Multi-layer co-extrusion nano ceramic coating high-barrier medicine packaging composite film and preparation method thereof

Abstract

The invention relates to the technical field of composite film preparation, in particular to a multi-layer co-extrusion nano ceramic coating high-barrier medicine packaging composite film and a preparation method thereof.The multi-layer co-extrusion nano ceramic coating high-barrier medicine packaging composite film comprises a base material layer, a gas barrier layer, a bonding transition layer and a nano ceramic functional coating; the base material layer comprises the following components in parts by mass: 80-100 parts of biaxially oriented polypropylene; 20 to 30 parts of metallocene linear low density polyethylene; 5 to 8 parts of nano titanium dioxide; 0.5 to 1 part of beta-(3, 5-di-tert-butyl-4-hydroxyphenyl) propionic acid; and 0.3 to 0.6 part of calcium stearate. Through the multi-layer co-extrusion and gradient curing technology and the five-layer co-extrusion technology, it is ensured that the thickness of a base film is uniform and interlayer bonding is firm, the adhesive force of the coating is enhanced through plasma surface treatment, and activity retention and uniform distribution of functional components are guaranteed through the segmented curing strategy of the nano ceramic coating; compared with a traditional hot-pressing compounding or solvent coating process of the composite film, the energy consumption and the solvent residue risk are greatly reduced, meanwhile, the production efficiency and the product consistency are improved, and large-scale application is provided for medicine packaging.

Description

Technical Field

[0001] The present invention relates to the technical field of composite film preparation, and specifically to a multilayer coextruded nano-ceramic coated high-barrier pharmaceutical packaging composite film and its preparation method. Background Art

[0002] A composite film is a film structure formed by combining multiple functional materials through precision processing technology, designed specifically to meet the stringent requirements of pharmaceutical packaging for high barrier properties, antibacterial properties, and mechanical stability. Its core value lies in the synergistic effect of each layer of material to effectively block external factors such as oxygen and water vapor, while also having the ability to inhibit microbial contamination. It is widely used in scenarios such as vaccine stoppers, injection packaging, and biologic sealing to ensure the safety and effectiveness of drugs during storage and transportation.

[0003] Traditional medical composite films mostly use basic polymers such as polyethylene and polypropylene simply compounded with aluminum foil or ordinary barrier layers (such as ethylene-vinyl alcohol copolymer). These materials have significant defects: the barrier performance is easily attenuated by humidity, the aluminum foil layer has poor flexibility and is prone to corrosion and perforation, the surface lacks antibacterial function, leading to the risk of microbial growth. In addition, the interlayer bonding force is insufficient, prone to peeling, and the active drug components may be damaged during the high-temperature and high-pressure processing. These problems directly threaten the stability of drugs and even cause secondary pollution.

[0004] Based on this, the present invention provides a multilayer coextruded nano-ceramic coated high-barrier pharmaceutical packaging composite film and its preparation method to solve the above-mentioned technical problems. Summary of the Invention

[0005] The purpose of the present invention is to provide a multilayer coextruded nano-ceramic coated high-barrier pharmaceutical packaging composite film and its preparation method to solve the problems mentioned in the above background art.

[0006] To achieve the above purpose, the present invention provides the following technical solutions: A multilayer coextruded nano-ceramic coated high-barrier pharmaceutical packaging composite film, comprising a substrate layer, a gas barrier layer, an adhesive transition layer, and a nano-ceramic functional coating; The substrate layer includes the following components by mass parts: biaxially oriented polypropylene: 80 - 100 parts; metallocene linear low-density polyethylene: 20 - 30 parts; nano-titanium dioxide: 5 - 8 parts; β-(3,5-di-tert-butyl-4-hydroxyphenyl) propionic acid: 0.5 - 1 part; calcium stearate: 0.3 - 0.6 part; The gas barrier layer includes the following components by mass parts: ethylene-vinyl alcohol copolymer: 40 - 60 parts; polyvinylidene chloride emulsion: 15 - 25 parts; nano-boron nitride flakes: 10 - 15 parts; modified montmorillonite: 8 - 12 parts; The adhesive transition layer comprises the following components by mass parts: maleic anhydride grafted polypropylene: 100 parts; nano silicon carbide whiskers: 3 - 5 parts; The nano ceramic functional coating comprises the following components by mass parts: nano zinc oxide / silver composite particles: 8 - 12 parts; fumed silica: 5 - 8 parts; KH-550 silane coupling agent: 2 - 4 parts; polyhexamethylene biguanide hydrochloride: 1 - 2 parts; perfluoroalkyl ethyl acrylate copolymer: 3 - 5 parts.

[0007] Preferably, the nano titanium dioxide is prepared by reacting tetrabutyl titanate in an acidic aqueous solution with pH = 1 - 3 through hydrothermal synthesis at 180 - 220 °C for 6 - 8 hours, with a purity ≥ 99.5% and a particle size of 20 - 50 nm.

