing composite technology, and the functional film is prepared by taking ethylene-vinyl acetate copolymer with the VA mass ratio being 28-33% as a base material layer; an ethylene-vinyl acetate copolymer with the mass ratio of VA being 18-22% is used as a transition layer, and polytetrafluoroethylene or high-density polyethylene is used as a functional layer. The novel laminated rubber plug with excellent sealing performance, chemical stability and sterilization compatibility is prepared by utilizing a gradient composite structure and a multi-step process optimization technology, and the laminated rubber plug is simple in preparation method, easy to process and form and wide in application prospect.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical materials technology, specifically a film-coated rubber stopper for oral liquids and its preparation method. Background Technology

[0002] Due to their excellent sealing performance, chemical stability, and hygienic safety, coated rubber stoppers have gradually become a key component in the oral liquid packaging field. However, existing coated rubber stoppers still have certain limitations in terms of manufacturing processes and performance optimization, especially in terms of compatibility during sterilization and long-term performance, which restricts their widespread application.

[0003] CN103269955B discloses a small bottle rubber stopper that solves the problem of rubber stoppers being scraped off and adhering to the pressure plate during use by using rubber materials of different hardness, thereby improving its durability and sealing performance. However, this solution does not fully consider the compatibility issues of the coated rubber stopper during high-temperature sterilization (such as 121℃ moist heat sterilization) or irradiation sterilization. Due to the large difference in the coefficients of thermal expansion between the film and the substrate (e.g., the difference in thermal expansion rates between PTFE and butyl rubber is about 3 times), it may lead to interface delamination after sterilization, affecting the sealing performance. In addition, high temperature and high humidity environments may accelerate film aging (e.g., PE oxidation embrittlement), adversely affecting the long-term performance of the coated rubber stopper. CN109330389B relates to a universal rubber stopper for 4.5-5 liter water bottles in vehicle-mounted water dispensers. This rubber stopper has a vent valve, a water inlet connector, and a vent connector, which can maintain the pressure balance inside the bottle during water dispensing and returning and ensure no leakage when placed in any orientation. However, this technology is primarily designed for large-capacity water tank applications, and its structural design and material selection fail to fully meet the stringent hygiene and sterilization requirements of oral liquid coated stoppers. For example, the coating material may experience thermal stress and chemical corrosion under high-temperature sterilization conditions, leading to film cracking or detachment, which in turn affects sealing performance and drug safety.

[0004] The above issues indicate that there is still room for improvement in the compatibility of existing coated rubber stoppers during sterilization, the bonding stability between the film and the substrate, and their long-term performance. Summary of the Invention

[0005] To overcome the above problems, this invention provides an oral liquid coated rubber stopper and its preparation method. By utilizing a gradient composite structure and multi-step process optimization technology, a novel coated rubber stopper with excellent sealing performance, chemical stability and sterilization compatibility is prepared. The preparation method is simple and easy to process and mold, and has broad application prospects.

[0006] To achieve the above-mentioned technical objectives, the technical solution adopted by the present invention is as follows: An oral liquid coated rubber stopper, comprising: A functional film is bonded to the surface of a vulcanized and halogenated butyl rubber substrate through a hot-pressing composite process. The functional film consists of an ethylene-vinyl acetate copolymer with VA content of 28-33% by mass as a substrate layer, an ethylene-vinyl acetate copolymer with VA content of 18-22% by mass as a transition layer, and polytetrafluoroethylene or high-density polyethylene as a functional layer. The thickness of the halogenated butyl rubber is 0.5-2 mm; the total thickness of the functional film is 50-200 μm, wherein the thickness ratio of the substrate layer, transition layer, and functional layer is (0.3-0.4):(0.4-0.5):(0.3-0.35); when polytetrafluoroethylene is used as the functional layer, its thickness is 30-50 μm; when high-density polyethylene is used as the functional layer, its thickness is 40-60 μm, and the density of the high-density polyethylene is not less than 0.95 g / cm³. 3 The melt flow index is 1-5 g / 10 min (190℃ / 2.16 kg). The selection and proportion of the above materials have been precisely controlled to meet the stringent requirements for sealing and stability in the pharmaceutical packaging industry.

[0007] Preferably, the halogenated butyl rubber is subjected to a mixing process before use, during which sulfur is added as a vulcanizing agent, zinc oxide and stearic acid as activators, carbon black or silica as fillers, and liquid paraffin as a plasticizer.

[0008] Halogenated butyl rubber requires compounding before use. During compounding, sulfur is added as a vulcanizing agent, zinc oxide and stearic acid as activators, carbon black or silica as fillers, and liquid paraffin as a plasticizer. The compounded material is uniformly dispersed and has good processing properties. The thickness of the halogenated butyl rubber is controlled within the range of 0.5-2 mm. A thickness less than 0.5 mm results in insufficient substrate strength, potentially leading to breakage during subsequent processing; a thickness greater than 2 mm results in an excessively thick substrate, affecting the flexibility and sealing performance of the final product. The total thickness of the functional film is 50-200 μm, with the thickness ratio of the substrate layer, transition layer, and functional layer being (0.3-0.4):(0.4-0.5):(0.3-0.35). This thickness ratio design gives the film a gradient structure, effectively mitigating differences in thermal expansion coefficients and reducing interfacial stress concentration. When polytetrafluoroethylene (PTFE) is used for the functional layer, its thickness is 30-50 μm; when high-density polyethylene (HDPE) is used for the functional layer, its thickness is 40-60 μm, and the density of HDPE is not less than 0.95 g / cm³. 3 With a melt flow index of 1-5 g / 10 min (190℃ / 2.16 kg), the functional layer is ensured to maintain dimensional stability under high-temperature sterilization conditions, while avoiding delamination caused by excessive thickness.

[0009] Preferably, the interface treatment between the substrate sheet and the functional film is characterized by plasma pretreatment or silane coupling agent coating; the plasma pretreatment uses a mixed gas of argon and oxygen with a volume ratio of 1-3:1, a power of 50-200W, and a treatment time of 30-120 seconds; the silane coupling agent coating uses γ-glycidyl etheroxypropyltrimethoxysilane, with a coating amount of 0.1-0.5 g / m³. 2 The drying temperature is 80-120℃, and the drying time is 5-15 minutes. This interface treatment method significantly improves the adhesion between the substrate and the functional film and reduces the risk of interface delamination.

