Pharmaceutical glass bottle and forming process thereof

Abstract

The application discloses a medicinal glass bottle and a forming process thereof, and belongs to the technical field of medical materials, and comprises a glass bottle body and a composite coating of the inner wall of the glass bottle; the forming process comprises the following steps: 1) glass substrate pretreatment; 2) composite layer construction; 3) barrier layer construction; 4) cross-linking and inactivation and post-treatment. The inner wall coating designed in the application adopts a sandwich structure, realizes strong adhesion of a bottom layer through amino silane, realizes stable antibiosis by in-situ anchoring of silver nanoparticles through a branched polyethylene imine network, constructs a dense zwitterionic polymer brush on the outermost layer through surface-initiated polymerization, provides a super-hydrophilic and bio-inert surface, and finally, through cross-linking and inactivation treatment, the stability and safety of the coating are greatly improved. The application solves the problems of drug adsorption, microbial breeding and unstable coating existing in traditional packaging materials, and provides a safe and reliable new solution for medicine packaging.

Description

Technical Field

[0001] This invention relates to the field of medical materials technology, and in particular to a pharmaceutical glass bottle and its molding process. Background Technology

[0002] Pharmaceutical glass vials are the mainstream packaging form for critical medicines such as injectables and vaccines, and the properties of their inner walls directly affect medication safety and efficacy. Traditional glass surfaces have two inherent defects:

[0003] First, its limited hydrophilicity makes it prone to adhering to the glass wall of biological agents such as proteins and peptides, resulting in drug loss and inaccurate dosage. Second, glass itself does not have antibacterial properties, posing a risk of microbial growth and contamination. Existing technologies attempt to improve this through inner wall coatings, such as coating with hydrophilic materials like polyvinylpyrrolidone to reduce adsorption, or introducing antibacterial agents such as silver ions.

[0004] However, these solutions are often limited in function and face the following problems: simple physical mixing or layering is difficult to achieve long-term stability, antibacterial components are prone to leaching, posing safety risks, and the active functional groups on the surface of the coating material used to fix the active ingredients may adsorb drugs or cause adverse reactions.

[0005] Therefore, developing a glass bottle inner wall coating technology that can synergistically achieve superhydrophilicity, strong antibacterial effect, extremely high stability, and high compatibility with drugs has become a key requirement for breaking through the bottleneck of high-end drug packaging and ensuring public drug safety. Summary of the Invention

[0006] The purpose of this invention is to address the shortcomings of existing technologies by proposing a pharmaceutical glass bottle and its molding process.

[0007] To achieve the above objectives, the present invention adopts the following technical solution:

[0008] A pharmaceutical glass bottle includes a glass bottle body and a composite coating on the inner wall of the glass bottle, wherein the composite coating comprises, from the inside out:

[0009] The bonding layer is bonded to the glass surface by an aminosilane coupling agent;

[0010] The silver particle composite layer, which is fixed to the bonding layer by covalent bonds, contains branched polyethyleneimine and silver nanoparticles generated in situ and anchored therein.

[0011] Barrier layer, a zwitterionic polymer surface layer formed by grafting through a surface-initiated atom transfer radical polymerization reaction;

[0012] The thickness of the bonding layer is 0.5-2 nm, the thickness of the silver particle composite layer is 50-150 nm, and the thickness of the barrier layer is 80-200 nm.

[0013] The surface layer of the zwitterionic polymer is a polysulfobetaine methacrylate layer.

[0014] The present invention also proposes a molding process for the aforementioned pharmaceutical glass bottle, comprising the following steps:

[0015] S1. Glass substrate pretreatment: sequential cleaning and drying, plasma activation, silanization reaction and curing are performed to form an aminosilanized layer, i.e. a bonding layer, on the inner wall of the glass substrate.

[0016] S2. Composite layer construction: The pretreated glass substrate is immersed in a branched polyethyleneimine aqueous solution for coating and drying, and then immersed in a mixed aqueous solution of silver ions and reducing agent for in-situ reduction reaction to form a silver particle composite layer of branched polyethyleneimine / silver nanoparticles.

[0017] After branched polyethyleneimine (bPEI) is firmly adsorbed and coated onto an aminosilanized glass surface, when immersed in AgNO3 solution, the numerous amino (-NH2) and imine (=NH) groups on the bPEI chain act as excellent ligands, rapidly capturing Ag through coordination. + This enriches it within and on the surface of the polymer network.

[0018] The added sodium citrate acts as a mild reducing agent, and its citrate ions will reduce Ag... + Reduced to silver atoms (Ag) 0 The amino group of bPEI can be oxidized, and at the same time, it prevents the aggregation of newly formed silver atoms through steric hindrance and coordination.

