TW202110415A - Packaging bottle and packaging kit for injection, and filling, stoppering and capping device and method - Google Patents

Abstract

A packaging bottle and packaging kit for an injection, and a filling, stoppering and capping device and method. The packaging bottle comprises: a bottle body; a rubber stopper assembly for plugging into the bottle mouth of the bottle body; and a cap disposed on the rubber stopper assembly to clip and fix the bottle mouth and the rubber stopper assembly, the rubber stopper assembly comprising a rubber stopper and a covering layer directly attached to the exposed surface of the rubber stopper facing the bottle mouth, there being no adhesive layer between the covering layer and the rubber stopper, the covering layer being a polytetrafluoroethylene layer, a polyvinylidene fluoride layer, a tetrafluoroethylene/hexafluoropropylene copolymer layer or a composite layer of at least two; a gap being formed on the top of the cap to expose the rubber stopper for easy puncture. Also provided are a corresponding packaging kit for AST-3424 injection and method. The requirements for the packaging bottle for AST-3424 injection that is separated from an ethanol/propylene glycol solvent to ensure the stability there is no contamination between the injection and the packaging bottle stopper can be satisfied.

Description

Pouring, stoppering and capping device and method for liquid medicine packaging bottle with protrusions

The present invention relates to a patent application PCT/US2016/021581, publication number WO2016145092A1, corresponding to Chinese application number 2016800150788, publication number CN107530556A disclosed compound TH-2870 and PCT/US2016/062114, publication number WO2017087428A1, corresponding to Chinese application number 2016800446081, published The research and development of the injection preparation of the S configuration compound in No. CN108290911A, especially the exclusive packaging bottle specially developed for the injection preparation, belongs to the field of pharmaceutical packaging.

AST-3424的化學結構式The DNA alkylation cancer therapeutic drug AST-3424 developed by our company (Mainland China Shenzhen Aixindawei Pharmaceutical Technology Co., Ltd.) targets the overexpression of aldehyde ketone reductase 1C3 (AKR1C3) (see patent application: DNA alkylating agent, Corresponding to PCT application number PCT/US2016/021581, publication number WO2016/145092, corresponding to Chinese application number 2016800150788, publication number CN107530556A discloses compound TH2870; (R)- and (S)-1-(3-(3-N, N -Dimethylaminocarbonyl)phenoxy-4-nitrophenyl)-1-ethyl-N, N'-bis(ethylene)amino phosphate, composition and its use and preparation method, corresponding PCT application number PCT/US2016/062114, publication number WO2017087428A1, corresponding to Chinese application number 2016800446081, the S configuration compound in publication number CN108290911A), the Chinese name is (S)-1-(3-(3-N, N-二) Methylaminocarbonyl)phenoxy-4-nitrophenyl)-1-ethyl-N, N'-bis(ethylene) phosphoramidate, also known as the S configuration of OBI-3424 and TH-2870 Compound), CAS number is 209713-69-2, and its structure is as follows:

The chemical structure of AST-3424

There have been industry authoritative documents (Kathryn Evans, Jian Xin Duan, Tara Pritchard, et al. OBI-3424, a novel AKR1C3-activated prodrug, exhibits potent efficacy against preclinical models of T-ALL [J], Clinical Cancer Research, 2019, DOI: 10. 1158/1078-0432. CCR-19-0551; Richard B. Lock, Kathryn Evans, Raymond Yung, Tara Pritchard, Beverly A. Teicher, Jian Xin Duan, Yuelong Guo, Stephen W. Erickson and Malcolm A. Smith, Abstract LB-B16:The AKR1C3-Activated Prodrug OBI-3424 Exerts Profound In Vivo Efficacy Against Preclinical Models of T-Cell Acute Lymphoblastic Leukemia (T-ALL); a Pediatric Preclinical Testing Consortium Study [C], AACR-NCI- EORTC International Conference: Molecular Targets and Cancer Therapeutics; October 26-30, 2017; Philadelphia, PA, DOI: 10. 1158/1535-7163.) confirmed that the compound is a broad-spectrum small molecule anti-cancer prodrug, which is effective against multiple entities Tumors and hematological tumors have curative effects.

In order to carry out subsequent clinical trials, it is necessary to prepare a suitable dosage form for human administration: usually oral or injection administration.

During the synthesis and preparation process, it was found that the substance was a light yellow oily substance, and there were many difficulties in storage, transportation and preparation: due to the structure of amide and phosphate ester, the development of tablets and oral liquid dosage forms for oral administration was inconvenient. However, research and development The team’s preliminary experiment found that the stability of conventional injections that use water as a solvent is not enough to meet the requirements of follow-up multi-center, multi-sample long-term clinical trials and commercial production and sales.

After experimental research, it is found that the compound can be better dissolved in similar solvent systems such as ethanol. Therefore, concentrated injection preparations prepared from solvents such as ethanol and propylene glycol have a higher content of ethanol. At the same time, the injection is still better than conventional water-based injections. The mobile phase is weak and viscous. The structure of the conventionally used water-based injection packaging bottle (medicine bottle or ampoule bottle) cannot meet the requirements:

As shown in Figure 8, a typical vial (refer to the Chinese New Bulletin CN201445645U, publication date 2010.05.05) includes a bottle body 1, a rubber stopper 2 and a cover 3, sometimes also set in the cover Protective cover 4. Since the rubber stoppers used are mostly rubber materials, the properties of AST-3424 compound are relatively active. Therefore, it is very likely that the rubber will dissolve in ethanol after contact with the injection solution, which will affect the stability of the injection solution.

A possible response strategy is to cover the conventional rubber stopper 2. A typical rubber stopper after film coating (see Chinese Utility Model Publication CN2612625Y, publication date 2004.04.21) has the structure shown in Figure 9. The rubber plug includes a base body 5, a plug body 6 and a covering film 7.

Obviously, it is a more suitable and economical choice to ensure the packaging stability of the injection solution by coating the film 7 on the surface of the plug body 6 to isolate the AST-3424 injection solution of ethanol/propylene glycol solvent.

The existing film-coated rubber stoppers directly bond the film material to the outer surface of the rubber stopper through a film or an adhesive. When in use: Need to use a syringe needle to pierce the membrane, and then suck a predetermined volume of injection, so that there are two punctures through the membrane, and because the membrane is adhered to the surface of the rubber stopper, there is contamination during the puncture process risks of.

In the industry, the liquid medicine, whether it is an injection for injection administration or an oral liquid for oral administration, is packaged with the structure of the above-mentioned Figures 8 and 9.

However, there is a problem with the above packaging. It is impossible to quickly know whether it has been used by its appearance: for injections or oral liquids, although the protective cover is removed, it means that the packaging is unsealed, but whether the syringe needle has been pierced and sucked by the liquid Or if it has been injected with other substances, it is not easy to detect quickly. Of course, it can be found by carefully observing the needle eye on the rubber stopper 2, but it is time-consuming and troublesome.

In addition, for the sealing effect of the packaging bottle with this structure, because the rubber stopper is plugged on the bottle mouth of the bottle body, and then the cover 3 is added for fixing and pressing, but in the long-term storage, if leakage occurs, the medicine Liquid deterioration cannot be quickly and intuitively judged by naked eye observation.

It is the subject of the present invention to find a suitable packaging bottle of AST-3424 injection that isolates the ethanol/propylene glycol solvent to ensure the stability of the injection and the packaging bottle stopper without contamination, and the rubber stopper film structure is the key.

Through investigation, there are many film-forming materials on the market. After the preliminary screening of medical materials, the most commonly used and easily available medical materials are obtained: polyether resin PES, polytetrafluoroethylene PTFE, polyvinylidene difluoride Experiments were carried out on membrane materials of different grades of ethylene PVDF, tetrafluoroethylene/hexafluoropropylene copolymer FEP.

The experiment used the following commercially available membrane materials, the specific conditions are as follows: Table 1: Filter membrane material parameter table of different materials and different brands Material Experimental group Grade Thickness μm Aperture μm Brand Polyether resin PES PES-1 Supor 132 0.1 Pall Corporation PES-2 Supor 145 0.2 Pall Corporation PES-3 Supor 140 0.45 Pall Corporation PTFE PTFE-1 TF-200 47 0.2 Pall Corporation PTFE-2 no 135 0.45 Pall Corporation Polyvinylidene fluoride PVDF PVDF-1 Biotrace 147 0.45 Pall Corporation Tetrafluoroethylene/hexafluoropropylene copolymer FEP FEP-1 no 44 Non-filter membrane Dupont FEP-2 no 75 Non-filter membrane Dupont FEP-3 no 125 Non-filter membrane Dupont Note: FEP membranes are not supplied with filter membranes.

In the experiment, the membrane of the corresponding material was used for soaking or the filter membrane was used for filtration to simulate the influence of the interaction of the ethanol/propylene glycol solvent AST-3424 injection on the stability of the injection.

Experiments have proved that the injection is essentially a solvent and bulk drug composed of 0.75 ml of absolute ethanol, 0.25 ml of anhydrous propylene glycol and 10 mg of AST-3424 bulk drug. This injection is used for experimental verification.

In the experimental verification, the coated control group used a rubber stopper with a polytetrafluoroethylene coated (adhered through an adhesive).

