Lyophilization method for lonapegsomatropin, lyophilized formulation of lonapegsomatropin, and injection

Abstract

Disclosed is a lyophilization method for lonapegsomatropin, comprising: adding a middle plug to a dual-chamber cartridge, filling the cartridge with lonapegsomatropin to be lyophilized, and placing and fixing the dual-chamber cartridge to a lyophilization support; limiting a top plug to the mouth of the dual-chamber cartridge; performing freezing, primary drying, and secondary drying on said lonapegsomatropin; and fixing the top plug with a top cap and sealing the mouth of the cartridge. The lyophilization method provided by the present application can provide high-quality lyophilization parameters and lyophilization operations, so as to use a top plug and a top cap to complete the integrated plugging and capping of a dual-chamber cartridge, so that the obtained lyophilized formulation of lonapegsomatropin retains better quality, improving the use effect and storage time thereof.

Description

Freeze-drying method of lonapegsomatropin, freeze-dried preparation of lonapegsomatropin and injection TECHNICAL FIELD

[0001] The present application relates to the field of biopharmaceuticals, and more particularly, to a freeze-drying method of lonapegsomatropin, a freeze-dried preparation of lonapegsomatropin and an injection. BACKGROUND

[0002] At present, most of the freeze-dried products on the market use a vial as a storage container. Before injection, a sterile syringe is used to extract a reconstituting agent from another container containing the reconstituting agent, and then the reconstituting agent is injected into the drug container for reconstitution, extraction and administration. The precision of administration and the use compliance are relatively poor, and a dual-chamber carton bottle package can provide a better choice. The dual-chamber carton bottle is divided into two chambers by a middle plug, wherein the front chamber is used to store freeze-dried drugs, and the rear chamber is used to store a reconstituting agent. During use, the reconstituting agent can flow into the front chamber through a bypass to reconstitute the freeze-dried drugs by pushing the bottom plug to the top.

[0003] Lonapegsomatropin, also known as somavub, is a once-weekly prodrug that releases unmodified growth hormone. It only needs to be injected once a week. After injection, the connecting structure automatically cleaves at a specific rate and releases unmodified growth hormone in a controlled manner. It is used to treat Chinese children with growth hormone deficiency (GHD). Using a dual-chamber carton bottle to store lonapegsomatropin and a reconstituting agent separately, medical personnel can easily reconstitute freeze-dried lonapegsomatropin and administer it, and patients can also quickly administer it with the help of caregivers. In this way, the administration process is simplified, and it also helps to maintain the stability of the active ingredients in lonapegsomatropin.

[0004] However, the conventional freeze-drying process requires separate sealing of the dual-chamber carton bottle after freeze-drying, which cannot be completed in the freeze-dryer as an integrated operation of freeze-drying lonapegsomatropin and sealing the dual-chamber carton bottle. Therefore, a freeze-drying method that integrates freeze-drying, plug pressing and capping is needed to meet the optimal freeze-drying parameter configuration during freeze-drying and the good sealing of the product after freeze-drying, so that the finished product of lonapegsomatropin has a good form, lower water content and a more suitable use method.

[0005] Therefore, there is an urgent need for a new freeze-drying method of lonapegsomatropin to solve the above problems, to improve freeze-drying efficiency and product quality, to fill the gap in the field of dual-chamber carton bottles for lonapegsomatropin freeze-drying technology, and to further enhance the core competitiveness of the finished product. SUMMARY

[0006] The present application aims to provide a solution that can overcome at least one of the above-mentioned defects of the prior art.

[0007] According to an aspect of the present application, a lyophilization method of long-acting growth hormone is provided, comprising:

[0008] A stopper is added to a double-cavity carton bottle, and then the long-acting growth hormone to be lyophilized is poured into the double-cavity carton bottle; after the top cover is assembled with the stopper, it is placed above the bottle opening of the double-cavity carton bottle, and the double-cavity carton bottle is placed and fixed on the customized lyophilization support; the long-acting growth hormone to be lyophilized is subjected to freezing, primary drying and secondary drying, respectively; the top cover is used to press the stopper and embed the double-cavity carton bottle, so as to seal the double-cavity carton bottle and fix the stopper, and make the stopper seal the bottle opening and the bottle neck of the double-cavity carton bottle.

[0009] The lyophilization method provided by the present application simultaneously performs stoppering and capping on the double-cavity carton bottle after lyophilization treatment by operating the top cover, thereby sealing the long-acting growth hormone lyophilized preparation in the double-cavity carton bottle and further sealing the double-cavity carton bottle. The long-acting growth hormone lyophilized preparation obtained by the lyophilization method also has a good lyophilized powder appearance and a low water content, which helps to meet the high demand for long-acting growth hormone use standards and ensure that the long-acting growth hormone maintains stable quality attributes for a long time.

[0010] In some embodiments of the present application, the lyophilization support is a stand-alone lyophilization support or a tray-type lyophilization support, preferably the lyophilization support is a tray-type lyophilization support; and the placement mode of the double-cavity carton bottle in the lyophilization support is upright or inverted, preferably the placement mode of the double-cavity carton bottle in the lyophilization support is upright.

[0011] In some embodiments of the present application, the temperature range set for freezing the long-acting growth hormone in the double-cavity carton bottle is -60℃ to -40℃; the temperature range for primary drying is -60℃ to 0℃, and the temperature range for secondary drying is 15℃ to 40℃; and the pressure range for primary drying and secondary drying is 0.02mbar-0.2mbar, preferably the pressure for primary drying and secondary drying is 0.06mbar, respectively.

[0012] In some embodiments of the present application, the use of the top cover to press the stopper and embed the double-cavity carton bottle further comprises: before pressing the stopper, nitrogen charging operation is performed on the double-cavity carton bottle to maintain the low moisture content of the long-acting growth hormone.

[0013] According to another aspect of the present application, a long-acting growth hormone lyophilized preparation is also provided, which is prepared according to the lyophilization method of long-acting growth hormone of any one of the above. The long-acting growth hormone lyophilized preparation has the characteristics of high lyophilized quality and low moisture, and when treating children with growth hormone deficiency, it can be quickly reconstituted for injection and provide better growth effect for the user.

[0014] According to another aspect of the present application, an injection is also provided, which can include a double-cavity carton bottle package for injection, a lyophilized preparation of long-acting growth hormone, and a reconstitution agent, and the reconstitution and injection of the lyophilized preparation of long-acting growth hormone can be completed by using the double-cavity carton bottle package for injection.

[0015] In some embodiments of the present application, the double-cavity carton bottle package for injection can include a double-cavity carton bottle and a bottle cap assembly, wherein the double-cavity carton bottle is used to contain the long-acting growth hormone, the lyophilized preparation of long-acting growth hormone, and the reconstitution agent; the bottle cap assembly includes a top plug and a top cap; the top plug seals the bottle mouth of the double-cavity carton bottle; the top cap is used to press and fix the top plug so that the top plug seals the bottle mouth of the double-cavity carton bottle; and the double-cavity carton bottle is sealed; wherein the process of pressing and fixing the top plug so that the top plug seals the bottle mouth of the double-cavity carton bottle includes the following steps:

[0016] The top plug is pre-assembled into the top cap; the top cap with the assembled top plug is placed above the bottle mouth of the double-cavity carton bottle, and the top cap is pressed downward. After the top plug is pre-assembled into the top cap, the top plug and the top cap can be integrally formed, and a plug assembly does not need to be introduced, and the top cap can directly realize the plug pressing and cap pressing by pressing the top plug, so as to improve the sealing efficiency of the double-cavity carton bottle in the lyophilization process, avoid the operation failure times caused by more operation steps, and ensure the lyophilization efficiency of the finished preparation when the error operation cannot be remedied in the lyophilization process in a conventional way.

[0017] In some embodiments of the present application, the double-cavity carton bottle can include an inner cavity, a bottle body, a bottle neck, and a bottle mouth, the center of the bottle mouth is provided with a bottle mouth opening connected with the inner cavity, the inner diameter of the bottle mouth opening is smaller than the inner diameters of the bottle mouth and the bottle neck; and the outer wall of one side of the bottle body has a bypass protrusion.

[0018] In some embodiments of the present application, the lyophilized preparation of long-acting growth hormone is the lyophilized preparation of long-acting growth hormone prepared according to the lyophilization method of long-acting growth hormone of any one of the above or the lyophilized preparation of long-acting growth hormone provided by the present application.

[0019] Compared with the prior art, the present application has at least one of the following technical effects:

[0020] 1. The present application provides an integrated sealing method for plug pressing and cap sealing of the double-cavity carton bottle package for injection in the lyophilization process of the preparation.

[0021] 2. The present application provides optimal lyophilization parameters and water removal operations of the lyophilization process of long-acting growth hormone, so that the long-acting growth hormone obtained by using the lyophilization method maintains optimal quality and is convenient for efficient storage and use.

[0022] 3. The application provides a high-quality Lonpise growth hormone lyophilized preparation prepared by the lyophilization method, which is used as a high-purity lyophilized drug for treating children with growth hormone deficiency, and can achieve better therapeutic effect than daily growth hormone preparations, and help the children to reach or approach normal height.

[0023] 4. The application provides an injection, which can store a Lonpise growth hormone lyophilized preparation and a reconstituting agent based on a double-cavity carton bottle package material for injection, and can be long-term and stable storage, and the Lonpise growth hormone lyophilized preparation and the reconstituting agent can be quickly mixed and reconstituted when the injection is used, so that the lyophilized preparation can be efficiently and conveniently used. BRIEF DESCRIPTION OF DRAWINGS

[0024] The above and other objects, features and advantages of the present application will become more apparent from the following detailed description of embodiments of the present application, taken in conjunction with the accompanying drawings. The drawings provided below are for illustrative purposes and are included to further clarify and explain the present application and are not intended to limit the present application. In the drawings, like reference numerals refer to like elements or steps throughout.

[0025] FIG. 1 illustrates a schematic diagram of a lyophilization support of the present application.

[0026] FIG. 2 illustrates a lyophilization curve schematic diagram of a Lonpise growth hormone lyophilized preparation of the present application.

[0027] FIG. 3 illustrates a schematic diagram of the appearance of a Lonpise growth hormone lyophilized preparation of the present application.

[0028] FIG. 4A illustrates a first schematic diagram of the appearance of another Lonpise growth hormone lyophilized preparation of the present application.

[0029] FIG. 4B illustrates a second schematic diagram of the appearance of another Lonpise growth hormone lyophilized preparation of the present application.

[0030] FIG. 5 illustrates a schematic diagram of the structure of a double-cavity carton bottle 1 and a top plug 2 of the present application.

[0031] FIG. 6A illustrates a schematic diagram of the structure of a top cover 3 of the present application.

[0032] FIG. 6B illustrates another schematic diagram of the structure of the top cover 3 of the present application.

[0033] FIG. 7 illustrates another schematic diagram of the structure of the top plug 2 and yet another schematic diagram of the structure of the top cover 3 of the present application.

[0034] FIG. 8A illustrates a schematic diagram of the structure of a top plug positioning point 303 of the present application.

[0035] FIG. 8B illustrates another schematic diagram of the structure of the top plug positioning point 303 of the present application.

[0036] FIG. 9 illustrates a schematic diagram of the structure of an upper end 30 of the present application.

[0037] Figure 10 illustrates a structural diagram of the maximum length of the protrusion 304 of the present application.

[0038] Figure 11 illustrates a structural diagram of the upper and lower cutting angles of the protrusion 304 of the present application.

[0039] Figure 12 illustrates a structural diagram of the double-cavity carton bottle packaging assembly of the present application.

[0040] Figure 13 illustrates a structural diagram of the double-cavity carton bottle 1' and the top plug 2' of the present application.

[0041] Figure 14A illustrates a structural diagram of the top cover 3' of the present application.

[0042] Figure 14B illustrates another structural diagram of the top cover 3' of the present application.

[0043] Figure 14C illustrates yet another structural diagram of the top cover 3' of the present application.

[0044] Figure 15A illustrates another structural diagram of the top plug 2' and yet another structural diagram of the top cover 3' of the present application.

[0045] Figure 15B illustrates a structural diagram of the fitting portion 306' of the top cover 3' of the present application.

[0046] Figure 16A illustrates a structural diagram of the top plug positioning point 303' of the present application.

[0047] Figure 16B illustrates another structural diagram of the top plug positioning point 303' of the present application.

[0048] Figure 16C illustrates a top view of the demolding hole 305' of the present application.

[0049] Figure 17 illustrates a structural diagram of the demolding hole 305' of the present application.

[0050] Figure 18 illustrates a structural diagram of the upper end 30' of the present application.

[0051] Figure 19 illustrates a structural diagram of the maximum length, upper and lower cutting angles of the protrusion 304' of the present application.

[0052] Figure 20 illustrates a structural diagram of the double-cavity carton bottle packaging assembly of the present application.

[0053] Figure 21A illustrates a structural diagram of the top plug 2" and the pressure plug assembly of the present application.

[0054] Figure 21B illustrates another structural diagram of the top plug 2" and the pressure plug assembly of the present application.

[0055] Figure 22 illustrates a structural diagram of the top cover 3" of the present application.

[0056] Explanation of Reference Signs 1 - Double-chambered Cartridge Bottle 2 - Top Plug 3 - Top Cap 4 - Sheath 1' - Double-chambered Cartridge Bottle 2' - Top Plug 3' - Top Cap 4' - Sheath 2" - Top Plug 3" - Top Cap 10 - Bottle Mouth 11 - Bottle Neck 12 - Bottle Body 13 - Inner Chamber 10' - Bottle Mouth 11' - Bottle Neck 12' - Bottle Body 13' - Inner Chamber 20 - Plug Cap 21 - Plug Column 22 - Sealing Portion 20' - Plug Cap 21' - Plug Column 22' - Sealing Portion 20" - Plug Cap 21" - Plug Column 30 - Upper End 31 - Middle End 32 - Lower End 30' - Upper End 31' - Bottom Disc 40' - Sheath Main Body 41' - Flange 31" - Bottom Disc 50 - Holding Jig 51 - Pressing Jig 100 - Bottle Mouth Opening 120 - Bypass Protrusion 100' - Bottle Mouth Opening 120 - Bypass Protrusion 200 - Gap Portion 200' - Gap Portion 300 - Top Disc 301 - Thread 302 - Opening 303 - Top Plug Positioning Point 304 - Protrusion Portion 310 - Protruding Ring 320 - Protruding Strip 321 - First Latch 300' - Top Disc 301' - Thread 302' - Opening 303' - Top Plug Positioning Point 304' - Protrusion Portion 305' - Demolding Hole 306' - Fitting Portion 310' - Internal Protruding Block 311' - Protruding Block Two-Side Opening 321' - First Latch 400' - Second Latch 300" - Top Disc 301" - Thread 500 - Protrusion Portion 510 - Pressing Column DETAILED DESCRIPTION

[0057] As described above, the freeze-drying method of long-acting growth hormone according to the present application includes: adding a middle plug into a double-chambered cartridge bottle 1, and then pouring long-acting growth hormone to be freeze-dried into the double-chambered cartridge bottle 1; assembling a top plug 2 with a top cap 3, and then placing the top cap 3 above a bottle mouth 10 of the double-chambered cartridge bottle 1, and placing and fixing the double-chambered cartridge bottle 1 on a customized freeze-drying support; respectively performing freezing, primary drying, and secondary drying on the long-acting growth hormone to be freeze-dried; and pressing the top plug 2 and the double-chambered cartridge bottle 1 using the top cap 3 to embed the top plug 2, to seal the double-chambered cartridge bottle 1 and fix the top plug 2, and to make the top plug 2 seal the bottle mouth 10 of the double-chambered cartridge bottle 1.