[0019] The network structure of bPEI effectively limits the excessive growth and migration of particles, anchoring them in situ onto the polymer chains. The reaction system turns yellowish-brown or brownish-yellow, a direct reflection of the plasmon resonance effect on the surface of the silver nanoparticles. The "silver particle composite layer" formed in this step firmly integrates antibacterial functional units (AgNPs) into the polymer matrix.

[0020] S3. Barrier layer construction: Initiator immobilization and surface-initiated atom transfer radical polymerization reaction are carried out sequentially to graft an amphoteric polymer surface layer onto the surface of the silver particle composite layer.

[0021] Under ice bath and alkaline conditions (triethylamine), the acyl bromide group (-COBr) of 2-bromoisobutyryl bromide (ATRP initiator) undergoes a nucleophilic substitution reaction with the primary amino group (-NH2) on the surface of the bPEI / AgNPs composite layer to generate an amide bond (-CO-NH-), thereby covalently bonding the initiator molecule with a bromine atom (Br) to the surface.

[0022] Under anhydrous and oxygen-free conditions, activated carbon free radicals initiate the polymerization of zwitterionic monomers such as sulfobetaine methacrylate.

[0023] S4, Crosslinking Inerting and Post-treatment: The glass substrate treated by S3 is immersed in an aqueous solution of crosslinking agent to carry out a crosslinking reaction, and then cured and treated with ultraviolet light to crosslink and inertate the active functional groups, thus obtaining a pharmaceutical glass bottle.

[0024] Preferably, the glass substrate is a vial, ampoule, or infusion bottle made of borosilicate glass or soda-lime glass; the aminosilanized layer is made of 3-aminopropyltriethoxysilane; the branched polyethyleneimine has an average molecular weight of 20,000-30,000 Da; and the crosslinking agent is ethylene glycol diglycidyl ether.

[0025] Ethylene glycol diglycidyl ether molecules contain two highly reactive epoxy groups. These epoxy groups can undergo ring-opening addition reactions with nucleophilic groups such as amino and hydroxyl groups in the coating (especially at the ends or side chains of zwitterionic polymer chains and as residual bPEI in the bottom layer). Through a mild crosslinking reaction, the overall stability of the coating is improved and potential active sites on the surface are passivated, thus completing the final curing.

[0026] By introducing covalent cross-linking points between different polymer chains or at different parts of the same polymer chain, a three-dimensional network is formed, which significantly enhances the mechanical strength, wear resistance and solvent immersion resistance of the coating, and prevents swelling and peeling during use or sterilization.

[0027] By consuming the small amount of active groups such as amino groups that may not have fully reacted on the surface, and converting them into inert ether bonds or hydroxyl groups, the risk of non-specific chemical adsorption or reaction between the coating and the drug is further reduced.

[0028] Preferably, in step S1, the cleaning and drying process includes ultrasonically cleaning the glass substrate sequentially with piranha cleaning solution, deionized water, and anhydrous ethanol for 15-25 minutes each, drying it in an oven at 100°C for 0.5-1.5 hours, and then heat-treating it in a muffle furnace at 300-400°C for 1.5-2.5 hours.

[0029] The conditions for plasma activation are: oxygen introduction, power of 40-60W, and processing time of 3-7 minutes;

[0030] The conditions for the silanization reaction are as follows: the activated glass substrate is immersed in a 1%-3% (v / v) 3-aminopropyltriethoxysilane ethanol solution for 0.5-1.5 h, the curing temperature is 100-120 °C, and the curing time is 0.5-1.5 h.

[0031] Preferably, in step S2, the mass-volume concentration of the branched polyethyleneimine aqueous solution is 0.5%-2%, the coating method is dip-coating, the coating speed is 80-120 mm / min, the drying temperature is 50-70℃, and the drying time is 20-40 min.

[0032] In the mixed aqueous solution of silver ions and reducing agent, the precursor of silver ions is silver nitrate, the reducing agent is sodium citrate, the concentration of silver ions is 0.5-2 mmol / L, the concentration of sodium citrate is 1-3 mmol / L, the in-situ reduction reaction temperature is 50-70℃, the reaction time is 1.5-2.5 h, and the reaction is carried out under light-protected conditions.

[0033] Preferably, in step S3, the initiator immobilization includes: placing the glass substrate treated in step S2 in an ice bath, adding anhydrous dichloromethane and triethylamine, then adding a dichloromethane solution of 2-bromoisobutyryl bromide dropwise, reacting under nitrogen protection for 0.5-1.5 h, and after the reaction, washing alternately with anhydrous dichloromethane and methanol and drying with nitrogen.

