Polyethylene butyl rubber plug for injection bottle and preparation process thereof

Abstract

The present invention belongs to the technical field of pharmaceutical packaging, and relates to a polyethylene butyl rubber plug for injection bottles and a preparation process thereof. The present invention aims to solve the problem that the coating layer of the traditional film-coated rubber plug cannot completely cover the surface of the rubber plug. The present invention synthesizes a fluorosilicone coating precursor by polymerization of fluorosilicone monomer and polyethylene monomer, and further disperses the synthesized fluorosilicone coating to obtain a modified fluorosilicone coating; the butyl rubber plug is post-vulcanized and edge-removed to obtain an edge-removed rubber plug; the edge-removed rubber plug is cleaned with an organic solvent and air plasma, and the surface is treated by dipping to obtain a pre-treated rubber plug; the modified fluorosilicone coating is coated on the surface of the pre-treated rubber plug by vacuum evaporation to form a fully covered polyethylene butyl rubber plug. The polyethylene butyl rubber plug prepared by the present invention meets the pharmaceutical standards and has strong antibacterial properties and chemical stability.

Description

Technical Field

[0001] The invention belongs to the technical field of medical packaging materials, and relates to a polyethylene butyl rubber plug for an injection bottle and a preparation process thereof. Background Art

[0002] With the development of medical technology, the dosage forms of drugs are becoming increasingly diversified, giving rise to various functional requirements for drug packaging. As an important component for drug packaging, rubber plugs can provide good sealing performance, prevent the volatilization, oxidation and contamination of drugs, and ensure the quality stability of drugs. However, traditional rubber plugs made of ordinary polymer materials have defects in chemical stability, biological stability and compatibility with drugs, resulting in an urgent need for a new type of rubber plug with good drug compatibility in the pharmaceutical industry. Therefore, film-coated rubber plugs came into being.

[0003] Film-coated rubber plugs refer to composite rubber plugs made by covering the surface of traditional rubber plugs with a layer of film. They have higher sealing and isolation effects, and their compatibility with drugs is greatly improved. However, the current mainstream process for preparing film-coated rubber plugs is to complete the film coating operation before the rubber plug edge removal process. As a result, after the rubber plug is edged, the newly generated part of its edge cannot be covered by the film layer, thus forming an exposed area. These exposed areas that are not covered by the film layer have many disadvantages: on the one hand, they are prone to produce insoluble particles, and the internal components of the rubber plug are also easy to migrate to the outside, which poses a potential threat to the quality of the drug; on the other hand, because the rubber part is directly exposed to the outside, its surface friction coefficient increases. In order to ensure that the rubber plug can run smoothly on the drug production line, it has to be siliconized. However, the silicone oil used for siliconization is actually a source of pollution for drugs, which is very likely to have an adverse effect on the purity, stability and safety of the drugs.

[0004] At present, the film layer of traditional film-coated rubber plugs cannot completely cover the surface of the rubber plug, which is still a major problem facing the industry.

[0005] To this end, a polyethylene butyl rubber plug for injection bottles and a preparation process thereof are proposed. Summary of the invention

[0006] The purpose of the present invention is to provide a polyethylene butyl rubber plug for injection bottles and a preparation process thereof. The present invention synthesizes a fluorosilicone coating precursor by polymerization of fluorosilicone monomer and polyethylene monomer, and further performs dispersion treatment to obtain a modified fluorosilicone coating; performs post-vulcanization treatment and edge removal treatment on the butyl rubber plug to obtain an edge-removed rubber plug; cleans the edge-removed rubber plug using an organic solvent and air plasma, and performs surface treatment by dipping to obtain a pre-treated rubber plug; and coats the modified fluorosilicone coating on the surface of the pre-treated rubber plug by vacuum evaporation to form a fully covered polyethylene butyl rubber plug.