Preparation of unfiltered AST-3424 injection: 100 ml of AST-3424 injection is prepared by dissolving 75 ml of absolute ethanol, 25 ml of anhydrous propylene glycol, and 1 g of AST-3424 bulk drug in the ratio of solvent and bulk drug.

Filter AST-3424 injection through filtration membranes of different materials and brands fixed on the glass filter holder: collect the first 10 ml AST-3424 filtrate obtained through membrane filtration as the initial filtrate, and collect the remaining part as the final filtrate.

Unfiltered AST-3424 injection was used as a blank control solution.

The FEP-1, FEP-2, and FEP-3 corresponding to the tetrafluoroethylene/hexafluoropropylene copolymer FEP film group are the solutions after immersing in the AST-3424 injection for 8 hours.

The film-coated control group soaking solution uses polyether resin, polytetrafluoroethylene film, and polyvinylidene fluoride rubber plugs adhered by an adhesive to the above 10 ml AST-3424, and the time is 8 hour.

After the puncture injection of the coated control group, a rubber stopper adhered by polyvinylidene fluoride through an adhesive was inserted into the mouth of the glass syrup bottle filled with the above-mentioned AST-3424 injection, and the needle of a 1 ml syringe was inserted into the rubber stopper. , By tilting a certain angle to release the needle from the injection solution to inhale a certain volume of injection solution, then withdraw the needle, invert the remaining injection solution twice in the bottle body, open the bottle stopper, and directly sample and analyze.

Visually inspect the appearance of the filtrate and analyze the content of AST-3424 and the content of impurities in the sample.

Directly, according to the actual situation, the above-mentioned different materials and different brands of membrane materials (not filter membranes) should be pasted on the rubber stoppers, and then these rubber stoppers should be covered with the above-mentioned AST-3424 injection solution. In the medicine bottle, and store according to the actual use environment, and then sample and test the injection in the medicine bottle after 24 months of design, and perform HPLC testing to investigate the material, brand, thickness and stability (content and impurities of these membranes) ), but in fact, this operation is unrealistic. For this reason, the idea of speeding up the development of this project is to use the filtration operation of the filter membrane material of the above-mentioned material, brand, thickness, and pore size to replace the long-term contact effect. This is Since the injection liquid flows out of the filter holes of these filter membranes, the actual non-porous impermeable membrane is replaced by a permeable filter membrane to simulate and strengthen this long-term contact effect, so the results of the filter membrane experiment performed above It can represent the influence of membrane material, brand and thickness on stability (content and impurities).

HPLC analysis was performed on the filtrate obtained from the above-mentioned filter membranes of different materials and different brands, the blank control solution, the soaking solution of the film-coated control group, and the injection solution of the film-coated control group.

HPLC method was used to determine the content: AST-3424 was used as an external standard for quantification.

UVDAD detector wavelength 230nm, C18 column, column temperature 25°C.

Mobile phase: A: 10 mmol/L ammonium acetate solution in which ammonium acetate is dissolved in a mixed solvent of 95% water and 5% acetonitrile by volume; B: 8 mmol/L ammonium acetate solution in which ammonium acetate is dissolved in a mixed solvent of 95% acetonitrile and 5% water by volume; Perform gradient elution.

The test results are shown in Table 2 below, and each sample is tested twice and the average value is taken. Table 2: AST-3424 content and impurity content of different samples Filter membrane material Exterior content% Impurities% Blank control solution Light yellow liquid 98.9 1.21 PES-1 Initial filtrate Light yellow liquid 100.6 1.24 Final filtrate Light yellow liquid 100.7 1.24 PES-2 Initial filtrate Light yellow liquid 100.3 1.23 Final filtrate Light yellow liquid 100.5 1.22 PES-3 Initial filtrate Light yellow liquid 99.8 1.24 Final filtrate Light yellow liquid 99.7 1.25 PTFE-1 Initial filtrate Light yellow liquid 100.5 1.26 Final filtrate Light yellow liquid 102.4 1.25 PTFE-2 Initial filtrate Light yellow liquid 100.9 1.26 Final filtrate Light yellow liquid 103.1 1.25 PVDF-1 Initial filtrate Light yellow liquid 100.4 1.16 Final filtrate Light yellow liquid 100.5 1.19 FEP-1 After soaking for 8 hours Light yellow liquid 99.8 1.20 FEP-2 After soaking for 8 hours Light yellow liquid 99.7 1.22 FEP-3 After soaking for 8 hours Light yellow liquid 99.1 1.21 Soaking solution for coated control group PES-1 Light yellow liquid 100.4 1.39 PTFE-1 Light yellow liquid 100.7 1.29 PVDF-1 Light yellow liquid 100.3 1.37 FEP-3 Light yellow liquid 99.8 1.31 Post-puncture injection for covered control group PVDF-1 Light yellow liquid 100.4 1.38 Experimental results

Among the three filtration membrane materials, except for the samples filtered through PTFE, the content determination level of all samples before and after filtration remained unchanged. The measured value of the sample filtered through PTFE increased slightly. The reason may be due to some evaporation of ethanol. The impurities of all samples did not change significantly during the test filtration process, but considering the long-term storage of the injection, compared with the other two membrane materials, the PVDF filtrate has the least impurities. Therefore, according to the experiment, it is recommended to use the most excellent PVDF membrane material for the rubber stopper packaging of AST-3424 injection.

Further analysis, comparing the impurity content of the soaking solution of the film-coated control group and the injection of the film-coated control group after puncture, it can be found that the impurity content is increased, and a new injection that is not in the filter membrane material group appears in the HPLC analysis peak. The new impurities appearing in the liquid, that is, AST-3424 injection is very likely to dissolve the adhesive used in the coated control group.

From the above comparison, it can be seen that the traditional film-coated rubber stopper has the risk of contamination to the packaging of AST-3424 injection. For this reason, the rubber stopper of the packaging bottle of the present invention should use the "deformation pressing" operation, without using any adhesive or other additives: when the rubber stopper is capped, the round film material should be placed on the rubber stopper Then press the film material first and the rubber plug on the bottom, and use the deformation (plastic deformation and/or elastic deformation) of the film material during the pressing process to adhere and seal with the rubber plug.

After the above-mentioned membrane material is determined, the test shows that the thickness of the membrane material has little effect, and those skilled in the art can independently choose according to the actual situation and the elasticity of the rubber stopper. According to the actual situation and cost, it can be clear that the above test shows that the film material with a thickness of 50-150 microns in the preferred range meets the requirements. Thicker or thinner film materials may make the pressing operation difficult or increase costs, and too thick film materials also have more risks of impurities. Therefore, the inventors give the above recommended values based on experience.

For this reason, based on the above experiments, the present invention provides the following solutions.

1. Packaging bottle Packaging bottle for AST-3424 injection. AST-3424 injection is essentially an injection consisting of 0.75 ml of absolute ethanol, 0.25 ml of anhydrous propylene glycol, and 10 mg of AST-3424 raw materials in the ratio of solvents and raw materials. include: Bottle body, used to hold AST-3424 injection; Rubber stopper assembly, used to plug into the mouth of the bottle; The cap is used to fix the bottle mouth and the rubber stopper assembly on the rubber stopper assembly, Wherein, the rubber stopper assembly includes a rubber stopper and a coating layer directly attached to the exposed surface of the rubber stopper facing the bottle mouth. There is no adhesive layer between the coating layer and the rubber stopper, and the coating layer is polytetrafluoroethylene. Vinyl fluoride layer, polyvinylidene fluoride layer, tetrafluoroethylene/hexafluoropropylene copolymer layer or a composite layer of at least two, A gap is formed on the top of the cover to expose the rubber plug for easy puncture.

Preferably, the covering layer is a polyvinylidene fluoride layer.

Alternatively, the covering layer is a two-layer composite layer on the surface and the inner layer, the surface layer is polyvinylidene fluoride, and the inner layer is a polytetrafluoroethylene layer and/or a tetrafluoroethylene/hexafluoropropylene copolymer layer.

It is recommended that the thickness of the covering layer is 50-150 microns.

Generally, the bottle body is a glass potion bottle.

Since the injection is stable under neutral or weak alkaline, the bottle body is a neutral or alkaline borosilicate glass bottle.

Further, since the injection solution will deteriorate and degrade under light conditions, the bottle body is an opaque or low light transmittance bottle body. Generally use brown glass bottles or the above-mentioned polytetrafluoroethylene, polyvinylidene fluoride, tetrafluoroethylene/hexafluoropropylene copolymer material bottle body (or other material bottle body but the inner wall has the above-mentioned material coating isolation ).

Further, the rubber plug includes a base body and a plug body connected to the base body. The outer end surface of the plug body has a concave structure; correspondingly, the covering layer is at least bonded to the surface of the plug body, but does not adhere to the inner wall formed by the concave structure so that A closed cavity is formed between the recessed structure and the covering layer.

It is recommended that the rubber stopper is a chlorinated butyl rubber stopper.

Further, the covering layer forms outward protrusions due to the action of the compressed gas in the closed cavity formed between the recessed structure and the covering layer.

