WO2021043275A1 - 注射液的包装瓶及包装套件、灌注加塞压盖装置和方法 - Google Patents

注射液的包装瓶及包装套件、灌注加塞压盖装置和方法 Download PDF

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Publication number
WO2021043275A1
WO2021043275A1 PCT/CN2020/113550 CN2020113550W WO2021043275A1 WO 2021043275 A1 WO2021043275 A1 WO 2021043275A1 CN 2020113550 W CN2020113550 W CN 2020113550W WO 2021043275 A1 WO2021043275 A1 WO 2021043275A1
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WIPO (PCT)
Prior art keywords
bottle
layer
rubber stopper
packaging
filling
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PCT/CN2020/113550
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English (en)
French (fr)
Inventor
段建新
蔡晓宏
李兵
何志成
黄文科
李瑞远
黄明安
孟繁英
李安蓉
蒋婷
Original Assignee
深圳艾欣达伟医药科技有限公司
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Priority claimed from CN201921470760.3U external-priority patent/CN210653722U/zh
Priority claimed from CN201910837741.8A external-priority patent/CN111572833B/zh
Priority claimed from CN201910837201.XA external-priority patent/CN111568759B/zh
Application filed by 深圳艾欣达伟医药科技有限公司 filed Critical 深圳艾欣达伟医药科技有限公司
Publication of WO2021043275A1 publication Critical patent/WO2021043275A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
    • A61J1/00—Containers specially adapted for medical or pharmaceutical purposes
    • A61J1/05—Containers specially adapted for medical or pharmaceutical purposes for collecting, storing or administering blood, plasma or medical fluids ; Infusion or perfusion containers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
    • A61J1/00—Containers specially adapted for medical or pharmaceutical purposes
    • A61J1/14—Details; Accessories therefor
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B65—CONVEYING; PACKING; STORING; HANDLING THIN OR FILAMENTARY MATERIAL
    • B65B—MACHINES, APPARATUS OR DEVICES FOR, OR METHODS OF, PACKAGING ARTICLES OR MATERIALS; UNPACKING
    • B65B3/00—Packaging plastic material, semiliquids, liquids or mixed solids and liquids, in individual containers or receptacles, e.g. bags, sacks, boxes, cartons, cans, or jars
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B65—CONVEYING; PACKING; STORING; HANDLING THIN OR FILAMENTARY MATERIAL
    • B65B—MACHINES, APPARATUS OR DEVICES FOR, OR METHODS OF, PACKAGING ARTICLES OR MATERIALS; UNPACKING
    • B65B7/00—Closing containers or receptacles after filling
    • B65B7/16—Closing semi-rigid or rigid containers or receptacles not deformed by, or not taking-up shape of, contents, e.g. boxes or cartons
    • B65B7/28—Closing semi-rigid or rigid containers or receptacles not deformed by, or not taking-up shape of, contents, e.g. boxes or cartons by applying separate preformed closures, e.g. lids, covers
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B65—CONVEYING; PACKING; STORING; HANDLING THIN OR FILAMENTARY MATERIAL
    • B65D—CONTAINERS FOR STORAGE OR TRANSPORT OF ARTICLES OR MATERIALS, e.g. BAGS, BARRELS, BOTTLES, BOXES, CANS, CARTONS, CRATES, DRUMS, JARS, TANKS, HOPPERS, FORWARDING CONTAINERS; ACCESSORIES, CLOSURES, OR FITTINGS THEREFOR; PACKAGING ELEMENTS; PACKAGES
    • B65D39/00—Closures arranged within necks or pouring openings or in discharge apertures, e.g. stoppers
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B65—CONVEYING; PACKING; STORING; HANDLING THIN OR FILAMENTARY MATERIAL
    • B65D—CONTAINERS FOR STORAGE OR TRANSPORT OF ARTICLES OR MATERIALS, e.g. BAGS, BARRELS, BOTTLES, BOXES, CANS, CARTONS, CRATES, DRUMS, JARS, TANKS, HOPPERS, FORWARDING CONTAINERS; ACCESSORIES, CLOSURES, OR FITTINGS THEREFOR; PACKAGING ELEMENTS; PACKAGES
    • B65D51/00—Closures not otherwise provided for
    • B65D51/18—Arrangements of closures with protective outer cap-like covers or of two or more co-operating closures
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B65—CONVEYING; PACKING; STORING; HANDLING THIN OR FILAMENTARY MATERIAL
    • B65D—CONTAINERS FOR STORAGE OR TRANSPORT OF ARTICLES OR MATERIALS, e.g. BAGS, BARRELS, BOTTLES, BOXES, CANS, CARTONS, CRATES, DRUMS, JARS, TANKS, HOPPERS, FORWARDING CONTAINERS; ACCESSORIES, CLOSURES, OR FITTINGS THEREFOR; PACKAGING ELEMENTS; PACKAGES
    • B65D53/00—Sealing or packing elements; Sealings formed by liquid or plastics material
    • B65D53/04—Discs

Definitions

  • 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
  • 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
  • a suitable dosage form for human administration usually oral or injection administration.
  • a typical vial includes a bottle body 1, a rubber stopper 2 and a cover 3, and sometimes a protective cover 4 is provided on the cover. 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.
  • the typical rubber stopper after the film coating (see Chinese Utility Model Publication CN2612625Y, Publication Date 2004.04.21) has a structure as shown in Figure 9.
  • the membrane rubber plug includes a base 5, a plug body 6 and a covering film 7.
  • 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.
  • polyethersulfone resin PES polytetrafluoroethylene PTFE
  • polyvinylidene fluoride Experiments were carried out on membrane materials of different grades of ethylene PVDF, tetrafluoroethylene/hexafluoropropylene copolymer FEP.
  • Table 1 Parameter table of filter membrane materials of different materials and grades
  • 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.
  • the injection is essentially composed of 0.75ml of absolute ethanol, 0.25ml of anhydrous propylene glycol and 10mg of AST-3424 raw material.
  • the injection is stable, and this injection is used for experimental verification. .
  • the coated control group in the experimental verification used a rubber stopper coated with polytetrafluoroethylene (adhered by an adhesive).
  • AST-3424 injection 100ml of AST-3424 injection is prepared by dissolving 75ml of absolute ethanol, 25ml of anhydrous propylene glycol and 1g of AST-3424 bulk drug in the proportion 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 10ml 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 soaking solution for the film control group uses polyethersulfone resin, polytetrafluoroethylene film, and polyvinylidene fluoride rubber stoppers adhered by an adhesive to the above 10ml AST-3424.
  • the time is 8 hours.
  • the rubber stopper adhered by polyvinylidene fluoride through the adhesive was inserted into the glass vial filled with the above-mentioned AST-3424 injection, and the needle of a 1ml syringe was inserted into the rubber stopper. Then, by tilting a certain angle to release the needle from the injection solution and suck in 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.
  • the above-mentioned different materials and different brands of membrane materials should be pasted on the rubber stoppers, and then these rubber stoppers should be covered with the above-mentioned AST-3424 injection solution.
  • Store in a vial according to the actual use environment and then sample and test the injection in the vial 24 months after the 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. Therefore, the accelerated thinking is used in the development of this project: the filtration operation of the filter membrane material of the above-mentioned material, brand, thickness and pore size is used to replace the long-term contact effect.
  • 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 coated control group, and the injection solution of the coated control group.
  • HPLC method was used to determine the content: AST-3424 was used as an external standard for quantification.
  • test results are shown in Table 2 below, and each sample is tested twice and the average value is taken.
  • 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.
  • the rubber stopper of the packaging bottle of the present invention should use the process of "deformation and pressing" without using any adhesives or other additives: when the rubber stopper is capped, the round film material should be placed in the glue The bottom of the plug is then pressed once in a manner that the film material is first and the rubber plug is on, 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.
  • 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 process 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.
  • the present invention provides the following solutions.
  • AST-3424 injection is essentially an injection consisting of 0.75ml of absolute ethanol, 0.25ml of anhydrous propylene glycol and 10mg of AST-3424 bulk drug in the ratio of solvent and bulk drug. ,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
  • the rubber stopper component includes a rubber stopper and a coating layer directly attached to the exposed surface of the rubber stopper facing the bottle mouth.
  • the coating layer is a poly Tetrafluoroethylene 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.
  • the covering layer is a polyvinylidene fluoride layer.
  • the covering layer is a two-layer composite layer on the surface and the inner layer
  • the surface layer is polyvinylidene fluoride
  • the inner layer is a polytetrafluoroethylene layer and/or a tetrafluoroethylene/hexafluoropropylene copolymer layer.
  • the thickness of the covering layer is 50-150 microns.
  • the bottle body is a glass vial.
  • the bottle body is a neutral or alkaline borosilicate glass bottle.
  • the bottle body is an opaque or low light transmittance bottle body.
  • the bottle body is an opaque or low light transmittance bottle body.
  • 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;
  • 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 rubber stopper is a chlorinated butyl rubber stopper.
  • 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 and compression” process: when capping the rubber stopper, the round film material (that is, the above-mentioned covering The layer) is placed under the rubber stopper, and then press-fitting is carried out according to the way that the film material is on the bottom and the rubber stopper is on the top.
  • the deformation of the film material plastic deformation and/or elastic deformation) during the pressing process is used to stick to the rubber stopper. Combined and sealed.
  • This design is for two purposes:
  • the solvent mainly ethanol
  • the solvent 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 be faster Dripping, so that the possibility of changing the concentration of the injection solution in the bottle is reduced.
  • AST-3424 is a highly active anti-tumor drug
  • 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.
  • 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.
  • 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:
  • Step 1 Dissolve and mix
  • Step 2-1 Add ethanol solution
  • Step 2-2 Add propylene glycol
  • step 2 The solution obtained in step 2 is sterilized.
  • Step 4 Aseptic filling and stoppering
  • 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
  • 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.
  • Sample AST-3424 injection for QC inspection and store it at -20°C during clinical use after QA release.
  • the liquid medicine filling method provided by the present invention does not use any adhesives or other additives due to the special "deformation and pressing" process: when pressing the rubber stopper, the circular membrane material (ie The above-mentioned covering layer) is placed under the rubber stopper, and then press-fitting is carried out in a way that the film material is on the bottom and the rubber stopper is on the top, and the deformation (plastic deformation and/or elastic deformation) of the film material during the pressing process is used to The rubber stopper is attached and sealed.
  • This design is for two purposes:
  • the solvent mainly ethanol
  • the solvent 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 be faster Dripping, so that the possibility of changing the concentration of the injection solution in the bottle is reduced.
  • AST-3424 is a highly active anti-tumor drug
  • 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.
  • 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 set on the rubber stopper assembly to clamp and fix the bottle mouth and the rubber stopper assembly,
  • 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
  • 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.
  • the rubber stopper is made of elastic material, preferably rubber, more preferably medicinal chlorinated butyl rubber.
  • the covering layer is a polytetrafluoroethylene layer, a polyvinylidene fluoride layer, a tetrafluoroethylene/hexafluoropropylene copolymer layer or at least Two kinds of composite layers.
  • the covering layer is a polyvinylidene fluoride layer.
  • the coating layer is a copolymer layer of tetrafluoroethylene/hexafluoropropylene.
  • the thickness of the covering layer is 50-150 microns.
  • the bottle body and rubber stopper of the packaging bottle provided above use conventional existing vials and corresponding rubber stoppers.