[0034] The concentration of 2-bromoisobutyryl bromide in dichloromethane solution is 0.05-0.15 mol / L, and the volume ratio of 2-bromoisobutyryl bromide to triethylamine is 1:0.8-1.2;

[0035] The conditions for surface-initiated atom transfer radical polymerization are as follows: the reaction solution is prepared in an anhydrous and oxygen-free glove box; the concentration of sulfobetaine methacrylate monomer in the reaction solution is 0.8-1.2 mol / L; the molar ratio of cuprous bromide to monomer is 1:80-120; the molar ratio of ligand to cuprous bromide is 1.5-2.5:1; the ligand is N,N,N′,N′′,N′′-pentamethyldiethylenetriamine; the polymerization temperature is 25-35℃; and the reaction time is 5-7 h.

[0036] Preferably, in step S4, the crosslinking agent aqueous solution is an aqueous solution of ethylene glycol diglycidyl ether with a volume ratio of 0.3%-0.7%, the crosslinking reaction temperature is room temperature, and the reaction time is 1.5-2.5 h;

[0037] The curing conditions are: curing in an 80℃ oven for 3-5 hours;

[0038] The conditions for ultraviolet light irradiation are: wavelength 365nm, light intensity 20-50mW / cm², and irradiation time 8-12min.

[0039] Compared with the prior art, the beneficial effects of the present invention are:

[0040] 1. Compared with existing technologies, the beneficial effects of this invention stem from its unique synergistic mechanism of "chemical anchoring - in-situ silver loading - controlled polymerization - inert encapsulation," achieving a unified breakthrough in functionality, stability, and safety. In existing technologies, the simple physical mixing or superposition of hydrophilic and antibacterial coatings often leads to the easy leaching of silver nanoparticles due to weak binding forces, and the surface of the active coating is prone to adverse reactions with drugs. This invention first constructs a covalently bonded molecular anchor layer on the glass surface through an aminosilane coupling agent. This is not only a physical adhesion point, but the amino groups at its ends also undergo strong coordination and chemical reactions with the upper polymer and silver ions, forming a gradient chemical bond from the glass substrate to the functional layer, fundamentally solving the problem of coating adhesion failure under moist heat sterilization and long-term storage.

[0041] 2. Existing technologies for loading silver nanoparticles mostly employ physical blending or simple adsorption, resulting in unstable loading. This invention utilizes the three-dimensional network of branched polyethyleneimine and its abundant amino / imine groups to achieve multiple coordination capture and in-situ controllable reduction of silver ions. This mechanism ensures that silver nanoparticles are "locked" within the polymer network at the moment of generation, forming a stable composite with the polymer as the framework and silver nanoparticles as the functional units, rather than a simple physical mixture of the two. This ensures that the silver nanoparticles do not detach under mechanical friction, liquid rinsing, or even sterilization conditions. The release of antibacterial components is precisely regulated by the slow-release mechanism of the polymer network, avoiding the risk of explosive silver release.

[0042] 3. Addressing the industry challenge of drug adsorption and denaturation caused by active sites on coating surfaces, this invention abandons simple material blending and innovatively employs surface-initiated atom transfer radical polymerization technology to grow a dense, brush-like surface layer of zwitterionic polymers in situ on a silver-loaded substrate. This mechanism ensures that the surface layer is firmly grafted through covalent bonds, forming a high-density, highly oriented molecular brush. Its strong ionic hydration constructs a stable superhydrophilic hydration layer on the outermost side of the coating. This physical barrier effectively prevents internal silver particles and active amino groups from contacting the drug solution, while virtually eliminating non-specific adsorption of biomolecules (such as proteins and peptides) through the dual effects of "steric hindrance" and "hydration repulsion," thus resolving the core contradiction that functional coatings often compromise drug compatibility.

[0043] 4. Finally, this invention employs a multi-component epoxy compound to perform overall crosslinking of the composite coating. This step mechanistically achieves the "stitching" of the three-layer structure and the "passivation" of surface functional groups. Crosslinking not only enhances the mechanical integrity and solvent resistance of the coating at the molecular level, but more importantly, it further eliminates potential chemical reaction sites by consuming residual active amino groups on the surface. This covalent bond construction strategy (silanization, polymerization, crosslinking) throughout the entire preparation process enables the coating to form a fully covalently bonded organic whole from the substrate to the surface. Its structural stability, functional durability, and safety in use are far superior to existing coating technologies that rely on physical adsorption or simple crosslinking, providing a reliable solution for high-end pharmaceutical packaging. Attached Figure Description

[0044] Figure 1 This is a conceptual diagram of the pharmaceutical glass bottle of the present invention;

[0045] The structure consists of: 1. Glass substrate; 2. Barrier layer; 3. Silver particle composite layer; 4. Bonding layer.

[0046] Figure 2 This is a process flow diagram of the pharmaceutical glass bottle of the present invention;

[0047] Figure 3 In this invention, sodium citrate is used as a reducing agent to reduce Ag. + Reduced to silver atoms (Ag) 0 A schematic diagram of a chemical reaction;

[0048] Figure 4 This is a schematic diagram of the chemical reaction involved in constructing the barrier layer of this invention. Detailed Implementation

[0049] The technical solutions in the embodiments of the present invention will be clearly and completely described below in conjunction with existing known technologies. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments.