The packaging bottle provided by the present invention does not use any adhesive or other auxiliaries due to the special "deformation pressing" operation: when pressing the rubber stopper, the round film material (that is, the above-mentioned covering Layer) is placed under the rubber stopper, and then presses the film material on the bottom and the rubber stopper on top. The deformation of the film material (plastic deformation and/or elastic deformation) during the pressing process is used to adhere to the rubber stopper. Sealing. In this process, because there is a cavity between the recessed structure of the rubber plug and the covering layer, and in the rapid pressing process, the gas (pressing under a protective gas atmosphere) is press-fitted and sealed in this cavity The cavity makes the internal pressure larger than the outside and forms a protruding bulge.

This design is for two purposes: Verify air tightness and verify whether the package is damaged. Since compressed gas is sealed in the protruding bulge, it can be pre-measured or marked (marked on the bottle body) according to the operating pressure during the capping operation. Once the airtightness fails or is used And piercing the bulge (whether maliciously or normally used) will cause the protruding bulge to collapse due to the escape of compressed gas. Therefore, by observing whether the protruding bulge collapses, whether it collapses beyond the mark set on the bottle body in advance, the air tightness can be verified, whether the package is damaged, and whether it has been used.

Quickly make the solvent evaporated in the injection drip into the bottle. Since the shape of the protruding bulge is almost "V" shape, the solvent (mainly ethanol) that evaporates and condenses from the injection liquid in the bottle can be collected to the lowest point of the center through this bulge, so as to drip faster. Falling, so that the possibility of changing the concentration of the injection solution in the bottle is reduced. Since AST-3424 is a highly active anti-tumor drug, and the injection volume is calculated according to the labeled concentration when using it, evaporation and condensation will make the actual concentration higher than the indicated concentration. The drug content of the injection volume calculated in this way is Will be higher than the predetermined amount, which will increase the risk of medication. The use of the above scheme can reduce this risk to a certain extent.

Furthermore, the packaging bottle also has a protective cover, The protective cover has a cylindrical cover part and a ring-shaped necked part connected with the cylindrical cover part, The cylindrical cap part is used to cover the substrate, and the neck part is used to cover the bottle mouth. The protective cover is buckled and covers the gap formed on the top of the cover so that the exposed rubber plug is covered.

2. Liquid medicine filling method Since a special protruding bulge structure is also designed between the rubber stopper and the covering layer of the present invention, the present invention actually provides a corresponding liquid medicine filling method for this purpose.

The method for producing a liquid medicine packaging bottle with a rubber stopper having a protruding structure includes the following operations: When pressing the rubber stopper, place the covering layer under the rubber stopper, and then perform a pressing process with the covering layer on the bottom and the rubber stopper on top. The deformation of the membrane material (plastic deformation and/or plastic deformation) is used during the pressing process. Or elastic deformation) to be attached to the rubber plug and sealed to complete the gland of the rubber plug.

The specific production flow chart of AST-3424 pharmaceutical preparations is shown in Figure 1. Step 1: Dissolve and mix Step 2-1: Add ethanol solution Weigh the prescription amount of AST-3424 API (with heat source removed) in a beaker, and put it into the ingredient tank. Add 50% of the prescription amount of medicinal absolute ethanol (the heat source has been removed) and stir to dissolve (dissolving time 15 min, stirring speed 50 HZ, or 50 revolutions per minute). Step 2-2: Add propylene glycol Add the prescription amount of propylene glycol (the heat source has been removed), and stir until it dissolves (dissolving time 15 min, stirring speed 50HZ, namely 50 revolutions per minute). Step 2-3: Mix Add 50% of the prescription amount of medicinal absolute ethanol (the heat source has been removed), and stir until it dissolves (dissolving time 15 min, stirring speed 50 HZ, or 50 revolutions per minute). Step 3: Sterilization The solution obtained in step 2 is sterilized. Step 4: Aseptic filling and stoppering Perform aseptic filling with 1.0-1.2 ml (0.860-1.032 g) of the above-mentioned AST-3424 injection. When the rubber stopper is added after filling, the covering layer is placed under the rubber stopper, and then the covering layer is on the bottom and the rubber stopper is on the top. The deformation of the film during the pressing process (plastic Deformation and/or elastic deformation) to adhere to the rubber plug and seal to complete the gland of the rubber plug. Step 5: Capping and visual inspection The filled medicine bottle is transferred to the capping room through the conveyor belt for capping: pressurized aluminum cap and protective cap. Perform visual inspection. Step 6: Release inspection Sample AST-3424 injection for QC inspection, and store it at -20 ℃ during clinical use after QA release.

The liquid medicine filling method provided by the present invention does not use any adhesives or other auxiliaries due to the special "deformation pressing" operation: when pressing the rubber stopper, the circular membrane material (that is, the above-mentioned The covering layer) is placed under the rubber stopper, and then presses the film material down and the rubber stopper up. The deformation of the film material (plastic deformation and/or elastic deformation) during the pressing process is used to combine with the rubber The plug is attached and sealed. In this process, due to the cavity between the concave structure of the rubber plug and the covering layer, the gas (compressed under a protective gas atmosphere) will be compressed and sealed during the rapid pressing process. In this cavity, the internal pressure is greater than the outside, and a protruding bulge is formed.

This design is for two purposes: Verify air tightness and verify whether the package is damaged. Since compressed gas is sealed in the protruding bulge, it can be pre-measured or marked (marked on the bottle body) according to the operating pressure during the capping operation. Once the airtightness fails or is used And piercing the bulge (whether maliciously or normally used) will cause the protruding bulge to collapse due to the escape of compressed gas. Therefore, by observing whether the protruding bulge collapses, whether it collapses beyond the mark set on the bottle body in advance, the air tightness can be verified, whether the package is damaged, and whether it has been used.

Quickly make the solvent evaporated in the injection drip into the bottle. Since the shape of the protruding bulge is almost "V" shape, the solvent (mainly ethanol) that evaporates and condenses from the injection liquid in the bottle can be collected to the lowest point of the center through this bulge, so as to drip faster. Falling, so that the possibility of changing the concentration of the injection solution in the bottle is reduced. Since AST-3424 is a highly active anti-tumor drug, and the injection volume is calculated according to the labeled concentration when using it, evaporation and condensation will make the actual concentration higher than the indicated concentration. The drug content of the injection volume calculated in this way is Will be higher than the predetermined amount, which will increase the risk of medication. The use of the above scheme can reduce this risk to a certain extent.

3. Liquid medicine packaging bottle with rubber stopper with protruding structure

Further, based on the above experiments and the analysis of the principle and beneficial effects of directly covering the film material on the rubber stopper to form a protruding structure (bulge), the present invention also provides the following solution for the liquid medicine packaging bottle with the protruding structure of the rubber stopper.

A liquid medicine packaging bottle with a rubber stopper with a protruding structure is used for packaging liquid medicine. The liquid medicine can be AST-3424 injection or other liquid medicine, which includes: Bottle body, used to contain liquid medicine; The rubber stopper assembly is used to plug into the mouth of the bottle body, including a rubber stopper and a coating layer directly attached to the exposed surface of the rubber stopper facing the mouth of the bottle; The cap is used to fix the bottle mouth and the rubber stopper assembly on the rubber stopper assembly, Wherein, the rubber plug includes a base body and a plug body connected to the base body, and the outer end surface of the plug body has a recessed structure, Correspondingly, the covering layer is at least bonded to the surface of the plug body, but does not adhere to the inner wall formed by the recessed structure so that a closed cavity is formed between the recessed structure and the covering layer, The covering layer forms outward protrusions or bulges due to the action of the compressed gas in the enclosed cavity formed between the recessed structure and the covering layer.

Obviously, the rubber stopper is made of elastic material, preferably rubber, more preferably medicinal chlorinated butyl rubber.

Further, there is no adhesive layer between the covering layer and the rubber stopper, and the covering layer is a polytetrafluoroethylene layer, a polyvinylidene fluoride layer, a tetrafluoroethylene/hexafluoropropylene copolymer layer or at least two Kind of composite layer.

Further, the covering layer is a polyvinylidene fluoride layer.

Furthermore, the coating layer is a copolymer layer of tetrafluoroethylene/hexafluoropropylene.

It is recommended that the thickness of the covering layer is 50-150 microns.

The bottle body and rubber stopper of the above-provided packaging bottle use conventional existing medicine bottle and corresponding rubber stopper. When the rubber stopper is capped after filling, the covering layer is placed under the rubber stopper, and then according to the covering layer. , The rubber plug is pressed together once, and the deformation (plastic deformation and/or elastic deformation) of the film material during the pressing process is used to adhere and seal the rubber plug to complete the gland of the rubber plug. In this process, because there is a cavity between the recessed structure of the rubber plug and the covering layer, the gas (compressed under a protective gas atmosphere) is compressed and sealed in this cavity during the rapid pressing process Make the internal pressure larger than the outside and form a protruding bulge.

This design is for two purposes: Verify air tightness and verify whether the package is damaged. Since compressed gas (mostly inert gas, such as nitrogen) is sealed in the bulge of this protrusion, the height of this bulge can be pre-measured or marked (marked on the bottle body) according to the operating pressure in the capping operation. Once Unqualified air-tightness or puncture of the bulge (whether malicious or normal use) will cause the protruding bulge to collapse due to the escape of compressed gas. Therefore, by observing whether the protruding bulge collapses, whether it collapses beyond the mark set on the bottle body in advance, the air tightness can be verified, whether the package is damaged, and whether it has been used.