[0058] In the present application, the intermediate plug added to the double-chambered vial 1 and the somatropin to be lyophilized can be any type of intermediate plug for double-chambered vials and somatropin that can be lyophilized, which are suitable for the size and configuration of the double-chambered vial 1. The freezing, primary drying and secondary drying operations can be performed in a lyophilizer that can accommodate the lyophilization rack used in the lyophilization method of the present application; the driving of the top cover 3 to press down can also be any driving method that can be performed in the lyophilizer, such as mechanical pressing, air pressure driving, pneumatic clamp driving or spring pressing.

[0059] In the present application, after the intermediate plug is added to the double-chambered vial 1, the somatropin to be lyophilized can be poured in, and in particular, the somatropin to be lyophilized can be somatropin that is added to the inner chamber 13 of the double-chambered vial 1 for lyophilization and short-term / long-term storage. The user can pour the somatropin solution into one of the inner chambers 13 of the double-chambered vial 1 to perform lyophilization using the lyophilization method of the present application.

[0060] In the present application, the lyophilization rack is a stand-alone lyophilization rack or a tray-type lyophilization rack, and the present application provides a lyophilization method using a lyophilization rack that is a stand-alone lyophilization rack or a tray-type lyophilization rack, and a person skilled in the art can select the specific model, size and working parameters in the lyophilizer of the lyophilization rack according to the actual lyophilization needs. Preferably, the lyophilization rack used is a tray-type lyophilization rack, which is easy to place a larger number of double-chambered vials 1.

[0061] In particular, the double-chambered vial 1 is placed in the lyophilization rack in an upright or inverted manner, and preferably, the double-chambered vial 1 is placed in the lyophilization rack in an upright manner, which facilitates uniform distribution of heat in the double-chambered vial 1 and improves the efficiency of solvent sublimation; in addition, it can also reduce the degree of sedimentation and aggregation of somatropin, to ensure uniform and stable appearance.

[0062] In the present application, the temperature range for freezing the somatotropin in the double-cavity carton bottle 1 can be a temperature range suitable for freeze-drying the somatotropin, and the freezing temperature is generally -60°C to -40°C, at which the somatotropin to be freeze-dried has a high freezing efficiency and maintains its own quality. Therefore, the freezing temperature is any one of -60°C, -59°C, -58°C, -57°C, -56°C, -55°C, -54°C, -53°C, -52°C, -51°C, -50°C, -49°C, -48°C, -47°C, -46°C, -45°C, -44°C, -43°C, -42°C, -41°C or -40°C. Specifically, the temperature range for freezing the somatotropin in the double-cavity carton bottle 1 is -60°C to -40°C, i.e., -60°C, -59°C, -58°C, -57°C, -56°C, -55°C, -54°C, -53°C, -52°C, -51°C, -50°C, -49°C, -48°C, -47°C, -46°C, -45°C, -44°C, -43°C, -42°C, -41°C or -40°C; the temperature range for primary drying is -60°C to 0°C, i.e., -60°C, -59°C, -58°C, -57°C, -56°C, -55°C, -54°C, -53°C, -52°C, -51°C, -50°C, -49°C, -48°C, -47°C, -46°C, -45°C, -44°C, -43°C, -42°C, -41°C, -40°C, -39°C, -38°C, -37°C, -36°C, -35°C, -34°C, -33°C, -32°C, -31°C, -30°C, -29°C, -28°C, -27°C, -26°C, -25°C, -24°C, -23°C, -22°C, -21°C, -20°C, -19°C, -18°C, -17°C, -16°C, -15°C, -14°C, -13°C, -12°C, -11°C, -10°C, -9°C, -8°C, -7°C, -6°C, -5°C, -4°C, -3°C, -2°C, -1°C or 0°C; and the temperature range for secondary drying is 15°C to 40°C, i.e., 15°C, 16°C, 17°C, 18°C, 19°C, 20°C, 21°C, 22°C, 23°C, 24°C, 25°C, 26°C, 27°C, 28°C, 29°C, 30°C, 31°C, 32°C, 33°C, 34°C, 35°C, 36°C, 37°C, 38°C, 39°C or 40°C.

[0063] Similarly, the temperature of the first drying and the second drying of the Lonapeenl can also be any temperature value in the range of -60°C to 0°C and 15°C to 40°C, respectively, to increase the sublimation rate of the water in the Lonapeenl lyophilized preparation. In addition, the pressure range of the first drying and the second drying can be any value in the range of 0.02 mbar to 0.2 mbar, and when the pressure of the first drying and the second drying is preferably 0.06 mbar, the drying efficiency can reach a peak. Specifically, the pressure range of the first drying and the second drying is 0.02 mbar to 0.2 mbar, i.e. 0.02 mbar, 0.03 mbar, 0.04 mbar, 0.05 mbar, 0.06 mbar, 0.07 mbar, 0.08 mbar, 0.09 mbar, 0.10 mbar, 0.11 mbar, 0.12 mbar, 0.13 mbar, 0.14 mbar, 0.15 mbar, 0.16 mbar, 0.17 mbar, 0.18 mbar, 0.19 mbar or 0.20 mbar, and preferably, the pressure of the first drying and the second drying is 0.06 mbar, respectively.

[0064] In the present application, the use of the top cover 3 to press the top plug 2 and embed the double-chamber carton bottle 1 also includes: before pressing the top plug 2, the double-chamber carton bottle 1 is subjected to a nitrogen filling operation to maintain the low moisture content of the Lonapeenl. Those skilled in the art can understand that the double-chamber carton bottle 1 is subjected to a nitrogen filling operation before the bottle opening 10 is closed, and the purpose is to make the nitrogen in the inner chamber 13 reach 1 standard atmosphere, on the one hand, the nitrogen can be used to maintain the low moisture content of the Lonapeenl, and on the other hand, the 1 standard atmosphere of nitrogen can also keep the position of the middle plug fixed in the double-chamber carton bottle.

[0065] In the present application, it also includes a Lonapeenl lyophilized preparation prepared according to the above lyophilization method. In particular, since the Lonapeenl to be lyophilized added to one of the inner chambers 13 of the double-chamber carton bottle 1 in the present application can be one of a plurality of Lonapeenls, the quality of the Lonapeenl lyophilized preparation obtained finally can also be different when the component content of the Lonapeenl to be lyophilized poured into the double-chamber carton bottle 1 is different; in addition, when the lyophilization parameters implemented in the lyophilization process of the Lonapeenl in the lyophilization method of the present application, such as the temperature and pressure of the first drying, are changed, different qualities or different properties of the Lonapeenl lyophilized preparation, such as different water contents, different solid forms of the preparation, etc., can also be produced after pouring the same kind of Lonapeenl to be lyophilized through the above lyophilization method.

[0066] In the present application, an injection is also included, which comprises: a double-chamber carton bottle package for injection, a lyophilized preparation of long-acting growth hormone and a reconstituting agent. It should be noted that the lyophilized preparation of long-acting growth hormone and the reconstituting agent can be any specification of lyophilized preparation of long-acting growth hormone and reconstituting agent suitable for the double-chamber carton bottle package for injection and the lyophilization process. Specifically, the lyophilized preparation of long-acting growth hormone can be any lyophilized preparation of long-acting growth hormone to be lyophilized that can be filled into the double-chamber carton bottle 1 of the present application and prepared by the lyophilization method of the present application, or the lyophilized preparation of long-acting growth hormone provided by the present application.

[0067] In addition, the reconstituting agent can be a reconstituting agent effective for reconstituting any lyophilized preparation of long-acting growth hormone prepared as described above, such as sterile water for injection, which can quickly reconstitute the lyophilized preparation of long-acting growth hormone provided by the present application before administration.

[0068] In the present application, the double-chamber carton bottle package for injection comprises: a double-chamber carton bottle 1 and a bottle cap assembly, wherein the double-chamber carton bottle 1 is used to contain the lyophilized preparation of long-acting growth hormone and the reconstituting agent. The bottle cap assembly comprises a top plug 2 and a top cap 3, which are used to seal the double-chamber carton bottle 1. The double-chamber carton bottle 1, as shown in FIG. 5, can be placed in a lyophilization support used in the existing lyophilization process, and the double-chamber carton bottle package can be fixed and placed upright or inverted in the lyophilization support and sheath; the bottle cap assembly can be made of any material suitable for achieving the sealing function of the bottle cap. The top plug 2 is limited in the top cap 3 and is used to seal the bottle mouth 10 of the double-chamber carton bottle 1; the top cap 3 is used to press and fix the top plug 2, so that the top plug 2 seals the bottle mouth 10 of the double-chamber carton bottle 1 and seals the double-chamber carton bottle 1; wherein the process of pressing and fixing the top plug 2 in the top cap 3 so that the top plug 2 seals the bottle mouth 10 of the double-chamber carton bottle 1 can include the following steps:

[0069] pre-assembling the top plug 2 into the top cap 3; and placing the top cap 3 with the assembled top plug 2 above the bottle mouth 10 of the double-chamber carton bottle 1 and pressing the top cap 3 downward to press the top plug 2. The driving mode of the top cap 3 downward can be mechanical compression, pneumatic driving, pneumatic clamp driving or spring pressing, etc.

[0070] In the present application, the double-chamber carton bottle 1 comprises: an inner chamber 13, a bottle body 12, a bottle neck 11 and a bottle mouth 10, the center of the bottle mouth 10 is provided with a bottle mouth opening 100 connected with the inner chamber 13, the inner diameter of the bottle mouth opening 100 is smaller than the inner diameter of the bottle mouth 10 and the bottle neck 11; the outer wall of one side of the bottle body 12 has a bypass protrusion 120. Those skilled in the art can understand that the size of the inner chamber 13, the bottle body 12, the bottle neck 11 and the bottle mouth 10 of the double-chamber carton bottle 1 can be adjusted to adapt to the size range of commonly used lyophilization supports, such as changing the vertical length of one or more parts of the double-chamber carton bottle 1, changing the radial length of one or more parts of the double-chamber carton bottle 1, etc., all of which do not deviate from the protection scope of the present application.

[0071] In the present application, the top plug 2 comprises a plug cap 20 and a plug column 21, the diameter of the plug column 21 can be equal to or slightly larger than the inner diameter of the bottle opening 100, after the plug column 21 is embedded in the bottle opening 100, the lower surface of the plug cap 20 is completely matched with the upper surface of the bottle opening 10 to achieve the sealing of the bottle opening 10. In particular, the top plug 2 is made of elastic rubber material, so the diameter of the plug column 21 can be adjusted within the diameter range of the bottle opening 100 after the plug column 21 is pressed by force, and the diameter of the plug column 21 can be slightly larger than the diameter of the bottle opening 100 to ensure the tightness of the sealing.

[0072] In the present application, the top cap 3 as shown in FIG. 6A comprises an upper end 30, a middle end 31 and a lower end 32; the upper end 30 has a top disc 300, a thread 301 and an opening 302, the middle end 31 has a convex ring 310, and the lower end 32 optionally has a convex strip 320, the inner wall of the top cap 3 is matched with the bottle opening 20, the bottle neck 21 and at least a part of the bottle body 22; when the top cap 3 is towards the bottle opening 10, the top disc 300 of the upper end 30 presses the top plug 2 to move into the bottle opening 10, so that the top plug 2 is embedded in the bottle opening 10. After the bottle opening 10 of the double-chamber carton bottle 1 is capped, the top disc 300 is tightly matched above the plug cap 20 to press the top plug 2. The opening 302 can discharge the sublimed solvent, such as water, in the somatropin, and the thread 301 is used for thread engagement with a sterile injection needle, and the convex ring 310 can match a protective sheath for protecting the double-chamber carton bottle.

[0073] It should be noted that the shape of the lower end 32 of the top cap 3 can be a cylinder or a prism as shown in FIG. 6B, and the length thereof in the vertical direction can be adjusted, so the lower end 32 can be matched with a small part of the bottle body 12, or can be matched with a large part or the whole of the bottle body 12 to achieve better capping tightness and to adapt to the size requirements of the top cap 3 in the freeze-drying process. The convex strip 320 is used to increase the friction between the lower end 32 and the matching sheath to improve the effect of mutual cooperation and fixation; in particular, the convex strip 320 can also be removed. The shape of the lower end 32 can be a cylinder or a multi-prism to avoid the top cap 3 from slipping off due to the rotational centrifugal force or from affecting the sealing performance due to the relative sliding with the double-chamber carton bottle 1.

[0074] In particular, the length of the middle end 31 of the top cover 3 along the direction of the bottle neck 11 and the bottle body 12 can be adjusted, and the convex ring 310 can be adjusted to the highest part to be attached to the lower part of the upper end 30, so as to adapt to the sealing requirement of the double-cavity carton bottle 1 to the different degrees of pressing cover of the top cover 3, for example, it is necessary to reduce the length of the top cover 3 along the direction of the bottle body 12 or the volume of the top cover 3 to adapt to the size requirement of the double-cavity carton bottle 1 and the top cover 3 to the freeze-drying support in the freeze-drying process. In particular, the center of the top disc 300 has a top disc opening, and the circumferential lower edge of the top disc opening to the upper edge thereof can have an inclination angle β in the vertical direction, and the circumferential upper edge of the top disc opening has a greater opening length than the circumferential lower edge; the circumferential edge surface of the top disc opening can be curved or flat.

[0075] In the present application, as shown in FIG. 7, the top plug 2 can further include a sealing portion 22 protruding above the plug cap 20, which can be inserted into the top disc opening, and when the top plug 2 is completely embedded in the bottle mouth 10, that is, the double-cavity carton bottle 1 is completed, the sealing portion 22 is embedded in the top disc opening and partially protrudes longitudinally from the top disc opening. Those skilled in the art can understand that the size of the sealing portion 22 can be slightly larger than the opening size of the circumferential lower edge of the top disc opening, and in the process of pre-assembling the top plug 2 into the top cover 3, the top plug 2 needs to be fixed by the upper end 30, and the surface of the sealing portion 22 can be slightly deformed to be inserted and embedded in the top disc opening from the circumferential lower edge of the top disc opening.