[0007] To achieve the above object, the present invention provides the following technical solutions:

[0008] A preparation process of a polyethylene butyl rubber plug for an injection bottle comprises the following steps:

[0009] Mixing fluorosilicone monomer and polyethylene monomer, and adding emulsifier to form a suspension;

[0010] After adding an initiator to the suspension, a polymerization reaction is carried out to obtain a fluorosilicone coating precursor;

[0011] The fluorosilicone coating precursor is subjected to dispersion treatment to obtain a modified fluorosilicone coating;

[0012] The butyl rubber plug is post-vulcanized to obtain a vulcanized rubber plug;

[0013] The vulcanized rubber plug is subjected to edge removal treatment to obtain an edge-removed rubber plug;

[0014] The edge-removed rubber plug is subjected to surface treatment to obtain a pre-treated rubber plug;

[0015] After the pretreated rubber plug is heat-treated, a modified fluorosilicone coating is used for vacuum evaporation to obtain a polyethylene butyl rubber plug.

[0016] Preferably, the fluorosilicone monomers include: trifluoroethyl methacrylate, methyl methacrylate and vinyl triethoxysilane; the polyethylene monomers include: vinyl alcohol and vinyl ether; the emulsifier is sodium dodecylbenzene sulfonate, and the addition amount is 0.5 parts; the addition amount of trifluoroethyl methacrylate is 30 parts, the addition amount of methyl methacrylate is 10-15 parts, the addition amount of vinyl triethoxysilane is 25 parts, the addition amount of vinyl alcohol is 10-15 parts, and the addition amount of vinyl ether is 5-8 parts.

[0017] Preferably, the polymerization process is: dissolving 100 parts of the suspension and 0.2 parts of the initiator in 300 parts of tetrahydrofuran, heating to 65-80°C after nitrogen protection for 30 minutes, stirring and reacting at a speed of 300-500rpm for 6-8 hours, cooling to 25°C and then removing tetrahydrofuran by rotary evaporation, washing with methanol and drying to obtain a fluorosilicone coating precursor; wherein the initiator is benzoyl peroxide.

[0018] Preferably, the dispersion treatment process is: heat 50 parts of fluorosilicone coating precursor to 50°C, disperse in a mixed solvent consisting of 100 parts of isopropanol and acetone, stir at a speed of 500-1000rpm for 30min, ultrasonically treat at an ultrasonic power of 200-220W for 20min, and filter using a filter membrane with a pore size of 0.45μm to obtain a modified fluorosilicone coating; wherein the mass ratio of isopropanol to acetone is 3:7.

[0019] Preferably, the post-vulcanization process is as follows: heating the butyl rubber plug to 110-140°C at a heating rate of 5°C / min, keeping the temperature for 6-12 hours, and cooling the plug to 25°C at a cooling rate of 10°C / min to obtain a vulcanized rubber plug.

[0020] Preferably, the surface treatment process is as follows: the edge-removed rubber plug is cleaned with ethanol and isopropanol and then dried, and then cleaned with air plasma for 3-5 minutes at an operating pressure of 10-30Pa to obtain an activated rubber plug; the activated rubber plug is immersed in a 0.1-0.2% by volume octyltrichlorosilane solution under nitrogen protection, and stirred at 25°C at a speed of 50-100rpm for 2 hours, and the activated rubber plug is taken out and washed with dichloromethane, dried with dry nitrogen, and then dried at 100°C for 30 minutes to obtain a pretreated rubber plug; wherein the octyltrichlorosilane solution is prepared by dissolving octyltrichlorosilane in dichloromethane.

[0021] Preferably, the process of vacuum evaporation is as follows: the pretreated rubber plug is heated to 60-70°C at an operating pressure of 15-20Pa and loaded into a vacuum evaporation device, and the modified fluorosilicone coating is delivered into the reaction chamber by argon as a carrier gas, the RF power is 0.2W / cm, the carrier gas flow rate is 20sccm, the evaporation temperature of the modified fluorosilicone coating is 40°C, the deposition time is 15-20min, and a polyethylene butyl rubber plug is obtained after the reaction is completed.

[0022] A polyethylene-coated butyl rubber plug for an injection bottle consists of a butyl rubber plug and a polyethylene-based coating, wherein the surface of the butyl rubber plug is completely covered by the polyethylene-based coating; wherein the butyl rubber plug includes 13 series, 20 series and 32 series rubber plugs.