Quickly make the solvent evaporated in the injection drip into the bottle. Since the shape of the protruding bulge is almost "V" shape, so that the condensed solvent (such as volatile ethanol or other liquid medicine containing volatile components) that evaporates from the injection liquid in the bottle can be collected through this bulge To the lowest point in the center, it will drop faster, so that the possibility of changing the concentration of the liquid medicine in the bottle is reduced.

Obviously, this design is very important for some highly active anti-tumor drugs or other injections: when these liquids are used, the extraction volume is calculated based on the labeled concentration. Evaporation and condensation will make the actual concentration higher than the indicated concentration. This calculation The drug content of the extracted volume of liquid medicine will be higher than the predetermined amount, which will increase the risk of medication. The use of the above scheme can reduce this risk to a certain extent.

Further, in order to make the position change of the above-mentioned bulge or protrusion more intuitive, a scale line is provided on the bottle body or the neck part of the bottle body (medicine bottle) to mark the design position of the protrusion or bulge.

It is recommended that the above-mentioned scale line is actually a wide marking band, which includes two engraved circles, the upper circle is the low temperature position during design, and the bottom circle is the high temperature position during design: that is, the packaging bottle is designed to accommodate the corresponding The lowest point of the protrusion or bulge is located at the upper ring corresponding to the low temperature position at the designed lowest temperature, and the lowest point of the protrusion or bulge is located at the lower ring corresponding to the high temperature position at the designed highest temperature.

Once the air tightness is unqualified or the bulge is pierced by use (either maliciously or normally), the protrusion or bulge will collapse due to the release of compressed gas. At this time, the protrusion or bulge must be positioned at the above-mentioned low temperature position. Above the upper circle (corresponding to unqualified air tightness) or disappear directly (corresponding to being used and piercing the bulge).

Four, packaging kit A packaging kit for AST-3424 injection, including: Packing box A gas protection bag, which is filled with a protection gas greater than atmospheric pressure, is set in the packaging box; The packaging bottle is enclosed in a gas protective bag; Among them, the packaging bottle is the aforementioned packaging bottle for AST-3424 injection. As a further protection, the gas protection bag is filled with nitrogen gas, and the material of the gas protection bag is aluminum-plastic double-layer composite material.

Generally, the packaging bottle is a brown, light-proof glass syrup bottle of 2/5/10 ml specification.

The present invention provides a filling, stoppering and capping device for a medicinal solution packaging bottle with protrusions, which integrally completes the filling, stoppering and capping of the medicinal solution, so the obtained packaging bottle can solve the above two problems.

The traditional film-coated rubber stopper is directly inserted into the bottle mouth. The rubber stopper of the packaging bottle of the present invention uses the "deformation pressing" operation, with or without any adhesive or other additives: when the rubber stopper is capped , Place the elastic covering layer (membrane material) under the rubber stopper, and then pre-press the covering layer (membrane material) to obtain a protruding structure, and then press the rubber stopper, using the membrane material in the pressing process The deformation (plastic deformation and/or elastic deformation) of the rubber plug is attached and sealed, and the re-deformation (plastic deformation and/or elastic deformation) of the covering layer (film material) during the pressing process is used to adhere and seal the rubber plug Complete the gland of the rubber stopper. In this process, because there is a cavity between the recessed structure of the rubber plug and the covering layer, and in the rapid pressing process, the gas (pressing under a protective gas atmosphere) is pressed and sealed in this cavity and In the protrusion structure formed by the coating layer, the internal pressure is larger than the outside, and more obvious protrusions or bulges are formed.

The same design of protrusions or bulges is for two purposes:

Verify air tightness and verify whether the package is damaged. Since compressed gas is sealed in the protruding bulge, it can be pre-measured or marked (marked on the bottle body) according to the operating pressure during the capping operation. Once the airtightness fails or is used And piercing the bulge (whether maliciously or normally used) will cause the protruding bulge to collapse due to the escape of compressed gas. Therefore, by observing whether the protruding bulge collapses, whether it collapses beyond the mark set on the bottle body in advance, the air tightness can be verified, whether the package is damaged, and whether it has been used.

Quickly make the solvent evaporated in the injection drop into the bottle. Since the shape of the protruding bulge is almost "V" shape, the solvent (such as volatile ethanol or other liquid medicine containing volatile components) that evaporates and condenses from the injection liquid in the bottle can be collected through this bulge At the lowest point in the center, the faster dripping reduces the possibility of changing the concentration of the liquid medicine in the bottle.

The perfusion, stoppering and capping device provided by the present invention firstly pre-presses the coating layer on the mouth of the medicine bottle to form protrusions, and then plugs and caps to complete the filling and sealing work. The pre-compression can make the formed protrusions more obvious, which is better To achieve the above effects, the comparison with naked eyes is also more convenient and faster.

Based on the above inventive idea, the present invention provides the following experimental scheme. Five, filling, plugging and capping device The filling, stoppering and capping device for a liquid medicine packaging bottle with protrusions includes: Conveying mechanism, used to clamp the fixed medicine bottle and move it to different positions; The filling mechanism, including the filling needle and the liquid medicine metering switch, is connected with the liquid storage tank, and is used for quantitatively injecting the medicine liquid into the empty medicine water bottle in the filling position; Feeding mechanism for conveying and placing the covering layer on the mouth of the liquid medicine bottle filled with liquid medicine at the pre-pressing position; The coating pre-pressing mechanism includes a driving element and a pre-compression die connected with the driving element, which is used to pre-press the coating layer placed on the mouth of the medicine bottle in the pre-pressing position into a shape with an arc-shaped protrusion downward ； The stopper mechanism is used to press the rubber stopper into the mouth of the medicine bottle in the stoppered position with the coating layer pre-compressed; and The capping mechanism is used to roll the aluminum cap onto the stopper of the medicine bottle in the capping position.

The purpose of the conveying mechanism is to orderly convey the empty medicine bottles to the predetermined position one by one.

Generally, there are two types of conveying mechanisms: disc type rotary conveying mechanism or linear conveying mechanism.

The basic principle of the disc type conveying mechanism is to set the main turntable, and set up the chuck matching the medicine bottle around the main turntable, and use the matching bottle unscrambler to clip each medicine bottle into the bayonet of the chuck. The medicine bottle is transported to the predetermined position during the rotation. Such mechanisms are more commonly used, such as a dual-position medicine bottle filling machine disclosed in Chinese Patent Document CN206544899U, a liquid filling and stoppering machine disclosed in CN206172956U, a filling and corking mechanism bottle device disclosed in CN203558514U, and a filling and sealing opening disclosed in CN207015615U The high-speed liquid filling and stoppering machine disclosed in CN1431141A uses this disc conveying mechanism to convey the medicine bottle.

The linear conveying mechanism is similar to the above-mentioned disc type, except that a structure with a bayonet is set on the conveyor belt, and the medicine bottle is conveyed to a predetermined position through the movement of the conveyor belt (intermittent or continuous movement).

The filling mechanism is a commonly used injection type filling structure, and the filling needle is driven into the bottle mouth by a cylinder, an actuator, etc., for filling. A quantitative switch is connected to the pipeline of the perfusion needle to ensure that the amount of perfusion is a predetermined amount each time.

The feeding mechanism is used for conveying and placing the covering layer on the mouth of the liquid medicine bottle filled with the liquid medicine in the pre-pressing position. Generally speaking, in preparation packaging machinery, there are many ways of feeding materials, which can be fed by air cylinders, actuators, electromagnets, manipulators, etc. In the present invention, since the coating layer is to be transported, the solution considered is to install a suction cup on a simple manipulator, and then transfer the coating layer to the mouth of the medicine bottle by the manipulator after sucking the coating layer through the suction cup.

The stoppering mechanism and the capping mechanism use the existing structure. The liquid filling and sealing machine disclosed in CN206172956U, the filling and sealing machine disclosed in CN207015615U, and the high-speed liquid filling and sealing machine disclosed in CN1431141A all disclose the corresponding structures and solutions. . Generally speaking, the stopper mechanism is to insert the rubber stopper with the correct stopper (the rubber stopper can be uniformly arranged with the small head down by the spiral vibration stopper machine) into the mouth of the medicine bottle, and the driving structure is generally an air cylinder. The capping mechanism is to directly press the aluminum cap onto the bottle mouth plugged with the rubber stopper, and then tighten the lower end of the aluminum cap so that the lower end shrinks and deforms and the rubber stopper is firmly fixed in the bottle mouth.

The covering layer pre-pressing mechanism is to pre-press the covering layer through a pre-pressing die to obtain a preliminary protrusion shape.

Further, it also includes a high-pressure gas blowing mechanism, which includes: Support rod, fixed at the stopper position; The blowing ring is a hollow ring with an air outlet on its inner wall, which is connected to a high-pressure gas source through a pipeline, and has an inner diameter greater than or equal to the mouth of the medicine bottle and is located on the mouth of the bottle, When the pre-compressed medicine bottle with the coating layer is transported to the stoppered position by the conveying mechanism, the blowing ring is just right on the bottle mouth and blowing, When the blowing ring blows high-pressure gas toward the coating layer having the arc-shaped protrusion shape, the plugging mechanism presses the plugging into the bottle mouth.