[0076] Therefore, in the process of pre-assembling the top plug 2 into the top cover 3, the sealing portion 22 can be embedded in the top disc opening, the edge portion thereof closely fits the circumferential outer edge of the top disc opening, and finally partially protrudes from the upper edge of the top disc opening; by setting the radial length L of the sealing portion to have a relatively long radial length, the close fitting of the edge portion thereof and the circumferential outer edge of the top disc opening is improved, and the top plug 2 is further prevented from slipping out of the top disc 300. In addition, by adjusting the size of β, the circumferential lower edge of the top disc opening and the sealing portion 22 can have a closer fit than the circumferential upper edge of the top disc opening, so that the top disc opening closely surrounds and fixes the sealing portion 22.

[0077] In some embodiments, the radial length L of the closure portion 22 can be 2.0 mm - 5.0 mm, in particular, the radial length L of the closure portion 22 can be 2.0 mm, 2.1 mm, 2.2 mm, 2.3 mm, 2.4 mm, 2.5 mm, 2.6 mm, 2.7 mm, 2.8 mm, 2.9 mm, 3.0 mm, 3.1 mm, 3.2 mm, 3.3 mm, 3.4 mm, 3.5 mm, 3.6 mm, 3.7 mm, 3.8 mm, 3.9 mm, 4.0 mm, 4.1 mm, 4.2 mm, 4.3 mm, 4.4 mm, 4.5 mm, 4.6 mm, 4.7 mm, 4.8 mm, 4.9 mm, or 5.0 mm; preferably, the radial length L of the closure portion 22 can be 3.0 mm - 4.0 mm, in particular, the radial length L of the closure portion 22 can preferably be 3.0 mm, 3.1 mm, 3.2 mm, 3.3 mm, 3.4 mm, 3.5 mm, 3.6 mm, 3.7 mm, 3.8 mm, 3.9 mm, or 4.0 mm. The inclination angle β can be 0°, 1°, 2°, 3°, 4°, 5°, 6°, 7°, 8°, 9°, or 10°, etc.

[0078] In some embodiments, the circumferential lower edge opening length of the top disc opening can be 1.5 mm - 5.0 mm, in particular, the circumferential lower edge opening length of the top disc opening can be 1.5 mm, 1.6 mm, 1.7 mm, 1.8 mm, 1.9 mm, 2.0 mm, 2.1 mm, 2.2 mm, 2.3 mm, 2.4 mm, 2.5 mm, 2.6 mm, 2.7 mm, 2.8 mm, 2.9 mm, 3.0 mm, 3.1 mm, 3.2 mm, 3.3 mm, 3.4 mm, 3.5 mm, 3.6 mm, 3.7 mm, 3.8 mm, 3.9 mm, 4.0 mm, 4.1 mm, 4.2 mm, 4.3 mm, 4.4 mm, 4.5 mm, 4.6 mm, 4.7 mm, 4.8 mm, 4.9 mm, or 5.0 mm; preferably, the circumferential lower edge opening length of the top disc opening can be 2.5 mm - 4.0 mm, in particular, the circumferential lower edge opening length of the top disc opening can preferably be 2.5 mm, 2.6 mm, 2.7 mm, 2.8 mm, 2.9 mm, 3.0 mm, 3.1 mm, 3.2 mm, 3.3 mm, 3.4 mm, 3.5 mm, 3.6 mm, 3.7 mm, 3.8 mm, 3.9 mm, or 4.0 mm.

[0079] By taking the radial length L of the sealing portion 22 slightly larger than the circumferential lower edge opening length of the top disc opening, the sealing portion 22 is more fitted with the circumferential lower edge of the top disc opening, so that the top disc opening as a whole effectively fits and fixes the sealing portion 22, and the circumferential edge provides further support, so that the top plug 2 as a whole does not slip off. Preferably, β is set to 0°, and when the top disc opening does not have an inclination angle in the vertical direction, the sealing portion 22 can be well fixed, and the sealing portion 22 can also be easily inserted into the top disc opening without being difficult to insert due to excessive resistance. In another case, when the top disc opening needs to have an inclination angle in the vertical direction to improve the limiting effect of the top disc 300 on the top plug 2, β can also be set to 5° to improve the fixing degree of the sealing portion 22, and the sealing portion 22 can also be inserted and embedded into the top disc opening by applying a certain pressure. Those skilled in the art can adjust the radial length L of the sealing portion 22, the inclination angle β and / or the circumferential lower edge opening length of the top disc opening according to the actual sealing condition of the bottle cap assembly to adaptively adjust the fixing degree of the sealing portion 22 and the top disc 300.

[0080] In particular, the diameter of the cap 20 of the top plug 2 can be slightly smaller than the inner diameter of the top cover 3. Since the top plug 2 is fixed to the bottle opening 100 through the cooperation of the top plug positioning point 303 and the cap 20, the top plug 2 can be tightly fixed to the bottle opening 100 to achieve sealing. In this case, the diameter of the cap 20 is set to be slightly smaller than the inner diameter of the top cover 3, so that a small gap part 200 is left between the surface of the cap 20 and the inner wall of the upper end 30, as shown in FIG. 9. In this way, when the top plug 2 is pressed by the top cover 3, the pressed volume of the cap 20 extends to the gap part 200 reserved around the cap 20, so that the cap 20 will not protrude upwardly to the top disc opening in the middle due to pressure, thereby avoiding affecting injection.

[0081] In some embodiments, the diameter of the plug cap 20 can range from 5.0 mm to 10.0 mm, in particular, the diameter of the plug cap 20 can be 5.0 mm, 5.1 mm, 5.2 mm, 5.3 mm, 5.4 mm, 5.5 mm, 5.6 mm, 5.7 mm, 5.8 mm, 5.9 mm, 6.0 mm, 6.1 mm, 6.2 mm, 6.3 mm, 6.4 mm, 6.5 mm, 6.6 mm, 6.7 mm, 6.8 mm, 6.9 mm, 7.0 mm, 7.1 mm, 7.2 mm, 7.3 mm, 7.4 mm, 7.5 mm, 7.6 mm, 7.7 mm, 7.8 mm, 7.9 mm, 8.0 mm, 8.1 mm, 8.2 mm, 8.3 mm, 8.4 mm, 8.5 mm, 8.6 mm, 8.7 mm, 8.8 mm, 8.9 mm, 9.0 mm, 9.1 mm, 9.2 mm, 9.3 mm, 9.4 mm, 9.5 mm, 9.6 mm, 9.7 mm, 9.8 mm, 9.9 mm, or 10.0 mm; preferably, the diameter of the plug cap 20 can range from 6.0 mm to 8.0 mm, in particular, the diameter of the plug cap 20 can preferably be 6.0 mm, 6.1 mm, 6.2 mm, 6.3 mm, 6.4 mm, 6.5 mm, 6.6 mm, 6.7 mm, 6.8 mm, 6.9 mm, 7.0 mm, 7.1 mm, 7.2 mm, 7.3 mm, 7.4 mm, 7.5 mm, 7.6 mm, 7.7 mm, 7.8 mm, 7.9 mm, or 8.0 mm.

[0082] In some embodiments, the diameter of the upper end 30 of the top cover 3 can range from 5.0 mm to 10.0 mm, in particular, the diameter of the upper end 30 can be 5.0 mm, 5.1 mm, 5.2 mm, 5.3 mm, 5.4 mm, 5.5 mm, 5.6 mm, 5.7 mm, 5.8 mm, 5.9 mm, 6.0 mm, 6.1 mm, 6.2 mm, 6.3 mm, 6.4 mm, 6.5 mm, 6.6 mm, 6.7 mm, 6.8 mm, 6.9 mm, 7.0 mm, 7.1 mm, 7.2 mm, 7.3 mm, 7.4 mm, 7.5 mm, 7.6 mm, 7.7 mm, 7.8 mm, 7.9 mm, 8.0 mm, 8.1 mm, 8.2 mm, 8.3 mm, 8.4 mm, 8.5 mm, 8.6 mm, 8.7 mm, 8.8 mm, 8.9 mm, 9.0 mm, 9.1 mm, 9.2 mm, 9.3 mm, 9.4 mm, 9.5 mm, 9.6 mm, 9.7 mm, 9.8 mm, 9.9 mm or 10.0 mm; preferably, the diameter of the upper end 30 can range from 6.0 mm to 8.0 mm, in particular, the diameter of the upper end 30 can preferably be 6.0 mm, 6.1 mm, 6.2 mm, 6.3 mm, 6.4 mm, 6.5 mm, 6.6 mm, 6.7 mm, 6.8 mm, 6.9 mm, 7.0 mm, 7.1 mm, 7.2 mm, 7.3 mm, 7.4 mm, 7.5 mm, 7.6 mm, 7.7 mm, 7.8 mm, 7.9 mm or 8.0 mm.

[0083] More preferably, the diameter of the plug cap 20 can be configured as 7.0 mm, and the inner diameter of the upper end 30 of the top cover 3 that cooperates with the plug cap 20 can be configured as 7.3 mm, so that a gap part 200 with a length of 0.3 mm is left between the surface of the plug cap 20 and the inner wall of the upper end 30, and the gap part 200 can accommodate the increased volume of the plug cap 20 caused by the extrusion of the plug cap 20 during the assembly of the stopper 2 or the insertion of the injection needle for the growth hormone, thereby avoiding the generation of upward pressure. It should be noted that in the bottle cap assembly according to the embodiments of the present application, those skilled in the art can appropriately adjust the diameter of the plug cap 20 and the diameter of the upper end 30 based on the above-mentioned parameter benchmarks according to the actual application of the bottle cap assembly, so as to adapt to the cooperation of the bottle cap assembly with the freeze-drying support of the freeze dryer, the cooperation with the sheath and / or the cooperation with the syringe. For example, the stability of the pre-assembly of the stopper 2 can be adjusted by appropriately adjusting the diameter of the plug cap 20; the more tightly sealed or more easily detached seal of the double-chamber carton bottle 1 can be maintained by appropriately adjusting the diameter of the upper end 30; and after adjusting the diameter of the plug cap 20 and the diameter of the upper end 30 respectively, in order to appropriately avoid the influence of the extrusion of the plug cap 20 on the assembly and use of the bottle cap assembly, the size relationship between the diameter of the plug cap 20 and the diameter of the upper end 30 can be appropriately adjusted to provide a suitable gap part 200, etc.

[0084] The stopper 2 can be stably fixed in the top cover 3 by inserting and fitting the sealing part 22 into the top disc opening during the pre-assembly of the top plug 2, and limiting the stopper 2 by the stopper positioning points 303. Therefore, the mechanical processes performed on the top cover 3 during the freeze-drying process, such as shaking and suspension, will not affect the fixation of the top plug 2 in the top cover 3, thereby avoiding the top plug 2 from falling off the top cover 3 before the capping operation, and ensuring the capping qualification rate after the freeze-drying. The gap part 200 of the stopper 20 can also avoid core taking when the injection needle is used, thereby ensuring the normal use of the freeze-dried somatropin preparation.

[0085] In the present application, the upper end 30 of the top cover 3 also has stopper positioning points 303, as shown in FIGS. 8A and 8B, which protrude from the inner wall of the upper end 30 in the direction of the axis of the top cover 3, and are used to fix the top plug 2 fitted into the bottle mouth 10. Specifically, the stopper positioning points 303 are evenly arranged in the inner wall of the upper end 30 along the radial direction and in a ring shape. The shape of the stopper positioning points 303 can be cylindrical or prismatic, and in addition, the number of the stopper positioning points 303 and the interval length / arc between the stopper positioning points 303 can be adjusted to maintain optimal fixation of the top plug 2.

[0086] In the present application, the number of the stopper positioning points 303 is 4 or 5 or more. In particular, the number of the stopper positioning points 303 can be even to maintain a symmetrical arrangement along the center of the upper end 30, thereby providing more stable fixation of the top plug 2. Preferably, the number of the stopper positioning points 303 is 4 or 8 to provide relatively stable fixation of the top plug 2, and more preferably, the number of the stopper positioning points 303 is 8 to provide the most stable fixation of the top plug 2. The stopper positioning points 303 can also be used for positioning the top plug 2 before it is pressed into the bottle mouth 10, and the top plug 2 is limited by the stopper positioning points 303 to avoid its voluntary sliding off the bottle mouth 10.

[0087] In the present application, the upper end 30 of the top cover 3 also has protrusions 304 protruding from the inner wall of the upper end 30 in the direction of the axis of the top cover 3, as shown in FIG. 10. The top cover 3 can be limited by the protrusions 304 on the bottle mouth 10 before capping, so that the sublimated solvent, such as water, in the inner cavity 13 can be discharged through the opening 302. Therefore, the provision of the protrusions 304 helps to provide gas exchange and sublimated water discharge for the double-cavity cartridge bottle 1 during the freeze-drying process. Those skilled in the art can understand that the protrusions 304 will not hinder the movement of the top plug 2 during the embedding of the top plug 2 into the bottle mouth 10, because the protrusions 304 are evenly distributed on the inner wall of the upper end 30, and the top disc 300 can uniformly apply pressure to the entire surface of the stopper 20 pre-assembled into the upper end 30 during capping. Therefore, the top plug 2 can be stably embedded into the bottle mouth 10 horizontally.

[0088] In the present application, the number of protrusions 304 is 2 or more than 3; preferably, the maximum length (D) of the protrusion 304 protruding towards the axis direction of the top cover 3 can be 0.10mm, 0.11mm, 0.12mm, 0.13mm, 0.14mm, 0.15mm, 0.16mm, 0.17mm, 0.18mm, 0.19mm, 0.20mm, 0.21mm, 0.22mm, 0.23mm, 0.24mm, 0.25mm, 0.26mm, 0.27mm, 0.28mm, 0.29mm or 0.30mm. Specifically, D can be 0.15mm-0.30mm; further preferably, D can be 0.20mm-0.28mm, which can make the top cover 3 not easy to deform due to excessive pressure when capping, and the sealing performance of the top cover 3 after capping is good and not easy to slip; more preferably, D can be 0.23mm-0.28mm, which can avoid the deformation of the top cover 3 due to pressure during capping, and the sealing performance of the top cover 3 after capping is good and not easy to slip. It should be noted that when the material of the protrusion 304 is different, the value of D can be adjusted to achieve the optimal limiting of the top cover 3 before capping and the optimal improvement of the fit between the upper end 30 and the double-cavity carton bottle 1. Preferably, when the outer diameter of the bottle mouth 10 is 7.3mm, D can be 0.23mm, 0.25mm or 0.28mm, and the protrusion 304 can provide optimal stability of the top cover 3 after capping.

[0089] In the present application, the shape of the protrusion 304 can be trapezoidal, semicircular, semi-elliptical or rectangular, preferably the shape of the protrusion 304 is trapezoidal. When the shape of the protrusion 304 is trapezoidal with its short side adjacent to the bottle mouth 10, the fit tightness of the upper end 30 and the bottle mouth 10 is relatively optimal, and the top cover 3 can be highly stably fitted on the double-cavity carton bottle 1 to maintain good sealing performance.