[0008] Preferably, the nano boron nitride sheets are prepared by mixing boron powder and urea in a molar ratio of 1:3, reacting at 1200 - 1400 °C for 2 - 4 hours through high-temperature chemical vapor deposition under an ammonia protection atmosphere, with a purity ≥ 99.9% and a thickness < 10 nm.

[0009] Preferably, the modified montmorillonite is prepared by treating natural sodium-based montmorillonite and cetyltrimethylammonium bromide in a mass ratio of 1:0.5 in an aqueous solution at 60 - 80 °C through ion exchange reaction for 12 - 24 hours, with a cation exchange capacity ≥ 100 mmol / 100 g.

[0010] Preferably, the maleic anhydride grafted polypropylene is prepared by melting and grafting isotactic polypropylene and maleic anhydride in a mass ratio of 100:5 under the action of diisopropylbenzene peroxide initiator at 180 - 200 °C and then pelletizing by extrusion, with a grafting rate of 1.2 - 1.8%.

[0011] Preferably, the nano zinc oxide / silver composite particles are prepared by dissolving zinc nitrate and silver nitrate in a molar ratio of 10:1, generating a precursor through coprecipitation under alkaline conditions with pH = 10 - 12, and then calcining at 400 - 500 °C for 2 hours, with a silver loading of 8 - 12 wt%.

[0012] Preferably, the fumed silica is prepared by instantaneously reacting silicon tetrachloride with a hydrogen / oxygen mixed gas in a hydrogen-oxygen flame high-temperature hydrolysis reactor at 1200 - 1500 °C, with a specific surface area of 200 - 400 m² / g.

[0013] Preferably, the polyhexamethylene biguanide hydrochloride is prepared by polycondensing guanidine hydrochloride and hexamethylenediamine in a molar ratio of 1:1.2 under nitrogen protection at 140 - 160 °C for 4 - 6 hours, with a degree of polymerization n = 20 - 30.

[0014] Based on the above composite film formulation, the present invention also provides a method for preparing a multilayer co-extruded nano-ceramic coated high-barrier pharmaceutical packaging composite film, comprising the following steps: S1. The following polymer particles used for the substrate layer, barrier layer and adhesive layer: Biaxially oriented polypropylene, metallocene linear low density polyethylene, ethylene-vinyl alcohol copolymer, polyvinylidene chloride emulsion and maleic anhydride grafted polypropylene are respectively put into a vacuum dryer and dried at 80-100°C for 4-6 hours to make the water content ≤ 0.02%; Meanwhile, nano-titanium dioxide, nano-boron nitride sheets, modified montmorillonite, and nano-silicon carbide whisker powder materials are placed in a nitrogen-protected ball mill and dispersed at a rotation speed of 300-400 revolutions per minute for 30-60 minutes to ensure uniform particle size distribution; S2. Use a five-layer co-extrusion blown film unit for melt co-extrusion: Substrate layer: Mix the pretreated biaxially oriented polypropylene: 80-100 parts, metallocene linear low density polyethylene: 20-30 parts with nano-titanium dioxide: 5-8 parts, β-(3,5-di-tert-butyl-4-hydroxyphenyl) propionic acid: 0.5-1 part, calcium stearate: 0.3-0.6 part, and melt-extrude through the main extruder at 190-210°C; Barrier layer: Extrude ethylene-vinyl alcohol copolymer: 40-60 parts, polyvinylidene chloride emulsion: 15-25 parts with nano-boron nitride sheets: 10-15 parts, modified montmorillonite: 8-12 parts through the second extruder at 200-230°C; Adhesive layer: Melt 100 parts of maleic anhydride grafted polypropylene with 3-5 parts of nano-silicon carbide whiskers through the third extruder at 180-200°C; After the melts of each layer are compounded by a distributor, they are extruded from an annular die head under a pressure of 0.8-1.2 MPa. The film bubble is cooled and shaped by an air ring, and the winding linear speed is 8-12 m / min, finally forming a three-layer composite base film with a total thickness of 80-120 μm; S3. Introduce the co-extruded base film into an atmospheric plasma processor and perform corona treatment in an oxygen / argon mixed gas environment. The treatment power density is 100-150 watts per square meter, and the residence time is 0.5-1.2 seconds to increase the surface tension to 50-55 mN / m and the dyne value ≥ 40; The treated base film needs to be left standing in a constant temperature and humidity chamber for 10-15 minutes to stabilize the surface state; S4. Use a microgravure roll coater to uniformly coat the nano-ceramic functional coating slurry on the surface of the base film: Mix nano-zinc oxide / silver composite particles: 8 - 12 parts, fumed silica: 5 - 8 parts, KH-550 silane coupling agent: 2 - 4 parts, polyhexamethylene biguanide hydrochloride: 1 - 2 parts, perfluoroalkyl ethyl acrylate copolymer: 3 - 5 parts with absolute ethanol in a mass ratio of 1:4, and treat it with an ultrasonic disperser for 30 - 40 minutes to form a stable suspension with a solid content of 20 - 25%; Set the coating roll speed ratio to 1:1.2 - 1.5, the base film tension to 8 - 10 N / cm², the wet film thickness to 10 - 15 μm. After coating, the film material immediately enters the infrared pre-drying area to make the solvent evaporation rate ≥ 85%; S5. Put the film material into a hot air circulation curing furnace, cure it by three-stage gradient heating, and quickly cool it to room temperature through a cold roll after curing. Finally, control the coating thickness within 2 - 3 μm; S6. Finally, use a numerical control slitter to slit the wide film material into the specified width, with a slitting speed of 20 - 30 m / min and a tension control of 5 - 8 N / cm².