  • the covering layer is placed under the rubber stopper, and then according to the covering layer
  • One pressing is performed on the bottom and the rubber plug on the top, and the deformation (plastic deformation and/or elastic deformation) of the membrane material during the pressing process is used to adhere and seal the rubber plug to complete the gland of the rubber plug.
  • the gas pressing under a protective gas atmosphere
  • This design is for two purposes:
  • the solvent such as volatile ethanol or other liquid medicine containing volatile components
  • the solvent that evaporates and condenses from the injection liquid in the bottle can be collected through this bulge To the lowest point of the center, so as to drip faster, so that the possibility of changing the concentration of the liquid medicine in the bottle is reduced.
  • 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 according to the marked concentration. Evaporation and condensation will make the actual concentration higher than the indicated concentration. 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.
  • a scale line is provided on the bottle body or the neck part of the bottle body (cillin bottle) to mark the design position of the protrusion or bulge.
  • 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.
  • the protrusion or bulge will collapse due to the release of compressed gas.
  • the protrusion or bulge must be positioned at the above-mentioned low temperature position. Above the upper ring (corresponding to unqualified air tightness) or disappear directly (corresponding to being used and piercing the bulge).
  • a packaging kit for AST-3424 injection including:
  • 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
  • the packaging bottle is the aforementioned packaging bottle for AST-3424 injection.
  • 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 bottle is a brown, light-proof glass vial of 2/5/10 ml.
  • the invention also provides a filling, stoppering and capping device for a medicinal solution packaging bottle with protrusions, which integrates the filling, stoppering and capping of the medicinal solution, and the obtained packaging bottle can solve the above two problems.
  • the traditional film-coated rubber stopper is directly inserted into the mouth of the bottle.
  • the rubber stopper of the packaging bottle of the present invention uses a "deformation pressing" process, with or without any adhesive or other additives:
  • the elastic coating layer membrane material
  • the coating layer membrane material
  • the rubber stopper is pressed, using the film in the pressing process
  • the deformation (plastic deformation and/or elastic deformation) of the material is used to adhere and seal the rubber stopper
  • the re-deformation (plastic deformation and/or elastic deformation) of the covering layer (film material) during the pressing process is used to adhere to the rubber stopper. Seal the gland of the rubber stopper.
  • the solvent such as volatile ethanol or other liquid medicine containing volatile components
  • the solvent that evaporates and condenses from the injection liquid in the bottle can be collected through this bulge To the lowest point of the center, so as to drip faster, so that the possibility of changing the concentration of the liquid medicine in the bottle is reduced.
  • the perfusion, stoppering and capping device provided by the present invention firstly pre-presses the coating layer on the mouth of the vial to form protrusions, then adds stoppers and caps to complete the filling and sealing work.
  • the pre-compression can make the formed protrusions more obvious and thus better To achieve the above effects, the comparison with naked eyes is also more convenient and faster.
  • the present invention provides the following experimental scheme.
  • the filling, stoppering and capping device for a liquid medicine packaging bottle with protrusions includes:
  • Conveying mechanism used to clamp and fix the vial and move it to different stations
  • the filling mechanism including the filling needle and the liquid medicine quantitative switch, is connected with the liquid storage tank, and is used for quantitatively injecting the liquid medicine into the empty vial at the filling station;
  • Feeding mechanism for conveying and placing the coating on the mouth of the vial filled with liquid medicine in the pre-pressing station
  • the coating pre-compression mechanism includes a driving device and a pre-compression die connected to the driving device, which is used to pre-compress the coating layer placed on the mouth of the vial in the pre-compression station into a downward arc-shaped protrusion shape;
  • the stopper mechanism is used to press the rubber stopper into the mouth of the vial in the stoppering station with the coating layer pre-pressed;
  • the capping mechanism is used to roll the aluminum cap onto the stopper of the vial in the capping station.
  • the purpose of the conveying mechanism is to orderly convey the empty vials to the predetermined station one by one.
  • the basic principle of the disc conveying mechanism is to set the main turntable, and set the chuck matching the vial around the main turntable, and use the matched bottle unscrambler to snap the vials into the bayonet of the chuck.
  • the vial is transported to the predetermined station during rotation.
  • Such mechanisms are more commonly used, such as a double-station vial 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 bottle device disclosed in CN207015615U
  • the filling and sealing machine and the high-speed liquid filling and stoppering machine disclosed in CN1431141A all use this disc conveying mechanism to convey the vial.
  • 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 vial is conveyed to the predetermined station through the movement of the conveyor belt (intermittent or continuous movement).
  • the filling mechanism is a commonly used injection type filling structure.
  • the filling needle is inserted into the mouth of the bottle through an air cylinder, an electric cylinder, 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 vial filled with liquid medicine in the pre-pressing station.
  • the feeding mechanism is used for conveying and placing the covering layer on the mouth of the vial filled with liquid medicine in the pre-pressing station.
  • there are many ways of feeding materials which can be fed by air cylinders, electric cylinders, electromagnets, manipulators, etc.
  • the solution considered is to install a suction cup on a simple manipulator, and then transfer the coating layer to the mouth of the vial by the manipulator after sucking the coating layer by the suction cup.
  • the stopper 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 structure and Program.
  • 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 vial, and the driving structure is generally an air cylinder.
  • the capping mechanism directly presses the aluminum cap onto the bottle mouth with the rubber stopper, and then tightens the lower end of the aluminum cap so that the lower end shrinks and deforms and the rubber stopper is firmly fixed on 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.
  • a high-pressure gas blowing mechanism which includes:
  • 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 vial and is located on the mouth of the bottle,
  • the blowing ring is just right on the bottle mouth and blowing
  • the plugging mechanism presses the plugging into the bottle mouth.
  • the air outlet is arranged obliquely downward, and the oblique arrangement can better allow the gas to be blown into the bottle mouth.
  • 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 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 device, and the pressing ring is connected with the second driving device,
  • the male mold can slide up and down in the pressure ring, and its lower end is a convex arc surface,
  • the second driving device 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 device
  • the male mold is driven to pass through the pressing ring to press down to pre-press the covering layer into a downward arc-shaped protrusion shape.
  • 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.
  • the first driving device and the second driving device are air cylinders, electric cylinders or electromagnets.
  • the conveying mechanism is a disk-type rotary conveying mechanism or a linear conveying mechanism.
  • a screw-type conveying mechanism can also be used.
  • AST-3424 injection filling, stoppering and capping device including the above-mentioned filling, stoppering and capping device for a medicinal solution packaging bottle with protrusions, and a liquid storage tank and a filling pipe connected to the liquid storage tank,
  • liquid storage tank, the irrigation pipeline, and the irrigation needle are all 316 stainless steel parts;
  • 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.
  • 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 chemical liquid are all coated with a polyvinylidene fluoride layer.
  • the present invention also provides a method for filling, stoppering and capping of a vial, which includes the step of pre-pressing the coating layer:
  • the coating layer is pre-compressed to make the coating layer adhere to the mouth of the vial and form a structure that protrudes into the mouth of the vial.
  • the method of filling, stoppering and capping of vials mainly includes a liquid filling step, a stoppering step and a capping (capping) step.
  • the above-mentioned covering pre-compression step is to perform the covering layer after the filling step and before the stoppering step. Pre-press to form a protruding structure.
  • the rubber stopper is quickly pressed into the bottle mouth where the coating layer is applied.
  • the quickness 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.
  • the coating layer placed on the bottle mouth is fixed and then pre-pressed with a male mold.
  • Figure 1 is a flow chart of the production process of AST-3424 pharmaceutical preparations
  • FIG. 2 is a schematic diagram of a specific structure of a packaging bottle for injection in some embodiments of the present invention
  • FIG. 3 is a schematic diagram of the specific structure of the bottle body of the packaging bottle for injection in some embodiments of the present invention.
  • FIG. 4 is a schematic diagram of a specific structure of a packaging bottle for injection in some embodiments of the present invention.
  • FIG. 5 is a schematic diagram of a specific structure of a rubber stopper assembly of a packaging bottle for injection in some embodiments of the present invention
  • FIG. 6 is a schematic diagram of the process of laminating the film by the "deformation pressing" process 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 vial 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.
  • FIG. 14 is a schematic diagram of the steps of a method of filling, stoppering and capping a vial 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.
  • FIG. 16 is a schematic diagram of the action of using the filling, stoppering and capping device provided by this embodiment to fill and stopper capping of a vial.
  • AST-3424 injection is essentially composed of 0.75ml of absolute ethanol, 0.25ml of anhydrous propylene glycol and 10mg of AST-3424 crude drug in a ratio of solvents and bulk drugs.
  • the injection includes a bottle body 10, a rubber stopper assembly 20, and a cover 30.
  • the bottle body 10 is used for accommodating AST-3424 injection, including a bottle neck 12 connecting the bottle body 11 and the bottle body 11, and a bottle mouth 13 is provided at the opening of the bottle neck.
  • 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.
  • 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 facing the bottle mouth. There is no adhesive layer between the plugs, and the covering layer is a polytetrafluoroethylene layer, a polyvinylidene fluoride layer, a tetrafluoroethylene/hexafluoropropylene copolymer layer or a composite layer of at least two.
  • the rubber stopper 21 with the adhesive coating film will bring the risk of contamination to the AST-3424 of the present invention, and the polyethersulfone resin PES, polytetrafluoroethylene PTFE, Polyvinylidene fluoride PVDF, tetrafluoroethylene/hexafluoropropylene copolymer FEP film material is prepared to obtain the coating layer 22, the impurities of the injection solution are improved, after comparison, the polytetrafluoroethylene layer and the polyvinylidene fluoride layer , Tetrafluoroethylene/hexafluoropropylene copolymer layer meets the requirements, then obviously the two-by-two mixing of these three materials or the film of the three mixed materials also meets the packaging of AST-3424 injection that isolates ethanol/propylene glycol solvent Bottle to ensure non-polluting stability between the injection solution and the packaging bottle stopper (rubber stopper 21) (that is, there will be no increase in impurities or
  • the rubber plug 21 is made of elastic material.
  • the cover 30 is configured to be set on the rubber stopper assembly 20 to clamp and fix the bottle mouth 13 and the rubber stopper assembly 20.
  • the upper end of an annular ring is sleeved on the rubber plug assembly 20, while the lower end clamps the bottleneck 12, and the bottleneck 12 has a circle of depressions for the lower end of the cover 30 to be hooked and fixed, so that the rubber plug
  • the 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.
  • the covering layer 22 is a polyvinylidene fluoride layer.
  • 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.
  • the thickness of the coating layer 22 is 50-150 microns.
  • the bottle body 10 is a glass vial.
  • the type of penicillin vial can be a regulated glass vial, or a molded glass vial. It is recommended to use a regulated glass vial.
  • the bottle body 10 is a neutral or alkaline borosilicate glass bottle.
  • the bottle body 10 is an opaque or low light transmittance bottle body. A brown bottle is recommended.
  • the rubber stopper 21 includes a base 211 And the plug body 212 connected to the base body, the outer end surface of the plug body 212 has a recessed structure 213;
  • 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.
  • the rubber stopper 21 is a chlorinated butyl rubber stopper .
  • 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 role of the formation of outward protrusions.
  • the packaging bottle 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 necking part 42 connected to the cylindrical cap part.
  • 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 notch 31 (circular hole) formed on the top of the cover 30 so that the exposed rubber plug 21 is covered.
  • a scale line is set on the bottle body 11 or the neck part 12 of the bottle (cillin bottle) to mark the design position of the protrusion or bulge.
  • 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.
  • Both the bottle body 10 and the rubber stopper 21 use conventional existing vials and corresponding rubber stoppers.