[0090] When the shape of the protrusion 304 is trapezoidal, preferably, the upper cutting angle (θ) of the side surface of the protrusion 304 towards the axis direction of the top cover 3 can be any angle between 0°-90°, as shown in FIG. 11. Further preferably, θ can be 30°-45°, specifically, θ can be 30°, 31°, 32°, 33°, 34°, 35°, 36°, 37°, 38°, 39°, 40°, 41°, 42°, 43°, 44° or 45°. It should be noted that when θ is less than 30°, the effect of the protrusion 304 on improving the fit tightness of the top cover 3 and the bottle mouth 10 may be significantly weakened; when θ is greater than 45°, the protrusion 304 may significantly hinder the capping process, causing the top cover 3 to deform or even be damaged during the capping process. Therefore, it can be preferred that θ is any angle in the range of 30°-45°; more preferably, θ can be 30°, so that the protrusion 304 can provide better fit effect of the top cover 3 and the bottle mouth 10, and also does not adversely hinder the capping process.

[0091] In addition, when the shape of the protruding portion 304 is trapezoidal, it is further preferred that the angle (a) between the face of the protruding portion 304 facing the axis of the cap 3 and the lower cutting angle of the side face is any angle between 0° and 90°. Since the pressure during the capping process is mainly affected by the size of θ, when a and θ have the same value, the protruding portion 304 can have a stable axisymmetric structure and is not prone to deformation or damage during the capping process or storage process. Therefore, it is further preferred that a is 30° in order to improve the use efficiency and deformation resistance of the protruding portion 304, and more preferably, θ and a of the protruding portion 304 are both 30°, so that the cap 3 will not be structurally damaged due to a larger force during the capping process, and at the same time, the cap 3 can be highly tightly fitted with the double-chamber carton bottle 1, which also improves the efficiency and accuracy of capping the double-chamber carton bottle 1.

[0092] The injection double-chamber carton bottle packaging material of the present application includes the bottle cap assembly and the double-chamber carton bottle 1 described above, and can be matched with a sheath to further form an injection double-chamber carton bottle packaging material assembly, which includes the injection double-chamber carton bottle packaging material and a sheath 4 used therewith. It should be noted that the injection double-chamber carton bottle packaging material can include any combination of the bottle cap assembly and the double-chamber carton bottle 1 that can be formed and / or maintained by any combination disclosed in the present application.

[0093] Specifically, the sheath 4 of the present application is an open-top octagonal prism, and its structure is shown in FIG. 12. The inner wall of the sheath 4 has an octagonal shape. After the double-chamber carton bottle 1 completes the freeze-drying process and is sealed by the cap 3, the double-chamber carton bottle 1 can be pressed into the sheath for effective storage protection. During this process, the lower end 32 of the cap 3 can be fitted with the inner wall of the sheath 4 to avoid relative sliding, and the bypass protrusion 120 of the bottle body 12 can also be clamped at the octagonal vertex of the inner wall of the sheath 4, preventing the double-chamber carton bottle 1 from sliding relative to the inner wall of the sheath 4. In this way, the sheath can stably protect the entire packaging material.

[0094] In the present application, the lower end 32 is in the shape of a cylinder or an octagonal prism, and can be preferably an octagonal prism, and is fixedly assembled with the sheath 4 used for storing the double-chamber carton bottle 1 through interference fit. Specifically, the lower end 32 has a first notch 321 near the upper outer edge of the middle end 31, the top end of the sheath 4 is stretched and located on the first notch 321, and the cap 3 and the sheath 4 are forced towards each other and clamped in the middle. Through this interference fit between the lower end 32 and the sheath 4, when the double-chamber carton bottle 1 is placed in the sheath 4, the cap 3 and the stopper 2 therein are more tightly fixed with the bottle mouth 10, effectively preventing the leakage, rotation, and falling off of the packaging material after freeze-drying, so as to ensure the high-quality storage of the somatotropin freeze-dried preparation.

[0095] Specifically, in some embodiments, the lyophilized preparation of long-acting growth hormone is reconstituted in water in the double-chamber carton bottle 1 and administered by injection through a needle, such as a microfine needle (MFN), the hub of the needle having a threaded structure that engages or disengages the threads 301 of the cap 3 by rotation when the MFN is mounted to or removed from the cap 3 for drawing or removing the long-acting growth hormone, in the process, the lower end 32 of the cap 3 is fixed against rotation by the octagonal inner wall of the sheath 4, and the bypass protrusion 120 of the double-chamber carton bottle 1 is also fixed against rotation by the vertex of the octagonal inner wall of the sheath 4. Thus, by using the lower end 32 in the shape of an octagonal prism and cooperating with the sheath 4, the double-chamber carton bottle packaging assembly can be kept from rotating when the needle is screwed on or off, avoiding idle rotation when the sterile needle is screwed on or off, and improving the efficiency of use of the lyophilized preparation of long-acting growth hormone and the convenience of operation.

[0096] The application provides a lyophilization method for long-acting growth hormone, which can also be used in cooperation with a double-chamber carton bottle 1' with a longer neck and a corresponding stopper 2' and cap 3', the specific implementation of which is described in detail below.

[0097] Specifically, when cooperating with the double-chamber carton bottle 1' with a long neck and the corresponding stopper 2' and cap 3', the lyophilization method comprises: adding a middle stopper into the double-chamber carton bottle 1', and then pouring the long-acting growth hormone to be lyophilized; assembling the stopper 2' and the cap 3', and placing them above the mouth 10' of the double-chamber carton bottle 1'; placing and fixing the double-chamber carton bottle 1' on a customized lyophilization support; freezing, primary drying, and secondary drying the long-acting growth hormone to be lyophilized, respectively; pressing the stopper 2' and the double-chamber carton bottle 1' together with the cap 3' to seal the double-chamber carton bottle 1' and fix the stopper 2', and make the stopper 2' seal the mouth 10' of the double-chamber carton bottle 1'.

[0098] In the lyophilization method, the middle stopper added into the double-chamber carton bottle 1' and the long-acting growth hormone to be lyophilized can also be any size and structure of the middle stopper for the double-chamber carton bottle 1' and the long-acting growth hormone to be lyophilized with a suitable content. The freezing, primary drying, and secondary drying operations can be performed in a lyophilization machine, which can accommodate the lyophilization support used in the lyophilization method of the application; during the process of fixing the stopper 2' with the cap 3' and sealing the mouth 10' of the double-chamber carton bottle 1' through the stopper 2', the driving mode of the cap 3' can be any driving mode that can be implemented in the lyophilization machine, such as mechanical pressing, pneumatic driving, pneumatic clamp driving, or spring pressing.

[0099] In the present application, after adding the middle plug into the double-cavity carton bottle 1', the solution of the somatropin to be lyophilized can be filled into the double-cavity carton bottle 1', and particularly, the solution of the somatropin to be lyophilized can be the somatropin to be lyophilized and stored for a short or long term in the inner cavity 13' of the double-cavity carton bottle 1'. The user can select any solution of the somatropin to be lyophilized and fill it into one of the inner cavities 13' of the double-cavity carton bottle 1' to lyophilize it by using the lyophilization method of the present application.

[0100] In the present application, the lyophilization support is a stand-alone lyophilization support or a tray-type lyophilization support. The present application sets the type of the lyophilization support used in the lyophilization method as a stand-alone lyophilization support or a tray-type lyophilization support. The person skilled in the art can select and adjust the specific model, size, and working parameters of the lyophilization support in the lyophilization machine according to the actual requirements. The present application only gives a preferred lyophilization method for the somatropin. Preferably, the lyophilization support is a tray-type lyophilization support, which is easy to place a larger number of double-cavity carton bottles 1'.

[0101] Particularly, the double-cavity carton bottle 1' is placed in the lyophilization support in an upright or inverted manner. Preferably, the double-cavity carton bottle 1' is placed in the lyophilization support in an upright manner, which is conducive to the uniform distribution of heat in the double-cavity carton bottle 1', improves the solvent sublimation efficiency, and in addition, can reduce the degree of sedimentation and aggregation of the somatropin, and keep the appearance of the somatropin uniform and stable.

[0102] In the present application, the temperature range for freezing the somatotropin in the double-cavity carton bottle 1' can be a temperature range suitable for freeze-drying the somatotropin, and the freezing temperature is generally -60°C to -40°C, at which the somatotropin to be freeze-dried has a high freezing efficiency and maintains its own quality. Therefore, the freezing temperature is any temperature value in the range of -60°C to -40°C. Specifically, the temperature range for freezing the somatotropin in the double-cavity carton bottle 1' is -60°C to -40°C, i.e., -60°C, -59°C, -58°C, -57°C, -56°C, -55°C, -54°C, -53°C, -52°C, -51°C, -50°C, -49°C, -48°C, -47°C, -46°C, -45°C, -44°C, -43°C, -42°C, -41°C, or -40°C; the temperature range for primary drying is -60°C to 0°C, i.e., -60°C, -59°C, -58°C, -57°C, -56°C, -55°C, -54°C, -53°C, -52°C, -51°C, -50°C, -49°C, -48°C, -47°C, -46°C, -45°C, -44°C, -43°C, -42°C, -41°C, -40°C, -39°C, -38°C, -37°C, -36°C, -35°C, -34°C, -33°C, -32°C, -31°C, -30°C, -29°C, -28°C, -27°C, -26°C, -25°C, -24°C, -23°C, -22°C, -21°C, -20°C, -19°C, -18°C, -17°C, -16°C, -15°C, -14°C, -13°C, -12°C, -11°C, -10°C, -9°C, -8°C, -7°C, -6°C, -5°C, -4°C, -3°C, -2°C, -1°C, or 0°C; and the temperature range for secondary drying is 15°C to 40°C, i.e., 15°C, 16°C, 17°C, 18°C, 19°C, 20°C, 21°C, 22°C, 23°C, 24°C, 25°C, 26°C, 27°C, 28°C, 29°C, 30°C, 31°C, 32°C, 33°C, 34°C, 35°C, 36°C, 37°C, 38°C, 39°C, or 40°C.

[0103] Similarly, the temperature of the first drying and the second drying of the Lonapeen can also be any temperature value in the range of -60℃ to 0℃ and 15℃ to 40℃, respectively, to increase the sublimation rate of water in the Lonapeen. In addition, the pressure range of the first drying and the second drying can be any value in the range of 0.02mbar to 0.2mbar, and when the pressure of the first drying and the second drying is preferably 0.06mbar, the drying efficiency can reach a peak. Specifically, the pressure range of the first drying and the second drying is 0.02mbar to 0.2mbar, i.e. 0.02mbar, 0.03mbar, 0.04mbar, 0.05mbar, 0.06mbar, 0.07mbar, 0.08mbar, 0.09mbar, 0.10mbar, 0.11mbar, 0.12mbar, 0.13mbar, 0.14mbar, 0.15mbar, 0.16mbar, 0.17mbar, 0.18mbar, 0.19mbar or 0.20mbar, and preferably, the pressure of the first drying and the second drying is 0.06mbar, respectively.

[0104] In the present application, the use of the top cover 3' to press the top plug 2' and the double-cavity carton bottle 1' is also included: before pressing the top plug 2', the double-cavity carton bottle 1' is subjected to nitrogen charging operation to maintain the low moisture content of the Lonapeen. Those skilled in the art can understand that the double-cavity carton bottle 1' is subjected to nitrogen charging operation before the bottle mouth 10' is closed, and the purpose is to make the nitrogen in the inner cavity 13' reach 1 standard atmosphere, on the one hand, the nitrogen can be used to maintain the low moisture content of the Lonapeen, on the other hand, the 1 standard atmosphere nitrogen can also make the position of the plug in the double-cavity carton bottle fixed.

[0105] In the present application, a Lonapeen freeze-dried preparation is also included, which is prepared according to the freeze-drying method described above. In particular, since the Lonapeen to be freeze-dried added to one of the inner cavities 13' of the double-cavity carton bottle 1' in the present application can be one of a plurality of Lonapeen, the quality of the Lonapeen freeze-dried preparation obtained finally can also be different when the content of the Lonapeen to be freeze-dried poured into the double-cavity carton bottle 1' is different; in addition, when the freeze-drying parameters, such as the temperature and pressure of the first drying, of the freeze-drying method of the present application are changed during the freeze-drying process of the Lonapeen, the same kind of Lonapeen to be freeze-dried is poured in, and different quality or different properties of the Lonapeen freeze-dried preparation can also be produced by the other freeze-drying method, such as different water content, different solid form of the Lonapeen freeze-dried preparation, etc.

[0106] In the present application, an injection is also included, which comprises: a double-cavity carton bottle package material for injection, a long-acting growth hormone lyophilized preparation and a reconstituting agent. It should be noted that the long-acting growth hormone lyophilized preparation and the reconstituting agent can be any long-acting growth hormone lyophilized preparation and reconstituting agent suitable for the double-cavity carton bottle package material for injection and the lyophilization process. Specifically, the long-acting growth hormone lyophilized preparation can be any long-acting growth hormone to be lyophilized that can be filled into the double-cavity carton bottle 1' of the present application and is prepared into a long-acting growth hormone lyophilized preparation by the lyophilization method of the present application, or can be the long-acting growth hormone lyophilized preparation provided by the present application.

[0107] In addition, the reconstituting agent can be a reconstituting agent for reconstituting any long-acting growth hormone lyophilized preparation prepared as described above, such as sterile water for injection, which can be used to reconstitute the long-acting growth hormone lyophilized preparation provided by the present application before administration.

[0108] In the present application, the double-cavity carton bottle package material for injection comprises: a double-cavity carton bottle 1' and another bottle cap assembly, wherein the double-cavity carton bottle 1' is used to contain a long-acting growth hormone lyophilized preparation and a reconstituting agent, as shown in FIG. 13. It should be noted that the double-cavity carton bottle package material for injection can comprise any combination formed and / or maintained by the combination of any bottle cap assembly and the double-cavity carton bottle 1' proposed in the present application.

[0109] In the present application, a bottle cap assembly is also proposed accordingly, wherein the bottle cap assembly comprises a top plug 2' and a top cap 3' for sealing the double-cavity carton bottle 1'. The double-cavity carton bottle 1' can be placed in a lyophilization support and a sheath 4' used in the existing lyophilization process, and the double-cavity carton bottle package material can be fixed and placed upright or inverted in the lyophilization support; the bottle cap assembly can be made of any material suitable for achieving the sealing function of the bottle cap. The top plug 2' is limited in the top cap 3' for sealing the bottle mouth 10' of the double-cavity carton bottle 1'; the top cap 3' is used to press and fix the top plug 2' so that the top plug 2' seals the bottle mouth 10' of the double-cavity carton bottle 1'; and seals the double-cavity carton bottle 1'; wherein the process of pressing and fixing the top plug 2' in the top cap 3' so that the top plug 2' seals the bottle mouth 10' of the double-cavity carton bottle 1' can comprise the following steps:

[0110] pre-assembling the top plug 2' into the top cap 3'; and placing the top cap 3' with the top plug 2' assembled thereon above the bottle mouth 10' of the double-cavity carton bottle 1' and pressing the top cap 3' downward. The driving mode of the top cap 3' downward can be mechanical compression, pneumatic driving, pneumatic clamp driving or spring pressing, etc.