In this way, by further designing the high-pressure gas blowing mechanism, it is possible to blow high-pressure gas into the protrusion structure before plugging after pre-pressing, so that when plugging, the air pressure in the protrusion can be made larger, and the corresponding protrusion degree is more obvious. Achieve a more intuitive effect.

Further, the air outlet is arranged obliquely downward, and the oblique arrangement can better allow the gas to be blown into the bottle mouth.

Further, the support rod is a hollow tube and functions as a pipeline. One end is connected with the high-pressure gas source, and the other end is connected with the blowing ring.

Further, the pre-compression mold includes a pressure ring and a male mold sleeved in the pressure ring, The upper end of the male mold is connected with the first driving element, and the pressing ring is connected with the second driving element, The male mold can slide up and down in the pressure ring, and its lower end is a convex arc surface, When the medicine bottle is transported to the pre-pressing position, the second driving element drives the pressing ring to press and fix the edge of the coating layer placed on the bottle mouth on the bottle mouth, and the first driving element drives The male mold is pressed down through the pressing ring, and the covering layer is pre-pressed into a shape having an arc-shaped protrusion downward.

Further, the ground of the pressure ring is provided with a rubber gasket for buffering. The addition of rubber gaskets can tightly laminate the overlay while not pulling or tearing the overlay due to excessive or fast downforce of the pre-compression mold.

Preferably, the first driving element and the second driving element are cylinders or actuators or electromagnets.

As an option, the conveying mechanism is a disk-type rotary conveying mechanism or a linear conveying mechanism. Of course, a screw-type conveying mechanism can also be used.

6. Perfusion, stoppering and capping device for AST-3424 injection

AST-3424 ((R)-1-(3-(3-(dimethylcarbamoyl)phenoxy)-4-nitrophenyl)ethyl di(aziridin-1-yl)phosphinate) injection perfusion and stopper capping device, including the above The protruding liquid medicine packaging bottle filling, plugging and capping device and the liquid storage tank and the liquid filling pipeline connected with the liquid storage tank, Wherein, the liquid storage tank, the liquid filling pipe, and the liquid filling needle are all 316 stainless steel parts; or The inner layer of the liquid storage tank, the irrigation pipe, and the liquid injection needle contacting the liquid medicine are all polyvinylidene fluoride layers.

Further, the covering layer is a polyvinylidene fluoride layer, and the feeding mechanism is made of 316 stainless steel parts; or the parts of the feeding mechanism contacting the chemical liquid are all coated with a polyvinylidene fluoride layer.

The reason why it is specifically required that some parts of the infusion, stoppering and capping device suitable for AST-3424 injection are directly in contact or may be in contact with the chemical liquid to use 316 stainless steel or polyvinylidene fluoride layer because the AST-3424 drug has been verified by comparison and experiment. Liquid contact with these two materials (8 hours or even 24 hours) will not react and produce impurities, that is, experiments have confirmed that these two materials are stable for AST-3424 liquid.

Seven, the method of filling, stoppering and capping of the medicine bottle

The present invention also provides a method for filling, stoppering and capping of a medicinal water bottle, which includes the step of pre-pressing the coating layer: After the medicinal solution is poured into the medicinal water bottle, the coating layer is pre-compressed to make the coating layer adhere to the mouth of the medicine bottle and form a structure protruding into the mouth of the bottle.

Generally, the method of filling, stoppering and capping of the medicine bottle mainly includes the filling step, the stoppering step and the capping (capping) step. The above-mentioned coating pre-compression step is to carry out the coating after the filling step and before the stoppering step. Pre-compression to form a protruding structure.

Further, during the stoppering step, the rubber stopper is quickly pressed into the bottle mouth to which the coating layer is attached. The quick here is to quickly press the gas (protective gas, such as nitrogen) in the protruding structure into the bottle mouth through the rubber stopper to make the protruding structure bulge.

Further, when the coating layer is pre-pressed, the coating layer placed on the bottle mouth is fixed and then pre-pressed with a male mold.

Specific Example 1

Packaging bottle 100 for AST-3424 injection. AST-3424 injection is essentially an injection consisting of 0.75 ml of absolute ethanol, 0.25 ml of anhydrous propylene glycol, and 10 mg of AST-3424 raw materials in the ratio of solvents and raw materials. , Package the bottle body 10, the rubber stopper assembly 20 and the cover 30.

As shown in FIG. 2, the bottle body 10 is used to contain the liquid medicine, and it includes a bottle neck 12 connected to the bottle body 11 and the bottle body 11, and a bottle mouth 13 is provided at the opening of the bottle neck.

According to actual needs, the shape of the bottle body 10 is optional, and is usually cylindrical or rectangular. Moreover, the bottle neck 12 is usually smaller than the bottle body 11, and the specific shape is shown in FIG. 2.

As shown in FIG. 3, the rubber stopper assembly 20 is used to plug into the bottle mouth 11 of the bottle body 10, and includes a rubber stopper 21 and a coating layer 22 directly attached to the exposed surface of the rubber stopper 21 facing the bottle mouth 13. There is no adhesive layer between the covering layer 22 and the rubber stopper 21. The covering layer 22 is a polytetrafluoroethylene layer, a polyvinylidene fluoride layer, a tetrafluoroethylene/hexafluoropropylene copolymer layer or at least the foregoing Two kinds of composite layers.

As disclosed in the Summary of the Invention, the rubber plug 21 with the adhesive coating film will bring the risk of contamination to the AST-3424 of the present invention, and the polyether resin PES, polytetrafluoroethylene PTFE, and polyvinylidene resin are used alone. After the coating layer 22 is prepared by the FEP membrane material of the ethylene difluoride PVDF and the copolymer of tetrafluoroethylene/hexafluoropropylene, the impurity of the injection solution is improved. After comparison, the polytetrafluoroethylene layer, the polyvinylidene fluoride layer, and the tetrafluoroethylene/hexafluoropropylene copolymer layer meet the requirements, so obviously the two-by-two mixture of these three materials or the film materials of the three mixed materials also meet the requirements Isolate the packaging bottle of AST-3424 injection with ethanol/propylene glycol solvent to ensure the non-polluting stability between the injection and the packaging bottle stopper (rubber stopper 21) (that is, no impurities will be caused by the contact between the injection and the coating Increase or emergence of new impurities) requirements.

The rubber plug 21 is made of elastic material.

The cover 30 is used to be arranged on the rubber stopper assembly 20 to clamp and fix the bottle mouth 13 and the rubber stopper assembly 20. As shown in FIG. 2, the cover 30 is an annular ring, the upper end of which is sleeved on the rubber plug assembly 20, and the lower end of the cap is clamped to the bottleneck 12. There is a circle of depressions 122 on the bottleneck 12 for the lower end of the cap 30 to be hooked and fixed, so that the rubber stopper assembly 20 can be firmly inserted and fixed in the bottle mouth 13. The cover 30 is generally made of aluminum.

A gap 31 (a circular hole) is formed on the top of the cover 30 to expose the rubber plug 21 for easy puncture.

Specific Example 2

Further, on the basis of the packaging bottle 100 of Embodiment 1, the covering layer 22 is a polyvinylidene fluoride layer.

Specific Example 3

Further, on the basis of the packaging bottle 100 of specific embodiments 1 and/or 2, the covering layer 22 is a two-layer composite layer inside the surface, the surface layer is polyvinylidene fluoride, and the inner layer is a polytetrafluoroethylene layer and/ Or a tetrafluoroethylene/hexafluoropropylene copolymer layer.

Specific Example 4

Further, on the basis of the packaging bottle 100 of specific embodiment 1 and/or 2 and/or 3, the thickness of the coating layer 22 is 50-150 microns.

Specific Example 5

Based on the packaging bottle 100 of specific embodiment 1 and/or 2 and/or 3 and/or 4, the bottle body 10 is a glass medicine bottle.

The type of penicillin vial can be a regulated glass potion bottle or a molded glass potion bottle. It is recommended to use a regulated glass potion bottle.

Specific Example 6

Based on the packaging bottles of specific embodiments 1 and/or 2 and/or 3 and/or 4 and/or 5, the bottle body 10 is a neutral or alkaline borosilicate glass bottle.

Specific Example 7

Based on the packaging bottles of specific examples 1 and/or 2 and/or 3 and/or 4 and/or 5 and/or 6, the bottle body 10 is an opaque or low light transmittance bottle body. A brown bottle is recommended.

Specific Example 8

As shown in Figure 4/5, on the basis of the packaging bottles of specific embodiments 1 and/or 2 and/or 3 and/or 4 and/or 5 and/or 6 and/or 7, the rubber stopper 21 includes a base 211 And the plug body 212 connected to the base 211, the outer end surface of the plug body 212 has a recessed structure 213.

Correspondingly, the covering layer 22 is at least bonded to the surface of the plug body 212, but does not adhere to the inner wall formed by the recessed structure 213, so that a closed cavity 214 is formed between the recessed structure 213 and the covering layer 22.

Specific Example 9

On the basis of the packaging bottles of specific embodiment 1 and/or 2 and/or 3 and/or 4 and/or 5 and/or 6 and/or 7 and/or 8, the rubber stopper 21 is a chlorinated butyl rubber stopper .