[0023] Compared with the prior art, the present invention has the following beneficial effects:

[0024] By using premixed fluorosilicone monomers and polyethylene monomers for polymerization, a high molecular network of fluorosilicone resin and a partially polymerized polyethylene network are constructed in the coating matrix in advance, so that the prepared rubber plug coating can easily cover the surface of the rubber plug in an all-round way and have a uniform thickness. On this basis, the three-dimensional network structure formed by the fluorosilicone resin and polyethylene network can effectively protect the materials inside the coating, prevent the penetration and erosion of chemical substances, and thus improve the chemical stability of the coated rubber plug.

[0025] The fluorosilicone coating precursor is dispersed before vacuum evaporation. After good dispersion, the pre-polymerized fluorosilicone coating precursor can be evenly distributed in the argon carrier gas during the subsequent evaporation process, thereby improving the uniformity of the coating. It can also adapt to the coating process of various specifications of rubber plugs without changing the operating method, thus ensuring the thermal stability of the coating.

[0026] The post-cured rubber plug was surface treated to further stabilize the structure of the vulcanized brominated butyl rubber. Furthermore, plasma cleaning was used to significantly increase the surface energy of the rubber plug, and a primer layer was formed on the surface of the rubber plug by impregnation with an octyltrichlorosilane solution, which significantly increased the uniformity of the film formed by the subsequent vacuum evaporation process, and the primer layer obtained after the impregnation increased the compatibility between the rubber plug and the film, and a partial cross-linked network was formed between the primer layer and the film formed by evaporation, which increased the durability and stability of the film and significantly increased the compatibility with drugs.

[0027] After post-vulcanization and edge removal of the rubber plug, the rubber plug is coated using a vacuum evaporation process. While the polyethylene-based film layer is covered on the surface of the rubber plug using a vapor deposition method, the cross-linking reaction of the fluorosilicone resin and the polymerization of the polyethylene network are carried out in situ, forming a composite coating with the stability of the polyethylene-based coating and the excellent hydrophobicity and processability of the fluorosilicone resin. The vacuum evaporation process ensures that the rubber plug is fully covered by the coating, and also allows the film layer and the rubber plug to be stably combined through a cross-linked network, which has hydrophobic and antibacterial properties. BRIEF DESCRIPTION OF THE DRAWINGS

[0028] Figure 1 The present invention is a flow chart of the preparation process of the polyethylene butyl rubber plug for injection bottles. DETAILED DESCRIPTION

[0029] The technical solution of the present invention will be clearly and completely described below through some embodiments and experimental examples. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of them. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0030] Reference Figure 1 As shown in the flow chart, the present invention provides a polyethylene butyl rubber plug for injection bottles and a preparation process thereof, and the technical scheme is as follows: Example

[0031] 30 parts of trifluoroethyl methacrylate, 15 parts of methyl methacrylate, 25 parts of vinyltriethoxysilane, 15 parts of vinyl alcohol, 8 parts of vinyl ether and 0.5 parts of sodium dodecylbenzenesulfonate were mixed to form a suspension.

[0032] 100 parts of the suspension and 0.2 parts of benzoyl peroxide were dissolved in 300 parts of tetrahydrofuran, and heated to 80°C under nitrogen protection for 30 minutes. The mixture was stirred at 500 rpm for 8 hours, and the tetrahydrofuran was removed by rotary evaporation after cooling to 25°C. The mixture was washed with methanol and dried to obtain a fluorosilicone coating precursor.

[0033] 50 parts of fluorosilicone coating precursor were heated to 50°C, dispersed in a mixed solvent consisting of 100 parts of isopropanol and acetone, stirred at a speed of 1000 rpm for 30 minutes, ultrasonically treated at an ultrasonic power of 220 W for 20 minutes, and filtered using a filter membrane with a pore size of 0.45 μm to obtain a modified fluorosilicone coating; wherein the mass ratio of isopropanol to acetone was 3:7.

[0034] The pre-cured 13 series brominated butyl rubber plugs were heated to 140°C at a heating rate of 5°C / min, kept at that temperature for 12 hours, and then cooled to 25°C at a cooling rate of 10°C / min to obtain vulcanized rubber plugs.