[0010] This solution also discloses a method for preparing the aforementioned oral liquid coated rubber stopper, including the following steps: S1: Substrate preparation: After mixing halogenated butyl rubber with vulcanizing agent, filler and plasticizer, it is molded into a substrate sheet with a thickness of 0.5-2mm by compression vulcanization. The vulcanization temperature is 150-180℃, the vulcanization pressure is 10-20MPa and the vulcanization time is 5-15min. S2: Interface treatment: Perform interface treatment on the surface of the substrate sheet obtained in S1. The interface treatment method includes any one or a combination of the following: (a) Plasma pretreatment: A mixed gas with an argon-oxygen volume ratio of 1-3:1 is used, with a power of 50-200W and a treatment time of 30-120 seconds; (b) Silane coupling agent coating: Coated with γ-glycidyl etheroxypropyltrimethoxysilane, with a coating amount of 0.1-0.5 g / m². 2 The drying temperature is 80-120℃, and the drying time is 5-15 minutes. When using plasma pretreatment, substrate sheets should be treated first; silane coupling agent coatings should be treated first for functional films. S3: Functional film preparation: Prepare a functional film comprising a substrate layer, a transition layer and a functional layer, wherein the substrate layer is an ethylene-vinyl acetate copolymer with a VA mass percentage of 28-33%, the transition layer is an ethylene-vinyl acetate copolymer with a VA mass percentage of 18-22%, and polytetrafluoroethylene or high-density polyethylene is used as the functional layer. The three layers are formed into a gradient structure through co-extrusion or lamination composite process, with a total thickness of 50-200μm. After crosslinking modification, the functional film is obtained. Co-extrusion process parameters: substrate layer 150-160℃, transition layer 155-165℃, functional layer (PTFE) 330-350℃ or (HDPE) 190-210℃, die pressure 15-25MPa; S4: Hot-press lamination: The substrate sheet treated in S2 and the functional film obtained in S3 are hot-pressed together at a temperature of 150-180℃ and a pressure of 5-10MPa for 5-10 minutes to form a prototype of the coated rubber stopper.

[0011] Before hot-press lamination, the functional film needs to be preheated to 120-140℃, and the substrate sheet needs to be preheated to 80-100℃. This preheating step reduces the adhesion resistance between materials, ensuring a tight interfacial bond during hot-press lamination. Crosslinking modification is performed using electron beam radiation crosslinking with a radiation dose of 60-80 kGy and a beam energy of 1.5-2.5 MeV under nitrogen protection. These process conditions enable the functional film to form a three-dimensional network structure, further improving its heat resistance and mechanical strength. These performance indicators show that the coated rubber stopper maintains excellent physical and chemical properties even under sterilization conditions. This invention significantly improves the overall performance of the coated rubber stopper by optimizing the interface treatment process between the substrate and the functional film, combined with gradient structure design and material modification technology. The bonding force between the substrate and the functional film is enhanced, reducing the risk of interfacial delamination; the heat resistance and chemical stability of the functional film are improved, enabling it to meet the requirements of high-temperature sterilization and irradiation sterilization; the long-term performance of the coated rubber stopper is improved, meeting the high standards required in the pharmaceutical packaging field. Appropriate process parameters and material selection further improve the sealing performance and service life of the coated rubber stopper.

[0012] Preferably, in S4, before hot pressing and laminating, the functional film needs to be preheated to 120-140°C and the substrate sheet needs to be preheated to 80-100°C.

[0013] As a preferred option, the following steps are also included: S5: Terminal sterilization: Moist heat sterilization is adopted, with a temperature of 115±2℃ and a time of 30±2min.

[0014] As a preferred method, crosslinking modification is performed using electron beam radiation crosslinking with a radiation dose of 60-80 kGy and a beam energy of 1.5-2.5 MeV, under a nitrogen-protected environment.

[0015] Preferably, after terminal sterilization, the tensile strength retention rate of the coated area is not less than 85%.

[0016] Preferably, the total thickness of the functional film is 50-200 μm, wherein the thickness ratio of the substrate layer, the transition layer and the functional layer is (0.3-0.4):(0.4-0.5):(0.3-0.35).

[0017] Compared to existing technologies, this solution has the following advantages: 1. This invention uses halogenated butyl rubber as the main substrate and ensures that the substrate has excellent flexibility and sealing performance by precisely controlling the mixing formula and vulcanization process; the functional film adopts a gradient structure design, which effectively alleviates the stress concentration problem caused by the difference in thermal expansion coefficient; the interface treatment process significantly improves the bonding force between the substrate and the functional film and reduces the risk of interface delamination. 2. Crosslinking modification further enhances the heat resistance and anti-aging properties of the functional film; terminal sterilization process verifies the reliability of the coated rubber stopper under extreme conditions.

[0018] 3. This solution significantly improves the sterilization compatibility, long-term performance, and sealing performance of coated rubber stoppers, meeting the pharmaceutical packaging industry's demand for efficient and safe coated rubber stoppers. Detailed Implementation

[0019] 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.

[0020] In the examples and comparative examples, the halogenated butyl rubber is brominated butyl rubber with a bromination degree of 1.5%.

[0021] Example 1 A method for preparing an oral liquid coated rubber stopper includes the following steps: S1: Substrate preparation: After mixing halogenated butyl rubber with vulcanizing agent, filler and plasticizer, it is molded into a substrate sheet with a thickness of 1.2 mm by compression vulcanization. The vulcanization temperature is 165℃, the vulcanization pressure is 15MPa and the vulcanization time is 10min. Add the following per 100 parts by weight of halogenated butyl rubber: 1.8 parts sulfur, 3 parts zinc oxide, 1.3 parts stearic acid, 25 parts silica and 10 parts liquid paraffin. S2: Interface treatment: The surface of the substrate sheet obtained in S1 is subjected to interface treatment. The interface treatment method is as follows: (a) Plasma pretreatment: A mixed gas of argon and oxygen in a volume ratio of 2:1 was used, with a power of 120W and a treatment time of 80 seconds; S3: Functional Thin Film Preparation: A functional thin film comprising a substrate layer, a transition layer, and a functional layer was prepared. The substrate layer was an ethylene-vinyl acetate copolymer with 30% VA by mass, the transition layer was an ethylene-vinyl acetate copolymer with 20% VA by mass, and the functional layer was polytetrafluoroethylene. The three layers were co-extruded to form a gradient structure with a total thickness of 120 μm. The thickness ratio of the substrate layer, transition layer, and functional layer was 0.35:0.45:0.32. After crosslinking modification, the functional thin film was obtained. The crosslinking modification was performed by electron beam radiation crosslinking with a radiation dose of 70 kGy and a beam energy of 2.0 MeV under nitrogen protection. S4: Hot-press lamination: The substrate sheet treated in S2 and the functional film obtained in S3 are hot-pressed together at a temperature of 165℃ and a pressure of 7MPa for 8 minutes to form a preliminary coated plug; the functional film is preheated to 130℃ and the substrate sheet is preheated to 90℃. S5: Terminal sterilization: The temperature of moist heat sterilization is 115℃ and the time is 30min; after terminal sterilization, the tensile strength retention rate of the film-coated area is 87%, and the oral liquid film-coated rubber stopper is obtained.