[0015] Preferably, the three-stage gradient heating curing in step S5 is respectively: The first stage: Keep warm at 80 - 100 °C for 2 - 3 minutes to promote the cross-linking of the silane coupling agent; The second stage: Treat at 120 - 140 °C for 5 - 8 minutes to achieve the melting and leveling of the perfluoroalkyl ethyl acrylate copolymer; The third stage: Rapidly cure at 160 - 180 °C for 30 - 60 seconds to form a dense nano-ceramic coating.

[0016] Compared with the prior art, the beneficial effects of the present invention are: In the present invention, the base material layer uses biaxially oriented polypropylene and metallocene polyethylene to synergistically enhance the mechanical properties. The gas barrier layer introduces nano-boron nitride flakes and modified montmorillonite to construct a multi-level barrier network. The surface nano-ceramic coating integrates zinc oxide / silver composite particles and perfluoropolymers, endowing the film material with self-cleaning and long-term antibacterial properties. It not only solves the defects of unstable barrier performance and easy pollution of traditional materials, but also avoids the imbalance of mechanical properties and flexibility through the precise dispersion of nano-fillers. At the same time, through the multi-layer co-extrusion and gradient curing technology, the five-layer co-extrusion process ensures uniform base film thickness and strong interfacial bonding. Plasma surface treatment enhances the coating adhesion. The segmented curing strategy of the nano-ceramic coating ensures the retention of the activity and uniform distribution of functional components. Compared with the hot pressing composite or solvent coating process of traditional composite films, it greatly reduces the energy consumption and the risk of solvent residue, while improving the production efficiency and product consistency, providing large-scale applications for pharmaceutical packaging. Specific embodiments

[0017] Next, in combination with the embodiments of the present invention, the technical solutions in the embodiments of the present invention will be clearly and completely described. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative efforts belong to the scope of protection of the present invention.

[0018] I. Materials: For the formulation components of the multi-layer co-extruded nano-ceramic coated high-barrier pharmaceutical packaging composite film of the present invention, unless otherwise specified, they are all commercially available. The present invention provides a multi-layer co-extruded nano-ceramic coated high-barrier pharmaceutical packaging composite film, which includes a substrate layer, a gas barrier layer, an adhesive transition layer, and a nano-ceramic functional coating. It should be noted that the substrate layer includes the following components by mass: biaxially oriented polypropylene: 80 - 100 parts; metallocene linear low-density polyethylene: 20 - 30 parts; nano-titanium dioxide: 5 - 8 parts; β-(3,5-di-tert-butyl-4-hydroxyphenyl) propionic acid: 0.5 - 1 part; calcium stearate: 0.3 - 0.6 part. The gas barrier layer includes the following components by mass: ethylene-vinyl alcohol copolymer: 40 - 60 parts; polyvinylidene chloride emulsion: 15 - 25 parts; nano-boron nitride flakes: 10 - 15 parts; modified montmorillonite: 8 - 12 parts. The adhesive transition layer includes the following components by mass: maleic anhydride grafted polypropylene: 100 parts; nano-silicon carbide whiskers: 3 - 5 parts. The nano-ceramic functional coating includes the following components by mass: nano-zinc oxide / silver composite particles: 8 - 12 parts; fumed silica: 5 - 8 parts; KH-550 silane coupling agent: 2 - 4 parts; polyhexamethylene biguanide hydrochloride: 1 - 2 parts; perfluoroalkyl ethyl acrylate copolymer: 3 - 5 parts.

[0019] Among them, it should also be noted that the nano-titanium dioxide is prepared by reacting tetrabutyl titanate in an acidic aqueous solution with pH = 1 - 3 by hydrothermal synthesis method at 180 - 220 °C for 6 - 8 hours, with a purity ≥ 99.5% and a particle size of 20 - 50 nm.

[0020] Among them, it should also be noted that the nano-boron nitride flakes are prepared by mixing boron powder and urea in a molar ratio of 1:3 and reacting at 1200 - 1400 °C for 2 - 4 hours by high-temperature chemical vapor deposition method under an ammonia protection atmosphere, with a purity ≥ 99.9% and a thickness < 10 nm.

[0021] Among them, it should also be noted that the modified montmorillonite is prepared by treating natural sodium-based montmorillonite and cetyltrimethylammonium bromide in an aqueous solution at 60 - 80 °C for 12 - 24 hours through an ion exchange reaction in a mass ratio of 1:0.5, and the cation exchange capacity is ≥100 mmol / 100 g.