[0111] In the present application, the double-cavity card bottle 1' comprises an inner cavity 13', a bottle body 12', a bottle neck 11' and a bottle mouth 10', the center of the bottle mouth 10' is provided with a bottle mouth opening 100' connected with the inner cavity 13', the inner diameter of the bottle mouth opening 100' is smaller than the inner diameter of the bottle mouth 10' and the bottle neck 11'; the outer wall of one side of the bottle body 12' has a bypass protrusion 120'. Those skilled in the art can understand that the size of the inner cavity 13', the bottle body 12', the bottle neck 11' and the bottle mouth 10' of the double-cavity card bottle 1' can be adjusted to adapt to the size range of commonly used lyophilized stents, such as changing the vertical length of one or more parts of the double-cavity card bottle 1', changing the radial length of one or more parts of the double-cavity card bottle 1', etc., without departing from the protection scope of the present application.

[0112] In the present application, the top plug 2' comprises a plug cap 20' and a plug column 21', the diameter of the plug column 21' can be equal to or slightly larger than the inner diameter of the bottle mouth opening 100', after the plug column 21' is embedded in the bottle mouth opening 100', the lower surface of the plug cap 20' completely matches the upper surface of the bottle mouth 10' to achieve sealing of the bottle mouth 10'. In particular, the top plug 2' is made of elastic rubber material, so the diameter of the plug column 21' can be adjusted within the diameter range of the bottle mouth opening 100' after the plug column 21' is pressed under force, and the diameter of the plug column 21' can be slightly larger than the diameter of the bottle mouth opening 100' to ensure the tightness of the sealing.

[0113] In the present application, the top cover 3' as shown in FIG. 14A comprises an upper end 30' and a bottom disc 31'; the upper end 30' has a top disc 300', a thread 301' and an opening 302', the inner wall of the top cover 3' matches the bottle mouth 10'; when the top cover 3' faces the bottle mouth 10', the top disc 300' of the upper end 30' presses the top plug 2' to move into the bottle mouth 10', so that the top plug 2' is embedded in the bottle mouth 10'. After the bottle mouth 10' of the double-cavity card bottle 1' is capped, the top disc 300' tightly matches above the plug cap 20' to press the top plug 2'. The opening 302' can discharge the sublimed solvent in the somatotropin, such as moisture; the thread 301' is used for thread engagement with the injection needle.

[0114] It should be noted that the length of the bottom disc 31' in the vertical direction can be adjusted, so the bottom disc 31' can only match the connecting part of the bottle neck 11' and the bottle body 12', or can additionally match at least part of the bottle body 12' to achieve better capping tightness and adapt to the size requirements of the lyophilization process for the top cover 3'. The shape of the bottom disc 31' can be set as a cylinder or a multi-prism, as shown in FIG. 14B, to avoid the top cover 3' slipping off or relative sliding with the double-cavity card bottle 1' under the action of rotational centrifugal force, which affects the sealing performance.

[0115] In particular, the center of the top disc 300' also has a top disc opening, the circumferential lower edge of the top disc opening can have an inclination angle β' in the vertical direction to its upper edge, and the circumferential upper edge of the top disc opening has a greater opening length than the circumferential lower edge; the circumferential edge surface of the top disc opening can be a curved surface or a flat surface.

[0116] In the present application, the top plug 2' can further comprise a sealing portion 22' protruding above the plug cap 20', as shown in FIG. 15A, the sealing portion 22' can be inserted into the top disc opening, when the top plug 2' is completely embedded in the bottle mouth 10', i.e. the double-cavity cartridge bottle 1' is completed, the sealing portion 22' of the top plug 2' is embedded in the top disc opening and partially protrudes longitudinally from the top disc opening. Those skilled in the art can understand that the size of the sealing portion 22' can be slightly larger than the opening size of the circumferential lower edge of the top disc opening, and in the process of pre-assembling the top plug 2' into the top cover 3', the top plug 2' needs to be fixed by the upper end 30', the surface of the sealing portion 22' can be slightly deformed to be inserted and embedded in the top disc opening from the circumferential lower edge of the top disc opening.

[0117] Therefore, in the process of pre-assembling the top plug 2' into the top cover 3', the sealing portion 22' can be embedded in the top disc opening, the edge portion thereof closely fits with the circumferential outer edge of the top disc opening, and finally partially protrudes from the upper edge of the top disc opening. The radial length L' of the sealing portion 22' can also be set to have a relatively long radial length, so as to improve the close fitting of the edge portion thereof with the circumferential outer edge of the top disc opening, so as to further prevent the top plug 2' from slipping out of the top disc 300'. In addition, by adjusting the size of β', the circumferential lower edge of the top disc opening and the sealing portion 22' have a closer fit than the circumferential upper edge of the top disc opening, so as to tightly surround the sealing portion 22' and fix it.

[0118] In some embodiments, the radial length L' of the closure portion 22' can be 2.0 mm - 5.0 mm, in particular, the radial length L' of the closure portion 22' can be 2.0 mm, 2.1 mm, 2.2 mm, 2.3 mm, 2.4 mm, 2.5 mm, 2.6 mm, 2.7 mm, 2.8 mm, 2.9 mm, 3.0 mm, 3.1 mm, 3.2 mm, 3.3 mm, 3.4 mm, 3.5 mm, 3.6 mm, 3.7 mm, 3.8 mm, 3.9 mm, 4.0 mm, 4.1 mm, 4.2 mm, 4.3 mm, 4.4 mm, 4.5 mm, 4.6 mm, 4.7 mm, 4.8 mm, 4.9 mm, or 5.0 mm; preferably, the radial length L' of the closure portion 22' can be 3.0 mm - 4.0 mm, in particular, the radial length L' of the closure portion 22' can preferably be 3.0 mm, 3.1 mm, 3.2 mm, 3.3 mm, 3.4 mm, 3.5 mm, 3.6 mm, 3.7 mm, 3.8 mm, 3.9 mm, or 4.0 mm. The inclination angle β' can be 0°, 1°, 2°, 3°, 4°, 5°, 6°, 7°, 8°, 9°, or 10°, etc.

[0119] In some embodiments, the circumferential lower edge opening length of the top disc opening can be 1.5 mm - 5.0 mm, in particular, the circumferential lower edge opening length of the top disc opening can be 1.5 mm, 1.6 mm, 1.7 mm, 1.8 mm, 1.9 mm, 2.0 mm, 2.1 mm, 2.2 mm, 2.3 mm, 2.4 mm, 2.5 mm, 2.6 mm, 2.7 mm, 2.8 mm, 2.9 mm, 3.0 mm, 3.1 mm, 3.2 mm, 3.3 mm, 3.4 mm, 3.5 mm, 3.6 mm, 3.7 mm, 3.8 mm, 3.9 mm, 4.0 mm, 4.1 mm, 4.2 mm, 4.3 mm, 4.4 mm, 4.5 mm, 4.6 mm, 4.7 mm, 4.8 mm, 4.9 mm, or 5.0 mm; preferably, the circumferential lower edge opening length of the top disc opening can be 2.5 mm - 4.0 mm, in particular, the circumferential lower edge opening length of the top disc opening can preferably be 2.5 mm, 2.6 mm, 2.7 mm, 2.8 mm, 2.9 mm, 3.0 mm, 3.1 mm, 3.2 mm, 3.3 mm, 3.4 mm, 3.5 mm, 3.6 mm, 3.7 mm, 3.8 mm, 3.9 mm, or 4.0 mm.

[0120] By taking the radial length L' of the sealing portion 22' slightly larger than the circumferential lower edge opening length of the top disc opening, the sealing portion 22' is more fitted with the circumferential lower edge of the top disc opening, and the top disc opening is effective to fit and fix the sealing portion 22' as a whole, and the circumferential edge provides further support on this basis, so that the whole top plug 2' does not slip off. Preferably, β' is set to 0°, and the top disc opening can provide good fixation to the sealing portion 22' without any inclination angle in the vertical direction, while avoiding excessive resistance when the sealing portion 22' is inserted into the top disc opening. In another case, when the top disc opening needs to be set with a certain inclination angle in the vertical direction to improve the limiting effect of the top disc 300' on the top plug 2, β' can also be set to 5° to improve the fixation of the sealing portion 22', while not affecting the insertion and embedding of the sealing portion 22' into the top disc opening. Those skilled in the art can adjust the radial length L' of the sealing portion 22', the inclination angle β' and the circumferential lower edge opening length of the top disc opening according to the actual operation of the bottle cap assembly in the growth hormone lyophilization process, to adaptively adjust the fitting and fixing degree of the sealing portion 22' and the top disc 300'.

[0121] In particular, the diameter of the plug cap 20' of the top plug 2' can be slightly smaller than the inner diameter of the top cover 3'. Since the top plug 2' is fixed with the top cover 3' through the cooperation of the top plug positioning point 303' and the plug cap 20', the top plug 2' can be tightly fixed with the top cover 3' to achieve sealing. In this case, the diameter of the plug cap 20' is designed to be slightly smaller than the inner diameter of the top cover 3', so that a small gap part 200' is left between the surface of the plug cap 20' and the inner wall of the upper end 30', as shown in FIG. 18. In this way, when the top plug 2' is pressed tightly by the top cover 3', the plug cap 20' will not protrude upwardly into the top disc opening in the middle due to the expansion of the compressed volume of the plug cap 20' to the gap part 200' reserved around it.

[0122] In some embodiments, the diameter of the plug cap 20' can range from 5.0 mm to 10.0 mm, in particular, the diameter of the plug cap 20' can be 5.0 mm, 5.1 mm, 5.2 mm, 5.3 mm, 5.4 mm, 5.5 mm, 5.6 mm, 5.7 mm, 5.8 mm, 5.9 mm, 6.0 mm, 6.1 mm, 6.2 mm, 6.3 mm, 6.4 mm, 6.5 mm, 6.6 mm, 6.7 mm, 6.8 mm, 6.9 mm, 7.0 mm, 7.1 mm, 7.2 mm, 7.3 mm, 7.4 mm, 7.5 mm, 7.6 mm, 7.7 mm, 7.8 mm, 7.9 mm, 8.0 mm, 8.1 mm, 8.2 mm, 8.3 mm, 8.4 mm, 8.5 mm, 8.6 mm, 8.7 mm, 8.8 mm, 8.9 mm, 9.0 mm, 9.1 mm, 9.2 mm, 9.3 mm, 9.4 mm, 9.5 mm, 9.6 mm, 9.7 mm, 9.8 mm, 9.9 mm, or 10.0 mm; preferably, the diameter of the plug cap 20' can range from 6.0 mm to 8.0 mm, in particular, the diameter of the plug cap 20' can preferably be 6.0 mm, 6.1 mm, 6.2 mm, 6.3 mm, 6.4 mm, 6.5 mm, 6.6 mm, 6.7 mm, 6.8 mm, 6.9 mm, 7.0 mm, 7.1 mm, 7.2 mm, 7.3 mm, 7.4 mm, 7.5 mm, 7.6 mm, 7.7 mm, 7.8 mm, 7.9 mm, or 8.0 mm.

[0123] In some embodiments, the diameter of the upper end 30' of the top cover 3' can range from 5.0 mm to 10.0 mm, specifically, the diameter of the upper end 30' can be 5.0 mm, 5.1 mm, 5.2 mm, 5.3 mm, 5.4 mm, 5.5 mm, 5.6 mm, 5.7 mm, 5.8 mm, 5.9 mm, 6.0 mm, 6.1 mm, 6.2 mm, 6.3 mm, 6.4 mm, 6.5 mm, 6.6 mm, 6.7 mm, 6.8 mm, 6.9 mm, 7.0 mm, 7.1 mm, 7.2 mm, 7.3 mm, 7.4 mm, 7.5 mm, 7.6 mm, 7.7 mm, 7.8 mm, 7.9 mm, 8.0 mm, 8.1 mm, 8.2 mm, 8.3 mm, 8.4 mm, 8.5 mm, 8.6 mm, 8.7 mm, 8.8 mm, 8.9 mm, 9.0 mm, 9.1 mm, 9.2 mm, 9.3 mm, 9.4 mm, 9.5 mm, 9.6 mm, 9.7 mm, 9.8 mm, 9.9 mm, or 10.0 mm; preferably, the diameter of the upper end 30' can range from 6.0 mm to 8.0 mm, specifically, the diameter of the upper end 30' can preferably be 6.0 mm, 6.1 mm, 6.2 mm, 6.3 mm, 6.4 mm, 6.5 mm, 6.6 mm, 6.7 mm, 6.8 mm, 6.9 mm, 7.0 mm, 7.1 mm, 7.2 mm, 7.3 mm, 7.4 mm, 7.5 mm, 7.6 mm, 7.7 mm, 7.8 mm, 7.9 mm, or 8.0 mm.

[0124] More preferably, the diameter of the plug cap 20' can be configured as 7.0 mm, and the inner diameter of the upper end 30' of the top cover 3' can be configured as 7.3 mm, so that there is a gap part 200' of 0.3 mm between the surface of the plug cap 20' and the inner wall of the upper end 30', and the plug cap 20' is extruded to increase in diameter during the assembly of the top plug 2' or the insertion of the injection needle, and the gap part 200' can accommodate the increased volume of the plug cap 20' to avoid upward pressure. It should be noted that in the bottle cap assembly according to the embodiments of the present application, those skilled in the art can adjust the diameter of the plug cap 20' and the diameter of the upper end 30' according to the actual application of the bottle cap assembly on the basis of the above-mentioned parameter benchmarks to adapt to the cooperation of the bottle cap assembly with the freeze-drying support of the freeze-dryer, the cooperation with the sheath of the double-cavity cartridge bottle 1', and / or the cooperation with the syringe for use. For example, the diameter of the plug cap 20' can be adjusted to adjust the stability of the pre-assembly of the top plug 2'; the diameter of the upper end 30' can be adjusted to keep a tighter or easier-to-disassemble seal on the double-cavity cartridge bottle 1'; and after adjusting the diameter of the plug cap 20' and the diameter of the upper end 30' respectively, the size relationship between the diameter of the plug cap 20' and the diameter of the upper end 30' can be adjusted to provide a suitable gap part 200' to avoid the influence of the pressure on the plug cap 20' on the assembly and use of the bottle cap assembly, and the like.

[0125] By inserting and fitting the sealing part 22' into the top disc opening during the pre-assembly of the top plug 2' and limiting the plug cap 20' in cooperation with the top plug positioning point 303', the top plug 2' can be stably positioned in the top cover 3'. Therefore, in actual production, when external forces such as shaking, hanging, etc. are applied to the top cover 3', the fixation of the top plug 2' in the top cover 3' will not be affected, thereby avoiding the top plug 2' from falling off from the top cover 3' before the capping operation, ensuring the capping qualification rate after freeze-drying, and further avoiding the core taking when the plug cap 20' is used with the injection needle, thereby ensuring the efficient use of the somatropin freeze-dried preparation.