[0022] Example 2 A method for preparing an oral liquid coated rubber stopper includes the following steps: S1: Substrate preparation: After mixing halogenated butyl rubber with vulcanizing agent, filler and plasticizer, it is molded into a substrate sheet with a thickness of 0.8 mm by compression vulcanization. The vulcanization temperature is 155℃, the vulcanization pressure is 12MPa and the vulcanization time is 12min. Add the following per 100 parts by weight of halogenated butyl rubber: 0.5 parts sulfur, 1 part zinc oxide, 0.5 parts stearic acid, 20 parts carbon black and 5 parts liquid paraffin. S2: Interface treatment: The surface of the substrate sheet obtained in S1 is subjected to interface treatment. The interface treatment method is as follows: (b) Silane coupling agent coating: coated with γ-glycidyl etheroxypropyltrimethoxysilane at a coating amount of 0.3 g / m 2 The drying temperature is 100℃ and the drying time is 10min; S3: Functional Thin Film Preparation: A functional thin film comprising a substrate layer, a transition layer, and a functional layer was prepared. The substrate layer was an ethylene-vinyl acetate copolymer with VA accounting for 28% by mass, the transition layer was an ethylene-vinyl acetate copolymer with VA accounting for 22% by mass, and the functional layer was high-density polyethylene. The three layers were laminated to form a gradient structure with a total thickness of 80 μm. The thickness ratio of the substrate layer, transition layer, and functional layer was 0.32:0.42:0.30. After crosslinking modification, the functional thin film was obtained. The crosslinking modification was carried out by electron beam radiation crosslinking with a radiation dose of 70 kGy and a beam energy of 2.0 MeV under nitrogen protection. S4: Hot-press lamination: The substrate sheet treated in S2 and the functional film prepared in S3 are hot-pressed together at a temperature of 160℃ and a pressure of 6MPa for 6 minutes to form a prototype of the coated plug; the functional film is preheated to 125℃ and the substrate sheet is preheated to 85℃. S5: Terminal sterilization: Moist heat sterilization is adopted; the temperature of moist heat sterilization is 115℃ and the time is 30min; after terminal sterilization, the tensile strength retention rate of the film-coated area is 90%, and the oral liquid film-coated rubber stopper is obtained.

[0023] Example 3 A method for preparing an oral liquid coated rubber stopper includes the following steps: S1: Substrate preparation: After mixing halogenated butyl rubber with vulcanizing agent, filler and plasticizer, it is molded into a substrate sheet with a thickness of 1.5 mm by compression vulcanization. The vulcanization temperature is 170℃, the vulcanization pressure is 18MPa and the vulcanization time is 8min. Add the following per 100 parts by weight of halogenated butyl rubber: 3 parts sulfur, 5 parts zinc oxide, 2 parts stearic acid, 30 parts silica and 15 parts liquid paraffin. S2: Interface treatment: The surface of the substrate sheet obtained in S1 is subjected to interface treatment. The interface treatment methods include: (a) Plasma pretreatment: A mixed gas of argon and oxygen in a volume ratio of 1:1 was used, with a power of 150W and a treatment time of 50 seconds; (b) Silane coupling agent coating: coated with γ-glycidyl etheroxypropyltrimethoxysilane at a coating amount of 0.2 g / m 2 The drying temperature is 90℃ and the drying time is 12min; S3: Functional Thin Film Preparation: A functional thin film comprising a substrate layer, a transition layer, and a functional layer was prepared. The substrate layer was an ethylene-vinyl acetate copolymer with VA accounting for 33% by mass, the transition layer was an ethylene-vinyl acetate copolymer with VA accounting for 18% by mass, and the functional layer was polytetrafluoroethylene. The three layers were co-extruded to form a gradient structure with a total thickness of 150 μm. The thickness ratio of the substrate layer, transition layer, and functional layer was 0.38:0.48:0.34. After crosslinking modification, the functional thin film was obtained. The crosslinking modification was carried out by electron beam radiation crosslinking with a radiation dose of 65 kGy and a beam energy of 1.8 MeV under nitrogen protection. S4: Hot-press lamination: The substrate sheet treated in S2 and the functional film obtained in S3 are hot-pressed together at a temperature of 175℃ and a pressure of 9MPa for 9 minutes to form a preliminary coated plug; the functional film is preheated to 135℃ and the substrate sheet is preheated to 95℃. S5: Terminal sterilization: The temperature of moist heat sterilization is 115℃ and the time is 30min; after terminal sterilization, the tensile strength retention rate of the film-coated area is 89%, and the oral liquid film-coated rubber stopper is obtained.