Specific Example 10

As shown in Figure 4/5, on the basis of the packaging bottles of specific embodiments 8 and/or 9, the coating layer 22 is due to the compressed gas contained in the closed cavity 214 formed between the recessed structure 213 and the coating layer 22 The bulge or protrusion 225 is formed by the action of

Specific Example 11 As shown in Figure 4/5, in specific embodiments 1 and/or 2 and/or 3 and/or 4 and/or 5 and/or 6 and/or 7 and/or 8 and/or 9 and/or 10 On the basis of the packaging bottle, it also includes a protective cap 40. The protective cap 40 has a cylindrical cap part 41 and a ring-shaped neck part 42 connected to the cylindrical cap part 41. The cylindrical cap part 41 is used to cover the base 211, The neck portion 42 is used to cover the bottle mouth 13.

The protective cover 40 is buckled and covers the gap 31 (circular hole) formed on the top of the cover 30 so that the exposed rubber plug 21 is covered.

Specific Example 13

As inspired by the content of the invention, in order to make the position change of the above-mentioned bulge or protrusion 225 (refer to FIG. 5) more intuitive, a scale line is set on the bottle body 11 or the neck 12 of the bottle (medicine bottle) to mark the protrusion or bulge. Design location. As shown in Fig. 4, the scale line 121 is a frosted ring belt with a width of 1.5 mm, and the ring belt is frosted at intervals, so that it is convenient to observe the position of the comparison protrusion or bulge.

Specific embodiment 14-1

The following embodiment uses FIG. 6 to illustrate the special "deformation pressing" operation.

Both the bottle body 10 and the rubber stopper 21 use conventional existing medicinal water bottles and the corresponding rubber stopper 21. When the rubber stopper 21 is capped after filling, the covering layer 22 is placed under the rubber stopper 21, as shown in the left picture of FIG. 6 .

Then perform a pressing process with the covering layer 22 on the bottom and the rubber plug 21 on the top. The deformation (plastic deformation and/or elastic deformation) of the film (covering layer) during the pressing process is used to adhere to the rubber plug and seal it. Complete the gland of the rubber stopper, as shown in the middle diagram of Figure 6.

In this pressing process, since there is a cavity between the recessed structure 213 of the rubber plug 21 and the covering layer 22, in the rapid pressing process, the gas (pressing under a protective gas atmosphere) is pressed and sealed. In this cavity, the internal pressure is larger than the outside to form a protrusion (bulge) 225 (please refer to FIG. 5), and then the cover 30 and the protective cover 40 are simultaneously pressurized to complete the fixing and sealing, as shown in the right diagram of FIG.

Specific embodiment 14-2

Please refer to FIG. 7, a packaging kit 1000 for AST-3424 injection, including a packaging box 1002, a gas protection bag 1003, and a packaging bottle 100.

A plurality of gas protection bags 1003 are connected to each other.

Specific Example 15

Based on the packaging kit of specific embodiment 14, the gas protection bag 1003 is filled with nitrogen gas, and the material of the gas protection bag is an aluminum-plastic double-layer composite material. The gas protection bag made of aluminum-plastic double-layer composite material has better light-proof performance.

Specific Example 16

In the packaging kit of specific embodiment 14 and/or 15, the packaging bottle 100 is a 2/5/10 ml brown light-proof glass medicine bottle.

Specific Example 17

This embodiment is a modified and expanded embodiment.

In the above embodiments, the material of the bottle body is a glass bottle, or a potion bottle of other materials. Further, the inner wall of a potion bottle made of other materials or glass may be coated with the coating layer 22, and the coating layer It is a polytetrafluoroethylene layer, a polyvinylidene fluoride layer, a tetrafluoroethylene/hexafluoropropylene copolymer layer or a composite layer of at least two, preferably a polyvinylidene fluoride layer.

The above embodiments give the structure of a liquid medicine packaging bottle with protrusions, and the following embodiments specifically illustrate the specific structure of the filling, plugging and capping device for a liquid medicine packaging bottle with protrusions provided by the present invention.

Specific Example 18

As shown in FIG. 10, the filling, stoppering and capping device 1500 of a medicinal liquid packaging bottle with protrusions includes a conveying mechanism 200 for clamping and fixing the medicinal liquid bottle and moving to different positions. In this embodiment, a disc-type conveying mechanism with a relatively compact structure is selected. The basic principle is to set a main turntable 210, and set a chuck 220 matching the medicine bottle around the main turntable, and use the matched bottle unscrambler LB to separate medicines one by one. The water bottle is stuck in the bayonet 221 of the chuck 220, and the medicine water bottle is transported to a predetermined position during rotation. Correspondingly, the predetermined position here is also set according to the circle. Of course, the number of bayonet openings driven by the driving machine (stepping motor) corresponding to the conveying mechanism 10 is also different according to the corresponding action mechanism set at each position. It is simple, for example, a chuck 220 is provided with 60 If there are two bayonet ports, the corresponding angle of each corresponding bayonet port is 6 degrees. If there are 10 liquid filling mechanisms 300, feeding mechanism 400, overlay pre-pressing mechanism 500, stoppering mechanism 600, and capping mechanism 700 in one position When corresponding operations are performed at the same time, the driving machine drives the turntable 210 to rotate 60 degrees each time; if five of the above-mentioned various mechanisms are set in one position, the driving machine drives the turntable 210 to rotate 30 degrees each time, and so on. In this embodiment, one chuck 220 is provided with 30 bayonet ports 221, and each corresponding bayonet port corresponds to an angle of 12 degrees, and a liquid filling mechanism 300, a feeding mechanism 400, and a coating layer are set in one position. The pressing mechanism 500, the stoppering mechanism 600, and the capping mechanism 700 perform corresponding operations at the same time, and the driving machine drives the turntable 210 to rotate 12 degrees each time.

11, the filling mechanism 300 includes a filling needle 310 and a liquid medicine metering switch 320, which are connected to the liquid storage tank C and used for quantitatively injecting the medicine liquid into the empty medicine water bottle in the filling position. The conventional structural scheme is used in this embodiment, as shown in Figure 11: the liquid medicine in the liquid storage tank C storing the injection liquid is quantitatively passed through the infusion needle under the action of the pump and the liquid medicine metering switch 320 310 is poured into the empty potion bottle.

Please refer to FIG. 10, the feeding mechanism 400 is used for conveying and placing the coating layer on the mouth of the liquid medicine bottle filled with the liquid medicine at the pre-pressing position. Since the feeding mechanism of this embodiment is to transport the coating layer, the solution considered is to install a suction cup on a simple manipulator, and then transfer the coating layer to the mouth of the medicine bottle by the manipulator after sucking the coating layer through the suction cup.

Please refer to FIG. 13, the coating pre-pressing mechanism 500 includes a driving element 510 and a pre-compression mold 520 connected to the driving element for pre-pressing the coating 22 placed on the mouth of the vial of the pre-pressing position Into the shape of downward arc-shaped protrusions.

Please refer to FIG. 10, the stopper mechanism 600 is used to press the rubber stopper into the bottle mouth of the medicine bottle in the stoppered position with the coating layer pre-compressed.

The capping mechanism 700 is used for rolling the aluminum cap onto the bottle mouth of the stoppered medicine bottle in the capping position.

The stoppering mechanism and the capping mechanism use the existing market-supplied structures. The liquid filling and sealing machine disclosed in CN206172956U, the filling and sealing machine disclosed in CN207015615U, and the high-speed liquid filling and sealing machine disclosed in CN1431141A all disclose the corresponding Structure and plan. Generally speaking, the stopper mechanism is to insert the rubber stopper with the correct stopper (the rubber stopper can be uniformly arranged with the small head down by the spiral vibration stopper machine) into the mouth of the medicine bottle, and the driving structure is generally an air cylinder. The capping mechanism directly presses the aluminum cap onto the bottle mouth plugged with the rubber stopper, and then tightens the lower end of the aluminum cap so that the lower end shrinks and deforms to firmly fix the rubber stopper on the bottle mouth.

Specific Example 19

On the basis of the foregoing embodiment 4, as shown in Fig. 10/12, a high-pressure gas blowing mechanism 800 is further included, which includes:

The support rod 810 is fixed at the plugging position.

The blowing ring 820 is a hollow ring with an air outlet 821 on its inner wall, which communicates with a high-pressure gas source G through a pipeline, and has an inner diameter greater than or equal to the mouth of the medicine bottle and is located on the mouth of the bottle.

When the pre-compressed medicine bottle with the coating layer is transported to the stoppered position by the conveying mechanism 200, the blowing ring is just on the bottle mouth and blowing, and the blowing ring 820 has an arc-shaped protrusion facing toward When high-pressure gas is blown from the covering layer of the shape, the stoppering mechanism 600 presses the rubber stopper into the bottle mouth.

Specific Example 20

On the basis of the above embodiments 18 and/or 19, the air outlet 821 is arranged obliquely downward, specifically, a hole is provided on the inner wall of the blowing ring 820, and then a short tube is welded, and the short tube is set obliquely down.