[0050] Example 1: A method for preparing a pharmaceutical glass bottle includes the following steps:

[0051] S1. Glass substrate pretreatment: sequential cleaning and drying, plasma activation, silanization reaction and curing are performed to form an aminosilanized layer, i.e. a bonding layer, on the inner wall of the glass substrate.

[0052] S2. Composite Layer Construction: The pretreated glass substrate is coated with a branched polyethyleneimine aqueous solution and dried. Then, it is immersed in a mixed aqueous solution of silver ions and a reducing agent for in-situ reduction, forming a branched polyethyleneimine / silver nanoparticle composite layer. Sodium citrate is added as a mild reducing agent; its citrate ions reduce Ag... + Reduced to silver atoms (Ag) 0The bPEI amino group can be oxidized, and at the same time, it prevents the aggregation of newly formed silver atoms through steric hindrance and coordination. The specific reaction is as follows: Figure 3 As shown;

[0053] S3. Barrier layer construction: Initiator immobilization and surface-initiated atom transfer radical polymerization reaction are carried out sequentially to graft an amphoteric polymer surface layer onto the surface of the silver particle composite layer.

[0054] Under ice bath and alkaline conditions (triethylamine), the acyl bromide group (-COBr) of 2-bromoisobutyryl bromide (ATRP initiator) undergoes a nucleophilic substitution reaction with the primary amino group (-NH2) on the surface of the bPEI / AgNPs composite layer, forming an amide bond (-CO-NH-). This covalently bonds the initiator molecule with a bromine atom (Br) to the surface. The specific reaction is as follows: Figure 4 As shown.

[0055] The surface layer of the zwitterionic polymer is a polysulfobetaine methacrylate layer.

[0056] S4, Crosslinking Inerting and Post-treatment: The glass substrate treated by S3 is immersed in an aqueous solution of crosslinking agent to carry out a crosslinking reaction, and then cured and treated with ultraviolet light to crosslink and inertate the active functional groups, thus obtaining a pharmaceutical glass bottle.

[0057] The glass substrate is a vial, ampoule, or infusion bottle made of borosilicate glass or soda-lime glass; the aminosilanized layer is made of 3-aminopropyltriethoxysilane; the branched polyethyleneimine has an average molecular weight of 20,000-30,000 Da; and the crosslinking agent is ethylene glycol diglycidyl ether.

[0058] In S1, the cleaning and drying process includes ultrasonically cleaning the glass substrate sequentially with piranha cleaning solution, deionized water, and anhydrous ethanol for 20 minutes each, drying it in a 100°C oven for 1 hour, and then heat-treating it in a 400°C muffle furnace for 2 hours.

[0059] The conditions for plasma activation were: oxygen introduction, power of 50W, and processing time of 5min.

[0060] The conditions for the silanization reaction are as follows: the activated glass substrate is immersed in a 1% (v / v) solution of 3-aminopropyltriethoxysilane ethanol for 1 hour, the curing temperature is 120℃, and the curing time is 1 hour.

[0061] In S2, the mass-volume concentration of the branched polyethyleneimine aqueous solution is 2%, the coating method is dip-coating, the coating speed is 100 mm / min, the drying temperature is 60℃, and the drying time is 30 min.

[0062] In the mixed aqueous solution of silver ions and reducing agent, the precursor of silver ions is silver nitrate, the reducing agent is sodium citrate, the concentration of silver ions is 0.5 mmol / L, the concentration of sodium citrate is 3 mmol / L, the in-situ reduction reaction temperature is 70℃, the reaction time is 2 h, and the reaction is carried out under light-protected conditions.

[0063] In S3, the initiator immobilization includes: placing the glass substrate treated in S2 in an ice bath, adding anhydrous dichloromethane and triethylamine, then adding a dichloromethane solution of 2-bromoisobutyryl bromide, reacting for 1 hour under nitrogen protection, and then washing with anhydrous dichloromethane and methanol alternately and drying with nitrogen after the reaction.

[0064] The concentration of 2-bromoisobutyryl bromide in dichloromethane solution is 0.05 mol / L, and the volume ratio of 2-bromoisobutyryl bromide to triethylamine is 1:1.2.

[0065] The surface-initiated atom transfer radical polymerization reaction was carried out under the following conditions: the reaction solution was prepared in an anhydrous and oxygen-free glove box; the concentration of sulfobetaine methacrylate monomer in the reaction solution was 0.8 mol / L; the molar ratio of cuprous bromide to monomer was 1:120; the molar ratio of ligand to cuprous bromide was 1.5-2.5:1; the ligand was N,N,N′,N′′,N′′-pentamethyldiethylenetriamine; the polymerization temperature was 30℃; and the reaction time was 6 h.