[0024] Example 4 A method for preparing an oral liquid coated rubber stopper includes the following steps: S1: Substrate preparation: After mixing halogenated butyl rubber with vulcanizing agent, filler, and plasticizer, it is molded into a substrate sheet with a thickness of 1.0 mm by compression vulcanization. The vulcanization temperature is 160℃, the vulcanization pressure is 14MPa, and the vulcanization time is 7min. The following are added per 100 parts by weight of halogenated butyl rubber: 1.8 parts of sulfur, 3 parts of zinc oxide, 1.3 parts of stearic acid, 25 parts of silica, and 10 parts of liquid paraffin. S2: Interface treatment: The surface of the substrate sheet obtained in S1 is subjected to interface treatment. The interface treatment method is as follows: (a) Plasma pretreatment: A mixed gas of argon and oxygen in a volume ratio of 3:1 was used, with a power of 180W and a treatment time of 100 seconds. S3: Functional Thin Film Preparation: A functional thin film comprising a substrate layer, a transition layer, and a functional layer was prepared. The substrate layer was an ethylene-vinyl acetate copolymer with 30% VA by mass, the transition layer was an ethylene-vinyl acetate copolymer with 20% VA by mass, and the functional layer was high-density polyethylene. The three layers were laminated to form a gradient structure with a total thickness of 60 μm. The thickness ratio of the substrate layer, transition layer, and functional layer was 0.31:0.41:0.31. After crosslinking modification, the functional thin film was obtained. The crosslinking modification was carried out by electron beam radiation crosslinking with a radiation dose of 60 kGy and a beam energy of 2.0 MeV under nitrogen protection. S4: Hot-press lamination: The substrate sheet treated in S2 and the functional film prepared in S3 are hot-pressed together at a temperature of 155℃ and a pressure of 5.5MPa for 5.5min to form a prototype of the coated plug; the functional film is preheated to 122℃ and the substrate sheet is preheated to 82℃. S5: Terminal sterilization: Moist heat sterilization is adopted; the temperature of moist heat sterilization is 116℃ and the time is 31min; after terminal sterilization, the tensile strength retention rate of the film-coated area is 92%, and the oral liquid film-coated rubber stopper is obtained.

[0025] Example 5 A method for preparing an oral liquid coated rubber stopper includes the following steps: S1: Substrate preparation: After mixing halogenated butyl rubber with vulcanizing agent, filler and plasticizer, it is molded into a substrate sheet with a thickness of 1.8 mm by compression vulcanization. The vulcanization temperature is 175℃, the vulcanization pressure is 19MPa and the vulcanization time is 14min. Add the following per 100 parts by weight of halogenated butyl rubber: 1.8 parts of sulfur, 3 parts of zinc oxide, 1.3 parts of stearic acid, 25 parts of silica and 10 parts of liquid paraffin. S2: Interface treatment: The surface of the substrate sheet obtained in S1 is subjected to interface treatment. The interface treatment method is as follows: (b) Silane coupling agent coating: coated with γ-glycidyl etheroxypropyltrimethoxysilane at a coating amount of 0.4 g / m 2 The drying temperature is 110℃ and the drying time is 8 minutes. S3: Functional Thin Film Preparation: A functional thin film comprising a substrate layer, a transition layer, and a functional layer was prepared. The substrate layer and the transition layer were both ethylene-vinyl acetate copolymers, and the functional layer was polytetrafluoroethylene. The three layers were co-extruded to form a gradient structure with a total thickness of 180 μm. The thickness ratio of the substrate layer, the transition layer, and the functional layer was 0.39:0.49:0.33. After crosslinking modification, the functional thin film was obtained. The crosslinking modification was performed using electron beam radiation crosslinking with a radiation dose of 75 kGy and a beam energy of 2.2 MeV under nitrogen protection. S4: Hot-press lamination: The substrate sheet treated in S2 and the functional film obtained in S3 are hot-pressed together at a temperature of 178℃ and a pressure of 8.5MPa for 7 minutes to form a prototype of the coated plug; the functional film is preheated to 138℃ and the substrate sheet is preheated to 98℃. S5: Terminal sterilization: Moist heat sterilization is adopted; the temperature of moist heat sterilization is 114℃ and the time is 29min; after terminal sterilization, the tensile strength retention rate of the film-coated area is 88%, and the oral liquid film-coated rubber stopper is obtained.

[0026] Comparative Example 1 A method for preparing an oral liquid coated rubber stopper includes the following steps: S1: Substrate preparation: After mixing halogenated butyl rubber with vulcanizing agent, filler and plasticizer, it is molded into a substrate sheet with a thickness of 1.2 mm by compression vulcanization. The vulcanization temperature is 165℃, the vulcanization pressure is 15MPa and the vulcanization time is 10min. Add the following per 100 parts by weight of halogenated butyl rubber: 1.8 parts sulfur, 3 parts zinc oxide, 1.3 parts stearic acid, 25 parts silica and 10 parts liquid paraffin. S2: Interface treatment: The surface of the substrate sheet obtained in S1 is subjected to interface treatment. The interface treatment method is as follows: (a) Plasma pretreatment: A mixed gas with an argon-oxygen volume ratio of 1:4 (exceeding the limit) was used, with a power of 120W and a treatment time of 80 seconds; S3: Functional Thin Film Preparation: A functional thin film comprising a substrate layer, a transition layer, and a functional layer was prepared. The substrate layer was an ethylene-vinyl acetate copolymer with 30% VA by mass, the transition layer was an ethylene-vinyl acetate copolymer with 20% VA by mass, and the functional layer was polytetrafluoroethylene. The three layers were co-extruded to form a gradient structure with a total thickness of 120 μm. The thickness ratio of the substrate layer, transition layer, and functional layer was 0.35:0.45:0.32. After crosslinking modification, the functional thin film was obtained. The crosslinking modification was performed by electron beam radiation crosslinking with a radiation dose of 70 kGy and a beam energy of 2.0 MeV under nitrogen protection. S4: Hot-press lamination: The substrate sheet treated in S2 and the functional film obtained in S3 are hot-pressed together at a temperature of 165℃ and a pressure of 7MPa for 8 minutes to form a preliminary coated plug; the functional film is preheated to 130℃ and the substrate sheet is preheated to 90℃. S5: Terminal sterilization: The temperature of moist heat sterilization is 115℃ and the time is 30min; after terminal sterilization, the tensile strength retention rate of the film-coated area is 75%, and the oral liquid film-coated rubber stopper is obtained.