[0035] The vulcanized rubber plug is subjected to edge removal treatment to obtain an edge-removed rubber plug.

[0036] The edge-removed rubber plug was cleaned with ethanol and isopropanol and then dried, and then cleaned with air plasma at an operating pressure of 30 Pa for 5 minutes to obtain an activated rubber plug; the activated rubber plug was immersed in a 0.2% by volume octyltrichlorosilane solution under nitrogen protection, and stirred at 25°C at a speed of 100 rpm for 2 hours. After the activated rubber plug was taken out, it was washed with dichloromethane, dried with dry nitrogen, and then dried at 100°C for 30 minutes to obtain a pretreated rubber plug; wherein the octyltrichlorosilane solution was prepared by dissolving octyltrichlorosilane in dichloromethane.

[0037] The pretreated rubber plug was heated to 70°C at an operating pressure of 20 Pa and loaded into a vacuum evaporation device. The modified fluorosilicone coating was delivered into the reaction chamber using argon as a carrier gas. The RF power was 0.2 W / cm, the carrier gas flow rate was 20 sccm, the evaporation temperature of the modified fluorosilicone coating was 40°C, and the deposition time was 20 min. After the reaction, a polyethylene butyl rubber plug was obtained.

[0038] The operating parameters and the rubber plug series of Examples 2-20 are different from those of Example 1, but the process steps are the same. The changes in parameters are summarized in Table 1, Table 2 and Table 3.

[0039] Table 1 Changes in operating parameters in Examples 1-20 (I)

[0040] Amount of methyl methacrylate (parts) Amount of vinyl alcohol (parts) Vinyl ether dosage (parts) Polymerization temperature (℃) Polymerization speed (rpm) Polymerization reaction time (hours) Example 1 15 15 8 80 500 8 Example 2 10 10 5 65 300 6 Example 3 14.5 14.5 7.5 78 495 7.5 Example 4 12.0 11.0 6.0 72 315 6.5 Example 5 13.5 13.0 6.5 75 380 7.0 Example 6 11.0 12.5 5.5 68 425 6.2 Example 7 10.5 10.5 5.2 70 345 6.8 Example 8 13.0 14.0 7.0 76 450 7.2 Example 9 11.5 11.5 6.8 74 360 7.8 Example 10 12.5 13.5 7.8 77 475 6.6 Embodiment 11 14.0 12.0 7.2 73 410 7.6 Example 12 10.0 10.2 5.8 66 305 6.3 Embodiment 13 13.5 11.8 6.2 71 355 7.3 Embodiment 14 11.0 13.8 5.6 69 400 6.7 Embodiment 15 12.0 10.8 6.6 79 330 7.7 Example 16 14.5 12.8 7.6 76 485 6.1 Embodiment 17 10.5 14.2 5.4 67 320 7.1 Embodiment 18 13.0 10.6 7.4 78 440 6.9 Embodiment 19 11.5 14.8 6.4 72 390 7.4 Embodiment 20 12.5 10.4 5.3 65 370 7.5

[0041] Table 2 Changes in operating parameters in Examples 1-20 (II)

[0042] Dispersion processing speed (rpm) Ultrasonic power (W) Post-vulcanization temperature (℃) Post-vulcanization holding time (hours) Air plasma cleaning pressure (Pa) Air plasma cleaning time (min) Example 1 1000 220 140 12 30 5 Example 2 500 200 110 6 10 3 Example 3 650 205 130 8 25 4 Example 4 900 215 115 10 12 3.5 Example 5 700 208 125 7 18 5 Example 6 850 212 135 9 22 4.5 Example 7 550 202 120 6.5 15 3.2 Example 8 950 218 118 11 28 4.8 Example 9 600 204 132 7.5 14 3.8 Example 10 800 210 128 8.5 20 4.2 Embodiment 11 750 206 122 6.8 16 3.6 Example 12 920 216 138 10.5 26 4.6 Embodiment 13 580 203 112 7.2 13 3.4 Embodiment 14 880 214 126 9.5 19 4.4 Embodiment 15 680 207 134 8.2 24 4.1 Example 16 780 209 124 7.8 17 3.7 Embodiment 17 980 217 116 11.5 27 4.7 Embodiment 18 520 201 114 6.2 11 3.3 Embodiment 19 820 213 136 9.8 23 4.3 Embodiment 20 720 205 127 8.8 18 3.9