  • the covering layer 22 is placed under the rubber stopper 21, as shown in the left diagram of FIG. 6.
  • a packaging kit 1000 for AST-3424 injection includes a packaging box 1002, a gas protection bag 1003, and a packaging bottle 100.
  • the packaging box 1002 is a usual paper packaging box.
  • the gas protection bag 1003 which is filled with a protection gas greater than atmospheric pressure, is set in the packaging box.
  • the packaging bottle 100 is packaged in a gas protection bag, and is the packaging bottle for AST-3424 injection in any one of Specific Examples 1-14.
  • a plurality of gas protection bags 1003 are connected to each other.
  • 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.
  • the packaging bottle 100 is a brown light-proof glass vial of 2/5/10 ml specification.
  • This embodiment is a modified and expanded embodiment.
  • the material of the bottle body is a glass bottle, or it can be a vial of other materials.
  • a coating layer can be coated on the inner wall of a vial of other materials or glass, and the coating layer is a poly A tetrafluoroethylene layer, a polyvinylidene fluoride layer, a tetrafluoroethylene/hexafluoropropylene copolymer layer, or a composite layer of at least two kinds, preferably a polyvinylidene fluoride layer.
  • the filling, stoppering and capping device 1000 for a liquid medicine packaging bottle with protrusions includes:
  • the conveying mechanism 200 is used to clamp and fix the vials and move them to different stations.
  • 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 vials around the main turntable.
  • the bottle is clamped into the bayonet of the chuck, and the vial is transported to the predetermined station during rotation.
  • the predetermined workstations here are also arranged according to the circumference.
  • the number of bayonet points driven by the driving machine (stepping motor) corresponding to the conveying mechanism 10 is also different.
  • a chuck 220 is provided with 60 If there are two bayonet ports, the corresponding angle of each corresponding bayonet 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 set on one station
  • the driving machine drives the turntable 210 to rotate 60 degrees each time; if one station is equipped with 5 of the above-mentioned various mechanisms, each time the driving machine drives the turntable 210 to rotate 30 degrees, and so on.
  • one chuck 220 is provided with 30 bayonet ports 221, and each corresponding bayonet port corresponds to an angle of 12 degrees.
  • One station is provided with a liquid filling mechanism 300, a feeding mechanism 400, and a covering layer.
  • the pre-pressing mechanism 500, the plugging mechanism 600, and the capping mechanism 700 perform corresponding operations at the same time, and then each time the driver drives the turntable 210 to rotate 12 degrees.
  • the liquid filling mechanism 300 includes a liquid filling needle 310 and a liquid medicine quantitative switch 320, which is connected to the liquid storage tank C and is used for quantitatively injecting liquid medicine into an empty vial at the filling station.
  • the conventional structural scheme is used in this embodiment, as shown in Figure 5: 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 an empty vial.
  • the feeding mechanism 400 is used for conveying and placing the coating on the mouth of the vial filled with liquid medicine in the pre-pressing station. Since the feeding mechanism of this embodiment is to convey 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 vial by the manipulator after sucking the coating layer through the suction cup.
  • the coating pre-compression mechanism 500 includes a driving device 510 and a pre-compression mold 520 connected to the driving device, and is used to pre-compress the coating layer placed on the mouth of the vial at the pre-compression station into a downward arc Shaped protrusion shape.
  • the stoppering mechanism 600 is used to press the rubber stopper into the mouth of the vial in the stoppering station with the coating layer pre-compressed.
  • the capping mechanism 700 is used for rolling the aluminum cap onto the stoppered vial of the vial in the capping station.
  • 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 The structure and program.
  • 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 vial, and the driving structure is generally an air cylinder.
  • the capping mechanism directly presses the aluminum cap onto the bottle mouth with the rubber stopper, and then tightens the lower end of the aluminum cap so that the lower end shrinks and deforms and the rubber stopper is firmly fixed on the bottle mouth.
  • a high-pressure gas blowing mechanism 800 which includes:
  • the support rod 810 is fixed on the stoppering station.
  • 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 (not shown in the figure) through a pipeline, and has an inner diameter greater than or equal to the mouth of the vial and is located on the mouth of the vial.
  • the blowing ring When the vial with the coating layer pre-compressed is transported to the stoppering station by the conveying mechanism 200, the blowing ring is just right on the bottle mouth and blowing, and the blowing ring 820 has an arc shape toward When the protruding coating layer blows high-pressure gas, the stopper mechanism 600 presses the rubber stopper into the bottle mouth.
  • the air outlet is arranged obliquely downward, specifically, a hole is provided on the inner wall of the blowing ring, and then a short tube is welded, and the short tube is set obliquely downward.
  • 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.
  • 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 to the first driving device 511, and the pressing ring 521 is connected to the second driving device 512.
  • the male mold 522 can slide up and down in the pressure ring 521, and its lower end is a convex arc surface.
  • the second driving device 512 drives the pressing ring 521 to press and fix the edge of the coating layer placed on the bottle mouth on the lower bottle mouth, and the first The driving device 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.
  • the bottom surface of the pressure ring 521 is provided with a rubber gasket for buffering.
  • the first driving device 511 and the second driving device 512 are air cylinders or electric cylinders or Electromagnet or electric push rod.
  • the first driving device 511 Since the first driving device 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 overlying layer. It may cause cracking or breaking. Therefore, it is preferable that the first driving device 511 use an electric cylinder that can accurately control the strength and the speed of the action, and preferably a servo electric cylinder.
  • AST-3424 injection filling, stoppering and capping device including any one of the above-mentioned specific embodiments 18-24, the filling, stoppering and capping device of a medicinal solution packaging bottle with protrusions, and a liquid storage tank C communicating with the liquid storage tank Liquid filling pipeline (not shown in the figure), wherein the liquid storage tank C, the liquid filling pipeline, and the liquid filling needle 310 are all 316 stainless steel parts; or the liquid storage tank C,
  • the inner layer of the irrigating pipe and the irrigating needle 310 that is in contact with the liquid medicine is a polyvinylidene fluoride layer.
  • 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.
  • this embodiment provides a method for filling, stoppering and capping of a vial, which sequentially includes a liquid filling step S1, a coating pre-compression step S2, a stoppering step S3, and a capping step S4.
  • a predetermined volume of liquid medicine is poured into the vial via the filling mechanism.
  • step S2 of pre-pressing the coating layer after the liquid medicine is poured into the vial, the coating layer is pre-compressed and formed so that the coating layer is attached to the mouth of the vial and forms a structure that protrudes into the mouth of the vial.
  • the coating layer placed on the bottle mouth is fixed and then pre-pressed with a male mold.
  • step S3 the rubber stopper is quickly pressed into the bottle mouth where the coating layer is applied. Fast is within 0.1 seconds or faster.
  • the aluminum cap is directly pressed onto the bottle mouth 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 cleaned vials are slowly pushed into the bayonet of the chuck 220 in the hopper LD of the unscrambler L by the push rod of the unscrambler. Then it is conveyed by the chuck of the conveying mechanism 200, and is filled by the filling mechanism when it is transferred to the filling station corresponding to the corresponding filling mechanism 300 ( Figure a);
  • the chuck continues to rotate, transports the filled vial to the pre-pressing station, and the feeding mechanism 400 moves to place the covering layer 22 on the vial (b);
  • 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 vial (c), and then the male mold 522 is driven to pre-press and form the covering layer. (Figure d);
  • the chuck continues to rotate and transports the vial to the stoppering station.
  • the high-pressure gas blowing mechanism 800 blows air (picture e), and the plugging mechanism 600 pushes the rubber stopper in after the high-pressure gas blowing mechanism leaves (picture f);
  • the chuck of the conveying mechanism 200 continues to rotate to convey the capped vials to the bottle outlet mechanism 900.
  • a bottle-shifting plate is provided on the edge of the hopper LD.
  • the bottle-shifting 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 the A chamfer (round chamfer or right-angle chamfer) is provided on the edge of the bayonet facing the bottle-shifting plate.
  • the design of the chamfer facilitates the insertion of the bottle-shifting plate into the bayonet 221 to pull out the vial.
  • the bottle shifting plate 910 When the chuck 220 continues to rotate to the position corresponding to the bottle ejection mechanism 900, the bottle shifting plate 910 will pull out the vials that are stuck into the bayonet 221 one by one and enter the bottle ejection channel 920, thus completing the ejection. Bottle process.