[0027] Comparative Example 2 A method for preparing an oral liquid coated rubber stopper includes the following steps: S1: Substrate preparation: After mixing halogenated butyl rubber with vulcanizing agent, filler and plasticizer, it is molded into a substrate sheet with a thickness of 1.2 mm by compression vulcanization. The vulcanization temperature is 165℃, the vulcanization pressure is 15MPa and the vulcanization time is 10min. Add the following per 100 parts by weight of halogenated butyl rubber: 1.8 parts sulfur, 3 parts zinc oxide, 1.3 parts stearic acid, 25 parts silica and 10 parts liquid paraffin. S2: Interface treatment: The surface of the substrate sheet obtained in S1 is subjected to interface treatment. The interface treatment method is as follows: (b) Silane coupling agent coating: coated with γ-glycidyl etheroxypropyltrimethoxysilane at a coating amount of 0.05 g / m 2 (Exceeding limits), the drying temperature is 100℃ and the drying time is 10min; S3: Functional Thin Film Preparation: A functional thin film comprising a substrate layer, a transition layer, and a functional layer was prepared. The substrate layer was an ethylene-vinyl acetate copolymer with 30% VA by mass, the transition layer was an ethylene-vinyl acetate copolymer with 20% VA by mass, and the functional layer was polytetrafluoroethylene. The three layers were co-extruded to form a gradient structure with a total thickness of 120 μm. The thickness ratio of the substrate layer, transition layer, and functional layer was 0.35:0.45:0.32. After crosslinking modification, the functional thin film was obtained. The crosslinking modification was performed by electron beam radiation crosslinking with a radiation dose of 70 kGy and a beam energy of 2.0 MeV under nitrogen protection. S4: Hot-press lamination: The substrate sheet treated in S2 and the functional film obtained in S3 are hot-pressed together at a temperature of 165℃ and a pressure of 7MPa for 8 minutes to form a preliminary coated plug; the functional film is preheated to 130℃ and the substrate sheet is preheated to 90℃. S5: Terminal sterilization: The temperature of moist heat sterilization is 115℃ and the time is 30min; after terminal sterilization, the tensile strength retention rate of the film-coated area is 68%, and the oral liquid film-coated rubber stopper is obtained.

[0028] Comparative Example 3 A method for preparing an oral liquid coated rubber stopper includes the following steps: S1: Substrate preparation: After mixing halogenated butyl rubber with vulcanizing agent, filler and plasticizer, it is molded into a substrate sheet with a thickness of 1.2 mm by compression vulcanization. The vulcanization temperature is 165℃, the vulcanization pressure is 15MPa and the vulcanization time is 10min. Add the following per 100 parts by weight of halogenated butyl rubber: 1.8 parts sulfur, 3 parts zinc oxide, 1.3 parts stearic acid, 25 parts silica and 10 parts liquid paraffin. S2: Interface treatment not performed (process missing); S3: Functional Thin Film Preparation: A functional thin film comprising a substrate layer, a transition layer, and a functional layer was prepared. The substrate layer was an ethylene-vinyl acetate copolymer with 30% VA by mass, the transition layer was an ethylene-vinyl acetate copolymer with 20% VA by mass, and the functional layer was polytetrafluoroethylene. The three layers were co-extruded to form a gradient structure with a total thickness of 120 μm. The thickness ratio of the substrate layer, transition layer, and functional layer was 0.35:0.45:0.32. After crosslinking modification, the functional thin film was obtained. The crosslinking modification was performed by electron beam radiation crosslinking with a radiation dose of 70 kGy and a beam energy of 2.0 MeV under nitrogen protection. S4: Hot-press lamination: The substrate sheet obtained in S1 and the functional film obtained in S3 are hot-pressed together at a temperature of 165℃ and a pressure of 7MPa for 8 minutes to form a pre-formed film-coated plug; the functional film is preheated to 130℃ and the substrate sheet is preheated to 90℃. S5: Material modification: The functional film in the pre-formed coated rubber stopper obtained in S4 is cross-linked modified; the cross-linking modification is carried out by electron beam radiation cross-linking, with a radiation dose of 70 kGy and a beam energy of 2.0 MeV, under nitrogen protection. S6: Terminal sterilization: The temperature of moist heat sterilization is 115℃ and the time is 30min; after terminal sterilization, the tensile strength retention rate of the film-coated area is 52%, and the oral liquid film-coated rubber stopper is obtained.

[0029] Comparative Example 4 A method for preparing an oral liquid coated rubber stopper includes the following steps: S1: Substrate preparation: After mixing halogenated butyl rubber with vulcanizing agent, filler and plasticizer, it is molded into a substrate sheet with a thickness of 1.2 mm by compression vulcanization. The vulcanization temperature is 165℃, the vulcanization pressure is 15MPa and the vulcanization time is 10min. Add the following per 100 parts by weight of halogenated butyl rubber: 1.8 parts sulfur, 3 parts zinc oxide, 1.3 parts stearic acid, 25 parts silica and 10 parts liquid paraffin. S2: Interface treatment: The surface of the substrate sheet obtained in S1 is subjected to interface treatment. The interface treatment method is as follows: (a) Plasma pretreatment: A mixed gas of argon and oxygen in a volume ratio of 2:1 was used, with a power of 120W and a treatment time of 80 seconds; S3: Functional Thin Film Preparation: A functional thin film comprising a substrate layer, a transition layer, and a functional layer was prepared. The substrate layer was an ethylene-vinyl acetate copolymer with 30% VA by mass, the transition layer was an ethylene-vinyl acetate copolymer with 20% VA by mass, and the functional layer was polytetrafluoroethylene (PTFE). The three layers were co-extruded to form a gradient structure with a total thickness of 120 μm. The thickness ratio of the substrate layer, transition layer, and functional layer was 0.35:0.45:0.32. After crosslinking modification, the functional thin film was obtained. The crosslinking modification was performed using electron beam radiation with a radiation dose of 70 kGy and a beam energy of 2.0 MeV under nitrogen protection. S4: Hot-press lamination: The substrate sheet treated in S2 and the functional film obtained in S3 are hot-pressed together at a temperature of 165℃ and a pressure of 7MPa for 8 minutes to form a preliminary coated plug; the functional film is preheated to 130℃ and the substrate sheet is preheated to 60℃ (exceeding the limit). S5: Terminal sterilization: The temperature of moist heat sterilization is 115℃ and the time is 30min; after terminal sterilization, the tensile strength retention rate of the film-coated area is 70%, and the oral liquid film-coated rubber stopper is obtained.