[0022] Among them, it should also be noted that maleic anhydride grafted polypropylene is prepared by melt grafting isotactic polypropylene and maleic anhydride in a mass ratio of 100:5 under the action of dicumyl peroxide initiator and extruding and pelletizing at 180 - 200 °C, and the grafting rate is 1.2 - 1.8%.

[0023] Among them, it should also be noted that the nano-zinc oxide / silver composite particles are prepared by dissolving zinc nitrate and silver nitrate in a molar ratio of 10:1, generating a precursor through a co-precipitation method under alkaline conditions with pH = 10 - 12, and then calcining at 400 - 500 °C for 2 hours, and the silver loading is 8 - 12 wt%.

[0024] Among them, it should also be noted that fumed silica is prepared by instantaneously reacting silicon tetrachloride with a hydrogen / oxygen mixed gas in a high-temperature hydrolysis reactor of a hydrogen-oxygen flame at 1200 - 1500 °C, and the specific surface area is 200 - 400 m² / g.

[0025] Among them, it should also be noted that polyhexamethylene biguanide hydrochloride is prepared by polycondensing guanidine hydrochloride and hexamethylenediamine in a molar ratio of 1:1.2 under nitrogen protection at 140 - 160 °C for 4 - 6 hours, and the degree of polymerization n = 20 - 30.

[0026] II. Process: Based on the above composite film formulation, the present invention also proposes a preparation method for a multilayer co-extruded nano-ceramic coated high-barrier pharmaceutical packaging composite film, including the following steps: S1. The following polymer particles used for the substrate layer, barrier layer and adhesive layer: Biaxially oriented polypropylene, metallocene linear low-density polyethylene, ethylene-vinyl alcohol copolymer, polyvinylidene chloride emulsion and maleic anhydride grafted polypropylene are respectively put into a vacuum dryer and dried at 80 - 100 °C for 4 - 6 hours to make the water content ≤0.02%; At the same time, nano-titanium dioxide, nano-boron nitride flakes, modified montmorillonite, and nano-silicon carbide whisker powder materials are placed in a nitrogen-protected ball mill and dispersed at a rotation speed of 300 - 400 revolutions per minute for 30 - 60 minutes to ensure uniform particle size distribution; S2. Perform melt co-extrusion using a five-layer co-extrusion blown film unit: Base material layer: Mix the pretreated biaxially oriented polypropylene: 80 - 100 parts, metallocene linear low density polyethylene: 20 - 30 parts with nano titanium dioxide: 5 - 8 parts, β-(3,5 - di - tert - butyl - 4 - hydroxyphenyl) propionic acid: 0.5 - 1 part, calcium stearate: 0.3 - 0.6 part, and melt - extrude through the main extruder at 190 - 210 °C; Barrier layer: Extrude ethylene - vinyl alcohol copolymer: 40 - 60 parts, polyvinylidene chloride emulsion: 15 - 25 parts with nano boron nitride sheets: 10 - 15 parts, modified montmorillonite: 8 - 12 parts through the second extruder at 200 - 230 °C; Adhesive layer: Melt maleic anhydride grafted polypropylene: 100 parts with nano silicon carbide whiskers: 3 - 5 parts through the third extruder at 180 - 200 °C; After the melts of each layer are compounded by the distributor, they are extruded from the annular die head at a pressure of 0.8 - 1.2 MPa. The film bubble is cooled and shaped by the air ring, and the winding linear speed is 8 - 12 m / min, finally forming a three - layer composite base film with a total thickness of 80 - 120 μm; S3. Introduce the co - extruded base film into an atmospheric plasma processor, and perform corona treatment in an oxygen / argon mixed gas environment. The treatment power density is 100 - 150 W / m², and the residence time is 0.5 - 1.2 s, so that the surface tension is increased to 50 - 55 mN / m, and the dyne value ≥ 40; The treated base film needs to be left standing in a constant temperature and humidity chamber for 10 - 15 minutes to stabilize the surface state; S4. Use a micro - gravure roll coater to evenly coat the nano - ceramic functional coating slurry on the surface of the base film: Mix nano zinc oxide / silver composite particles: 8 - 12 parts, fumed silica: 5 - 8 parts, KH - 550 silane coupling agent: 2 - 4 parts, polyhexamethylene biguanide hydrochloride: 1 - 2 parts, perfluoroalkyl ethyl acrylate copolymer: 3 - 5 parts with absolute ethanol in a mass ratio of 1:4, and treat with an ultrasonic disperser for 30 - 40 minutes to form a stable suspension with a solid content of 20 - 25%; Set the coating roll speed ratio to 1:1.2 - 1.5, the base film tension to 8 - 10 N / cm², the wet film thickness to 10 - 15 μm. After coating, the film material immediately enters the infrared pre - drying area to make the solvent evaporation rate ≥ 85%; S5. Put the film material into a hot - air circulation curing furnace, cure it by three - stage gradient heating, and quickly cool it to room temperature through a cold roll after curing. Finally, control the coating thickness within 2 - 3 μm; S6. Finally, use a numerical control slitter to slit the wide - width film material into the specified width, with a slitting speed of 20 - 30 m / min and a tension control of 5 - 8 N / cm².