[0126] In the present application, the upper end 30' of the top cover 3' also has a top plug positioning point 303', as shown in FIGS. 16A and 16B, the top plug positioning point 303' protrudes from the inner wall of the upper end 30' in the direction of the axis of the top cover 3', and is used to fix the top plug 2' fitted with the bottle mouth 10'. Specifically, the top plug positioning point 303' is uniformly arranged along the radial direction of the upper end 30' and is arranged in a ring shape, and the shape of the top plug positioning point 303' can be a cylinder or a prism, and in addition, the number of the top plug positioning point 303' and the interval length / arc between the plurality of top plug positioning points 303' can be adjusted to maintain the optimal fixation of the top plug 2'.

[0127] In the present application, the number of the top plug positioning points 303' is 4 or 5 or more. In particular, the number of the top plug positioning points 303' can be even to keep its symmetrical arrangement along the center of the upper end 30' to provide more stable fixing function for the top plug 2'. Preferably, the number of the top plug positioning points 303' is 4 or 8 to provide more stable fixing function for the top plug 2'; more preferably, the number of the top plug positioning points 303' is 8 to provide the most stable fixing function for the top plug 2'. The top plug positioning points 303' can also be used for the positioning of the top plug 2' before it is pressed into the bottle mouth 10', and the top plug 2' is limited by the top plug positioning points 303' to avoid its autonomous slipping off the bottle mouth 10'.

[0128] In the present application, the upper end 30' of the top cover 3' is further provided with a protruding part 304' on its inner wall, which protrudes towards the axis of the top cover 3'. The top cover 3' can be limited by the protruding part 304' on the bottle mouth 10' before it is pressed, so that the sublimation moisture in the inner cavity 13' can be discharged through the opening 302'; therefore, the provision of the protruding part 304' helps to provide gas exchange and moisture discharge for the double-cavity carton bottle 1'. Those skilled in the art can understand that the protruding part 304' will not hinder the movement of the top plug 2' during the process of embedding the top plug 2' into the bottle mouth 10', because the protruding part 304' is uniformly distributed on the inner wall of the upper end 30', and the top disc 300' can uniformly apply pressure to the entire surface of the plug cap 20' pre-assembled into the upper end 30' when pressing the plug, so that the top plug 2' can be stably embedded into the bottle mouth 10'.

[0129] In the present application, the number of protrusions 304' is 2 or more than 3; preferably, the maximum length (D') of the protrusion 304' protruding towards the axis direction of the top cover 3' can be 0.10mm, 0.11mm, 0.12mm, 0.13mm, 0.14mm, 0.15mm, 0.16mm, 0.17mm, 0.18mm, 0.19mm, 0.20mm, 0.21mm, 0.22mm, 0.23mm, 0.24mm, 0.25mm, 0.26mm, 0.27mm, 0.28mm, 0.29mm or 0.30mm. Specifically, D' can be 0.15mm-0.30mm; further preferably, D' can be 0.20mm-0.28mm, which can make the top cover 3' not easy to deform due to excessive pressure when pressing the cover, and the sealing performance of the top cover 3' after pressing the cover is good and not easy to slip; more preferably, D' can be 0.23mm-0.28mm, which can avoid the deformation of the top cover 3' due to pressure when pressing the cover, and the sealing performance of the top cover 3' after pressing the cover is good and not easy to slip. It should be noted that when the material of the protrusion 304' is different, the value of D' can be adjusted to achieve the optimal limiting of the top cover 3' before pressing the cover and the optimal improvement of the fit between the upper end 30' and the double-cavity carton bottle 1'. When the outer diameter of the bottle mouth 10' is 7.3mm, D' is preferably 0.23mm, 0.25mm or 0.28mm, so that the protrusion 304' can provide the most stable fixation for the top cover 3'.

[0130] In the present application, the shape of the protrusion 304' can be trapezoidal, semicircular, semi-elliptical or rectangular, preferably the shape of the protrusion 304' is trapezoidal. When the shape of the protrusion 304' is trapezoidal with the short side close to the bottle mouth 10', the fit tightness of the upper end 30' and the bottle mouth 10' is better, and the top cover 3' can be highly stably fitted on the double-cavity carton bottle 1' to maintain good sealing performance.

[0131] When the shape of the protrusion 304' is trapezoidal, the upper cutting angle (θ') of the side surface of the face of the protrusion 304' towards the axis direction of the top cover 3' can be any angle between 0° and 90°, as shown in FIG. 19. Further, θ' can be 30°-45°, specifically, θ' can be 30°, 31°, 32°, 33°, 34°, 35°, 36°, 37°, 38°, 39°, 40°, 41°, 42°, 43°, 44° or 45°. It should be noted that when θ' is less than 30°, the effect of the protrusion 304' on improving the close-fitting of the top cover 3' and the bottle mouth 10' can be significantly weakened; when θ' is greater than 45°, the protrusion 304' can significantly hinder the capping process, causing the top cover 3' to deform or even be damaged during the capping process. Therefore, it can be preferred that θ' be any angle in the range of 30°-45°; more preferably, θ' can be 30°, so that the protrusion 304' can provide a better close-fitting effect of the top cover 3' and the bottle mouth 10' and not adversely hinder the capping process.

[0132] In addition, when the shape of the protrusion 304' is trapezoidal, it is further preferred that the lower cutting angle (α') of the side surface of the face of the protrusion 304' towards the axis direction of the top cover 3' can also be any angle between 0° and 90°. Since the pressure of the capping process is mainly affected by the size of θ', when α' and θ' have the same value, the protrusion 304' can have the most stable axisymmetric structure and is not prone to deformation or damage during the capping process or storage process. Therefore, it is further preferred that α' can be 30° to improve the use efficiency and deformation resistance of the protrusion 304'. More preferably, θ' and α' of the protrusion 304' are both 30°, which will not cause structural damage to the top cover 3' due to excessive capping force, while also maintaining a high close-fitting of the top cover 3' and the double-chamber carton bottle 1', which can improve the capping efficiency and accuracy of the double-chamber carton bottle 1' in the recombinant human growth hormone lyophilization process.

[0133] In the present application, the upper end 30' of the bottle cap assembly also has a demolding hole 305', as shown in FIGS. 16C and 17, the demolding hole 305' is located at the connection between the top disc 300' and the thread 301', and the two sides of the top disc opening are partially communicated through the demolding hole 305', so that during the manufacturing of the top cover 3', the mold set can conveniently open the mold through the demolding hole 305' for closing, thereby facilitating the batch manufacturing of the entire top cover 3' and improving the efficiency of the lyophilization process. The number of demolding holes 305' can be 4 or 5 or more, for example, 4 holes evenly distributed on the outer periphery of the top disc 300' of the upper end 30'. This arrangement of demolding holes 305' does not affect the cooperation of the sealing part 22' or the top plug positioning point 303' with the surrounding top cover 3' or top plug 2'' of the top cover 3', and therefore does not affect the air tightness of the top cover 3'.

[0134] In the present application, the upper end 30' also has a fitting part 306', as shown in FIG. 15B, which is located on the side of the top disc opening of the top disc 300' close to the top plug 2', i.e. the side in contact with the plug cap 20'. The sealing part 22' can be matched with the fitting part 306' to be inserted into the top disc opening of the top disc 300' of the top cover 3'. Specifically, the fitting part 306' has a slope towards the top plug 3', which smoothly tightens the contact surface of the top disc 300' and the top plug 2' from the side of the top disc opening close to the top plug 2' to the other side, i.e. chamfered shape, so that when the sealing part 22' of the top plug 2' is fitted into the top disc opening, the outer edge thereof can slide along the slope of the fitting part 306', reducing the force required during fitting, to further improve the success rate of fitting the sealing part 22' into the top disc opening, to improve the sealing efficiency and improve the freeze-drying efficiency.

[0135] In the present application, the bottom disc 31' can also have an internal protrusion 310', as shown in FIG. 14C, which is located on the inner wall of the bottom disc 31' away from the upper end 30', i.e. the top cover 3; the inner wall of the lowermost end, and protrudes in the axial direction towards the top cover 3'. When the top cover 3' is sealed to the double-chamber carton bottle 1', due to the presence of the internal protrusion 310', the contact pressure between the bottle body 12' and the bottom disc 31' at the internal protrusion 310' is increased, and the fit is tighter, enhancing the fixation stability of the top cover 3' on the double-chamber carton bottle 1', making the entire packaging material have better airtightness. The number of internal protrusions 310' can be an appropriate number, for example, 2 or 3 or 4 or 5 or more, and preferably evenly distributed on the radial section of the bottom disc 31' to form a stable shape, thereby improving the fixation stability of the top cover 3'. In addition, when multiple internal protrusions are evenly distributed on the inner side of the bottom disc, for example, 4 internal protrusions 310' are evenly distributed at 90° on the inner side of the bottom disc at the lower edge of the cylindrical bottom disc 31', the stress received by the bottom disc can be effectively dispersed, making the bottom disc 31' less likely to gradually loosen due to long-term airtight use or temperature changes, to further improve the anti-loosening ability of the top cover.

[0136] Advantageously, the bottom disc 31' can also be provided with protrusion side openings 311' on both sides of the internal protrusion 310' along the edge of the bottom disc 31' away from the upper end 30', i.e. the edge of the top cover 3' at the lowermost end. The number of protrusion side openings 311' can be matched with the number of internal protrusions 310', so the number thereof can be 4 or 6 or 8 or 10 or more. When the top cover 3' is fitted with the bottle body 12' and the internal protrusion 310' is extruded, the protrusion side openings 311' on one side / two sides can be deformed and extended, reducing the force required for sealing, to improve the sealing and freeze-drying efficiency.

[0137] The present application also proposes another injection dual-chamber carton bottle packaging material comprising the above-mentioned another bottle cap assembly and the dual-chamber carton bottle 1', and proposes another injection dual-chamber carton bottle packaging material assembly comprising the above-mentioned another injection dual-chamber carton bottle packaging material and the sheath 4' used in cooperation therewith, as shown in FIG. 20. It is to be noted that the injection dual-chamber carton bottle packaging material can comprise any combination of the bottle cap assembly and the dual-chamber carton bottle 1' capable of being formed and / or maintained by any combination proposed in the present application.

[0138] The bottom disc 31' has a first protrusion 321' near the upper outer edge of the upper end 30'. The top end of the inner wall of the sheath 4' is stretched to form a protrusion in the horizontal direction and is limited to the first protrusion 321' of the bottom disc 31'. The top cap 3' and the sheath 4' achieve interference fit, and the top plug 2' and the dual-chamber carton bottle 1' are clamped in the middle. In addition, the bypass protrusion 120' of the bottle body 12' is clamped at the octagonal vertex of the inner wall of the sheath 4' and cannot slide relative to the inner wall of the sheath 4'. In the above manner, when the dual-chamber carton bottle packaging material is placed in the sheath 4', the top cap 3' and the top plug 2' therein are more tightly fixed with the bottle mouth 10', effectively avoiding air leakage, rotation, falling off, etc.

[0139] In the present application, the bottom disc 31' is in the shape of a cylinder or an octagonal prism, and the sheath 4' comprises a sheath body 40' and a flange 41'. When the top cap 3' and the sheath 4' are interference fit, the top cap 3' and the dual-chamber carton bottle 1' are tightly fixed with each other. Since the bottle mouth 10', the bottle neck 11' and the bottle body 12' of the dual-chamber carton bottle 1' are in the shape of a cylinder, during the process of screwing and / or detaching the injection needle with / from the top cap 3', the top cap 3' is forced to drive the dual-chamber carton bottle 1' to co-rotate. When the bottom disc 31' is in the shape of a cylinder, its smooth outer surface is difficult to be well limited by the inner wall of the sheath 4'. When a lyophilized preparation is used, the injection needle needs to be screwed / detached, and the top cap 3' may drive the entire dual-chamber carton bottle 1' to co-rotate, so that the injection needle is idle and cannot be fixed / unfixed with / from the top cap 3'.

[0140] Therefore, the bottom disc 31' of the bottle cap assembly of the packaging material assembly is in the shape of an octagonal prism, and the sheath body 40' is in the shape of an octagonal prism, so that the outer wall of the bottom disc 31' and the inner wall of the sheath body 40' are both octagonal, as shown in FIG. 20. In this way, the bypass protrusion 120' of the dual-chamber carton bottle 1' of the packaging material assembly can be limited to the octagonal vertex (B'-B') of the inner wall of the sheath 4', and the bottle body 12' will generate a large friction force with the inner wall of the bottom disc 31' during capping; when the top cap 3' is forced by an external force such as an injection needle, the interference fit between the bottom disc 31' and the inner wall of the sheath 4' and the mutual fixation (A'-A') make the top cap 3' not slide off or relatively slide with the dual-chamber carton bottle 1', further making the entire packaging material stable and immovable, avoiding the influence on the air tightness of the dual-chamber carton bottle 1' and improving the use efficiency.

[0141] In particular, the lower end of the sheath 4' can also have an interference fit structure, and the lower end of the sheath body 40' can be provided with a second protrusion 400', which is clamped on the flange 41' by pressing, so that the sheath body 40' and the flange 41' are interference fitted and fixed to each other (C'-C'). In this way, the fixing stability of the sheath body 40' can be improved, and the sheath body 40' can be prevented from rotating with the packaging material.

[0142] Specifically, in some embodiments, the above-mentioned another lyophilized preparation of long-acting growth hormone is reconstituted in the double-chamber carton bottle 1' and then injected into children for treatment through an injection needle. The hub of the injection needle has a threaded structure. When the injection needle is installed on the top cover 3' for long-acting growth hormone injection or removed from the top cover 3', the threaded structure of the hub is engaged with or removed from the threads 301' of the top cover 3' by rotating. During this process, the bottom disc 31' of the top cover 3' is fixed and prevented from rotating by the octagonal inner wall of the sheath 4', and the bypass protrusion 120' of the double-chamber carton bottle 1' is also fixed and prevented from rotating by the vertex of the inner wall of the sheath 4'. Therefore, by selecting an octagonal bottom disc 31' and cooperating with the sheath 4', the double-chamber carton bottle packaging assembly can be prevented from rotating when the threaded injection needle is screwed on or removed, so as to avoid idle rotation when the sterile injection needle is screwed on or removed, and improve the use efficiency and operation convenience of the double-chamber carton bottle packaging assembly.

[0143] In the present application, a bottle cap assembly is also provided, as shown in FIGS. 21A, 21B and 22, which includes a top plug 2" and a top cover 3" and can be used in cooperation with the pressure plug assembly to seal the bottle opening of the double-chamber carton bottle 1 or 1', in particular the bottle opening of the double-chamber carton bottle 1'. The bottle cap assembly can be used as a supplementary or alternative configuration of the aforementioned two bottle cap assemblies for sealing the double-chamber carton bottle in the lyophilization process, for example, when the lyophilization process does not require an integrated packaging of the top plug and the top cover.