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Abstract

注射液的包装瓶（100）及包装套件（1000）、灌注加塞压盖装置和方法，包装瓶（100）包括：瓶体（10）；胶塞组件（20），用于塞入瓶体（10）的瓶口（13）中；封盖（30），用于设置在胶塞组件（20）上卡合固定瓶口（13）和胶塞组件（20），胶塞组件（20）包括胶塞（21）以及直接附着在胶塞（21）的朝向瓶口（13）的暴露面上的覆着层（22），在覆着层（22）与胶塞（21）之间无粘附剂层，覆着层（22）为聚四氟乙烯层、聚偏二氟乙烯层、四氟乙烯/六氟丙烯的共聚物层或至少两种的复合层，封盖（30）顶部形成缺口（31）而使得胶塞（21）露出，便于穿刺。还提供对应的用于AST-3424注射液的包装套件（1000）及方法。满足隔离乙醇/丙二醇溶剂的AST-3424注射液的包装瓶（100）以保证注射液与包装瓶塞之间无污染的稳定性的要求。

Description

注射液的包装瓶及包装套件、灌注加塞压盖装置和方法 技术领域
本发明涉及对专利申请PCT/US2016/021581，公开号WO2016145092A1，对应中国申请号2016800150788，公开号CN107530556A所公开的化合物TH-2870以及PCT/US2016/062114，公开号WO2017087428A1，对应中国申请号2016800446081，公开号CN108290911A中的S构型化合物的注射液制剂的研发，特别是专为该注射液制剂研发的专属包装瓶，属于药品包装领域。
背景技术
我公司开发的以过表达醛酮还原酶1C3(AKR1C3)为标靶的DNA烷化癌症治疗药物AST-3424(参见专利申请：DNA烷化剂，对应PCT申请号PCT/US2016/021581,公开号WO2016/145092，对应中国申请号2016800150788，公开号CN107530556A中公开化合物TH2870；(R)-及(S)-1-(3-(3-N,N-二甲基胺基羰基)苯氧基-4-硝苯基)-1-乙基-N,N’-双(伸乙基)胺基磷酸酯、组合物及其使用及制备方法，对应PCT申请号PCT/US2016/062114,公开号WO2017087428A1，对应中国申请号2016800446081，公开号CN108290911A中的S构型化合物)，中文名为(S)-1-(3-(3-N,N-二甲氨基羰基)苯氧基-4-硝基苯基)-1-乙基-N,N'-双(亚乙基)氨基磷酸酯，也称为OBI-3424、TH-2870的S构型化合物)，CAS号为2097713-69-2，其结构如下：
Figure PCTCN2020113550-appb-000001
AST-3424的化学结构式
已有行业权威文献(Kathryn Evans,JianXin Duan,Tara Pritchard,et al.OBI-34 24,a novel AKR1C3-activated prodrug,exhibits potent efficacy agains tpreclinical 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,JianXin Duan,Yuelong Guo,Stephen W.Erickson and Malcolm A.Smith，A bstract LB-B16:The AKR1C3-Activated Prodrug OBI-3424 Exerts Profound InVi vo Efficacy Against Preclinical Models of T-Cell Acute Lymphoblastic Leukemi a(T-ALL)；a Pediatric Preclinical Testing Consortium Study[C]，AACR-NCI-EORT C International Conference:Molecular Targetsand Cancer Therapeutics；October26-30,2017；Philadelphia,PA，DOI:10.1158/1535-7163.)证实该化合物为一种广谱的小分子抗癌前药，对多种实体肿瘤和血液肿瘤具有疗效。
为了进行后续的临床试验，需要制备合适的剂型进行人体给药：通常是口服或是注射给药。
在合成制备过程中发现该物质为淡黄色油状物，在储运、制剂方面存在着多种困难：由于酰胺、磷酸酯结构使得口服给药剂型的片剂和口服液剂型开发不便，然而研发团队初步试验发现常规的以水作为溶剂的注射液稳定性不够，无法满足后续多中心、多样本的长期临床试验和商业生产销售的要求。
经过实验研究发现该化合物能较好的溶解在乙醇等类似溶剂体系中，因此乙醇和丙二醇等溶剂所制备的浓缩注射液制剂具有较高含量的乙醇，同时注射剂依然较之常规的水基注射液流动相弱，比较粘稠，常规使用的水基注射液的包装瓶(西林瓶或安剖瓶)的结构不能满足要求：
如图8所示，典型的西林瓶(参见中国实用新型公开文件CN201445645U， 公开日2010.05.05)包括瓶体1、胶塞2以及封盖3，有时也会在封盖设置保护盖4。由于使用的胶塞多为橡胶材质，AST-3424化合物的性质比较活泼，因此橡胶极有可能与注射液接触后，使得橡胶溶解在乙醇中，进而影响注射液的稳定性。
一种可能的应对策略是在常规的胶塞2上进行覆膜，典型的覆膜后的胶塞(参见中国实用新型公开文件CN2612625Y，公开日2004.04.21)结构如图9所示，该覆膜胶塞包括基体5、塞体6以及覆膜7。
显然通过在塞体6的表面涂覆覆膜7来隔离乙醇/丙二醇溶剂的AST-3424注射液来保证注射液的包装稳定性是一个比较合适、经济的选择。
现有的覆膜胶塞是直接通过覆膜或粘附剂将膜材料直接结合在胶塞外表面的。使用时：需要使用注射器针头刺破该覆膜，然后吸取预定体积的注射液，如此就有两次穿刺通过这个覆膜，而由于覆膜是粘附结合在胶塞外表的，穿刺过程中存在污染的风险。
行业上对于药液，无论是用于注射给药的注射剂或是口服给药的口服液都是使用上述图8、9的结构进行包装。
然而上述的包装存在一个问题，无法通过外观快速的知道是否被使用：对于注射剂或口服液，虽然取下保护盖后即意味着包装被拆封，但是否有被注射器针头刺入吸取过药液或是注入过其他物质，都是不容易、快速察觉的。当然通过仔细观察胶塞2上的针眼可以发现，但耗时而且麻烦。
另外，对于该种结构的包装瓶的密封效果，由于是将胶塞塞在瓶体的瓶口上，然后加上封盖3进行固定压合，但在长时间的储存中，如果发生泄漏导致药液变质，通过肉眼的观察也是无法快速、直观的判断的。
发明内容
寻找合适的隔离乙醇/丙二醇溶剂的AST-3424注射液的包装瓶以保证注射液与包装瓶塞之间无污染的稳定性是本发明的课题，而其中的胶塞覆膜结构是关键。
通过调查，市面上具有的成膜材料比较多，经过前期医药用材料筛选，得出最常用、易得的几种医药用材料：聚醚砜树脂PES、聚四氟乙烯PTFE、聚偏二氟乙烯PVDF、四氟乙烯/六氟丙烯的共聚物FEP的不同牌号的膜材进行实验。
实验使用的是以下商业可购买的膜材，具体情况如下表：
表1：不同材质、不同牌号的过滤膜材参数表
Figure PCTCN2020113550-appb-000002
注：FEP膜无过滤膜供应。
实验中是使用对应材料的膜进行浸泡或者过滤膜进行过滤来模拟乙醇/丙二醇溶剂的AST-3424注射液的相互作用对注射液稳定性的影响。
经过实验证明，实质由0.75ml的无水乙醇和0.25ml的无水丙二醇以及10mg的AST-3424原料药这样比例的溶剂、原料药组成注射剂是稳定的，本实验即用该注射剂来进行实验验证。
实验验证中的覆膜对照组使用的是聚四氟乙烯覆膜(通过粘附剂粘附)的胶塞。
制备未经过滤的AST-3424注射液：由75ml的无水乙醇和25ml的无水丙二醇以及1g的AST-3424原料药这样比例的溶剂、原料药溶解制备100ml的AST-3424注射液。
分别通过固定在玻璃滤器支架上的不同材质、牌号的过滤膜过滤AST-3424注射液：收集通过膜过滤得到的第一个10ml AST-3424滤液作为初始滤液，收集剩余部分作为最终滤液。
未过滤的AST-3424注射液用作空白对照液。
四氟乙烯/六氟丙烯的共聚物FEP膜组对应的FEP-1、FEP-2、FEP-3分别是浸泡在AST-3424注射液后8小时后的溶液。
覆膜对照组浸泡液，使用的是聚醚砜树脂、聚四氟乙烯覆膜、聚偏二氟乙烯通过粘附剂粘附的胶塞浸泡到上述的10ml的AST-3424中，其时间为8小时。
覆膜对照组穿刺后注射液，使用聚偏二氟乙烯通过粘附剂粘附的胶塞塞进灌注有上述的AST-3424注射剂的玻璃西林瓶口后，将1ml注射器的针头扎入胶塞后，通过倾斜一定角度来使得针头与注射液解除而吸入一定体积的注射液，然后抽出针头，将剩下的注射液在瓶体中来回颠倒两次，打开瓶塞，直接取样后进行分析。
目视检查滤液的外观并分析样品中AST-3424的含量和杂质含量。
直接的，应该根据实际的情况，将上述的不同材质、不同牌号的膜材(不是过滤膜)贴敷在胶塞上，然后将这些胶塞加盖到装有上述的AST-3424注射液的西林瓶中，并按照实际使用的环境进行存放，然后在设计的24个月后取样检测西林瓶中的注射液，进行HPLC检测以考察这些膜材材质、牌号、厚度对稳定性(含量以及杂质)的影响，但实际上这样操作不现实，为此本项目研发时使用 的是加速的思路：使用上述材质、牌号、厚度、孔径的过滤膜材的过滤操作来代替长时间接触作用，这是由于注射液是从这些过滤膜材的过滤孔中流出，即将实际中使用的无孔的不透膜替换为透过的过滤膜来模拟强化这个长时间的接触作用，因此以上进行的过滤膜实验结果能够代表膜材材质、牌号、厚度对稳定性(含量以及杂质)的影响。
分别将上述的不同材质、不同牌号的过滤膜得到的过滤液、空白对照液、覆膜对照组浸泡液、覆膜对照组穿刺后注射液进行HPLC分析。
使用HPLC法测定含量：以AST-3424作为外标进行定量。
UVDAD检测器波长230nm，C18柱，柱温25℃。
流动相：
A：乙酸铵溶于95％水和5％乙腈体积比的混合溶剂的10mmol/L乙酸铵溶液；
B：乙酸铵溶于95％乙腈和5％水体积比的混合溶剂的8mmol/L乙酸铵溶液；
进行梯度洗脱。
测试结果如下表2所示，每个样品均进行两次测试后取均值。
表2：不同样品的AST-3424含量以及杂质含量表
Figure PCTCN2020113550-appb-000003
Figure PCTCN2020113550-appb-000004
实验结论