[0027] Among them, it should also be noted that the three - stage gradient heating curing in step S5 is respectively: The first stage: Keep the temperature at 80 - 100 °C for 2 - 3 minutes to promote the cross-linking of the silane coupling agent; The second stage: Treat at 120 - 140 °C for 5 - 8 minutes to achieve the melt leveling of the perfluoroalkyl ethyl acrylate copolymer; The third stage: Rapidly cure at 160 - 180 °C for 30 - 60 seconds to form a dense nano-ceramic coating.

[0028] Example 1, in this example, a preparation method of a multi-layer co-extruded nano-ceramic coating high-barrier pharmaceutical packaging composite film includes the following steps: S1. Raw material pretreatment: The polymer particles are dried in a vacuum dryer at a temperature of 90 °C for 5 hours; the powder material is dispersed in a nitrogen-protected ball mill at a rotation speed of 350 revolutions per minute for 45 minutes; S2. Co-extrusion molding: The temperature of the main extruder is 200 °C, the temperature of the second extruder is 215 °C, and the temperature of the third extruder is 190 °C; the die head pressure is 1.0 MPa, the air ring wind speed is 18 m / s, and the winding line speed is 10 meters per minute; S3. Plasma treatment: The power density is 125 watts per square meter, and the residence time is 0.8 seconds; S4. Coating application: The solid content of the slurry is 22.5%, the coating roll speed ratio is 1:1.3, and the pre-drying temperature is 70 °C; S5. Gradient curing: Keep the temperature at 90 °C for 2.5 minutes in the first stage; treat at 130 °C for 6 minutes in the second stage; cure at 170 °C for 45 seconds in the third stage; Example 2: 8 parts of nano-titanium dioxide, and other process parameters and component parameters are the same as those in Example 1; Example 3: 15 parts of nano-boron nitride sheets, and other process parameters and component parameters are the same as those in Example 1; Example 4: 12 parts of modified montmorillonite, and other process parameters and component parameters are the same as those in Example 1; Example 5: 12 parts of nano-zinc oxide / silver composite particles, and other process parameters and component parameters are the same as those in Example 1; The component parameters in Examples 1 to 5 are shown in Table 1: Table 1 Component parameter table in Examples 1 to 5 Material Name Example 1 Example 2 Example 3 Example 4 Example 5 Biaxially Oriented Polypropylene 90 80 100 90 90 Metallocene Linear Low Density Polyethylene 25 30 20 25 25 Nano Titanium Dioxide 6 8 5 6 6 Nano Boron Nitride Nanoplatelets 12 10 15 12 12 Modified Montmorillonite 10 8 12 10 10 Nano Zinc Oxide / Silver Composite Particles 10 8 12 10 10 Comparative Example 1: 3 parts of nano-titanium dioxide, lower than the lower limit of the interval, and other process parameters and component parameters are the same as those in Example 1; Comparative Example 2: 10 parts of nano-titanium dioxide, higher than the upper limit of the interval, and other process parameters and component parameters are the same as those in Example 1; Comparative Example 3: The amount of nano boron nitride sheets is 18 parts, which is higher than the upper limit of the range, and other process parameters and component parameters are the same as those in Example 1; Comparative Example 4: The amount of modified montmorillonite is 5 parts, which is lower than the lower limit of the range, and other process parameters and component parameters are the same as those in Example 1; Comparative Example 5: The amount of nano zinc oxide / silver composite particles is 5 parts, which is lower than the lower limit of the range, and other process parameters and component parameters are the same as those in Example 1; The component parameters in Comparative Examples 1 to 5 are shown in Table 2: Table 2 Component parameter table in Examples 1 to 5 Material Name Comparative Example 1 Comparative Example 2 Comparative Example 3 Comparative Example 4 Comparative Example 5 Biaxially Oriented Polypropylene 90 90 90 90 90 Metallocene Linear Low Density Polyethylene 25 25 25 25 25 Nano Titanium Dioxide 3 10 6 6 6 Nano Boron Nitride Nanoplatelets 12 12 18 12 12 Modified Montmorillonite 10 10 10 5 15 Nano Zinc Oxide / Silver Composite Particles 10 10 10 10 5 III. Performance testing: Prepare composite film samples according to the examples and comparative examples respectively, and test the oxygen transmission rate, water vapor transmission rate, Escherichia coli antibacterial rate and tensile strength of the samples. The steps are as follows: a. Oxygen transmission rate (OTR) test: The standard is based on international standards: ISO15105-1 (differential pressure method) or ASTM D3985 (isobaric method), and the rate of oxygen penetrating through a unit area of the film at a constant temperature and humidity is measured; a1. Sample preparation: Dimensions: Circular specimens with a diameter ≥ 100 mm, uniform thickness, and no defects; Quantity: At least 3 parallel samples; a2. Test conditions: Temperature: 23 ± 1 °C; Relative humidity: 0% RH (dry method) or 50% RH (wet method); a3. Equipment operation: Clamp the sample in the test chamber, introduce pure oxygen (pressure 0.1 MPa) on one side, and nitrogen carrier gas on the other side; Use a gas sensor to detect the amount of permeated oxygen and record the stable data within 24 hours; Result calculation: Oxygen transmission rate = permeation amount / (time × area × pressure difference), unit: cm³ / (m²·day·atm); b. Water vapor transmission