[0144] In particular, referring to the examples of FIGS. 21A-22, as shown in FIG. 21A, the top plug 2" of the bottle cap assembly is used to seal the bottle mouth 10' of the double- cavity carton bottle 1', and the top plug 2" can include a plug cap 20" and a plug column 21". As shown in FIG. 22, the top cover 3" is used to fix the top plug 2" and seal the bottle mouth 10' of the double-cavity carton bottle 1'; the top cover 3" can include a main body and a bottom disc 31", and the main body can include a top disc 300" and an annular thread 301". With continued reference to FIG. 21A, the press plug assembly can include a press-in jig 51 and a holding jig 50, the press-in jig 51 can include a press column 510, and the holding jig 50 can include a protrusion 500. In the freeze-drying method provided in the present application, for the bottle cap assembly, the top plug 2" is not assembled with the top cover 3" before freezing, but is first fixed to the bottle mouth 10' by the press plug assembly after the product to be freeze-dried is frozen, primary dried, and secondary dried, and then the press plug assembly is removed and the entire bottle mouth 10' is sealed by the top cover 3". That is, for the present bottle cap assembly, after freeze-drying is completed, the press plug assembly is used to press the top plug 2" to fit with the double-cavity carton bottle 1', rather than directly using the top cover 3" to press the top plug 2" as in the two previous bottle cap assemblies, and the sealing process is as follows:

[0145] The process of using the press plug assembly to press the top plug 2" to fit with the double-cavity carton bottle 1' to achieve sealing of the double-cavity carton bottle 1' includes the following steps: placing the top plug 2" in the holding jig 50 by fitting the holding jig 50 with the outer wall of the bottle mouth 10' of the double-cavity carton bottle 1' to achieve positioning of the top plug 2" relative to the bottle mouth 10' of the double-cavity carton bottle 1'; pressing the top plug 2" by the press-in jig 51 to fit into the bottle mouth 10' of the double-cavity carton bottle 1'; and removing the press-in jig 51 and the holding jig 50. It should be noted that when the size of part or all of the structure of the double-cavity carton bottle 1' changes, the size of the top plug 2", the press-in jig 51, and the holding jig 50 can also change to adapt to the size of the double-cavity carton bottle 1' (especially when the bottle neck 11' needs to be further adjusted) to complete the sealing of the bottle mouth 10'.

[0146] In addition, in another configuration of the bottle cap assembly shown in FIG. 21B, the inner wall of the central recess of the press-in jig 51 of the press plug assembly is no longer provided with the press column 510, and when the top plug 2" moves towards the bottle mouth 10', the press-in jig 51 directly abuts against the top plug 2" in the central recess to press it to move towards the bottle mouth 10'. In this way, without using the holding jig 50 with a long protruding length at the upper end, the press-in jig 51 can also provide sufficient press plug length to the top plug 2" without additionally providing multiple press columns 510 to ensure that the top plug 2" is firmly fitted in the bottle mouth 10'. This simplifies the manufacturing process of the press plug assembly.

[0147] In addition, before the double-chambered carton bottle 1' is placed and fixed on the customized freeze-drying support, the bottle cap assembly needs to be pre-assembled with the compression plug assembly and the top plug 2" to avoid the top plug 2" from falling into the bottle mouth 10' during the freeze-drying process and affecting the drainage process of the freeze-dried preparation. The specific pre-assembly process is as follows: the top plug 2" is placed on the upper end of the holding jig 50, protruding from the protruding part 500 of the holding jig 50, the protruding part 500 can hold the plug cap 20" to fix the position of the top plug 2", prevent it from falling prematurely, and make the plug column 21" align with the bottle mouth opening 100', which is beneficial to the plug column 21" quickly embedded in the bottle mouth opening 100' when it is pressed down by the compression jig 51 after the freeze-drying is completed.

[0148] In particular, in addition to the two points of before and after the freeze-drying operation described above, the process of the freeze-drying process using the bottle cap assembly does not change compared with the process of the freeze-drying process using the two bottle cap assemblies described above. During the process of successively sealing the bottle mouth 10' with the top plug 2" and the top cap 3", the driving mode of the compression jig 51 of the compression plug assembly and the driving mode of the top cap 3" pressed down to the bottle mouth 10' can be any driving mode that can be implemented inside the freeze-drying machine, such as mechanical compression, air pressure driving, pneumatic clamp driving or spring pressing.

[0149] In the present application, a freeze-dried preparation can also be included, which is prepared according to the freeze-drying method implemented by using the bottle cap assembly with a compression plug assembly, and the double-chambered carton bottle selected can be the double-chambered carton bottle 1 or the double-chambered carton bottle 1', especially 1'. In particular, since the product to be freeze-dried added to one of the inner chambers 13' of the double-chambered carton bottle 1' in the present application can be one of a variety of products, the final freeze-dried preparation obtained can also be different when the double-chambered carton bottle 1' is filled with different products to be freeze-dried; in addition, when the freeze-drying parameters implemented by the freeze-drying method in the process of freeze-drying the product, such as the temperature and pressure of the first drying, are changed, the freeze-dried preparation obtained after filling the same product to be freeze-dried can also be of different quality or different properties, such as freeze-dried preparations with different water contents, different solid forms, etc.

[0150] In the present application, an injection also includes a double-chambered carton bottle package, a freeze-dried preparation and a reconstitution agent. It should be noted that the freeze-dried preparation and the reconstitution agent can be any freeze-dried preparation and reconstitution agent suitable for the double-chambered carton bottle package and the freeze-drying process. In particular, the freeze-dried preparation can be any product to be freeze-dried that can be filled into the double-chambered carton bottle 1' of the present application, any freeze-dried preparation prepared by the freeze-drying method implemented by using the bottle cap assembly with a compression plug assembly of the present application, or the freeze-dried preparation provided by the present application.

[0151] In addition, the reconstituting agent can be a reconstituting agent for reconstituting any one of the above prepared lyophilized preparations, such as sterile water for injection (which can contain bacteriostatic agents, such as phenol, m-cresol, benzyl alcohol, etc.), normal saline, 5% glucose solution, and other buffers, such as phosphate buffer, citric acid buffer, acetic acid buffer, histidine buffer, succinic acid buffer, tris-hydroxymethyl aminomethane hydrochloride buffer, etc., which can be used to reconstitute the lyophilized preparation provided in the present application before administration.

[0152] The two kinds of lyophilized preparations of long-acting growth hormone provided in the present application are any one of the lyophilized preparations of long-acting growth hormone prepared according to any one of the above lyophilization methods provided in the present application or any one of the two kinds of lyophilized preparations of long-acting growth hormone provided in the present application. It can be understood that these lyophilized preparations of long-acting growth hormone can all be used in the field of growth hormone. The various lyophilized preparations of long-acting growth hormone obtained by the present application have the characteristics of high integrity, high purity and low moisture, and are excellent therapeutic products for children with growth hormone deficiency.

[0153] Examples

[0154] The materials used in the experiments and the experimental methods are generally and / or specifically described in the present application. The reagents or instruments used are not specified by the manufacturer, and are all conventional reagent products that can be obtained from the market.

[0155] Example 1

[0156] A bottle cap assembly includes a top plug 2 and a top cap 3 for sealing a double-cavity carton bottle 1. The structure of the top cap 3 is shown in FIG. 6A. The double-cavity carton bottle 1 is sealed by the top plug 2 through the top cap 3, and the bottle opening 10 of the double-cavity carton bottle 1 is closed by the top plug. Specifically,

[0157] First, the top plug 2 is positioned inside the top cap 3 by the top plug positioning point 303, and the top cap 3 is placed on the bottle opening 10, so that the plug column 21 naturally faces the bottle opening 100, and the freeze-drying is performed.

[0158] Then, after the freeze-drying is completed, the top plug 2 is pressed into the bottle opening 10 of the double-cavity carton bottle 1 by the top cap 3, and the top cap 3 includes an upper end 30, a middle end 31 and a lower end 32, the upper end 30 has a top disc 300 located at the center thereof, a thread 301 and an opening 302 located at the edge of the upper end 30, the middle end 31 is arranged above the lower end 32, and the lower end 32 is located below the middle end 31, and the lower end 32 is open below; after the top plug 2 is initially embedded in the bottle opening 10, the top cap 3 is pressed downward until the upper end 30 is completely fitted on the bottle opening 10, and in this process, the inner wall of the upper end 30 is fitted with the bottle opening 10 and the bottle neck 11, and the inner walls of the middle end 31 and the lower end 32 are fitted with the bottle body 12.

[0159] The top disc 300 is a hollow cylindrical structure with a middle shortened part. During the process of pressing the top cover 3 downward by external force, the top plug 2 is pressed to the bottle mouth 10 by the lower surface of the top disc 300, so that the top plug 2 is further embedded into the bottle mouth 10 until the plug column 21 with a diameter slightly larger than the inner diameter of the bottle mouth is completely embedded into the bottle mouth 10 under the pressure, and the lower surface of the plug cap 20 completely fits the upper surface of the bottle mouth 10, so as to seal the double-cavity carton bottle 1 by the top plug 2, without the participation of additional plug pressing devices, thereby reducing the additional processes and time required for sealing the double-cavity carton bottle 1, and avoiding the influence of inaccurate sealing on the production efficiency of the freeze-drying process.

[0160] In particular, when the top cover 3 is pressed to completely embed the top plug 2 into the bottle mouth 10, the inner wall of the upper surface of the middle end 31 can also completely fit the upper surface of the bottle body 12; therefore, while the top cover 3 seals the bottle mouth opening 100 by the top plug 2, the top cover 3 also seals the top plug 2 embedded in the bottle mouth, and seals the bottle mouth 10, the bottle neck 11 and at least a part of the bottle body 12 through the top plug 2, so as to realize the overall sealing of the double-cavity carton bottle 1.

[0161] The upper end 30 has a gap part 200 with a diameter of 7.3 mm and the plug cap 20 with a diameter of 7.0 mm; the upper end 30 also has a top plug positioning point 303, as shown in FIG. 6A, which is located below the top disc 300 and protrudes from the inner wall of the upper end 30 in the direction of the axis of the top cover 3. After the top plug 2 is completely embedded into the bottle mouth 10, the top plug positioning point 303 fits the plug cap 20, and the plug cap 20 is pressed by the top plug positioning point 303 in the direction of the axis of the top cover 3, so as to increase the friction between the plug cap 20 and the inner wall of the upper end 30, thereby preventing the top plug 2 from loosening or slipping out of the top cover 3 during the pre-assembly process due to loose fitting. The number of top plug positioning points 303 is four, which are evenly distributed on the inner wall of the upper end 30.

[0162] The upper end 30 also has a protruding part 304, as shown in FIG. 10, which is arranged below the top plug positioning point 303 and protrudes from the inner wall of the upper end 30 in the direction of the axis of the top cover 3. After the top plug 2 is completely embedded into the bottle mouth 10, the protruding part 304 fits the outer wall of the bottle mouth 10, and the bottle mouth 10 is pressed by the protruding part 304 in the direction of the axis of the top cover 3, so as to increase the friction between the bottle mouth 10 and the inner wall of the upper end 30, thereby preventing the top cover 3 from slipping out after sealing due to loose fitting, and improving the sealing performance of the double-cavity carton bottle 1. The maximum length of the protruding part 304 protruding from the inner wall of the upper end 30 is set to 0.23 mm, and the shape of the protruding part 304 is set to trapezoidal with a number of two, which are distributed on both sides of the inner wall of the upper end 30, and the upper cutting angle is 30°.

[0163] The lower end 32 is in the shape of a cylinder. The convex ring 310 of the middle end 31 and the convex strip 320 of the lower end 32 can increase the fit of the top cover 3 and the bottle body 22 after the top cover 3 is attached to the double-cavity carton bottle 1, and further improve the stability of the fit of the top cover 3 and the double-cavity carton bottle 1.

[0164] The compression plug and compression cap sealing test of the bottle cap assembly shows that the fit of the top plug 2 and the top cap 3 is high, the top plug 2 does not slip out of the top cap 3; a certain pressure needs to be applied during the compression cap process, but it does not cause deformation and damage to part of the structure of the top cap 3; the fit of the top cap 3 and the mouth 10 of the double-cavity carton bottle 1 is obviously improved and is not pulled out after a larger force is applied.

[0165] Example 2

[0166] The maximum length of the convex part 304 protruding from the inner wall of the upper end 30 is replaced with 0.25 mm, and other structures and parameters are the same as in Example 1. The compression plug and compression cap sealing test of the bottle cap assembly shows that the fit of the top plug 2 and the top cap 3 is high, the top plug 2 does not slip out of the top cap 3; after the maximum length of the convex part 304 protruding from the inner wall of the upper end 30 is replaced with 0.25 mm, a certain pressure needs to be applied during the compression cap process, but it does not cause deformation and damage to part of the structure of the top cap 3; the fit of the top cap 3 and the mouth 10 of the double-cavity carton bottle 1 is also obviously improved and is not pulled out after a larger force is applied.

[0167] Example 3

[0168] The maximum length of the convex part 304 protruding from the inner wall of the upper end 30 is replaced with 0.28 mm, and other structures and parameters are the same as in Example 1. The compression plug and compression cap sealing test of the bottle cap assembly shows that the fit of the top plug 2 and the top cap 3 is high, the top plug 2 does not slip out of the top cap 3; after the maximum length of the convex part 304 protruding from the inner wall of the upper end 30 is replaced with 0.28 mm, a larger pressure needs to be applied during the compression cap process, but it does not cause deformation and damage to part of the structure of the top cap 3; the fit of the top cap 3 and the mouth 10 of the double-cavity carton bottle 1 is obviously improved and is not pulled out after a larger force is applied.

[0169] Example 4

[0170] The injection double-cavity carton bottle packaging material is used for the freeze-drying process of long-acting growth hormone, and the long-acting growth hormone freeze-dried preparation is obtained. The injection double-cavity carton packaging material in Examples 1-3 is selected for 20 parts respectively, and the steps of the freeze-drying process and the freeze-dried preparation are as follows:

[0171] (1) Add a middle plug to each double-chamber carton bottle 1, and then fill the to-be-lyophilized Lonapegsomatropin. The Lonapegsomatropin includes two types, wherein the first type of Lonapegsomatropin comprises: 22.0 mg hGH / mL Lonapegsomatropin, 10 mM succinic acid, 74.0 mg / mL trehalose dihydrate, and an appropriate amount of tromethamine to adjust the pH value to pH 5.0; wherein the second type of Lonapegsomatropin comprises: 11.0 mg hGH / mL Lonapegsomatropin, 10 mM succinic acid, 83.0 mg / mL trehalose dihydrate, and an appropriate amount of tromethamine to adjust the pH value to pH 5.0. Place and fix the double-chamber carton bottle 1 on the lyophilization support, wherein the lyophilization support is selected from a tray type lyophilization support, as shown in FIG. 1, and the double-chamber carton bottle 1 is placed in the lyophilization support in an upright manner.