[0066] In step S4, the crosslinking agent aqueous solution is an aqueous solution of ethylene glycol diglycidyl ether with a volume ratio of 0.7%, the crosslinking reaction temperature is room temperature, and the reaction time is 2 hours.

[0067] The curing conditions are: curing in an oven at 80℃ for 4 hours;

[0068] The conditions for ultraviolet light irradiation are: wavelength 365nm, light intensity 40mW / cm². 2 The irradiation time is 10 minutes.

[0069] The thickness of the bonding layer is 0.5-2 nm, the thickness of the silver particle composite layer is 50-150 nm, and the thickness of the barrier layer is 80-200 nm.

[0070] Example 2: A method for preparing a pharmaceutical glass bottle includes the following steps:

[0071] S1. Glass substrate pretreatment: sequential cleaning and drying, plasma activation, silanization reaction and curing are performed to form an aminosilanized layer, i.e. a bonding layer, on the inner wall of the glass substrate.

[0072] S2. Composite layer construction: The pretreated glass substrate is immersed in a branched polyethyleneimine aqueous solution for coating and drying, and then immersed in a mixed aqueous solution of silver ions and reducing agent for in-situ reduction reaction to form a silver particle composite layer of branched polyethyleneimine / silver nanoparticles.

[0073] S3. Barrier layer construction: Initiator immobilization and surface-initiated atom transfer radical polymerization reaction are carried out sequentially to graft an amphoteric polymer surface layer onto the surface of the silver particle composite layer.

[0074] The surface layer of the zwitterionic polymer is a polysulfobetaine methacrylate layer.

[0075] S4, Crosslinking Inerting and Post-treatment: The glass substrate treated by S3 is immersed in an aqueous solution of crosslinking agent to carry out a crosslinking reaction, and then cured and treated with ultraviolet light to crosslink and inertate the active functional groups, thus obtaining a pharmaceutical glass bottle.

[0076] The glass substrate is a vial, ampoule, or infusion bottle made of borosilicate glass or soda-lime glass; the aminosilanized layer is made of 3-aminopropyltriethoxysilane; the branched polyethyleneimine has an average molecular weight of 20,000-30,000 Da; and the crosslinking agent is ethylene glycol diglycidyl ether.

[0077] In S1, the cleaning and drying process includes ultrasonically cleaning the glass substrate sequentially with piranha cleaning solution, deionized water, and anhydrous ethanol for 20 minutes each, drying it in a 100°C oven for 1 hour, and then heat-treating it in a 400°C muffle furnace for 2 hours.

[0078] The conditions for plasma activation were: oxygen introduction, power of 50W, and processing time of 5min.

[0079] The conditions for the silanization reaction are as follows: the activated glass substrate is immersed in a 2% (v / v) solution of 3-aminopropyltriethoxysilane ethanol for 1 hour, the curing temperature is 120℃, and the curing time is 1 hour.

[0080] In S2, the mass-volume concentration of the branched polyethyleneimine aqueous solution is 0.5%, the coating method is dip-coating, the coating speed is 100 mm / min, the drying temperature is 60℃, and the drying time is 30 min.

[0081] In the mixed aqueous solution of silver ions and reducing agent, the precursor of silver ions is silver nitrate, the reducing agent is sodium citrate, the concentration of silver ions is 1.2 mmol / L, the concentration of sodium citrate is 2 mmol / L, the in-situ reduction reaction temperature is 70℃, the reaction time is 2 h, and the reaction is carried out under light-protected conditions.

[0082] In S3, the initiator immobilization includes: placing the glass substrate treated in S2 in an ice bath, adding anhydrous dichloromethane and triethylamine, then adding a dichloromethane solution of 2-bromoisobutyryl bromide, reacting for 1 hour under nitrogen protection, and then washing with anhydrous dichloromethane and methanol alternately and drying with nitrogen after the reaction.

[0083] The concentration of 2-bromoisobutyryl bromide in dichloromethane solution is 0.1 mol / L, and the volume ratio of 2-bromoisobutyryl bromide to triethylamine is 1:1;

[0084] The surface-initiated atom transfer radical polymerization reaction was carried out under the following conditions: the reaction solution was prepared in an anhydrous and oxygen-free glove box; the concentration of sulfobetaine methacrylate monomer in the reaction solution was 1 mol / L; the molar ratio of cuprous bromide to monomer was 1:100; the molar ratio of ligand to cuprous bromide was 1.5-2.5:1; the ligand was N,N,N′,N′′,N′′-pentamethyldiethylenetriamine; the polymerization temperature was 30℃; and the reaction time was 6 h.