rate (WVTR) test: The standard is based on international standards: ASTM E96 (cup method) or ISO15106-3 (infrared sensor method), and the mass of water vapor permeating through a unit area of the film per unit time is measured; b1. Sample preparation: Dimensions: Circular specimens with a diameter ≥ 70 mm, sealed at the edge without leakage; Quantity: At least 5 parallel samples; b2. Test conditions: Temperature: 38 ± 0.5 °C; Relative humidity gradient: 90%RH (inside) → 50%RH (outside); b3. Equipment operation (cup method): Seal the test specimen to the mouth of a moisture-permeable cup containing desiccant (anhydrous calcium chloride), and weigh it regularly; Measure continuously until the weight change stabilizes (48 - 72 hours); Result calculation: Water vapor transmission rate = (weight change × 24) / (time × area), unit: g / (m²·day); c. Escherichia coli antibacterial rate test: The standard is based on the international standard: ISO22196 (Determination of antibacterial properties on plastic surfaces). Calculate the antibacterial effect by comparing the bacterial survival rates of the test specimen and the control sample; c1. Sample preparation: Dimensions: 50mm × 50mm square test specimen, with the thickness consistent with the actual use; Pretreatment: Ultraviolet sterilization for 30 minutes; c2. Bacterial suspension inoculation: Use an Escherichia coli (ATCC25922) suspension with a concentration of 1×10 5 ~5×10 5 CFU / mL; Drop 0.4 mL of the bacterial suspension onto the surface of the sample, and cover it with a polyethylene film to prevent evaporation; c3. Incubation conditions: Temperature 37 ± 1 °C, humidity ≥ 90%, incubate for 24 hours; c4. Colony counting: Elute the bacteria with a neutralizing solution, dilute it and spread it on an agar plate, and count the colonies after incubating at 37 °C for 24 hours; Result calculation: Antibacterial rate = [(colony count of control sample - colony count of test specimen) / colony count of control sample] × 100%; d. Tensile strength test: The standard is based on the international standards: ASTM D882 (Test method for tensile properties of thin plastics) or ISO 527-3, measure the maximum stress of the film before tensile fracture; d1. Sample preparation: Dimensions: dumbbell-shaped test specimen (Type V), gauge length 25 mm, width 5 mm, total length ≥ 150 mm; Direction: Cut 5 test specimens along the longitudinal (MD) and transverse (TD) directions of the film respectively; d2. Test conditions: Temperature: 23 ± 2 °C, tensile speed: 500 mm / min; d3. Equipment operation: Clamp the specimen in the fixture of a tensile testing machine and start the test until fracture; Record the maximum tensile force value and the elongation at break; Result calculation: Tensile strength = maximum tensile force (N) / specimen cross-sectional area (mm²), unit: MPa; The performance parameters of the composite films prepared in Examples 1 to 5 are shown in Table 3: Table 3 Performance parameter table of the composite films prepared in Examples 1 to 5 Performance Index Example 1 Example 2 Example 3 Example 4 Example 5 Oxygen Transmission Rate (cm³ / (m²·day·atm)) 0.04 0.05 0.03 0.04 0.06 Water Vapor Transmission Rate (g / (m²·day)) 0.8 1.2 0.7 0.9 1.1 Escherichia coli Bacteriostasis Rate (%) 99.9 99.5 99.9 99.8 99.7 Tensile Strength (MPa) 48 45 50 47 44 The performance parameters of the composite films prepared in Comparative Examples 1 to 5 are shown in Table 4: Table 4 Performance parameter table of the composite films prepared in Comparative Examples 1 to 5 Performance Index Comparative Example 1 Comparative Example 2 Comparative Example 3 Comparative Example 4 Comparative Example 5 Oxygen Transmission Rate (cm³ / (m²·day·atm)) 0.12 0.07 0.02 0.15 0.09 Water Vapor Transmission Rate (g / (m²·day)) 2.5 1.5 0.6 3.0 1.8 Escherichia coli Bacteriostasis Rate (%) 98.5 99.2 99.9 97.8 95.0 Tensile Strength (MPa) 38 42 55 35 40 IV. Analysis conclusion: Combined with the data in Tables 1 to 4, it can be seen that: The oxygen and water vapor transmission rates of the examples are better than those of the comparative examples, which proves that the components within the interval can balance the dispersibility of the nano-fillers and the denseness of the polymer matrix. The antibacterial rate of the examples is stably ≥ 99.5%, while the antibacterial rate of Comparative Example 5 drops sharply to 95.0% due to insufficient silver content. Comparative Example 3 has increased brittleness due to excessive boron nitride, with a tensile strength of 55 MPa but the film material is easily broken. The 48 MPa of Example 1 is more in line with the requirements of flexible packaging. Therefore, the process parameters and components of Examples 1 - 5 are more advantageous within the interval during the preparation of the multi-layer co-extruded nano-ceramic coated high-barrier pharmaceutical packaging composite film of the present invention; Also, because the material values in Example 1 avoid agglomeration caused by excessive amounts or functional deficiencies caused by insufficient amounts, the plasma treatment power density of 125 watts per square meter precisely activates the surface, the coating solid content of 22.5% achieves uniform coverage, the oxygen transmission rate of 0.04, the antibacterial rate of 99.9%, and the tensile strength of 48 MPa all meet the core requirements of pharmaceutical packaging for high barrier, strong antibacterial, and resistance to mechanical stress. In summary, Example 1 is the best example of the present invention.