在三种过滤膜材中，除了通过PTFE过滤的样品之外，所有样品在过滤之前和之后的含量测定水平保持不变。通过PTFE过滤的样品的测定值略有增加。原因可能是由于乙醇的一些蒸发。所有样品的杂质在试验过滤过程中没有显着变化，但考虑到注射液的长期存储，相比较而言，与其他两种膜材相比，PVDF的滤液杂质最少。因此，根据实验推荐将最优异的PVDF膜材用于AST-3424注射液的胶塞包装。
进一步分析，比较覆膜对照组浸泡液、覆膜对照组穿刺后注射液的杂质含量，可以发现其杂质含量升高，而且在HPLC分析峰中出现了新的未在过滤膜材组对应的注射液中出现的新杂质，也就是说，AST-3424注射液极有可能会溶解覆膜对照组所使用的粘附剂。
由以上的对比可知，传统的覆膜胶塞对于AST-3424注射液的包装存在污染的风险。为此，本发明的包装瓶的胶塞应该使用“变形压合”的工艺，而不使用任何粘合剂或其他助剂：在压盖胶塞时，应将圆形的膜材置于胶塞的下方，然后按照膜材在先、胶塞在上的方式进行一次压合，利用压合过程中膜材的变形(塑性变形和/或弹性变形)来与胶塞贴合并密封。
在确定了上述的膜材材质后，试验表明膜材厚度影响不大，本领域技术人 员根据实际情况以及胶塞的弹性大小可以自主选择。根据实际情况以及成本可以明确，上述试验表明，优选范围的50-150微米厚度的膜材满足要求。更厚或更薄的膜材可能会使得压合工艺困难或增加成本，过厚的膜材也存在杂质更多的风险，因此发明人根据经验给出上述推荐值。
为此基于以上的实验，本发明给出以下的方案。
一、包装瓶
用于AST-3424注射液的包装瓶，AST-3424注射液为实质由0.75ml的无水乙醇和0.25ml的无水丙二醇以及10mg的AST-3424原料药这样比例的溶剂、原料药组成的注射剂，包括：
瓶体，用于容纳AST-3424注射液；
胶塞组件，用于塞入瓶体的瓶口中；
封盖，用于设置在胶塞组件上卡合固定瓶口和胶塞组件，
其中，胶塞组件包括胶塞以及直接附着在该胶塞的朝向瓶口的暴露面上的覆着层，在该覆着层与胶塞之间无粘附剂层，该覆着层为聚四氟乙烯层、聚偏二氟乙烯层、四氟乙烯/六氟丙烯的共聚物层或至少两种的复合层，
封盖顶部形成缺口而使得胶塞露出，便于穿刺。
优选的，覆着层为聚偏二氟乙烯层。
或者，覆着层为表内两层的复合层，表层为聚偏二氟乙烯，内层为聚四氟乙烯层和/或四氟乙烯/六氟丙烯的共聚物层。
推荐的，覆着层的厚度为50-150微米。
一般的，瓶体为玻璃西林瓶。
由于注射液在中性或弱碱性下稳定，瓶体为中性或碱性的硼硅玻璃瓶。
进一步的，由于注射液在光照情况下会发生变质降解，瓶体为不透光或透光率低的瓶体。一般选用棕色的玻璃瓶或上述的聚四氟乙烯、聚偏二氟乙烯、四氟乙烯/六氟丙烯的共聚物材质的瓶体(或其他材料的瓶体但内壁具有上述材料涂层隔离)。
进一步，胶塞包括基体和连接在该基体上的塞体，塞体的外端面具有凹陷结构；
对应的，覆着层至少结合在塞体表面，但不与凹陷结构形成的内壁贴合使得凹陷结构与覆着层之间形成封闭空腔。
推荐的，胶塞为氯化丁基橡胶塞。
进一步，覆着层因凹陷结构与覆着层之间形成的封闭空腔内具有的压缩气体的作用而形成向外的突起。
本发明提供的包装瓶，由于采用特别的“变形压合”的工艺，而不使用任何粘合剂或其他助剂：在压盖胶塞时，应将圆形的膜材(即上述的覆着层)置于胶塞的下方，然后按照膜材在下、胶塞在上的方式进行一次压合，利用压合过程中膜材的变形(塑性变形和/或弹性变形)来与胶塞贴合并密封，在这个过程中，由于胶塞的凹陷结构与覆着层之间具有空腔，而在快速的压合过程中，会将气体(在保护气体气氛下压合)压合密封在这个空腔内使得内部压强较外界大而形成突起的鼓包。
如此设计是出于两个目的：
验证气密性、验证包装是否被破坏。由于这个突起的鼓包内封存了压缩气体，根据压盖操作中的操作压力可以预先测定或标记(在瓶体上标记)这个鼓包向外鼓起的高度，一旦气密性不合格或是被使用而刺破鼓包(无论是恶意还是正常被 使用)都会使得这个突起的鼓包因压缩气体泄出而塌陷。因此通过观察这个突起的鼓包是否塌陷，是否塌陷超过预先设置在瓶体上的标记可以验证气密性，验证包装是否被破坏，验证是否已经被使用过。
快速的使得注射液中蒸发的溶剂滴落到瓶体中。由于这个突起的鼓包的形状是近乎“V”形，这样从瓶体的注射液中蒸发而凝结的溶剂(主要是乙醇)可以通过这个这个鼓包被汇集到中心的最低点处，从而更快的滴落，使得瓶体中注射液的浓度的改变可能性减小。由于AST-3424为高活性抗肿瘤药物，而注射液在使用时是根据标识的浓度来计算抽取体积的，蒸发凝结会使得实际浓度比表示浓度高，这样计算的抽取体积的注射液的药物含量会比预定的量高，如此会增加用药的风险。而使用上述的方案就能一定程度上减小这个风险。
进一步，该包装瓶还具有保护盖，
保护盖具有圆柱形盖部分和与圆柱形盖部分连接的圈形的收颈部分，
圆柱形盖部分用于包覆基体，收颈部分用于套住瓶口，
保护盖扣合且覆盖在封盖顶部形成的缺口而使得露出的胶塞被覆盖。
二、药液灌装方法
由于本发明的胶塞和覆着层之间还设计了特别的突起鼓包结构，为此本发明实际上提供了一种对应的药液灌装方法。
胶塞具有突起结构的药液包装瓶的生产方法，其包括以下操作：
在压盖胶塞时，将覆着层置于胶塞的下方，然后按照覆着层在下、胶塞在上的方式进行一次压合，利用压合过程中膜材的变形(塑性变形和/或弹性变形)来与胶塞贴合并密封完成胶塞的压盖。
具体的AST-3424药物制剂的生产工艺流程图见图1。
步骤1：溶解与混合
步骤2-1：加乙醇溶液
用烧杯称取处方量的AST-3424原料药(已除热原)，投入配料罐中。加入处方量50％的药用无水乙醇(已除热原)搅拌至溶解(溶解时间15min，搅拌速度50HZ即50转每分钟)。
步骤2-2：加丙二醇
加入处方量丙二醇(已除热原)，搅拌至溶解(溶解时间15min，搅拌速度50HZ即50转每分钟)。
步骤2-3：混合
加入处方量50％的药用无水乙醇(已除热原)，搅拌至溶解(溶解时间15min，搅拌速度50HZ即50转每分钟)。
步骤3：除菌
对步骤2中得到的溶液进行除菌操作。
步骤4：无菌灌装并加塞
进行无菌灌装，装量为1.0-1.2ml(0.860-1.032g)的上述AST-3424注射液。
在灌装后加盖胶塞时，将覆着层置于胶塞的下方，然后按照覆着层在下、胶塞在上的方式进行一次压合，利用压合过程中膜材的变形(塑性变形和/或弹性变形)来与胶塞贴合并密封完成胶塞的压盖。
步骤5：轧盖和外观检查
灌装好的药瓶经输送网带传至轧盖间进行轧盖：加压铝封盖和保护盖。
进行外观检查。
步骤6：放行检验
取样AST-3424注射液供QC检验，QA放行后的供临床使用期间在-20℃贮藏。
本发明提供的药液灌装方法，由于采用特别的“变形压合”的工艺，而不使用任何粘合剂或其他助剂：在压盖胶塞时，应将圆形的膜材(即上述的覆着层)置于胶塞的下方，然后按照膜材在下、胶塞在上的方式进行一次压合，利用压合过程中膜材的变形(塑性变形和/或弹性变形)来与胶塞贴合并密封，在这个过程中，由于胶塞的凹陷结构与覆着层之间具有空腔，而在快速的压合过程中，会将气体(在保护气体气氛下压合)压合密封在这个空腔内使得内部压强较外界大而形成突起的鼓包。
如此设计是出于两个目的：
验证气密性、验证包装是否被破坏。由于这个突起的鼓包内封存了压缩气体，根据压盖操作中的操作压力可以预先测定或标记(在瓶体上标记)这个鼓包向外鼓起的高度，一旦气密性不合格或是被使用而刺破鼓包(无论是恶意还是正常被使用)都会使得这个突起的鼓包因压缩气体泄出而塌陷。因此通过观察这个突起的鼓包是否塌陷，是否塌陷超过预先设置在瓶体上的标记可以验证气密性，验证包装是否被破坏，验证是否已经被使用过。
快速的使得注射液中蒸发的溶剂滴落到瓶体中。由于这个突起的鼓包的形状是近乎“V”形，这样从瓶体的注射液中蒸发而凝结的溶剂(主要是乙醇)可以通过这个这个鼓包被汇集到中心的最低点处，从而更快的滴落，使得瓶体中注射液的浓度的改变可能性减小。由于AST-3424为高活性抗肿瘤药物，而注射液在使用时是根据标识的浓度来计算抽取体积的，蒸发凝结会使得实际浓度比表示浓度高，这样计算的抽取体积的注射液的药物含量会比预定的量高，如此会增加用药 的风险。而使用上述的方案就能一定程度上减小这个风险。
三、胶塞具有突起结构的药液包装瓶
进一步，根据以上的实验和直接将膜材覆着在胶塞上形成突起结构(鼓包)的原理和有益效果的分析，本发明还提供如下方案的胶塞具有突起结构的药液包装瓶。
一种胶塞具有突起结构的药液包装瓶，用于包装药液，所述药液可以是AST-3424注射液也可以是其他药液，其包括：
瓶体，用于容纳药液；
胶塞组件，用于塞入瓶体的瓶口中，包括胶塞以及直接附着在该胶塞的朝向瓶口的暴露面上的覆着层；
封盖，用于设置在胶塞组件上卡合固定瓶口和胶塞组件，
其中，胶塞包括基体和连接在该基体上的塞体，塞体的外端面具有凹陷结构，
对应的，覆着层至少结合在塞体表面，但不与凹陷结构形成的内壁贴合使得凹陷结构与覆着层之间形成封闭空腔，
覆着层因凹陷结构与覆着层之间形成的封闭空腔内具有的压缩气体的作用而形成向外的突起或鼓包。
显然，胶塞为弹性材料制成，优选为橡胶，更优选为药用的氯化丁基橡胶。
进一步的，在该覆着层与胶塞之间无粘附剂层，该覆着层为聚四氟乙烯层、聚偏二氟乙烯层、四氟乙烯/六氟丙烯的共聚物层或至少两种的复合层。
进一步的，覆着层为聚偏二氟乙烯层。
更加进一步的，覆着层为四氟乙烯/六氟丙烯的共聚物层。
推荐的，覆着层的厚度为50-150微米。
上述提供的包装瓶的瓶体和胶塞均使用常规现有的西林瓶和对应的胶塞在灌装后加盖胶塞时，将覆着层置于胶塞的下方，然后按照覆着层在下、胶塞在上的方式进行一次压合，利用压合过程中膜材的变形(塑性变形和/或弹性变形)来与胶塞贴合并密封完成胶塞的压盖。在这个过程中，由于胶塞的凹陷结构与覆着层之间具有空腔，而在快速的压合过程中，会将气体(在保护气体气氛下压合)压合密封在这个空腔内使得内部压强较外界大而形成突起的鼓包。
如此设计是出于两个目的：
验证气密性、验证包装是否被破坏。由于这个突起的鼓包内封存了压缩气体(多为惰性气体，如氮气)，根据压盖操作中的操作压力可以预先测定或标记(在瓶体上标记)这个鼓包向外鼓起的高度，一旦气密性不合格或是被使用而刺破鼓包(无论是恶意还是正常被使用)都会使得这个突起的鼓包因压缩气体泄出而塌陷。因此通过观察这个突起的鼓包是否塌陷，是否塌陷超过预先设置在瓶体上的标记可以验证气密性，验证包装是否被破坏，验证是否已经被使用过。
快速的使得注射液中蒸发的溶剂滴落到瓶体中。由于这个突起的鼓包的形状是近乎“V”形，这样从瓶体的注射液中蒸发而凝结的溶剂(比如挥发性的乙醇或其他含有挥发性成分的药液)可以通过这个这个鼓包被汇集到中心的最低点处，从而更快的滴落，使得瓶体中药液的浓度的改变可能性减小。