[0085] In step S4, the crosslinking agent aqueous solution is an aqueous solution of ethylene glycol diglycidyl ether with a volume ratio of 0.4, the crosslinking reaction temperature is room temperature, and the reaction time is 2 hours.

[0086] The curing conditions are: curing in an oven at 80℃ for 4 hours;

[0087] The conditions for ultraviolet light irradiation are: wavelength 365nm, light intensity 40mW / cm². 2 The irradiation time is 10 minutes.

[0088] The thickness of the bonding layer is 0.5-2 nm, the thickness of the silver particle composite layer is 50-150 nm, and the thickness of the barrier layer is 80-200 nm.

[0089] Example 3: A method for preparing a pharmaceutical glass bottle includes the following steps:

[0090] S1. Glass substrate pretreatment: sequential cleaning and drying, plasma activation, silanization reaction and curing are performed to form an aminosilanized layer, i.e. a bonding layer, on the inner wall of the glass substrate.

[0091] S2. Composite layer construction: The pretreated glass substrate is immersed in a branched polyethyleneimine aqueous solution for coating and drying, and then immersed in a mixed aqueous solution of silver ions and reducing agent for in-situ reduction reaction to form a silver particle composite layer of branched polyethyleneimine / silver nanoparticles.

[0092] S3. Barrier layer construction: Initiator immobilization and surface-initiated atom transfer radical polymerization reaction are carried out sequentially to graft an amphoteric polymer surface layer onto the surface of the silver particle composite layer.

[0093] The surface layer of the zwitterionic polymer is a polysulfobetaine methacrylate layer.

[0094] S4, Crosslinking Inerting and Post-treatment: The glass substrate treated by S3 is immersed in an aqueous solution of crosslinking agent to carry out a crosslinking reaction, and then cured and treated with ultraviolet light to crosslink and inertate the active functional groups, thus obtaining a pharmaceutical glass bottle.

[0095] The glass substrate is a vial, ampoule, or infusion bottle made of borosilicate glass or soda-lime glass; the aminosilanized layer is made of 3-aminopropyltriethoxysilane; the branched polyethyleneimine has an average molecular weight of 20,000-30,000 Da; and the crosslinking agent is ethylene glycol diglycidyl ether.

[0096] In S1, the cleaning and drying process includes ultrasonically cleaning the glass substrate sequentially with piranha cleaning solution, deionized water, and anhydrous ethanol for 20 minutes each, drying it in a 100°C oven for 1 hour, and then heat-treating it in a 400°C muffle furnace for 2 hours.

[0097] The conditions for plasma activation were: oxygen introduction, power of 50W, and processing time of 5min.

[0098] The conditions for the silanization reaction are as follows: the activated glass substrate is immersed in a 3% (v / v) solution of 3-aminopropyltriethoxysilane ethanol for 1 hour, the curing temperature is 120℃, and the curing time is 1 hour.

[0099] In S2, the mass-volume concentration of the branched polyethyleneimine aqueous solution is 0.5%, the coating method is dip-coating, the coating speed is 100 mm / min, the drying temperature is 60℃, and the drying time is 30 min.

[0100] In the mixed aqueous solution of silver ions and reducing agent, the precursor of silver ions is silver nitrate, the reducing agent is sodium citrate, the concentration of silver ions is 2 mmol / L, the concentration of sodium citrate is 1 mmol / L, the in-situ reduction reaction temperature is 70℃, the reaction time is 2 h, and the reaction is carried out under light-protected conditions.

[0101] In S3, the initiator immobilization includes: placing the glass substrate treated in S2 in an ice bath, adding anhydrous dichloromethane and triethylamine, then adding a dichloromethane solution of 2-bromoisobutyryl bromide, reacting for 1 hour under nitrogen protection, and then washing with anhydrous dichloromethane and methanol alternately and drying with nitrogen after the reaction.

[0102] The concentration of 2-bromoisobutyryl bromide in dichloromethane solution is 0.15 mol / L, and the volume ratio of 2-bromoisobutyryl bromide to triethylamine is 1:0.8;

[0103] The surface-initiated atom transfer radical polymerization reaction was carried out under the following conditions: the reaction solution was prepared in an anhydrous and oxygen-free glove box; the concentration of sulfobetaine methacrylate monomer in the reaction solution was 1.2 mol / L; the molar ratio of cuprous bromide to monomer was 1:80; the molar ratio of ligand to cuprous bromide was 2.5:1; the ligand was N,N,N′,N′′,N′′-pentamethyldiethylenetriamine; the polymerization temperature was 30℃; and the reaction time was 6 h.

[0104] In step S4, the crosslinking agent aqueous solution is an aqueous solution of ethylene glycol diglycidyl ether with a volume ratio of 0.3%, the crosslinking reaction temperature is room temperature, and the reaction time is 2 hours.