Specific implementation 21

On the basis of the above embodiments 18 and/or 19 and/or 20, the support rod 810 is a hollow tube and functions as a pipeline. One end is connected to the high-pressure gas source, and the other end is connected to the blowing gas. The ring is connected.

Specific Example 22

On the basis of the above-mentioned embodiments 18 and/or 19 and/or 20 and/or 21, as shown in FIG. 13, the driving element 510 is arranged on the bracket 530, and the bracket 530 is fixed at the pre-compression position. The pre-compression mold 520 includes a pressure ring 521 and a male mold 522 nested in the pressure ring.

The upper end of the male mold 522 is connected with the first driving element 511, and the pressing ring 521 is connected with the second driving element 512. The male mold 522 can slide up and down in the pressure ring 521, and its lower end is a convex arc surface.

When the medicine bottle is transported to the pre-pressing position, the second driving element 512 drives the pressing ring 521 to press and fix the edge of the coating layer placed on the bottle mouth on the bottle mouth, and the first drive The element 511 drives the male mold 522 to pass through the pressing ring 521 and press down to pre-press the covering layer 22 into a downward arc-shaped protrusion shape.

Specific Example 23

On the basis of the above embodiments 18 and/or 19 and/or 20 and/or 21 and/or 22, the bottom surface of the pressure ring 521 is provided with a rubber gasket for buffering.

Specific Example 24

On the basis of the above embodiment 18 and/or 19 and/or 20 and/or 21 and/or 22 and/or 23, the first driving element 511 and the second driving element 512 are cylinders or actuators Or electromagnet or electric push rod.

Since the first driving element 511 is used to drive the male mold 522 to press the film, the speed and force of the male mold movement during the film pressing process will directly affect the shape of the covering layer. It may cause cracking or breaking. Therefore, it is preferable that the first driving element 511 use an actuator that can accurately control the force and the speed of movement, and it is preferable to be a servo actuator.

Specific Example 25

Please refer to Figure 11, the filling, stoppering and capping device of AST-3424 injection includes the filling, stoppering and capping device of any one of the above-mentioned specific embodiments 4-10 of the medicinal solution packaging bottle with protrusions, and the liquid storage tank C and the The liquid filling pipe (not shown in the figure) connected with the liquid storage tank, wherein the liquid storage tank C, the liquid filling pipe, and the liquid filling needle 310 are all 316 stainless steel parts; or the storage tank The inner layer of the liquid tank C, the liquid filling pipe, and the liquid filling needle 310 that contacts the liquid medicine are all polyvinylidene fluoride layers.

Specific Example 26

On the basis of Example 24, the covering layer is a polyvinylidene fluoride layer,

The feeding mechanism 400 is made of 316 stainless steel parts; or the parts of the feeding mechanism 400 contacting the chemical liquid are all coated with a polyvinylidene fluoride layer.

Specific Example 27

As shown in FIG. 14, this embodiment provides a method for filling, stoppering and capping of a medicine bottle, which sequentially includes a filling step S1, a coating pre-compression step S2, a stoppering step S3, and a capping step S4.

In the liquid filling step S1, a predetermined volume of liquid medicine is poured into the liquid medicine bottle through the liquid filling mechanism.

In step S2 of pre-pressing the coating layer, after the medicinal solution is poured into the vial, the coating layer is pre-compressed and molded so that the coating layer is attached to the mouth of the vial and forms a structure protruding into the mouth of the bottle.

Preferably, when the coating layer is pre-compressed, the coating layer placed on the bottle mouth is fixed, and then a male mold is used for pre-compression.

Stoppering step S3, quickly press the rubber stopper into the bottle mouth to which the coating layer is attached. Fast is within 0.1 seconds or faster.

In the capping step S4, the aluminum cap is directly pressed onto the bottle mouth plugged with the rubber stopper, and then the lower end of the aluminum cap is tightened so that the lower end is reduced and deformed to firmly fix the rubber stopper on the bottle mouth.

The working process of the entire device will be introduced below in conjunction with Fig. 10 and Figs. 14 and 16.

The cleaned medicine bottle is slowly pushed into the bayonet 211 of the chuck 220 by the push rod of the bottle unscrambler in the hopper LD of the unscrambler LB. Then it is conveyed by the chuck of the conveying mechanism 200, and when it is conveyed to the corresponding filling position of the corresponding filling mechanism 300, it is filled by the filling mechanism (figure a in Figure 16);

The chuck continues to rotate, and after the liquid-filled medicine bottle is transported to the pre-pressing position, the feeding mechanism 400 operates to place the covering layer 22 on the mouth of the medicine bottle (figure b in Fig. 16);

After the covering layer is placed, the pressing ring 521 of the covering layer pre-pressing mechanism 500 is driven to fix the periphery of the covering layer on the mouth of the medicine bottle (figure c in Fig. 16), and then the male mold 522 is driven to cover the layer Pre-compression molding (figure d in figure 16);

The chuck continues to rotate to transport the medicine bottle to the stopper position. The high-pressure gas blowing mechanism 800 acts to blow air (figure e in Figure 10). After the high-pressure gas blowing mechanism leaves, the stopper mechanism 600 presses the rubber stopper in (Figure 16). Figure f);

When the chuck rotates to transport the corked medicine bottle to the capping position, the capping mechanism 700 completes the capping (figure g in Figure 16), and the protective cap pressing mechanism BH will press the protective cap (Figure 16). Figure h in Figure 2), and finally get the packaging bottle shown in Figure 2.

The chuck of the conveying mechanism 200 continues to rotate to convey the capped medicine bottle to the bottle outlet mechanism 900.

As shown in Figure 15, a bottle-pull plate is provided on the edge of the hopper LD. The bottle-pull plate 910 is in the shape of a broken line or arc toward the chuck 220, and its tip extends into the bayonet 221 of the chuck 220, corresponding to An edge of the bayonet facing the bottle-sucking plate is provided with a chamfer (round chamfer or right-angle chamfer), and the design of the chamfer is convenient for inserting the bottle-sucking plate into the bayonet 221 to pull out the medicine bottle.

When the chuck 220 continues to rotate to the position corresponding to the bottle ejection mechanism 900, the bottle dial plate 910 will pull out the medicine bottles that are stuck in the bayonet 221 one by one and enter the bottle outlet channel 920, thus completing the bottle ejection. process.

1, 10: bottle body 100: packaging bottle 1000: Packing kit 1002: packing box 1003: Gas protection bag 1500: Filling, stoppering and capping device 11: Bottle body 12: bottleneck 121: sunken 13: Bottle mouth 2, 21: Rubber stopper 20: Rubber plug assembly 200: Conveying mechanism 210: Main turntable 211: Matrix 212: plug body 213: Recessed structure 214: closed cavity 22: Overlay 220: chuck 221: bayonet 225: bulge or protrusion 3.30: capping 300: irrigation mechanism 31: gap 310: Irrigation needle 320: Liquid dosing switch 4.40: Protective cover 400: feeding mechanism 41: Cylindrical cover part 42: Neck part 5: Matrix 500: Overlay pre-compression mechanism 510: drive element 511: first drive element 512, 522: pressure ring 520: Pre-compression mold 522: male model 530: bracket 6: plug body 600: Gasoline Agency 7: Laminating 700: gland mechanism 800: High-pressure gas blowing mechanism 810: support rod 820: Blow Ring 821: Vent Hole 900: Bottle-out mechanism 910: Dial the bottle board 920: Bottle Out Channel BH: Protective cover pressing mechanism C: Reservoir G: High pressure gas source LB: Bottle unscrambler LD: Hopper S1-S4: steps

Figure 1 is the production flow chart of AST-3424 pharmaceutical preparations; Figure 2 is a schematic diagram of a specific structure of a liquid medicine packaging bottle in some embodiments of the present invention; 3 is a schematic diagram of the specific structure of the body of the liquid medicine packaging bottle in some embodiments of the present invention; 4 is a schematic diagram of a specific structure of a liquid medicine packaging bottle in some embodiments of the present invention; 5 is a schematic diagram of the specific structure of the rubber stopper element of the packaging bottle for injection in some embodiments of the present invention; 6 is a schematic diagram of the process of laminating the film by the operation of "deformation and pressing" in the embodiment of the present invention; Figure 7 is a schematic structural diagram of a packaging kit in some embodiments of the present invention; Figure 8 is a schematic structural diagram of a typical medicine bottle in the prior art; Figure 9 is a schematic diagram of the structure of a typical film-coated rubber stopper in the prior art; Figure 10 is a schematic structural diagram of a filling, plugging and capping device in some embodiments of the present invention; Figure 11 is a schematic structural diagram of a filling mechanism in some embodiments of the present invention; Figure 12 is a schematic structural view of a high-pressure gas blowing mechanism in some embodiments of the present invention; Figure 13 is a schematic structural view of a pre-compression mechanism for a covering layer in some embodiments of the present invention; 14 is a schematic diagram of the steps of a method for filling, stoppering and capping of a medicine water bottle in some embodiments of the present invention; 15 is a schematic diagram of the structure of the bottle ejecting mechanism in some embodiments of the present invention; and FIG. 16 is a schematic diagram of the action of filling, plugging and capping of the vial by using the filling, stoppering and capping device provided by this embodiment.