[0043] Table 3 Changes in operating parameters in Examples 1-20 (III)

[0044] Dipping solution concentration (%) Dipping speed (rpm) Vacuum evaporation pressure (Pa) Vacuum evaporation temperature (℃) Deposition time (min) Butyl rubber plug series Example 1 0.1 100 20 70 20 13 Example 2 0.2 50 15 60 15 13 Example 3 0.15 60 18 65 16 20 Example 4 0.1 80 17 62 18 13 Example 5 0.2 90 16 68 17 32 Example 6 0.15 70 19 66 19 13 Example 7 0.2 55 15 63 16 32 Example 8 0.1 85 18 64 17 20 Example 9 0.15 65 17 67 18 32 Example 10 0.1 75 20 69 19 13 Embodiment 11 0.2 52 16 61 15 20 Example 12 0.15 82 19 66 17 32 Embodiment 13 0.1 72 17 63 18 20 Embodiment 14 0.2 58 15 62 16 13 Embodiment 15 0.15 68 18 65 19 20 Example 16 0.1 78 16 68 17 32 Embodiment 17 0.2 56 19 64 18 13 Embodiment 18 0.15 88 17 67 16 20 Embodiment 19 0.1 76 20 61 19 32 Embodiment 20 0.2 54 15 60 17 13

[0045] Comparative Example 1

[0046] The difference from Example 1 is that no polyethylene monomer is added, and other process parameters and operation methods are the same.

[0047] Comparative Example 2

[0048] The difference from Example 1 is that no fluorine silicon monomer is added, and other process parameters and operation methods are the same.

[0049] Comparative Example 3

[0050] The difference from Example 1 is that no polymerization reaction is carried out, and other process parameters and operation methods are the same.

[0051] Comparative Example 4

[0052] The difference from Example 6 is that the fluorosilicone coating precursor is not dispersed, and other process parameters and operation methods are the same.

[0053] Comparative Example 5

[0054] The difference from Example 6 is that the order of dispersion treatment and polymerization reaction is exchanged, and other process parameters and operation methods are the same.

[0055] Comparative Example 6

[0056] The difference from Example 11 is that ethanol and isopropanol cleaning are not performed, and other process parameters and operation methods are the same.

[0057] Comparative Example 7

[0058] The difference from Example 11 is that vacuum evaporation is performed before edge removal, and other process parameters and operation methods are the same.

[0059] Comparative Example 8

[0060] The difference from Example 11 is that air plasma cleaning is not performed, and other process parameters and operation methods are the same.

[0061] Comparative Example 9

[0062] The difference from Example 11 is that the impregnation with the octyltrichlorosilane solution is not performed, and the other process parameters and operation methods are the same.

[0063] Comparative Example 10

[0064] Different from Example 16, the modified fluorosilicone coating is directly coated on the surface of the rubber plug by spraying, and other process parameters and operation methods are the same.

[0065] Experimental Example 1

[0066] Drug dissolution experiments were performed on the polyethylene butyl rubber plugs prepared in Examples 1-5 and Comparative Examples 1-3 to characterize their chemical stability.

[0067] The rubber stoppers were soaked in physiological saline, 5% glucose solution for injection, and 20% mannitol solution for injection, respectively. The soaking temperature was 37°C and the soaking time was 24 hours. HPLC was used to detect the changes in the components of different solutions before and after soaking. The impurity content was represented by the proportion of impurity peak area. The relevant results are summarized in Table 4.

[0068] When soaking, soak one rubber stopper for every 50 mL of solution.