显然，这样的设计对于一些高活性抗肿瘤药物或其他注射剂是十分重要的：这些药液在使用时是根据标识的浓度来计算抽取体积的，蒸发凝结会使得实际浓度比表示浓度高，这样计算的抽取体积的药液的药物含量会比预定的量高，如此会增加用药的风险。而使用上述的方案就能一定程度上减小这个风险。
进一步为了使得上述鼓包或突起的位置变化更加直观，在瓶体(西林瓶)的瓶身或瓶颈部分上设置的刻度线来标记突起或鼓包的设计位置。
推荐的，上述的刻度线其实是有宽度的标记带圈，其包括两个刻画圈，上圈为设计时的低温位置，下圈为设计时的高温位置：即根据设计该包装瓶在容纳对应的药液后，处于设计的最低温度时该突起或鼓包的最低点位于该低温位置对应的上圈，处于设计的最高温度时该突起或鼓包的最低点位于该高温位置对应的下圈。
而一旦气密性不合格或是被使用而刺破鼓包(无论是恶意还是正常被使用)都会使得这个突起或鼓包因压缩气体泄出而塌陷，此时突起或鼓包必定位于上述的低温位置对应的上圈之上(对应气密性不合格)或直接消失(对应被使用而刺破鼓包)。
四、包装套件
一种用于AST-3424注射液的包装套件，包括：
包装盒；
气体保护袋，其内填充有大于大气压的保护气体，被设置在包装盒中；
包装瓶，被封装在气体保护袋中；
其中，包装瓶为上述的用于AST-3424注射液的包装瓶。
作为一种进一步的保护，气体保护袋填充气体为氮气，气体保护袋的材质为铝塑双层复合材料。
一般的，包装瓶为2/5/10毫升规格的棕色避光玻璃西林瓶。
本发明还提供一种具有突起的药液包装瓶的灌注加塞压盖装置，其一体化的完成药液的灌注、加塞以及压盖问题，得到的包装瓶能解决上述两个问题。
传统的覆膜胶塞是直接塞入到瓶口的，本发明的包装瓶的胶塞使用“变形压合”的工艺，使用或不使用任何粘合剂或其他助剂：在压盖胶塞时，将弹性的覆着层(膜材)置于胶塞的下方，然后将覆着层(膜材)先进行预压后得到突起的结构，再压上胶塞，利用压合过程中膜材的变形(塑性变形和/或弹性变形)来与胶塞贴合并密封，利用压合过程中覆着层(膜材)的再次变形(塑性变形和/或弹性变形)来与胶塞贴合并密封完成胶塞的压盖。在这个过程中，由于胶塞的凹陷结构与覆着层之间具有空腔，而在快速的压合过程中，会将气体(在保护气体气氛下压合)压合密封在这个空腔与上述覆着层形成的突起结构内使得内部压强较外界大而形成更加明显的突起或鼓包。
同样设计突起或鼓包是出于两个目的：
验证气密性、验证包装是否被破坏。由于这个突起的鼓包内封存了压缩气体，根据压盖操作中的操作压力可以预先测定或标记(在瓶体上标记)这个鼓包向外鼓起的高度，一旦气密性不合格或是被使用而刺破鼓包(无论是恶意还是正常被使用)都会使得这个突起的鼓包因压缩气体泄出而塌陷。因此通过观察这个突起的鼓包是否塌陷，是否塌陷超过预先设置在瓶体上的标记可以验证气密性，验证包装是否被破坏，验证是否已经被使用过。
快速的使得注射液中蒸发的溶剂滴落到瓶体中。由于这个突起的鼓包的形状是近乎“V”形，这样从瓶体的注射液中蒸发而凝结的溶剂(比如挥发性的乙醇或其他含有挥发性成分的药液)可以通过这个这个鼓包被汇集到中心的最低点处，从而更快的滴落，使得瓶体中药液的浓度的改变可能性减小。
本发明提供的灌注加塞压盖装置通过先将覆着层预压在西林瓶瓶口上形成突起，然后再加塞、压盖完成灌封工作，通过预压可以使得形成的突起更明显， 从而更好的达到上述效果，肉眼观察的对比也更方便、快捷。
基于以上的发明思路，本发明提供以下的实验方案。
五、灌注加塞压盖装置
具有突起的药液包装瓶的灌注加塞压盖装置，包括：
输送机构，用于夹持固定西林瓶并移动到不同工位；
灌液机构，包括灌液针头和药液定量开关，与储液箱连接，用于定量将药液注入到处于灌液工位的空西林瓶中；
送料机构，用于输送并将覆着层放置在预压工位的灌注有药液的西林瓶的瓶口上；
覆着层预压机构，包括驱动器件以及与该驱动器件连接的预压模，用于将放置在处于预压工位的西林瓶瓶口上的覆着层预压成向下具有弧形突起的形状；
加塞机构，用于将胶塞压入到预压了覆着层的处于加塞工位的西林瓶的瓶口上；以及
压盖机构，用于将铝盖轧到加塞了的处于压盖工位的西林瓶的瓶口上。
输送机构的目的就是将空的西林瓶一个一个有序的输送到预定的工位上。
通常的，输送机构有两类：圆盘式旋转输送机构或直线式输送机构。
圆盘式输送机构，基本原理就是设置主转盘，并在主转盘的四周设置与西林瓶相匹配的卡盘，通过匹配的理瓶机将一个个西林瓶卡入卡盘的卡口中，在旋转中将西林瓶输送到预定的工位上。这类机构比较常用，比如中国专利文献CN206544899U中公开的一种双工位西林瓶灌装机、CN206172956U中公开的液体灌装加塞机、CN203558514U中公开的灌装加塞机理瓶装置、CN207015615U中公开的灌装封口机、CN1431141A中公开的高速液体灌装加塞机均使用这种圆 盘式输送机构进行西林瓶的输送。
直线式输送机构，与上述的圆盘式类似，只是在传送带上设置了具有卡口的结构，通过输送带的运动(间歇或连续运动)将西林瓶输送到预定的工位。
灌液机构，为常用的注入式灌注结构，通过气缸、电动缸等驱动灌液针头插入到瓶口中，进行灌注。在灌液针头的管路上连接有定量的开关，保证每次灌注的量都是预定的量。
送料机构，用于输送并将覆着层放置在预压工位的灌注有药液的西林瓶的瓶口上。一般而言，在制剂包装机械中，送料的方式比较多，可以通过气缸、电动缸、电磁铁、机械手等进行送料。而本发明中，由于要输送的是覆着层，因此考虑的方案是在简单的机械手上安装吸盘，通过吸盘吸取覆着层后依靠机械手将覆着层转运到西林瓶的瓶口上。
加塞机构、压盖机构使用的是现有的结构，CN206172956U中公开的液体灌装加塞机、CN207015615U中公开的灌装封口机、CN1431141A中公开的高速液体灌装加塞机均公开了相应的结构和方案。一般而言，加塞机构就是将理好塞(可以通过螺旋振动理塞机将橡胶塞统一整理为小头朝下)的橡胶塞塞入到西林瓶的瓶口中，驱动结构一般为气缸。压盖机构是将铝盖直接压到塞了胶塞的瓶口上，然后收紧铝盖的下端使得下端缩小变形而将胶塞牢固固定在瓶口。
覆着层预压机构，就是通过预压模将覆着层进行预压，得到初步的突起形状。
进一步，还包括高压气体吹入机构，其包括：
支撑杆，固定在加塞工位上；
吹气环，为空心的圆环，其内壁具有出气孔，通过管路和高压气源连通，内径大于或等于所述西林瓶的瓶口而位于瓶口上，
当预压了覆着层的西林瓶被所述输送机构输送到处于加塞工位时，所述吹气环即刚好处于瓶口上并进行吹气，
在所述吹气环朝具有弧形突起形状的所述覆着层吹送高压气体时，所述加塞机构将所述加塞压入瓶口。
这样通过进一步设计高压气体吹入机构，可以在预压后，加塞前向突起结构中吹入高压气体，这样在加塞时，可以使得突起中的气压更大，对应的突起的程度也更明显，从而达到更直观的效果。
进一步，所述出气孔是斜向下设置的，倾斜设置可以更好的让气体吹入到瓶口。
进一步，所述支撑杆是中空的管状，起到管路的作用，一端与所述高压气源连通，另一端与所述吹气环连通。
进一步，所述预压模包括压环以及套装在该压环内的阳模，
所述阳模上端与第一驱动器件连接，所述压环与第二驱动器件连接，
所述阳模可在所述压环内上下滑动，其下端为凸起的弧面，
当西林瓶被输送到处于预压工位时，所述第二驱动器件驱动所述压环将放置在瓶口上的所述覆着层的边缘压紧固定下瓶口上，所述第一驱动器件驱动所阳模穿过所述压环下压将所述覆着层预压成向下具有弧形突起的形状。
进一步，所述压环的地面设置有缓冲用的橡胶垫圈。增加橡胶垫圈可以将覆着层压紧同时也不会因为预压模的下压力过大、过快而将覆着层拉破或是撕裂。
推荐的，所述第一驱动器件、所述第二驱动器件为气缸或电动缸或电磁铁。
作为一种选择，所述输送机构为圆盘式旋转输送机构或直线式输送机构。当然也可以采用螺旋杆式的输送机构。
六、AST-3424注射液的灌注加塞压盖装置
AST-3424注射液的灌注加塞压盖装置，包括上述的具有突起的药液包装瓶的灌注加塞压盖装置以及储液箱和该储液箱连通的灌液管路，
其中，所述储液箱、所述灌液管路、所述灌液针头均为316牌号不锈钢部件；
或
所述储液箱、所述灌液管路、所述灌液针头的接触药液的内层均为聚偏氟乙烯层。
进一步，所述覆着层为聚偏氟乙烯层，
所述送料机构均为316牌号不锈钢部件；或所述送料机构接触药液的部件均涂覆有为聚偏氟乙烯层。
之所以特别要求适用于AST-3424注射液的灌注加塞压盖装置的一些直接接触或有可能接触药液的部件使用316牌号不锈钢或聚偏氟乙烯层是因为经过实验对比验证了AST-3424药液与这两种材料接触(8小时甚至24小时)不会发生反应使得杂质变得，即实验证实了这两种材质对于AST-3424药液而言是稳定的。
七、西林瓶的灌注加塞压盖方法
本发明还提供一种西林瓶的灌注加塞压盖方法，其包括覆着层预压步骤：
在药液灌注到西林瓶后，对覆着层进行预压成型使得覆着层贴敷在西林瓶瓶口并形成向瓶口内的突起的结构。
一般，西林瓶的灌注加塞压盖方法主要包括灌液步骤、加塞步骤和压盖(轧盖)步骤，上述的覆着层预压步骤就是在灌液步骤后、加塞步骤前将覆着层进行预压而形成突起结构。
进一步的，加塞步骤时将胶塞快速的压入贴敷了覆着层的瓶口。这里的快速 是为了尽快的将突起结构中的气体(保护气体，比如氮气)通过胶塞快速压入到瓶口中，使得突起结构鼓起。
进一步的，在进行覆着层预压时，将放置在瓶口上的覆着层固定后使用阳模预压。
附图说明
图1为AST-3424药物制剂的生产工艺流程图；
图2为本发明的某些实施例中注射液的包装瓶的具体结构示意图；
图3为本发明的某些实施例中注射液的包装瓶的瓶体具体结构示意图；
图4为本发明的某些实施例中注射液的包装瓶的具体结构示意图；
图5为本发明的某些实施例中注射液的包装瓶的胶塞组件具体结构示意图；
图6为本发明的实施例中“变形压合”的工艺来进行压合覆膜的过程示意图；
图7为本发明的某些实施例中包装套件的结构示意图；
图8为现有技术中典型的西林瓶的结构示意图；
图9为现有技术中典型的覆膜胶塞的结构示意图；
图10为本发明的某些实施例中灌注加塞压盖装置的结构示意图；
图11为本发明的某些实施例中灌液机构的结构示意图；
图12为本发明的某些实施例中高压气体吹入机构的结构示意图；
图13为本发明的某些实施例中覆着层预压机构的结构示意图；
图14为本发明的某些实施例中西林瓶的灌注加塞压盖方法步骤示意图；
图15为本发明的某些实施例中出瓶机构的结构示意图；以及
图16为使用本实施例提供的灌注加塞压盖装置进行西林瓶的灌注加塞压盖的动作示意图。
具体实施方式
具体实施例1
用于AST-3424注射液的包装瓶100，AST-3424注射液为实质由0.75ml的无水乙醇和0.25ml的无水丙二醇以及10mg的AST-3424原料药这样比例的溶剂、原料药组成的注射剂，包瓶体10、胶塞组件20、封盖30。