[0105] The curing conditions are: curing in an oven at 80℃ for 4 hours;

[0106] The conditions for ultraviolet light irradiation are: wavelength 365nm, light intensity 40mW / cm². 2 The irradiation time is 10 minutes.

[0107] The thickness of the bonding layer is 0.5-2 nm, the thickness of the silver particle composite layer is 50-150 nm, and the thickness of the barrier layer is 80-200 nm.

[0108] The following comparison model was also set:

[0109] Comparative Example 1: Based on Example 2, the difference is that the aminosilane coupling agent layer is omitted, and the branched polyethyleneimine / silver nanoparticle layer and subsequent coating are directly coated on the plasma-activated glass. The rest is the same as in Example 2.

[0110] Comparative Example 2: Based on Example 2, the difference is that instead of in-situ reduction of loaded silver nanoparticles, the pre-prepared silver nanoparticle sol and branched polyethyleneimine solution were directly mixed and then coated. The rest is the same as in Example 2.

[0111] Comparative Example 3: Based on Example 2, the difference is that after completing the construction of the branched polyethyleneimine / silver nanoparticle layer, the surface-initiated atom transfer radical polymerization growth of the zwitterionic polymer surface layer and the subsequent crosslinking steps are omitted, and it is used directly. The rest is the same as Example 2.

[0112] Comparative Example 4: Based on Example 2, the difference is that a physical coating double-layer structure is adopted, that is, a layer of silver-containing hydrophobic antibacterial coating is first coated, and then a layer of hydrophilic coating (polyvinylpyrrolidone) is physically coated. The rest is the same as Example 2.

[0113] Performance testing: Cytotoxicity was tested according to ISO 10993 "Biological evaluation of medical devices"; antimicrobial properties were tested according to ISO 22196 "Determination of antimicrobial activity of plastics and other nonporous surfaces"; coating adhesion was tested according to D3359 "Coating adhesion test"; and basic safety was tested according to YBB 00142002 "Leachate test for pharmaceutical glass containers". The results are shown in Table 1.

[0114] Table 1. Test results of various coating properties

[0115]

[0116] Data Analysis:

[0117] The three embodiments all exhibit excellent performance, the key to which lies in the chemical synergy of each step:

[0118] The aminosilane layer achieves strong anchoring through Si-O-Si covalent bonds (adhesion 5B); in-situ reduction allows silver nanoparticles to grow on the polymer network via coordination bonds, achieving highly efficient antibacterial activity and extremely low release (silver release <5 µg / L); the zwitterionic polymer brush constructed by surface-initiated polymerization provides an ultra-low adsorption interface through strong hydration (protein adsorption <0.6%); overall cross-linking further enhances the stability of this gradient network (intact after boiling). Although the parameters of all embodiments differ, this fundamental mechanism remains unchanged, thus the performance is consistent and excellent.

[0119] The comparative examples then reveal the consequences of missing any one of the chemical bonding steps:

[0120] Comparative Example 1 lacks covalent anchoring, resulting in weak interfacial bonding (adhesion 2B, blistering and peeling).

[0121] Comparative Example 2 changed the in-situ chemical anchoring to physical blending, resulting in weak silver binding and a high risk of explosive release (release > 50 µg / L).

[0122] Comparative Example 3 lacked an inert encapsulation layer, which directly exposed the active amino groups and silver, resulting in high protein adsorption (5.2%) and high silver release (35 µg / L).

[0123] Comparative Example 4 uses a physical double layer, which is very easy to separate due to the lack of chemical bonding between the layers (adhesion 1B, separation and peeling).

[0124] Data shows that attempts to simplify or replace core chemical bonding steps are likely to compromise the integrity of the system, leading to systemic defects in adhesion, safety, or compatibility.

[0125] The above description is only a preferred embodiment of the present invention, but the scope of protection of the present invention is not limited thereto. Any equivalent substitutions or modifications made by those skilled in the art within the scope of the technology disclosed in the present invention, based on the technical solution and inventive concept of the present invention, should be covered within the scope of protection of the present invention.

Claims

1. A pharmaceutical glass bottle, characterized in that, A composite coating comprising a glass bottle body and an inner wall thereof, wherein the composite coating comprises, from the inside out: The bonding layer is bonded to the glass surface by an aminosilane coupling agent; The silver particle composite layer, which is fixed to the bonding layer by covalent bonds, contains branched polyethyleneimine and silver nanoparticles generated in situ and anchored therein. Barrier layer, a zwitterionic polymer surface layer formed by grafting through a surface-initiated atom transfer radical polymerization reaction; The thickness of the bonding layer is 0.5-2 nm, the thickness of the silver particle composite layer is 50-150 nm, and the thickness of the barrier layer is 80-200 nm. The surface layer of the zwitterionic polymer is a polysulfobetaine methacrylate layer.