[0029] In the description of this specification, the description referring to terms such as "one embodiment", "example", "specific example", etc. means that the specific features, structures, materials, or characteristics described in connection with that embodiment or example are included in at least one embodiment or example of the present invention. In this specification, the schematic representations of the above terms do not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials, or characteristics described can be combined in a suitable manner in any one or more embodiments or examples.

[0030] The preferred embodiments of the present invention disclosed above are only used to help illustrate the present invention. The preferred embodiments do not describe all the details in detail, nor do they limit the invention to the specific embodiments described. Obviously, many modifications and variations can be made according to the content of this specification. These embodiments are selected and specifically described in this specification to better explain the principles and practical applications of the present invention, so that those skilled in the art can well understand and utilize the present invention. The present invention is only limited by the claims and their full scope and equivalents.

Claims

1. Multi-layer co-extruded nano-ceramic coating high barrier pharmaceutical packaging composite film, characterized in that: It includes a substrate layer, a gas barrier layer, an adhesive transition layer and a nano-ceramic functional coating; The substrate layer comprises the following components by weight: biaxially oriented polypropylene: 80-100 parts; metallocene linear low-density polyethylene: 20-30 parts; nano titanium dioxide: 5-8 parts; β-(3,5-di-tert-butyl-4-hydroxyphenyl)propionic acid: 0.5-1 part; Calcium stearate: 0.3-0.6 parts; The gas barrier layer comprises the following components by weight: 40-60 parts of ethylene-vinyl alcohol copolymer; 15-25 parts of polyvinylidene chloride emulsion; Nano boron nitride flakes: 10-15 parts; modified montmorillonite: 8-12 parts; The bonding transition layer comprises the following components by mass: maleic anhydride grafted polypropylene: 100 parts; Nano silicon carbide whiskers: 3-5 parts; The nano ceramic functional coating comprises the following components by mass: 8-12 parts of nano zinc oxide / silver composite particles; Fumed silica: 5-8 parts; KH-550 silane coupling agent: 2-4 parts; polyhexamethylene biguanide hydrochloride: 1-2 parts; perfluoroalkyl ethyl acrylate copolymer: 3-5 parts.

2. The multi-layer co-extruded nano-ceramic coating high-barrier pharmaceutical packaging composite film according to claim 1, characterized in that: The nano titanium dioxide is prepared by reacting tetrabutyl titanate in an acidic aqueous solution with a pH of 1-3 at 180-220° C. for 6-8 hours through a hydrothermal synthesis method, with a purity of ≥99.5% and a particle size of 20-50 nm.

3. The multi-layer co-extruded nano-ceramic coating high barrier pharmaceutical packaging composite film according to claim 2, characterized in that: The nano boron nitride sheet is prepared by mixing boron powder and urea in a molar ratio of 1:3, reacting at 1200-1400°C for 2-4 hours under an ammonia protective atmosphere through a high-temperature vapor deposition method, with a purity of ≥99.9% and a thickness of <10nm.

4. The multi-layer co-extruded nano-ceramic coating high barrier pharmaceutical packaging composite film according to claim 1, characterized in that: The modified montmorillonite is prepared by treating natural sodium montmorillonite and hexadecyltrimethylammonium bromide in a mass ratio of 1:0.5 in a 60-80° C. aqueous solution through an ion exchange reaction for 12-24 hours, and the cation exchange capacity is ≥100mmol / 100g.

5. The multi-layer co-extruded nano-ceramic coating high-barrier pharmaceutical packaging composite film according to claim 4, characterized in that: The maleic anhydride grafted polypropylene is prepared by extruding and granulating isotactic polypropylene and maleic anhydride at a mass ratio of 100:5 under the action of dicumyl peroxide initiator through a melt grafting method at 180-200° C., with a grafting rate of 1.2-1.8%.

6. The multi-layer co-extruded nano-ceramic coating high barrier pharmaceutical packaging composite film according to claim 4, characterized in that: The nano zinc oxide / silver composite particles are prepared by dissolving zinc nitrate and silver nitrate in a molar ratio of 10:1, generating a precursor by a coprecipitation method under alkaline conditions of pH = 10-12, and then calcining at 400-500° C. for 2 hours, with a silver loading of 8-12 wt%.