瓶体10，用于容纳AST-3424注射液，包括瓶身11与瓶身11连接的瓶颈12，在瓶颈的开口设置有瓶口13。
根据实际，瓶体10的形状是可选的，通常为圆柱形或长方形。而且，通常瓶颈12要小于瓶身11，具体形状如图2所示。
胶塞组件20，用于塞入瓶体10的瓶口11中，包括胶塞21以及直接附着在该胶塞的朝向瓶口的暴露面上的覆着层22，在该覆着层与胶塞之间无粘附剂层，该覆着层为聚四氟乙烯层、聚偏二氟乙烯层、四氟乙烯/六氟丙烯的共聚物层或至少两种的复合层。
正如发明内容部分所公开的，具有粘附剂的粘附覆膜的胶塞21会给本发明的AST-3424带来污染的风险，而单独使用聚醚砜树脂PES、聚四氟乙烯PTFE、聚偏二氟乙烯PVDF、四氟乙烯/六氟丙烯的共聚物FEP膜材制备得到覆着层22后，注射液的杂质得到改善，经过比较，聚四氟乙烯层、聚偏二氟乙烯层、四氟乙烯/六氟丙烯的共聚物层符合要求，那么显然这三种材料的两两混合或三种混合后的材料的膜材也符合隔离乙醇/丙二醇溶剂的AST-3424注射液的包装瓶，以保证注射液与包装瓶塞(胶塞21)之间无污染的稳定性(即不会因为注射液和覆着层接触而使得杂质增多或出现新的杂质)要求。
胶塞21为弹性材质制作。
封盖30，用于设置在胶塞组件20上卡合固定瓶口13和胶塞组件20。如图2所示，就是一个环形的圈上端套在胶塞组件20上，同时下端卡住瓶颈12，瓶颈12上有一圈凹陷，用于封盖30的下端卡合勾住固定，使得胶塞组件20能够牢固的塞入固定在瓶口13中。封盖30一般为铝材制作。
封盖30顶部形成缺口31(圆形的洞子)而使得胶塞21露出，便于穿刺。
具体实施例2
进一步的，在具体实施例1的包装瓶100基础上，覆着层22为聚偏二氟乙烯层。
具体实施例3
进一步的，在具体实施例1和/或2的包装瓶100基础上，覆着层22为表内两层的复合层，表层为聚偏二氟乙烯，内层为聚四氟乙烯层和/或四氟乙烯/六氟丙烯的共聚物层。
具体实施例4
进一步的，在具体实施例1和/或2和/或3的包装瓶100基础上，覆着层22的厚度为50-150微米。
具体实施例5
在具体实施例1和/或2和/或3和/或4的包装瓶100基础上，瓶体10为玻璃西林瓶。
玻璃西林瓶(penicillin vial)的类型可以是管制玻璃西林瓶，或者是模制玻璃西林瓶，推荐使用管制玻璃西林瓶。
具体实施例6
在具体实施例1和/或2和/或3和/或4和/或5的包装瓶的基础上，瓶体10 为中性或碱性的硼硅玻璃瓶。
具体实施例7
在具体实施例1和/或2和/或3和/或4和/或5和/或6的包装瓶的基础上，瓶体10为不透光或透光率低的瓶体。推荐使用棕色瓶。
具体实施例8
如图4/5所示，在具体实施例1和/或2和/或3和/或4和/或5和/或6和/或7的包装瓶的基础上，胶塞21包括基体211和连接在该基体上的塞体212，塞体212的外端面具有凹陷结构213；
对应的，覆着层22至少结合在塞体212表面，但不与凹陷结构213形成的内壁贴合，如此将使得凹陷结构213与覆着层22之间形成封闭空腔214。
具体实施例9
在具体实施例1和/或2和/或3和/或4和/或5和/或6和/或7和/或8的包装瓶的基础上，胶塞21为氯化丁基橡胶塞。
具体实施例10
如图4/5所示，在具体实施例8和/或9的包装瓶的基础上，覆着层22因凹陷结构213与覆着层22之间形成的封闭空腔214内具有的压缩气体的作用而形成向外的突起。
具体实施例11
如图4/5所示，在具体实施例1和/或2和/或3和/或4和/或5和/或6和/或7和/或8和/或9和/或10的包装瓶的基础上，还包括保护盖40，保护盖40具有圆柱形盖部分41和与圆柱形盖部分连接的圈形的收颈部分42，圆柱形盖部分41用于包覆基体211，收颈部分42用于套住瓶口13。保护盖40扣合且覆盖在封盖 30顶部形成的缺口31(圆形的洞子)而使得露出的胶塞21被覆盖。
具体实施例13
如同发明内容所启发的，进为了使得上述鼓包或突起的位置变化更加直观，在瓶体(西林瓶)的瓶身11或瓶颈12部分上设置刻度线来标记突起或鼓包的设计位置。如图4所示，该刻度线121就是一个宽为1.5mm的磨砂环带，且该环带是间隔磨砂的，这样便于观察比对突起或鼓包的位置。
具体实施例14
以下实施例通过附图6来说明特别的“变形压合”的工艺。
瓶体10和胶塞21均使用常规现有的西林瓶和对应的胶塞在灌装后加盖胶塞时，将覆着层22置于胶塞21的下方，如图6的左图。
然后按照覆着层22在下、胶塞21在上的方式进行一次压合，利用压合过程中膜材(覆着层)的变形(塑性变形和/或弹性变形)来与胶塞贴合并密封完成胶塞的压盖，如图6的中图。
在这个压合过程中，由于胶塞21的凹陷结构213与覆着层22之间具有空腔，而在快速的压合过程中，会将气体(在保护气体气氛下压合)压合密封在这个空腔内使得内部压强较外界大而形成突起(鼓包)，然后同时加压封盖30和保护盖40，完成固定和密封，如图6的右图。
具体实施例14
一种用于AST-3424注射液的包装套件1000，包括包装盒1002、气体保护袋1003、包装瓶100。
包装盒1002，为通常的纸质包装盒。
气体保护袋1003，其内填充有大于大气压的保护气体，被设置在包装盒中。
包装瓶100，被封装在气体保护袋中，具体实施例1-14中任意一项的用于AST-3424注射液的包装瓶。
多个气体保护袋1003相互连接在一起。
具体实施例15
在具体实施例14的包装套件基础上，气体保护袋1003填充气体为氮气，气体保护袋的材质为铝塑双层复合材料。铝塑双层复合材料材质的气体保护袋的避光性能更好。
具体实施例16
在具体实施例14和/或15的包装套件，其中，包装瓶100为2/5/10毫升规格的棕色避光玻璃西林瓶。
具体实施例17
此实施例为变形扩展实施例。
以上实施例中，瓶体的材质为玻璃瓶，也可以为其他材质的西林瓶，进一步的，可以在其他材质或玻璃材质的西林瓶的内壁涂覆覆着层，而该覆着层为聚四氟乙烯层、聚偏二氟乙烯层、四氟乙烯/六氟丙烯的共聚物层或至少两种的复合层，优选为聚偏二氟乙烯层。
以上实施例给出了具有突起的药液包装瓶的结构，以下实施例具体说明本发明提供的具有突起的药液包装瓶的灌注加塞压盖装置的具体结构。
具体实施例18
如图4所示，具有突起的药液包装瓶的灌注加塞压盖装置1000，包括：
输送机构200，用于夹持固定西林瓶并移动到不同工位。本实施例选用结构比较紧凑的圆盘式输送机构，基本原理就是设置主转盘210，并在主转盘的四周 设置与西林瓶相匹配的卡盘220，通过匹配的理瓶机LB将一个个西林瓶卡入卡盘的卡口中，在旋转中将西林瓶输送到预定的工位上。对应的，这里的预定工位也是依照圆周设置的。当然，根据每个工位上设置的对应动作机构的不同，输送机构10对应的驱动机(步进电机)所驱动转过的卡口数也不同，简单的，比如一个卡盘220上设置有60个卡口，则每个对应的卡口对应的角度为6度，如果一个工位上设置10个灌液机构300、送料机构400、覆着层预压机构500、加塞机构600、压盖机构700同时进行对应的操作，那么每次驱动机驱动转盘210旋转60度；如果一个工位设置5个上述的各种机构，则每次驱动机驱动转盘210旋转30度，以此类推。本实施例中一个卡盘220上设置有30个卡口221，则每个对应的卡口对应的角度为12度，一个工位上设置1个灌液机构300、送料机构400、覆着层预压机构500、加塞机构600、压盖机构700同时进行对应的操作，那么每次驱动机驱动转盘210旋转12度。
灌液机构300，包括灌液针头310和药液定量开关320，与储液箱C连接，用于定量将药液注入到处于灌液工位的空西林瓶中。本实施例中使用的就是常规的结构方案，如图5所示：储存有注射液的储液箱C中的药液在泵和药液定量开关320的作用下，被定量的通过灌液针头310注入到空的西林瓶中。
送料机构400，用于输送并将覆着层放置在预压工位的灌注有药液的西林瓶的瓶口上。本实施例送料机构由于要输送的是覆着层，因此考虑的方案是在简单的机械手上安装吸盘，通过吸盘吸取覆着层后依靠机械手将覆着层转运到西林瓶的瓶口上。
覆着层预压机构500，包括驱动器件510以及与该驱动器件连接的预压模520，用于将放置在处于预压工位的西林瓶瓶口上的覆着层预压成向下具有弧形突起 的形状。
加塞机构600，用于将胶塞压入到预压了覆着层的处于加塞工位的西林瓶的瓶口上。
压盖机构700，用于将铝盖轧到加塞了的处于压盖工位的西林瓶的瓶口上。
加塞机构、压盖机构使用的是现有市面上供应的结构，CN206172956U中公开的液体灌装加塞机、CN207015615U中公开的灌装封口机、CN1431141A中公开的高速液体灌装加塞机均公开了相应的结构和方案。一般而言，加塞机构就是将理好塞(可以通过螺旋振动理塞机将橡胶塞统一整理为小头朝下)的橡胶塞塞入到西林瓶的瓶口中，驱动结构一般为气缸。压盖机构是将铝盖直接压到塞了胶塞的瓶口上，然后收紧铝盖的下端使得下端缩小变形而将胶塞牢固固定在瓶口。
具体实施例19
在上述实施例4的基础上，如图10/12所示，还包括高压气体吹入机构800，其包括：
支撑杆810，固定在加塞工位上。
吹气环820，为空心的圆环，其内壁具有出气孔821，通过管路和高压气源(图中未示出)连通，内径大于或等于所述西林瓶的瓶口而位于瓶口上。
当预压了覆着层的西林瓶被所述输送机构200输送到处于加塞工位时，所述吹气环即刚好处于瓶口上并进行吹气，在所述吹气环820朝具有弧形突起形状的所述覆着层吹送高压气体时，所述加塞机构600将所述胶塞压入瓶口。
具体实施例20
在上述实施例18和/或19的基础上，所述出气孔是斜向下设置的，具体就是 在吹气环的内壁上设置孔，然后焊接短管，将短管设置为斜向下。
具体实施21
在上述实施例18和/或19和/或20的基础上，所述支撑杆810是中空的管状，起到管路的作用，一端与所述高压气源连通，另一端与所述吹气环连通。
具体实施例22
在上述实施例18和/或19和/或20和/或21的基础上，如图13所示，其中，所述驱动器件510倍设置在支架530上，支架530固定在预压工位上。所述预压模520包括压环521以及套装在该压环内的阳模522。
所述阳模522上端与第一驱动器件511连接，所述压环521与第二驱动器件512连接。所述阳模522可在所述压环521内上下滑动，其下端为凸起的弧面。
当西林瓶被输送到处于预压工位时，所述第二驱动器件512驱动所述压环521将放置在瓶口上的所述覆着层的边缘压紧固定下瓶口上，所述第一驱动器件511驱动所阳模522穿过所述压环521下压将所述覆着层22预压成向下具有弧形突起的形状。
具体实施例23