10: Bottle body

11: Bottle body

12: bottleneck

13: Bottle mouth

121: sunken

20: Rubber plug assembly

211: Matrix

213: Recessed structure

214: closed cavity

22: Overlay

30: capping

31: gap

40: Protective cover

41: Cylindrical cover part

42: Neck part

Claims (28)

A packaging bottle for AST-3424 injection, wherein AST-3424 injection is an injection composed of absolute ethanol, anhydrous propylene glycol and AST-3424 raw materials, including: A bottle for AST-3424 injection; A rubber stopper assembly for plugging into the mouth of the bottle, wherein the rubber stopper assembly includes: A rubber stopper; and A coating layer directly attached to the exposed surface of the rubber stopper facing the bottle mouth. There is no adhesive layer between the coating layer and the rubber stopper. The coating layer is a polytetrafluoroethylene layer, a poly Difluoroethylene layer, tetrafluoroethylene/hexafluoropropylene copolymer layer or a composite layer of at least two of the foregoing; and The sealing cover is used for fixing the bottle mouth and the rubber stopper assembly on the rubber stopper assembly, and the top of the sealing cover forms a gap so that the rubber stopper is exposed, facilitating puncture. According to the packaging bottle for AST-3424 injection according to claim 1, the coating layer is a polyvinylidene fluoride layer. According to the packaging bottle for AST-3424 injection according to claim 1, the covering layer is a two-layer composite layer inside the surface, the surface layer is a polyvinylidene fluoride layer, and the inner layer is a polytetrafluoroethylene layer or four Copolymer layer of vinyl fluoride and hexafluoropropylene. According to the packaging bottle for AST-3424 injection according to claim 1, the thickness of the coating layer is 50-150 microns. The packaging bottle for AST-3424 injection according to claim 1, wherein the bottle body is a glass medicine bottle. The packaging bottle for AST-3424 injection according to claim 1, wherein the bottle body is a neutral or alkaline borosilicate glass bottle. The packaging bottle for AST-3424 injection according to claim 1, wherein the bottle body is a bottle body with opaque or low light transmittance. A packaging bottle for AST-3424 injection, including: A bottle for containing liquid medicine; A rubber stopper assembly for plugging into the mouth of the bottle, wherein the rubber stopper assembly includes: A rubber stopper; and A coating layer directly attached to the exposed surface of the rubber stopper facing the bottle mouth. There is no adhesive layer between the coating layer and the rubber stopper. The coating layer is a polytetrafluoroethylene layer, a poly Difluoroethylene layer, tetrafluoroethylene/hexafluoropropylene copolymer layer or a composite layer of at least two of the foregoing; and A cover is used to fix the bottle mouth and the rubber stopper assembly on the rubber stopper assembly. A gap is formed on the top of the cover so that the rubber stopper is exposed, facilitating piercing of the rubber stopper, including the base and the rubber stopper. The plug body on the base body has a recessed structure on the outer end of the plug body; The covering layer is at least combined with the surface of the plug body, but does not adhere to the inner wall formed by the recessed structure, so that a closed cavity is formed between the recessed structure and the covering layer. The packaging bottle for AST-3424 injection according to claim 8, wherein the coating layer is formed by the compressed gas in the closed cavity formed between the recessed structure and the coating layer. Outside the protrusion. The packaging bottle for AST-3424 injection according to claim 9, wherein a scale line is provided on the bottle body or the neck part of the bottle body to mark the design position of the protrusion or bulge. The packaging bottle for AST-3424 injection according to claim 1 and claim 8, further comprising a protective cover, which is buckled and covers the gap formed on the top of the cover, so that the exposed The rubber stopper is covered, and the protective cover has: A cylindrical cover part for covering the base; and The ring-shaped necking part connected with the cylindrical cover part is used to cover the bottle mouth. A packaging kit for AST-3424 injection, including: A box A gas protection bag filled with a protection gas greater than atmospheric pressure, which is set in the packaging box; A packaging bottle, enclosed in the gas protection bag; Wherein, the packaging bottle is the packaging bottle for AST-3424 injection described in any one of Claims 1-11. The packaging kit for AST-3424 injection according to claim 12, wherein the gas protection bag is filled with nitrogen gas, and the material of the gas protection bag is aluminum-plastic double-layer composite material. The packaging kit for AST-3424 injection according to claim 12, wherein the packaging bottle is a 2/5/10 ml brown light-proof glass syrup bottle. The method for producing a packaging bottle for AST-3424 injection according to any one of claims 1-11, which includes the following operations: When pressing the rubber stopper, place the covering layer under the rubber stopper, and then press the covering layer at the bottom and the rubber plug at the top, and use the deformation of the covering layer during the pressing process. Come to attach to the rubber stopper and seal to complete the gland of the rubber stopper. A device for filling, plugging and capping of a liquid medicine packaging bottle with protrusions includes: A conveying mechanism, used to clamp the fixed medicine bottle and move it to different positions; A liquid filling mechanism, including a liquid filling needle and a liquid medicine metering switch, connected with the liquid storage tank, for quantitatively injecting liquid medicine into the empty medicine water bottle in the filling position; A feeding mechanism for conveying and placing the covering layer on the mouth of the liquid medicine bottle filled with liquid medicine at the pre-pressing position; A coating pre-pressing mechanism, including a driving element and a pre-compression die connected to the driving element, for pre-pressing the coating layer placed on the mouth of the vial in the pre-pressing position into a downward arc shape The shape of the protrusion; A stopper mechanism for pressing a rubber stopper onto the bottle mouth of the medicine bottle in the stoppered position with the coating layer pre-pressed; and The capping mechanism is used to roll the aluminum cap onto the stopper of the medicine bottle in the capping position. The filling, stoppering and capping device for a medicinal solution packaging bottle with protrusions according to claim 16, further comprising a high-pressure gas blowing mechanism, which includes: A support rod, fixed at the stopper position; A blowing ring is a hollow ring with an air outlet on its inner wall, which is connected to a high-pressure gas source through a pipeline, and has an inner diameter greater than or equal to the mouth of the medicine bottle and is located on the mouth of the bottle, When the pre-compressed medicine bottle with the coating layer is transported to the stoppered position by the conveying mechanism, the blowing ring is just right on the bottle mouth and blowing, When the blowing ring blows high-pressure gas toward the coating layer having the arc-shaped protrusion shape, the plugging mechanism presses the plugging into the bottle mouth. According to the filling, stoppering and capping device for a medicinal solution packaging bottle with protrusions according to claim 17, the air outlet is set obliquely downward. According to the filling, plugging and capping device according to claim 17, the support rod is a hollow tube and functions as a pipeline. One end is connected with the high-pressure gas source, and the other end is connected with the blowing ring. The pouring, stoppering and capping device for a medicinal solution packaging bottle with protrusions according to claim 16, wherein the pre-compression mold includes a pressure ring and a male mold sleeved in the pressure ring, The upper end of the male mold is connected with the first driving element, and the pressing ring is connected with the second driving element, The male mold can slide up and down in the pressure ring, and its lower end is a convex arc surface, When the medicine bottle is transported to the pre-pressing position, the second driving element drives the pressing ring to press and fix the edge of the coating layer placed on the bottle mouth on the lower bottle mouth, and the first driving element drives the male mold to pass through Pressing down through the pressing ring pre-presses the covering layer into a shape having an arc-shaped protrusion downward. According to claim 20, the pouring, stoppering and capping device for a medicinal solution packaging bottle with protrusions, wherein the ground of the pressure ring is provided with a rubber gasket for buffering. According to claim 20, the filling, stoppering and capping device for a medicinal solution packaging bottle with protrusions, wherein the first driving element and the second driving element are air cylinders, actuators, or electromagnets. The filling, stoppering and capping device for a medicinal solution packaging bottle with protrusions according to claim 16, wherein the conveying mechanism is a disc-type rotary conveying mechanism or a linear conveying mechanism. A perfusion, stopper and capping device for AST-3424 injection, including the perfusion, stoppering and capping device for a protruding medicinal solution packaging bottle described in any one of Claims 16-23, and a liquid storage tank communicating with the liquid storage tank Filling line, Wherein, the liquid storage tank, the filling pipe, and the filling needle are all 316 stainless steel parts; or The inner layer of the liquid storage tank, the liquid filling pipe, and the liquid filling needle contacting the liquid medicine are all polyvinylidene fluoride layers. According to claim 24, the AST-3424 injection filling, plugging and capping device, wherein the covering layer is a polyvinylidene fluoride layer, The feeding mechanism is made of 316 stainless steel parts; or The parts of the feeding mechanism contacting the liquid medicine are all coated with a polyvinylidene fluoride layer. A method for filling, stoppering and capping of a medicinal water bottle includes the step of pre-pressing the coating layer: After the liquid medicine is poured into the medicine bottle, the coating layer is pre-compressed to make the coating layer adhere to the mouth of the medicine bottle and form a structure that protrudes into the mouth of the bottle. The method for filling, stoppering and capping of a medicinal water bottle according to claim 26, wherein the rubber stopper is quickly pressed into the mouth of the bottle to which the coating layer is attached during the stoppering step. The method for filling, stoppering and capping of a medicine bottle according to claim 26, wherein when the coating layer is pre-compressed, the coating layer placed on the bottle mouth is fixed and then pre-compressed using a male mold.

Images