7. The multi-layer co-extruded nano-ceramic coating high-barrier pharmaceutical packaging composite film according to claim 1, characterized in that: The fumed silicon dioxide is produced by instantaneously reacting silicon tetrachloride with a hydrogen / oxygen mixed gas at 1200-1500° C. in a hydrogen-oxygen flame high-temperature hydrolysis reactor, with a specific surface area of ​​200-400 m² / g and a purity of ≥99.8%.

8. The multi-layer co-extruded nano-ceramic coating high barrier pharmaceutical packaging composite film according to claim 1, characterized in that: The polyhexamethylene biguanide hydrochloride is prepared by polymerizing guanidine hydrochloride and hexamethylene diamine at a molar ratio of 1:1.2 at 140-160° C. for 4-6 hours under nitrogen protection through a polycondensation reaction, with a polymerization degree n=20-30 and a purity of ≥98%.

9. The method for preparing a multi-layer co-extruded nano-ceramic coating high-barrier pharmaceutical packaging composite film according to any one of claims 1 to 8, characterized in that: The following steps are involved: S1. The following polymer particles are used for the substrate layer, barrier layer and adhesive layer: Biaxially oriented polypropylene, metallocene linear low-density polyethylene, ethylene-vinyl alcohol copolymer, polyvinylidene chloride emulsion and maleic anhydride grafted polypropylene are respectively put into a vacuum dryer and dried at 80-100°C for 4-6 hours to make the water content ≤0.02%; At the same time, the nano titanium dioxide, nano boron nitride flakes, modified montmorillonite, and nano silicon carbide whisker powder materials are placed in a nitrogen-protected ball mill and dispersed at a speed of 300-400 rpm for 30-60 minutes to ensure uniform particle size distribution; S2. Use five-layer co-extrusion film blowing unit for melt co-extrusion: Substrate layer: 80-100 parts of pretreated biaxially oriented polypropylene, 20-30 parts of metallocene linear low-density polyethylene, 5-8 parts of nano titanium dioxide, 0.5-1 parts of β-(3,5-di-tert-butyl-4-hydroxyphenyl) propionic acid, and 0.3.3-0.6 parts of calcium stearate are mixed and melt-extruded at 190-210° C. through a main extruder; Barrier layer: 40-60 parts of ethylene-vinyl alcohol copolymer, 15-25 parts of polyvinylidene chloride emulsion, 10-15 parts of nano boron nitride sheet, and 8-12 parts of modified montmorillonite are extruded at 200-230° C. through a second extruder; Adhesive layer: 100 parts of maleic anhydride grafted polypropylene and 3-5 parts of nano silicon carbide whiskers are melted at 180-200°C through a third extruder; After the melts of each layer are compounded by the distributor, they are extruded from the annular die head at a pressure of 0.8-1.2MPa. The film bubble is cooled and shaped by the air ring. The winding line speed is 8-12 m / min, and finally a three-layer composite base film with a total thickness of 80-120μm is formed. S3. The co-extruded base film is introduced into an atmospheric plasma treatment machine and corona treated in an oxygen / argon mixed gas environment with a treatment power density of 100-150 watts / square meter and a residence time of 0.5-1.2 seconds to increase the surface tension to 50-55mN / m and a dyne value ≥40; After treatment, the basement membrane needs to be placed in a constant temperature and humidity chamber for 10-15 minutes to stabilize the surface state; S4. Use a micro gravure roll coater to evenly coat the nano ceramic functional coating slurry on the surface of the base film: 8-12 parts of nano zinc oxide / silver composite particles, 5-8 parts of fumed silica, 2-4 parts of KH-550 silane coupling agent, 1-2 parts of polyhexamethylene biguanide hydrochloride, 3-5 parts of perfluoroalkyl ethyl acrylate copolymer and anhydrous ethanol are mixed in a mass ratio of 1:4, and treated with an ultrasonic disperser for 30-40 minutes to form a stable suspension with a solid content of 20-25%; Set the coating roller speed ratio to 1:1.2-1.5, the base film tension to 8-10N / cm², the wet film thickness to 10-15μm, and the film material immediately enters the infrared pre-drying area after coating to make the solvent volatilization rate ≥85%; S5. Put the film into a hot air circulation curing furnace, and cure it in three stages of gradient temperature increase. After curing, it is quickly cooled to room temperature by a cold roller. The final coating thickness is controlled at 2-3μm. S6. Finally, a CNC slitting machine is used to slit the wide film into specified widths, with a slitting speed of 20-30 m / min and a tension control of 5-8 N / cm².

10. The method for preparing the multi-layer co-extruded nano-ceramic coating high-barrier pharmaceutical packaging composite film according to claim 9, characterized in that: The three stages of gradient temperature rise curing in step S5 are: The first stage: keep warm at 80-100℃ for 2-3 minutes to promote the cross-linking of silane coupling agent; The second stage: 120-140°C treatment for 5-8 minutes to achieve melt leveling of the perfluoroalkyl ethyl acrylate copolymer; The third stage: rapid curing at 160-180℃ for 30-60 seconds to form a dense nano-ceramic coating.