[0030] Comparative Example 5 A method for preparing an oral liquid coated rubber stopper includes the following steps: S1: Substrate preparation: After mixing halogenated butyl rubber with vulcanizing agent, filler and plasticizer, it is molded into a substrate sheet with a thickness of 1.2 mm by compression vulcanization. The vulcanization temperature is 165℃, the vulcanization pressure is 15MPa and the vulcanization time is 10min. Add the following per 100 parts by weight of halogenated butyl rubber: 1.8 parts sulfur, 3 parts zinc oxide, 1.3 parts stearic acid, 25 parts silica and 10 parts liquid paraffin. S2: Interface treatment: The surface of the substrate sheet obtained in S1 is subjected to interface treatment. The interface treatment method is as follows: (a) Plasma pretreatment: A mixed gas of argon and oxygen in a volume ratio of 2:1 was used, with a power of 120W and a treatment time of 80 seconds; S3: Functional Thin Film Preparation: A functional thin film comprising a substrate layer, a transition layer, and a functional layer was prepared. The substrate layer was an ethylene-vinyl acetate copolymer with 30% VA by mass, the transition layer was an ethylene-vinyl acetate copolymer with 20% VA by mass, and the functional layer was polytetrafluoroethylene. The three layers were co-extruded to form a gradient structure with a total thickness of 120 μm. The thickness ratio of the substrate layer, transition layer, and functional layer was 0.35:0.45:0.32. After crosslinking modification, the functional thin film was obtained. The crosslinking modification was performed by electron beam radiation crosslinking with a radiation dose of 85 kGy (exceeding the limit) and a beam energy of 2.0 MeV under nitrogen protection. S4: Hot-press lamination: The substrate sheet treated in S2 and the functional film obtained in S3 are hot-pressed together at a temperature of 165℃ and a pressure of 7MPa for 8 minutes to form a preliminary coated plug; the functional film is preheated to 130℃ and the substrate sheet is preheated to 90℃. S5: Terminal sterilization: The temperature of moist heat sterilization is 115℃ and the time is 30min; after terminal sterilization, the tensile strength retention rate of the film-coated area is 48%, and the oral liquid film-coated rubber stopper is obtained.

[0031] Comparative Example 6 A method for preparing an oral liquid coated rubber stopper includes the following steps: S1: Substrate preparation: After mixing halogenated butyl rubber with vulcanizing agent, filler and plasticizer, it is molded into a substrate sheet with a thickness of 1.2 mm by compression vulcanization. The vulcanization temperature is 165℃, the vulcanization pressure is 15MPa and the vulcanization time is 10min. Add the following per 100 parts by weight of halogenated butyl rubber: 1.8 parts sulfur, 3 parts zinc oxide, 1.3 parts stearic acid, 25 parts silica and 10 parts liquid paraffin. S2: Interface treatment: The surface of the substrate sheet obtained in S1 is subjected to interface treatment. The interface treatment method is as follows: (a) Plasma pretreatment: A mixed gas of argon and oxygen in a volume ratio of 2:1 was used, with a power of 120W and a treatment time of 80 seconds; S3: Functional Thin Film Preparation: A functional thin film comprising a substrate layer, a transition layer, and a functional layer was prepared. The substrate layer was an ethylene-vinyl acetate copolymer with 30% VA by mass, the transition layer was an ethylene-vinyl acetate copolymer with 20% VA by mass, and the functional layer was polytetrafluoroethylene. The three layers were co-extruded to form a gradient structure with a total thickness of 120 μm. The thickness ratio of the substrate layer, transition layer, and functional layer was 0.35:0.45:0.32. After crosslinking modification, the functional thin film was obtained. The crosslinking modification was performed by electron beam radiation crosslinking with a radiation dose of 70 kGy and a beam energy of 2.0 MeV under nitrogen protection. S4: Hot-press lamination: The substrate sheet treated in S2 and the functional film obtained in S3 are hot-pressed together at a temperature of 165℃ and a pressure of 7MPa for 8 minutes to form a preliminary coated plug; the functional film is preheated to 130℃ and the substrate sheet is preheated to 90℃. S5: Terminal sterilization: Moist heat sterilization was used; the temperature for moist heat sterilization was 125℃ (exceeding the limit), and the time was 30 min; after terminal sterilization, the tensile strength retention rate of the coated area was 41%. Oral liquid coated rubber stoppers were obtained.

[0032] Comparative Example 7 A method for preparing an oral liquid coated rubber stopper includes the following steps: S1: Substrate preparation: After mixing halogenated butyl rubber with vulcanizing agent, filler and plasticizer, it is molded into a substrate sheet with a thickness of 1.2 mm by compression vulcanization. The vulcanization temperature is 165℃, the vulcanization pressure is 15MPa and the vulcanization time is 10min. Add the following per 100 parts by weight of halogenated butyl rubber: 1.8 parts sulfur, 3 parts zinc oxide, 1.3 parts stearic acid, 25 parts silica and 10 parts liquid paraffin. S2: Interface treatment: The surface of the substrate sheet obtained in S1 is subjected to interface treatment. The interface treatment method is as follows: (a) Plasma pretreatment: A mixed gas of argon and oxygen in a volume ratio of 2:1 was used, with a power of 120W and a treatment time of 80 seconds; S3: Functional Thin Film Preparation: A functional thin film comprising a substrate layer, a transition layer, and a functional layer was prepared. The substrate layer was an ethylene-vinyl acetate copolymer with VA accounting for 30% by mass, the transition layer was an ethylene-vinyl acetate copolymer with VA accounting for 20% by mass, and the functional layer was polytetrafluoroethylene. The three layers were co-extruded to form a gradient structure with a total thickness of 30 μm (exceeding the limit). The thickness ratio of the substrate layer, transition layer, and functional layer was 0.35:0.45:0.32. After crosslinking modification, the functional thin film was obtained. The crosslinking modification was carried out by electron beam radiation crosslinking with a radiation dose of 70 kGy and a beam energy of 2.0 MeV under nitrogen protection. S4: Hot-press lamination: The substrate sheet treated in S2 and the functional film obtained in S3 are hot-pressed together at a temperature of 165℃ and a pressure of 7MPa for 8 minutes to form a preliminary coated plug; the functional film is preheated to 130℃ and the substrate sheet is preheated to 90℃. S5: Terminal sterilization: The temperature of moist heat sterilization is 115℃ and the time is 30min; after terminal sterilization, the tensile strength retention rate of the film-coated area is 65%, and the oral liquid film-coated rubber stopper is obtained.