[0069] Table 4 Impurity content of the rubber plugs prepared in Examples 1-5 and Comparative Examples 1-3 after immersion

[0070] Impurity content after soaking in saline solution (%) Impurity content after soaking in 5% glucose solution for injection (%) Impurity content after soaking in 20% mannitol solution for injection (%) Example 1 0.01 0.01 0.02 Example 2 0.01 0.01 0.01 Example 3 0.02 0.01 0.01 Example 4 0.01 0.01 0.01 Example 5 0.01 0.02 0.01 Comparative Example 1 0.04 0.03 0.03 Comparative Example 2 0.11 0.15 0.10 Comparative Example 3 0.08 0.06 0.09

[0071] As shown in the impurity content data in Table 4, although the operating parameters of Examples 1-5 are different, the obtained plugs all have good chemical stability, and no large amount of impurities are leached after being soaked in physiological saline, 5% glucose solution for injection, and 20% mannitol solution for injection. Comparative Example 1 Due to the lack of polyethylene monomer, the polyethylene-based film structure cannot be formed during the film formation process, and the simple fluorosilicone resin film structure has certain defects, resulting in an increase in the dissolution amount of some substances, and the chemical stability of the film-coated plug is affected. Due to the lack of fluorosilicone monomer, Comparative Example 2 can only form a simple polyethylene-based film layer, and the hydrophobicity and chemical stability are significantly reduced, and the dissolved impurities in the three drug solutions are also significantly increased. Comparative Example 3 Since the polymerization reaction was not carried out in advance, the polymerization reaction in the vacuum evaporation process was not enough to form a dense cross-linked film, so the chemical stability of the product plug was reduced. In summary, the compounding of polyethylene monomer and fluorosilicone monomer and the polymerization reaction carried out in advance effectively construct a cross-linked network of fluorosilicone resin and partially polymerized polyethylene, improve the chemical stability of the film layer, and are suitable for the sealed packaging of a variety of drugs.

[0072] Experimental Example 2

[0073] The thermal stability test of the coating was carried out on the rubber plugs prepared in Examples 6-10 and Comparative Examples 4-5, and the thermal cracking temperatures of the coatings were recorded and summarized in Table 5.

[0074] Table 5 Thermal cracking temperature of the films of the rubber plugs prepared in Examples 6-10 and Comparative Examples 4-5

[0075] Thermal cracking temperature of film (℃) Example 6 485 Example 7 488 Example 8 479 Example 9 486 Example 10 478 Comparative Example 4 264 Comparative Example 5 301

[0076] As shown in the thermal cracking temperature data in Table 5, the coatings of the rubber plugs prepared in Examples 6-10 all have relatively high thermal cracking temperatures, indicating that these coated rubber plugs have excellent thermal stability. In Comparative Example 4, since the fluorosilicone coating precursor was not dispersed, it was difficult to form a uniform evaporation atmosphere through the carrier gas during the vacuum evaporation process, resulting in uneven coating and poor adhesion, and thermal cracking occurred at a relatively low temperature. In Comparative Example 5, since dispersion was performed before polymerization, the dispersion after entering the vacuum evaporation stage was still poor, resulting in a decrease in the uniformity of the coating, and then a decrease in thermal stability. In summary, dispersing the pre-polymerized fluorosilicone coating precursor before vacuum evaporation can ensure the uniformity of the coating distribution in the argon carrier gas during the evaporation process, forming a more uniform and more bonded coating, so that the coating has higher thermal stability.

[0077] Experimental Example 3

[0078] The film-coated rubber plugs prepared in Examples 11-15 and Comparative Examples 6-9 were tested for drug compatibility. In the field of pharmaceutical packaging, the compatibility of rubber products with drugs can be characterized by the leaching amount of several key substances. The film-coated rubber plugs were extracted with dichloromethane as a solvent for 24 hours, and the contents of sulfur, benzothiazole and other polycyclic aromatic hydrocarbons were detected in ppm. The extraction temperature was 50°C. In order to verify the performance of the film, the film-coated rubber plugs were placed intact in the Soxhlet extractor without cutting or other treatments. The amount of dichloromethane used was 100 mL for each rubber plug. The results are summarized in Table 6.