在上述实施例18和/或19和/或20和/或21和/或22的基础上，所述压环521的底面设置有缓冲用的橡胶垫圈。
具体实施例24
在上述实施例18和/或19和/或20和/或21和/或22和/或23的基础上，所述第一驱动器件511、所述第二驱动器件512为气缸或电动缸或电磁铁或电动推杆。
由于第一驱动器件511是用于驱动阳模522进行压膜的，而压膜过程中阳模 运动的快慢和力量大小将直接影响覆着层被压成的形状，过快或力量过大都将导致拉裂或拉断，因此优选推荐第一驱动器件511使用能精确控制力量大小和动作快慢的电动缸，而且最好是伺服电动缸。
具体实施例25
AST-3424注射液的灌注加塞压盖装置，包括上述具体实施例18-24中任意一项的具有突起的药液包装瓶的灌注加塞压盖装置以及储液箱C和该储液箱连通的灌液管路(图中未示出)，其中，所述储液箱C、所述灌液管路、所述灌液针头310均为316牌号不锈钢部件；或所述储液箱C、所述灌液管路、所述灌液针头310的接触药液的内层均为聚偏氟乙烯层。
具体实施例26
在实施例24的基础上，所述覆着层为聚偏氟乙烯层，
所述送料机构400均为316牌号不锈钢部件；或所述送料机构400接触药液的部件均涂覆有为聚偏氟乙烯层。
具体实施例27
如图14所示，本实施例提供西林瓶的灌注加塞压盖方法，依次包括灌液步骤S1、覆着层预压步骤S2、加塞步骤S3以及压盖步骤S4。
灌液步骤S1，通过灌液机构将预定体积的药液灌注到西林瓶中。
覆着层预压步骤S2，在药液灌注到西林瓶后，对覆着层进行预压成型使得覆着层贴敷在西林瓶瓶口并形成向瓶口内的突起的结构。
优选的，在进行覆着层预压时，将放置在瓶口上的覆着层固定后使用阳模预压。
加塞步骤S3，将胶塞快速的压入贴敷了覆着层的瓶口。快速是在0.1秒内 或更快的速度。
压盖步骤S4，将铝盖直接压到塞了胶塞的瓶口上，然后收紧铝盖的下端使得下端缩小变形而将胶塞牢固固定在瓶口。
以下结合附图10以及附图14、16对整个装置的工作过程进行介绍。
整理洗净的西林瓶在理瓶机L的料斗LD中被理瓶机的推杆慢慢的推送到卡盘220的卡口中。然后被输送机构200的卡盘输送，在输送到对应的灌液机构300对应的灌液工位时被灌液机构灌液(a图)；
卡盘继续旋转，将灌液后的西林瓶输送打击预压工位，送料机构400动作，将覆着层22放置在西林瓶口(b图)；
待放置后覆着层后，覆着层预压机构500的压环521被驱动将覆着层的周边固定在西林瓶口上(c图)，然后阳模522被驱动将覆着层预压成型(d图)；
卡盘继续旋转，将西林瓶运送到加塞工位，高压气体吹入机构800动作吹气(e图)，在高压气体吹入机构离开后加塞机构600将胶塞压入(f图)；
当卡盘旋转将压塞后的西林瓶输送到压盖工位后，压盖机构700动作完成压盖(g图)，保护盖压合机构BH随即将保护盖压合(h图)，最后得到图2所示的包装瓶。
输送机构200的卡盘继续旋转，将压盖后的西林瓶输送至出瓶机构900。
如图15所示，在料斗LD的边沿设置有拨瓶板，该拨瓶板910呈朝向卡盘220的折线状或弧状，且其尖端伸入卡盘220的卡口221中，对应的该卡口的朝向该拨瓶板的一个边缘设置有倒角(圆倒角或直角倒角)，倒角的设计便于拨瓶板插入到卡口221中将西林瓶拨出。
当卡盘220继续旋转至出瓶机构900对应的工位时，拨瓶板910会将卡入 卡口221的西林瓶一个一个的拨出而进入到出瓶通道920中，如此即完成了出瓶过程。

Claims (28)

  1. 用于AST-3424注射液的包装瓶，AST-3424注射液为实质由无水乙醇和无水丙二醇以及AST-3424原料药组成的注射剂，包括：
    瓶体，用于容纳AST-3424注射液；
    胶塞组件，用于塞入所述瓶体的瓶口中；
    封盖，用于设置在所述胶塞组件上卡合固定所述瓶口和所述胶塞组件，
    其中，
    所述胶塞组件包括胶塞以及直接附着在该胶塞的朝向所述瓶口的暴露面上的覆着层，在该覆着层与所述胶塞之间无粘附剂层，该覆着层为聚四氟乙烯层、聚偏二氟乙烯层、四氟乙烯/六氟丙烯的共聚物层或至少两种的复合层，
    所述封盖顶部形成缺口而使得所述胶塞露出，便于穿刺。
  2. 根据权利要求1所述的包装瓶，所述覆着层为聚偏二氟乙烯层。
  3. 根据权利要求1所述的包装瓶，所述覆着层为表内两层的复合层，表层为聚偏二氟乙烯，内层为聚四氟乙烯层和/或四氟乙烯/六氟丙烯的共聚物层。
  4. 根据权利要求1所述的包装瓶，所述覆着层的厚度为50-150微米。
  5. 根据权利要求1所述的包装瓶，其中，所述瓶体为玻璃西林瓶。
  6. 根据权利要求1所述的包装瓶，其中，所述瓶体为中性或碱性的硼硅玻璃瓶。
  7. 根据权利要求1所述的包装瓶，其中，所述瓶体为不透光或透光率低的瓶体。
  8. 包装瓶，包括：
    瓶体，其用于容纳药液；
    胶塞组件，用于塞入所述瓶体的瓶口中；
    封盖，用于设置在所述胶塞组件上卡合固定所述瓶口和所述胶塞组件，
    所述胶塞组件包括胶塞以及直接附着在该胶塞的朝向所述瓶口的暴露面上的覆着层，在该覆着层与所述胶塞之间无粘附剂层，该覆着层为聚四氟乙烯层、聚偏二氟乙烯层、四氟乙烯/六氟丙烯的共聚物层或至少两种的复合层，
    所述封盖顶部形成缺口而使得所述胶塞露出，便于穿刺。
    其中，所述胶塞包括基体和连接在该基体上的塞体，所述塞体的外端面具有凹陷结构；
    对应的，所述覆着层至少结合在所述塞体表面，但不与所述凹陷结构形成的内壁贴合使得所述凹陷结构与所述覆着层之间形成封闭空腔。
  9. 根据权利要求8所述的包装瓶，其中，所述覆着层因所述凹陷结构与所述覆着层之间形成的封闭空腔内具有的压缩气体的作用而形成向外的突起。
  10. 根据权利要求9所述的包装瓶，其中，在所述瓶体的瓶身或瓶颈部分上设置刻度线来标记突起或鼓包的设计位置。
  11. 根据权利要求1或8所述的包装瓶，还包括保护盖，
    所述保护盖具有圆柱形盖部分和与圆柱形盖部分连接的圈形的收颈部分，
    所述圆柱形盖部分用于包覆所述基体，所述收颈部分用于套住所述瓶口，
    所述保护盖扣合且覆盖在所述封盖顶部形成的缺口而使得露出的所述胶塞被覆盖。
  12. 一种用于AST-3424注射液的包装套件，包括：
    包装盒；
    气体保护袋，其内填充有大于大气压的保护气体，被设置在所述包装盒中；
    包装瓶，被封装在所述气体保护袋中；
    其中，所述包装瓶为权利要求1-11中任意一项所述的用于AST-3424注射液的包装瓶。
  13. 根据权利要求12所述的包装套件，其中，所述气体保护袋填充气体为氮气，气体保护袋的材质为铝塑双层复合材料。
  14. 根据权利要求12所述的包装套件，其中，所述包装瓶为2/5/10毫升规格的棕色避光玻璃西林瓶。
  15. 权利要求1-11中任意一项所述的包装瓶的生产方法，其包括以下操作：
    在压盖胶塞时，将所述覆着层置于胶塞的下方，然后按照覆着层在下、胶塞在上的方式进行一次压合，利用压合过程中所述覆着层的变形来与胶塞贴合并密封完成胶塞的压盖。
  16. 具有突起的药液包装瓶的灌注加塞压盖装置，包括：
    输送机构，用于夹持固定西林瓶并移动到不同工位；
    灌液机构，包括灌液针头和药液定量开关，与储液箱连接，用于定量将药液注入到处于灌液工位的空西林瓶中；
    送料机构，用于输送并将覆着层放置在预压工位的灌注有药液的西林瓶的瓶口上；
    覆着层预压机构，包括驱动器件以及与该驱动器件连接的预压模，用于将放置在处于预压工位的西林瓶瓶口上的覆着层预压成向下具有弧形突起的形状；
    加塞机构，用于将胶塞压入到预压了覆着层的处于加塞工位的西林瓶的瓶口上；以及
    压盖机构，用于将铝盖轧到加塞了的处于压盖工位的西林瓶的瓶口上。
  17. 根据权利要求16所述的灌注加塞压盖装置，还包括高压气体吹入机构，其包括：
    支撑杆，固定在加塞工位上；
    吹气环，为空心的圆环，其内壁具有出气孔，通过管路和高压气源连通，内径大于或等于所述西林瓶的瓶口而位于瓶口上，
    当预压了覆着层的西林瓶被所述输送机构输送到处于加塞工位时，所述吹气环即刚好处于瓶口上并进行吹气，
    在所述吹气环朝具有弧形突起形状的所述覆着层吹送高压气体时，所述加塞机构将所述加塞压入瓶口。
  18. 根据权利要求17所述的灌注加塞压盖装置，所述出气孔是斜向下设置的。
  19. 根据权利要求17所述的灌注加塞压盖装置，所述支撑杆是中空的管状，起到管路的作用，一端与所述高压气源连通，另一端与所述吹气环连通。
  20. 根据权利要求16所述的灌注加塞压盖装置，其中，所述预压模包括压环以及套装在该压环内的 阳模，
    所述阳模上端与第一驱动器件连接，所述压环与第二驱动器件连接，
    所述阳模可在所述压环内上下滑动，其下端为凸起的弧面，
    当西林瓶被输送到处于预压工位时，所述第二驱动器件驱动所述压环将放置在瓶口上的所述覆着层的边缘压紧固定下瓶口上，所述第一驱动器件驱动所阳模穿过所述压环下压将所述覆着层预压成向下具有弧形突起的形状。
  21. 根据权利要求20所述的灌注加塞压盖装置，其中，所述压环的地面设置有缓冲用的橡胶垫圈。
  22. 根据权利要求20所述的灌注加塞压盖装置，其中，所述第一驱动器件、所述第二驱动器件为气缸或电动缸或电磁铁。
  23. 根据权利要求16所述的灌注加塞压盖装置，其中，所述输送机构为圆盘式旋转输送机构或直线式输送机构。
  24. AST-3424注射液的灌注加塞压盖装置，包括上述16-23中任意一项所述的具有突起的药液包装瓶的灌注加塞压盖装置以及储液箱和该储液箱连通的灌液管路，
    其中，所述储液箱、所述灌液管路、所述灌液针头均为316牌号不锈钢部件；
    或
    所述储液箱、所述灌液管路、所述灌液针头的接触药液的内层均为聚偏氟乙烯层。
  25. 根据权利要求24所述的灌注加塞压盖装置，其中，所述覆着层为聚偏氟乙烯层，
    所述送料机构均为316牌号不锈钢部件；或所述送料机构接触药液的部件均涂覆有为聚偏氟乙烯层。
  26. 西林瓶的灌注加塞压盖方法，其包括覆着层预压步骤：
    在药液灌注到西林瓶后，对覆着层进行预压成型使得覆着层贴敷在西林瓶瓶口并形成向瓶口内的突起的结构。
  27. 根据权利要求26所述的灌注加塞压盖方法，其中，加塞步骤时将胶塞快速的压入贴敷了覆着层的瓶口。
  28. 根据权利要求26所述的灌注加塞压盖方法，其中，在进行覆着层预压时，将放置在瓶口上的覆着层固定后使用阳模预压。
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