[0033] Comparative Example 8 A method for preparing an oral liquid coated rubber stopper includes the following steps: S1: Substrate preparation: After mixing halogenated butyl rubber with vulcanizing agent, filler and plasticizer, it is molded into a substrate sheet with a thickness of 1.2 mm by compression vulcanization. The vulcanization temperature is 165℃, the vulcanization pressure is 15MPa and the vulcanization time is 10min. Add the following per 100 parts by weight of halogenated butyl rubber: 1.8 parts sulfur, 3 parts zinc oxide, 1.3 parts stearic acid, 25 parts silica and 10 parts liquid paraffin. S2: Interface treatment: The surface of the substrate sheet obtained in S1 is subjected to interface treatment. The interface treatment method is as follows: (a) Plasma pretreatment: A mixed gas of argon and oxygen in a volume ratio of 2:1 was used, with a power of 120W and a treatment time of 80 seconds; S3: Functional Thin Film Preparation: A functional thin film comprising a substrate layer, a transition layer, and a functional layer was prepared. The substrate layer was an ethylene-vinyl acetate copolymer (VA content 28-33%), and the transition layer was an ethylene-vinyl acetate copolymer with a VA mass percentage of 18-22% (VA content 8%, exceeding the limit). The functional layer was polytetrafluoroethylene. The three layers were co-extruded to form a gradient structure with a total thickness of 120 μm. The thickness ratio of the substrate layer, transition layer, and functional layer was 0.35:0.45:0.32. After crosslinking modification, the functional thin film was obtained. The crosslinking modification was carried out by electron beam radiation crosslinking with a radiation dose of 70 kGy and a beam energy of 2.0 MeV under nitrogen protection. S4: Hot-press lamination: The substrate sheet treated in S2 and the functional film obtained in S3 are hot-pressed together at a temperature of 165℃ and a pressure of 7MPa for 8 minutes to form a preliminary coated plug; the functional film is preheated to 130℃ and the substrate sheet is preheated to 90℃. S5: Terminal sterilization: The temperature of moist heat sterilization is 115℃ and the time is 30min; after terminal sterilization, the tensile strength retention rate of the film-coated area is 73%, and the oral liquid film-coated rubber stopper is obtained.

[0034] Comparative Example 9 A method for preparing an oral liquid coated rubber stopper includes the following steps: S1: Substrate preparation: After mixing halogenated butyl rubber with vulcanizing agent, filler and plasticizer, it is molded into a substrate sheet with a thickness of 1.2 mm by compression vulcanization. The vulcanization temperature is 165℃, the vulcanization pressure is 15MPa and the vulcanization time is 10min. Add the following per 100 parts by weight of halogenated butyl rubber: 1.8 parts sulfur, 3 parts zinc oxide, 1.3 parts stearic acid, 25 parts silica and 10 parts liquid paraffin. S2: Interface treatment: The surface of the substrate sheet obtained in S1 is subjected to interface treatment. The interface treatment method is as follows: (a) Plasma pretreatment: A mixed gas of argon and oxygen in a volume ratio of 2:1 was used, with a power of 120W and a treatment time of 80 seconds; S3: Functional film preparation: A bilayer composite film (lacking a transition layer) consisting of a substrate layer and a functional layer was prepared. The substrate layer was an ethylene-vinyl acetate copolymer, and the functional layer was polytetrafluoroethylene (PTFE). The composite was prepared by co-extrusion. The substrate layer was an ethylene-vinyl acetate copolymer with a VA mass ratio of 30% and a total thickness of 120 μm. The thickness ratio of the substrate layer to the functional layer was 0.55:0.57. After crosslinking modification, the functional film was obtained. The crosslinking modification was carried out by electron beam radiation crosslinking with a radiation dose of 70 kGy and a beam energy of 2.0 MeV under nitrogen protection. S4: Hot-press lamination: The substrate sheet treated in S2 and the functional film obtained in S3 are hot-pressed together at a temperature of 165℃ and a pressure of 7MPa for 8 minutes to form a preliminary coated plug; the functional film is preheated to 130℃ and the substrate sheet is preheated to 90℃. S5: Terminal sterilization: The temperature of moist heat sterilization is 115℃ and the time is 30min; after terminal sterilization, the tensile strength retention rate of the film-coated area is 58%, and the oral liquid film-coated rubber stopper is obtained.

[0035] Comparative Example 10 A method for preparing an oral liquid coated rubber stopper includes the following steps: S1: Substrate preparation: After mixing halogenated butyl rubber with vulcanizing agent, filler and plasticizer, it is molded into a substrate sheet with a thickness of 1.2 mm by compression vulcanization. The vulcanization temperature is 165℃, the vulcanization pressure is 15MPa and the vulcanization time is 10min. Add the following per 100 parts by weight of halogenated butyl rubber: 1.8 parts sulfur, 3 parts zinc oxide, 1.3 parts stearic acid, 25 parts silica and 10 parts liquid paraffin. S2: Interface treatment: The surface of the substrate sheet obtained in S1 is subjected to interface treatment. The interface treatment method is as follows: (a) Plasma pretreatment: A mixed gas of argon and oxygen in a volume ratio of 2:1 was used, with a power of 120W and a treatment time of 80 seconds; S3: Functional Thin Film Preparation: A functional thin film (inverted gradient structure) consisting of a functional layer, a substrate layer, and a transition layer was prepared. The substrate layer was an ethylene-vinyl acetate copolymer with 30% VA by mass, and the transition layer was an ethylene-vinyl acetate copolymer with 20% VA by mass. The total thickness was 120 μm, and the thickness ratio of the substrate layer, transition layer, and functional layer was 0.35:0.45:0.32. After crosslinking modification, the functional thin film was obtained. The crosslinking modification was performed using electron beam radiation with a radiation dose of 70 kGy and a beam energy of 2.0 MeV under nitrogen protection. S4: Hot-press lamination: The substrate sheet treated in S2 and the functional film obtained in S3 are hot-pressed together at a temperature of 165℃ and a pressure of 7MPa for 8 minutes to form a preliminary coated plug; the functional film is preheated to 130℃ and the substrate sheet is preheated to 90℃. S5: Terminal sterilization: The temperature of moist heat sterilization is 115℃ and the time is 30min; after terminal sterilization, the tensile strength retention rate of the film-coated area is 62%, and the oral liquid film-coated rubber stopper is obtained.

[0036] The detection methods are shown in Table 1: Table 1 Test Methods and Performance Requirements

[0037] Table 2 Performance data for examples and comparative examples

[0038] Traditional coated rubber stoppers are commercially available products.

[0039] In terms of material architecture, the halogenated butyl rubber substrate forms an elastic network through vulcanization. In the gradient coating structure, the high-VA-content EVA substrate layer forms physical entanglement with rubber molecules through polar acetate groups. The medium-VA-content EVA transition layer bridges the substrate layer and the low-polarity PTFE / PE functional layer through molecular chain compatibility. This gradient design ensures a smooth transition in the thermal expansion coefficients of the three layers, significantly suppressing interfacial shear stress during thermal cycling. In terms of process, plasma pretreatment or silane coupling agent coating constructs chemically active sites at the substrate / film interface. Combined with graded preheating of the substrate and film during the hot-pressing composite stage, this allows the EVA segments to undergo directional relaxation at temperatures below their crystallization melting point, promoting interfacial molecular diffusion. Electron beam radiation crosslinking forms a three-dimensional network within the functional layer, enhancing its resistance to molecular chain de-entanglement caused by moist heat sterilization, thus giving it excellent mechanical properties.