[0079] Table 6 Drug compatibility of rubber plugs prepared in Examples 11-15 and Comparative Examples 6-9

[0080] Sulfur content (ppm) Benzothiazole content (ppm) Other PAHs content (ppm) Embodiment 11 ＜10 ＜20 Not detected Example 12 ＜10 ＜20 Not detected Embodiment 13 ＜10 ＜20 Not detected Embodiment 14 ＜10 ＜20 Not detected Embodiment 15 ＜10 ＜20 Not detected Comparative Example 6 ＜10 37 Not detected Comparative Example 7 44 58 36 Comparative Example 8 36 33 Not detected Comparative Example 9 27 40 52

[0081] As shown in the drug compatibility data of Table 6, the rubber plugs prepared in Examples 11-15 can ensure that sulfur, benzothiophene and polycyclic aromatic hydrocarbons are not leached after extraction with dichloromethane, and can ensure good drug compatibility during drug packaging without contaminating drugs. In Comparative Example 6, because no organic solvent was used to clean organic matter, pollutants and impurities were present on the surface of the rubber plug, and there were coating defects after vacuum evaporation, resulting in some benzothiazole being extracted and detected. In Comparative Example 7, because the edge cutting was performed after vacuum evaporation, the coating could not fully cover the surface of the rubber plug, and all impurities were detected in large quantities. In Comparative Example 8, because no air plasma cleaning was performed, the immersion process could not form a uniform primer layer, resulting in poor adhesion of the coating formed by vacuum evaporation. In Comparative Example 9, because no immersion treatment was performed, no uniform primer layer was formed, resulting in the inability of vacuum evaporation to form a dense and uniform polyethylene-based coating, and all three impurities were detected in large quantities. In summary, the surface treatment is carried out after the edge removal treatment. At the same time, the pollutants on the surface of the rubber plug are removed by organic cleaning and air plasma cleaning, and a uniform primer layer is formed by immersion. Then, a dense and stable coating can be obtained by vacuum evaporation, which significantly improves the compatibility of the rubber plug and the drug.

[0082] Experimental Example 4

[0083] The antibacterial performance of the rubber plugs prepared in Examples 16-20 and Comparative Example 10 was tested to characterize their reliability in pharmaceutical packaging applications. Uncoated bromobutyl rubber plugs were used as the control group, and cultured Escherichia coli and Staphylococcus aureus were inoculated on the rubber plugs in the experimental group and the control group, respectively. After 48 hours of culture, the difference in the number of cultured colonies between the control group and the experimental group and the ratio of the number of colonies in the control group were used as the antibacterial efficiency.

[0084] The contact angle test was performed on the rubber plugs prepared in Examples 16-20 and Comparative Example 10 to characterize the hydrophobicity of the coatings.

[0085] The relevant data are summarized in Table 7.

[0086] Table 7 Antibacterial and hydrophobic properties of the rubber plugs prepared in Examples 16-20 and Comparative Example 10

[0087]

[0088] As shown in the antibacterial properties and contact angle data in Table 7, the film-coated rubber plugs prepared in Examples 16-20 have good antibacterial effects and strong hydrophobicity. Comparative Example 10 did not use the vacuum evaporation process, but directly coated the rubber plug by spraying. The obtained film-coated rubber plug was significantly weaker in antibacterial effect and hydrophobic effect than the rubber plug prepared by the vacuum evaporation process. In summary, the coating prepared by the vacuum evaporation process has a uniform and dense surface, and due to the formation of a cross-linked network of fluorosilicone resin and in-situ polymerization of the polyethylene matrix, it has higher stability, and has both antibacterial and hydrophobic properties while ensuring drug compatibility, and can completely cover the rubber plug.

[0089] Although embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that various changes, modifications, substitutions and variations may be made to the embodiments without departing from the principles and spirit of the present invention, and that the scope of the present invention is defined by the appended claims and their equivalents.