2. The molding process for a pharmaceutical glass bottle according to claim 1, characterized in that, Includes the following steps: S1. Glass substrate pretreatment: sequential cleaning and drying, plasma activation, silanization reaction and curing are performed to form an aminosilanized layer, i.e. a bonding layer, on the inner wall of the glass substrate. S2. Composite layer construction: The pretreated glass substrate is immersed in a branched polyethyleneimine aqueous solution for coating and drying, and then immersed in a mixed aqueous solution of silver ions and reducing agent for in-situ reduction reaction to form a silver particle composite layer of branched polyethyleneimine / silver nanoparticles. S3. Barrier layer construction: Initiator immobilization and surface-initiated atom transfer radical polymerization reaction are carried out sequentially to graft an amphoteric polymer surface layer onto the surface of the silver particle composite layer. S4, Crosslinking Inerting and Post-treatment: The glass substrate treated by S3 is immersed in an aqueous solution of crosslinking agent to carry out a crosslinking reaction, and then cured and treated with ultraviolet light to crosslink and inertate the active functional groups, thus obtaining a pharmaceutical glass bottle.

3. The molding process for a pharmaceutical glass bottle according to claim 2, characterized in that, The glass substrate is a vial, ampoule, or infusion bottle made of borosilicate glass or soda-lime glass; the aminosilanized layer is made of 3-aminopropyltriethoxysilane; the branched polyethyleneimine has an average molecular weight of 20,000-30,000 Da; and the crosslinking agent is ethylene glycol diglycidyl ether.

4. The molding process for a pharmaceutical glass bottle according to claim 2, characterized in that, In step S1, the cleaning and drying process includes ultrasonically cleaning the glass substrate sequentially with piranha cleaning solution, deionized water, and anhydrous ethanol for 15-25 minutes each, drying it in a 100°C oven for 0.5-1.5 hours, and then heat-treating it in a muffle furnace at 300-400°C for 1.5-2.5 hours. The conditions for plasma activation are: oxygen introduction, power of 40-60W, and processing time of 3-7 minutes; The conditions for the silanization reaction are as follows: the activated glass substrate is immersed in a 1%-3% (v / v) 3-aminopropyltriethoxysilane ethanol solution for 0.5-1.5 h, the curing temperature is 100-120 °C, and the curing time is 0.5-1.5 h.

5. The molding process for a pharmaceutical glass bottle according to claim 2, characterized in that, In S2, the mass-volume concentration of the branched polyethyleneimine aqueous solution is 0.5%-2%, the coating method is dip-coating, the coating speed is 80-120 mm / min, the drying temperature is 50-70℃, and the drying time is 20-40 min. In the mixed aqueous solution of silver ions and reducing agent, the precursor of silver ions is silver nitrate, the reducing agent is sodium citrate, the concentration of silver ions is 0.5-2 mmol / L, the concentration of sodium citrate is 1-3 mmol / L, the in-situ reduction reaction temperature is 50-70℃, the reaction time is 1.5-2.5 h, and the reaction is carried out under light-protected conditions.

6. The molding process for a pharmaceutical glass bottle according to claim 2, characterized in that, In step S3, the initiator immobilization includes: placing the glass substrate treated in step S2 in an ice bath, adding anhydrous dichloromethane and triethylamine, then adding a dichloromethane solution of 2-bromoisobutyryl bromide dropwise, reacting under nitrogen protection for 0.5-1.5 h, and after the reaction, washing alternately with anhydrous dichloromethane and methanol and drying with nitrogen. The concentration of 2-bromoisobutyryl bromide in dichloromethane solution is 0.05-0.15 mol / L, and the volume ratio of 2-bromoisobutyryl bromide to triethylamine is 1:0.8-1.2; The conditions for surface-initiated atom transfer radical polymerization are as follows: the reaction solution is prepared in an anhydrous and oxygen-free glove box; the concentration of sulfobetaine methacrylate monomer in the reaction solution is 0.8-1.2 mol / L; the molar ratio of cuprous bromide to monomer is 1:80-120; the molar ratio of ligand to cuprous bromide is 1.5-2.5:1; the ligand is N,N,N′,N′′,N′′-pentamethyldiethylenetriamine; the polymerization temperature is 25-35℃; and the reaction time is 5-7 h.

7. The molding process for a pharmaceutical glass bottle according to claim 2, characterized in that, In step S4, the crosslinking agent aqueous solution is an aqueous solution of ethylene glycol diglycidyl ether with a volume ratio of 0.3%-0.7%, the crosslinking reaction temperature is room temperature, and the reaction time is 1.5-2.5 h; The curing conditions are: curing in an 80℃ oven for 3-5 hours; The conditions for ultraviolet light irradiation are: wavelength 365nm, light intensity 20-50mW / cm². 2 The irradiation time is 8-12 minutes.

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