[0040] In the comparative examples, the lack of a transition layer directly disrupts the gradient structure of the functional film, preventing a gradual transition in the coefficient of thermal expansion. This leads to significant concentration of interfacial stress, resulting in a substantial decrease in tensile strength retention and noticeable delamination. This fully demonstrates the crucial role of the transition layer in alleviating thermal stress and ensuring structural stability. Without interfacial treatment, there is a lack of effective adhesion between the substrate and the film, with severe delamination and a sharp drop in tensile properties and puncture life. This highlights the core value of interfacial treatment processes such as plasma pretreatment or silane coupling agent coating in enhancing adhesion. When the moist heat sterilization temperature exceeds the set range, the high temperature accelerates the oxidation and degradation of the material, almost resulting in the loss of tensile strength retention. This confirms the importance of matching the terminal sterilization parameters with the material's tolerance limit. When the gradient structure is reversed, the connection logic between the functional layer and the substrate layer is disrupted, increasing the difference in thermal expansion and causing a comprehensive decline in performance. This further proves the scientific nature of the gradient composite structure design. These comparative examples, from the opposite perspective, demonstrate the decisive role of the inventive points of this invention—gradient composite structure, interfacial treatment process, and sterilization parameter matching—in improving the overall performance of the coated rubber stopper.

Claims

1. An oral liquid film-coated stopper, characterized by, The application relates to a vulcanized halogenated butyl rubber-based film-coated rubber stopper, which comprises the following steps: S1: preparing a substrate: mixing halogenated butyl rubber with a vulcanizing agent, a filler and a plasticizer, and then performing mold vulcanization to form a substrate sheet with a thickness of 0.5-2 mm, wherein the vulcanization temperature is 150-180 DEG C, the vulcanization pressure is 10-20 MPa, and the vulcanization time is 5-15 min; S2: interface treatment: performing interface treatment on the surface of the substrate sheet obtained in S1; The halogenated butyl rubber has a thickness of 0.5-2 mm; the total thickness of the functional film is 50-200 μm, wherein the thickness ratio of the substrate layer, the transition layer and the functional layer is (0.3-0.4):(0.4-0.5):(0.3-0.35); when the functional layer is selected from polytetrafluoroethylene, the thickness is 30-50 μm; when the functional layer is selected from high-density polyethylene, the thickness is 40-60 μm, and the density of the high-density polyethylene is not less than 0.95 g / cm 3 , and the melt index is 1-5 g / 10 min (190°C / 2.16 kg).

2. The laminated plug of claim 1 wherein, The interface treatment between the substrate sheet and the functional film adopts plasma pretreatment or silane coupling agent coating; the plasma pretreatment selects the mixed gas with the volume ratio of argon and oxygen being 1-3:1, the power being 50-200W, and the processing time being 30-120 seconds; the silane coupling agent coating selects γ-glycidoxypropyltrimethoxysilane, the coating amount being 0.1-0.5g / m 2 , and the drying temperature being 80-120℃, and the drying time being 5-15min.

3. A method for preparing a film-coated rubber stopper for oral solution, for preparing the film-coated rubber stopper for oral solution according to any one of claims 1 to 2, characterized in that, S3: preparing a functional film: preparing a functional film comprising a substrate layer, a transition layer and a functional layer, wherein the substrate layer is ethylene-vinyl acetate copolymer with a VA mass percentage of 28-33%, the transition layer is ethylene-vinyl acetate copolymer with a VA mass percentage of 18-22%, and polytetrafluoroethylene or high-density polyethylene is used as the functional layer; the three layers form a gradient structure through a laminating process, and the total thickness is 50-200 microns; and the functional film is obtained after cross-linking modification; S4: hot-pressing: hot-pressing the substrate sheet treated in S2 and the functional film obtained in S3 at a temperature of 150-180 DEG C and a pressure of 5-10 MPa for 5-10 min to form a film-coated rubber stopper blank; S5: terminal sterilization, and obtaining a film-coated rubber stopper for oral solution. In S4, the functional film needs to be preheated to 120-140 DEG C, and the substrate sheet needs to be preheated to 80-100 DEG C before hot-pressing. The terminal sterilization adopts moist heat sterilization; the temperature of the moist heat sterilization is 115 DEG C + / - 2 DEG C, and the time is 30 min + / - 2 min. The cross-linking modification adopts electron beam radiation cross-linking, the radiation dose is 60-80 kGy, the beam energy is 1.5-2.5 MeV, and the process is carried out in a nitrogen protection environment.

4. The method for preparing an oral liquid coated rubber stopper as described in claim 3, characterized in that, After terminal sterilization, the tensile strength retention rate of the film-coated area is not less than 85%.

5. The method for preparing an oral liquid coated rubber stopper as described in claim 3, characterized in that, The mixing ratio of the halogenated butyl rubber, the vulcanizing agent, the filler and the plasticizer is as follows: 0.5-3 parts of sulfur, 1-5 parts of zinc oxide, 0.5-2 parts of stearic acid, 15-30 parts of carbon black / white carbon black and 5-15 parts of liquid paraffin are added per 100 parts of the halogenated butyl rubber.

6. The method for preparing an oral liquid coated rubber stopper as described in claim 3, characterized in that, The interface treatment mode comprises any one or a combination of the following modes:

7. The method for preparing an oral liquid coated rubber stopper as described in claim 3, characterized in that, (a) plasma pretreatment: a mixed gas with an argon-oxygen volume ratio of 1-3:1 is used, the power is 50-200 W, and the treatment time is 30-120 seconds.

8. The method for preparing an oral liquid coated rubber stopper as described in claim 3, characterized in that, ​ 9. The method for preparing an oral liquid coated rubber stopper as described in claim 3, characterized in that, ​ ​ (b) Silane coupling agent coating: coated with γ-glycidoxypropyltrimethoxysilane at a coating amount of 0.1-0.5 g / m 2 at a drying temperature of 80-120 °C and a drying time of 5-15 min.

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