Claims

1. A process for preparing a polyethylene butyl rubber plug for an injection bottle, characterized in that: The preparation process is as follows: Mixing fluorosilicone monomer and polyethylene monomer, and adding emulsifier to form a suspension; After adding an initiator to the suspension, a polymerization reaction is carried out to obtain a fluorosilicone coating precursor; The polymerization reaction process is as follows: 100 parts of the suspension and 0.2 parts of the initiator are dissolved in 300 parts of tetrahydrofuran, heated to 65-80°C after nitrogen protection for 30 minutes, stirred at a speed of 300-500 rpm for 6-8 hours, cooled to 25°C and then evaporated to remove the tetrahydrofuran, washed with methanol and dried to obtain the fluorosilicone coating precursor; The fluorosilicone monomer includes: trifluoroethyl methacrylate, methyl methacrylate and vinyl triethoxysilane; the polyethylene monomer includes: vinyl alcohol and vinyl ether; the addition amount of the trifluoroethyl methacrylate is 30 parts, the addition amount of the methyl methacrylate is 10-15 parts, the addition amount of the vinyl triethoxysilane is 25 parts, the addition amount of the vinyl alcohol is 10-15 parts, and the addition amount of the vinyl ether is 5-8 parts; The fluorosilicone coating precursor is subjected to a dispersion treatment to obtain a modified fluorosilicone coating; The butyl rubber plug is heated to 110-140°C at a heating rate of 5°C / min, kept at this temperature for 6-12 hours, and then cooled to 25°C at a cooling rate of 10°C / min to obtain a vulcanized rubber plug; The vulcanized rubber plug is subjected to edge removal treatment to obtain an edge-removed rubber plug; The edge-removed rubber plug is subjected to surface treatment to obtain a pre-treated rubber plug; After the pretreated rubber plug is heat-treated, the modified fluorosilicone coating is used for vacuum evaporation to obtain the polyethylene butyl-coated rubber plug.

2. The process for preparing a polyethylene butyl rubber plug for injection bottles according to claim 1, characterized in that: The emulsifier is sodium dodecylbenzene sulfonate.

3. The process for preparing a polyethylene butyl rubber plug for injection bottles according to claim 1, characterized in that: The initiator is benzoyl peroxide.

4. The process for preparing a polyethylene butyl rubber plug for an injection bottle according to claim 1, characterized in that: The dispersion treatment process is as follows: 50 parts of the fluorosilicone coating precursor are heated to 50° C., dispersed in a mixed solvent consisting of 100 parts of isopropanol and acetone, stirred at a speed of 500-1000 rpm for 30 minutes, ultrasonically treated at an ultrasonic power of 200-220 W for 20 minutes, and filtered using a filter membrane with a pore size of 0.45 μm to obtain the modified fluorosilicone coating; wherein the mass ratio of the isopropanol to the acetone is 3:

7.

5. The process for preparing a polyethylene butyl rubber plug for injection bottles according to claim 1, characterized in that: The surface treatment process is as follows: the edge-removed rubber plug is cleaned with ethanol and isopropanol and then dried, and then cleaned with air plasma for 3-5 minutes at an operating pressure of 10-30Pa to obtain an activated rubber plug; the activated rubber plug is immersed in a 0.1-0.2% by volume octyltrichlorosilane solution under nitrogen protection, and stirred at 25°C at a speed of 50-100rpm for 2 hours, and the activated rubber plug is taken out and washed with dichloromethane, dried with dry nitrogen, and then dried at 100°C for 30 minutes to obtain the pretreated rubber plug; wherein the octyltrichlorosilane solution is prepared by dissolving octyltrichlorosilane in dichloromethane.

6. The process for preparing a polyethylene butyl rubber plug for injection bottles according to claim 1, characterized in that: The vacuum evaporation process is as follows: the pretreated rubber plug is heated to 60-70°C at an operating pressure of 15-20Pa and loaded into a vacuum evaporation device, the modified fluorosilicone coating is delivered into a reaction chamber by using argon as a carrier gas, the radio frequency power is 0.2W / cm, the carrier gas flow rate is 20sccm, the evaporation temperature of the modified fluorosilicone coating is 40°C, the deposition time is 15-20min, and the polyethylene butyl rubber plug is obtained after the reaction is completed.

7. A polyethylene butyl rubber plug for an injection bottle, characterized in that: The polyethylene-coated butyl rubber plug is prepared by the preparation process described in any one of claims 1 to 6; the polyethylene-coated butyl rubber plug consists of a butyl rubber plug and a polyethylene coating; the surface of the butyl rubber plug is completely covered by the polyethylene coating; the butyl rubber plug includes 13 series, 20 series and 32 series rubber plugs.

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