[0172] (2) Pre-assemble the top plug 2 and the top cover 3 in Example 1-Example 3, and place them at the bottle opening 10 of the double-chamber carton bottle 1. Specifically, the top plug 2 is inserted into the cavity of the upper end 30 from the opening of the lower end 32 until the upper surface of the plug cap 20 is in contact with the lower end of the top disc 300, and the plug cap 20 is limited in the upper end 30 by the support of the top plug positioning point 303; align the bottle opening 10 with the opening of the lower end 32, and place the top plug 2 naturally at the bottle opening 10 as a whole.

[0173] (3) Perform the lyophilization process of freezing, primary drying, secondary drying, and plate lamination plug and cover pressing on the to-be-lyophilized Lonapegsomatropin, respectively, and the specific operation process is shown in Table 1:

[0174] Table 1 Lyophilization process and parameter settings of Lonapegsomatropin

[0175] Wherein, Atm is 1 standard atmosphere. In the lyophilization process, the lyophilization curve of the to-be-lyophilized Lonapegsomatropin is shown in FIG. 2, and the injection double-chamber carton bottle package material after unloading from the box has a low water content and a low moisture content.

[0176] (4) After the lyophilization process is completed, nitrogen charging operation is performed on the double-chamber carton bottle 1 to maintain the low moisture content of the lyophilized preparation, and then the plug pressing and cover sealing are simultaneously performed. Specifically,

[0177] After the freeze-drying is completed, the top cover 3 is pushed down to press the top plug 2 to fit into the bottle mouth 10 of the double-cavity carton bottle 1. In the process of embedding the top plug 2 into the bottle mouth 10, the top cover 3 is pressed down until the upper end 30 is completely sleeved on the bottle mouth 10. In this process, the inner wall of the upper end 30 is attached to the bottle mouth 10, and the inner walls of the middle end 31 and the lower end 32 are attached to the bottle body 12. Until the plug column 21 is completely embedded into the bottle mouth 10, and the lower surface of the plug cap 20 is completely attached to the upper surface of the bottle mouth 10, the sealing of the double-cavity carton bottle 1 by the top plug 2 is achieved, and no additional plug pressing component is needed.

[0178] (5) The double-cavity carton bottle 1 is taken out of the freeze-drying machine, and the final somatotropin freeze-dried preparation is obtained.

[0179] The appearance and moisture of the somatotropin freeze-dried preparation prepared in the double-cavity carton bottle 1 by the freeze-drying method are detected, and the detection results are shown in Table 2:

[0180] Table 2: Appearance and moisture detection results of somatotropin freeze-dried preparation

[0181] As can be seen from Table 2, the appearance detection result of the somatotropin freeze-dried preparation shows that the appearance is good, and the average moisture detection result of 6 times of detection is low, and the freeze-drying effect is good.

[0182] In addition, the freeze-drying machine plate layer pressing cover operation is performed on the three kinds of injection double-cavity carton bottle packaging materials in Example 1-Example 3 (without adding freeze-dried somatotropin), and the CCIT (vacuum decay method) detection is performed on the pressed packaging materials, and the results show that the sealing properties of the three kinds of packaging materials are good.

[0183] In summary, the freeze-drying process described above can be completed by using the packaging materials in Example 1-Example 3, which can meet the requirements of somatotropin freeze-drying process and sealing property. The somatotropin freeze-dried preparation obtained by the freeze-drying method described above can meet the appearance and moisture requirements.

[0184] Example 5

[0185] The structure of the top cover 3 of the bottle cap assembly in Example 1 is adjusted to reduce the volume of the top cover 3, as shown in FIG. 6B. Specifically, the length of the top cover 3 extending along the neck 11 and the bottle body 12 in Example 2 is shortened, the length of the middle end 31 is shortened, the position of the convex ring 310 relative to the neck 11 and the bottle body 12 is further moved upward, and the lower part of the upper end 30 is attached. In addition, the convex strip 320 of the lower end 32 is removed, and the non-convex strip part of the lower end 32 is extended downward along the bottle body 12, the lower end 32 near the upper part of the middle end 31 is shortened in the radial direction, and the first notch 321 is formed.

[0186] It should be noted that the shape of the extended lower end 32 in this embodiment is set as an octagonal prism, the inner wall of which can still fit at least part of the bottle body 12 of the double-chamber carton bottle 1, and the structure of the adjusted top cover 3 except the middle end 31 and the lower end 32 is the same as that of the top cover 3 in Embodiment 10. The number of top plug positioning points 303 is 8, which are evenly distributed in the inner wall of the upper end 30.

[0187] The bottle cap assembly was subjected to plug pressing and cap sealing test, and it was found that the fit degree of the top plug 2 and the top cover 3 was high, and the top plug 2 did not slip out of the top cover 3; a large pressure was required during the cap pressing process, but no deformation and damage of part of the structure of the top cover 3 occurred; the fit degree of the top cover 3 and the bottle mouth 10 of the double-chamber carton bottle 1 was obviously improved, and the top cover 3 was not pulled out after a large force was applied.

[0188] Embodiment 6

[0189] The maximum length of the protruding part 304 protruding from the inner wall of the upper end 30 was replaced with 0.25 mm, and the other structures and parameters were the same as those of Embodiment 5. The bottle cap assembly was subjected to plug pressing and cap sealing test, and it was found that the fit degree of the top plug 2 and the top cover 3 was high, and the top plug 2 did not slip out of the top cover 3; a large pressure was required during the cap pressing process, but no deformation and damage of part of the structure of the top cover 3 occurred; the fit degree of the top cover 3 and the bottle mouth 10 of the double-chamber carton bottle 1 was obviously improved, and the top cover 3 was not pulled out after a large force was applied.

[0190] Embodiment 7

[0191] The maximum length of the protruding part 304 protruding from the inner wall of the upper end 30 was replaced with 0.2 mm, and the other structures and parameters were the same as those of Embodiment 5. The bottle cap assembly was subjected to plug pressing and cap sealing test, and it was found that the fit degree of the top plug 2 and the top cover 3 was high, and the top plug 2 did not slip out of the top cover 3; a large pressure was required during the cap pressing process, but no deformation and damage of part of the structure of the top cover 3 occurred; the fit degree of the top cover 3 and the bottle mouth 10 of the double-chamber carton bottle 1 was obviously improved, and the top cover 3 was not pulled out after a large force was applied.

[0192] Embodiment 8

[0193] The injection double-chamber carton bottle packaging material was used for the freeze-drying process of long-acting growth hormone, and the long-acting growth hormone freeze-dried preparation was obtained. The injection double-chamber carton packaging material in Embodiments 5-7 was selected for 25 parts respectively, and the steps of the freeze-drying process and the long-acting growth hormone freeze-dried preparation were as follows:

[0194] (1) Add a middle plug to each double-chamber carton bottle 1, and then fill the double-chamber carton bottle 1 with the long-acting growth hormone to be lyophilized, wherein the long-acting growth hormone comprises 22.0 mg hGH / mL long-acting growth hormone, 10 mM succinic acid, 74.0 mg / mL trehalose dihydrate, and an appropriate amount of tromethamine to adjust the pH value to pH 5.0. Place and fix the double-chamber carton bottle 2 on a lyophilization support, wherein the lyophilization support is a tray-type lyophilization support, as shown in FIG. 1, and the double-chamber carton bottle 1 is placed in the lyophilization support in an upright manner.

[0195] (2) After pre-assembling the top plug 2 and the cap 3 in Example 5-Example 7, place the pre-assembled combination of the top plug 2 and the cap 3 at the bottle opening 10 of the double-chamber carton bottle 1, and the pre-assembled combination of the top plug 2 and the cap 3 is in the same manner as in Example 4.

[0196] (3) Perform the lyophilization process of freezing, primary drying, secondary drying, and plate lamination plug pressure covering on the long-acting growth hormone to be lyophilized, respectively, and the specific operation method is the same as in Example 4.

[0197] (4) After the lyophilization process is completed, perform nitrogen filling operation on the double-chamber carton bottle 1 to maintain the low moisture content of the long-acting growth hormone lyophilized preparation, and then perform pressure covering sealing; the pressure covering sealing method is the same as in Example 4.

[0198] (5) Take out the double-chamber carton bottle 4 from the lyophilization machine to obtain the final long-acting growth hormone lyophilized preparation therein.

[0199] Perform appearance detection and moisture detection on the long-acting growth hormone lyophilized preparation prepared in the double-chamber carton bottle 4 through the above lyophilization method, and the detection results are shown in Table 3:

[0200] Table 3 Appearance detection, moisture detection, and CCIT detection results of the long-acting growth hormone lyophilized preparation

[0201] As can be seen from Table 3, the appearance detection result of the long-acting growth hormone lyophilized preparation shows that the appearance is good, and the average moisture detection result is low; in addition, the injection double-chamber carton bottle packaging material in Example 5-Example 7 has good sealing performance in the lyophilization process, which can meet the sealing requirement of the lyophilized preparation.

[0202] Example 9

[0203] An injection double-chamber carton bottle packaging material comprises a double-chamber carton bottle 1' and a bottle cap assembly. The structure of the double-chamber carton bottle 1' is shown in FIG. 13, which comprises a bottle opening 10', a bottle neck 11', a bottle body 12', and an inner chamber 13'. The bottle cap assembly comprises a top plug 2' and a cap 3', wherein the structure of the top plug 2' is shown in FIG. 13, and the structure of the cap 3' is shown in FIG. 14A. The cap 3' seals the bottle opening 10' by using the top plug 2', and simultaneously covers the bottle opening 10' of the double-chamber carton bottle 1'.

[0204] The top cover 3' includes an upper end 30' and a bottom disc 31'. The upper end 30' has a central top disc 300', an edge screw thread 301', and an opening 302' of the lower outer wall. The bottom disc 31' is open at the bottom and has a cavity inside the opening. After the pre-assembled top plug 2' is fitted into the upper end 30' of the top cover 3', the top cover 3' is pressed down as a whole until the upper end 30' is sleeved on the bottle mouth 10'. In this process, the inner wall of the upper end 30' is in contact with the bottle mouth 10', and the inner wall of the bottom disc 31' is in contact with the joint of the bottle neck 11' and the bottle body 12'. The top disc 300' is in contact with the upper surface of the cap 20' of the pre-assembled top plug 2'. During the pressing down of the top cover 3' as a whole, the top disc 300' simultaneously presses down the top plug 2', so that the top plug 2' is embedded in the bottle mouth 10'. Therefore, the top cover 3' can also be used to simultaneously perform plug sealing and capping, without the participation of an additional plug pressing assembly or in multiple steps, thereby reducing the time required for the sealing process of the double-cavity carton bottle 1' and avoiding sealing failure.

[0205] The upper end 30' has eight evenly distributed top plug positioning points 303'. The top plug positioning points 303' are located at the lower end of the top disc 300' and protrude from the inner wall of the upper end 30' toward the axis of the top cover 3'. After the top plug 2' is embedded in the bottle mouth 10', the top plug positioning points 303' are in contact with the cap 20'. The cap 20' is pressed by the top plug positioning points 303' toward the axis of the top cover 3', and the frictional resistance between the cap 20' and the inner wall of the upper end 30' is increased, thereby preventing the top plug 2' from slipping out of or popping out of the top cover 3', and avoiding sealing failure.

[0206] The upper end 30' also has a protruding part 304'. The protruding part 304' is arranged below the top plug positioning points 303' and protrudes from the inner wall of the upper end 30' toward the axis of the top cover 3'. Before the top plug 2' is embedded in the bottle mouth 10', the protruding part 304' is placed on the bottle mouth to ensure that the sublimated moisture can be discharged from the opening 302'. After the top plug 2' is embedded in the bottle mouth 10', the protruding part 304' is in contact with the outer wall of the bottle mouth 10', so that the bottle mouth 10' is pressed by the protruding part 304' toward the axis of the top cover 3', thereby increasing the frictional force between the bottle mouth 10' and the inner wall of the upper end 30' and preventing the top cover 3' from slipping out of or popping out of the bottle mouth 10'.

[0207] The maximum length of the protruding part 304' protruding from the inner wall of the upper end 30' is 0.23 mm. The shape of the protruding part 304' is trapezoidal.

[0208] Example 10

[0209] A double-cavity carton bottle package for injection, comprising a double-cavity carton bottle 1' and a bottle cap assembly, the bottle cap assembly comprising a top plug 2' and a top cap 3'. Wherein the maximum length of the protruding part 304' protruding from the inner wall of the upper end 30' is replaced by 0.25mm, and the other structures and parameters are the same as those of embodiment 9.

[0210] Example 11

[0211] A double-cavity carton bottle package for injection, comprising a double-cavity carton bottle 1' and a bottle cap assembly, the bottle cap assembly comprising a top plug 2' and a top cap 3'. Wherein the maximum length of the protruding part 304' protruding from the inner wall of the upper end 30' is replaced by 0.25mm, and the other structures and parameters are the same as those of embodiment 9.

[0212] Example 12

[0213] The double-cavity carton bottle package for injection is used to carry out the freeze-drying process of long-acting growth hormone, and obtain the long-acting growth hormone freeze-dried preparation. The double-cavity carton bottle package for injection is selected from the double-cavity carton bottle package for injection in embodiments 9-11, each 20 parts, and the steps of carrying out the freeze-drying process and obtaining the long-acting growth hormone freeze-dried preparation are as follows:

[0214] (1) Add a middle plug into each double-cavity carton bottle 1' of the double-cavity carton bottle package for injection, then fill the long-acting growth hormone to be freeze-dried, and place and fix the double-cavity carton bottle 1' on the freeze-drying support. Wherein the freeze-drying support is selected from a tray type freeze-drying support, as shown in Figure 1, and the double-cavity carton bottle 1' is placed in the freeze-drying support in an upright manner.

[0215] (2) Pre-assemble and combine the top plug 2' with the top cap 3' in embodiments 9-11, respectively, and place it at the bottle mouth 10' of the double-cavity carton bottle 1'. Specifically, the top cap 3' is limited in the bottle mouth 10' by the support of the protruding part 303', the top plug 2' is embedded into the cavity of the upper end 30' from the opening of the bottom disc 31' until the upper surface of the plug cap 20' is in contact with the lower end of the top disc 300', and the plug cap 20' is limited in the internal cavity of the upper end 30' by the support of the top plug positioning point 303'.

[0216] In this way, the bottle mouth 10' is aligned with the opening of the bottom disc 31', and the top plug 2' is limited above the bottle mouth 10' as a whole.

[0217] (3) Freeze, primary drying, secondary drying and plate layering and plug capping of the long-acting growth hormone to be freeze-dried are carried out, respectively, and the specific operation process is shown in Table 4:

[0218] Table 4 Freeze-drying process flow and parameter setting of long-acting growth hormone

[0219] Wherein, Atm refers to 1 standard atmosphere.

[0220] (4) After the freeze-drying process is completed, nitrogen is filled into the dual-chamber carton bottle 1' to maintain the low moisture content of the somatotropin freeze-dried preparation, and then the cap is sealed. Specifically,

[0221] After the freeze-drying process is completed, the top cover 3' is pushed down to press the plug 2' so that the plug 2' is embedded into the bottle mouth 10' of the dual-chamber carton bottle 1'. At the same time that the plug 2' is embedded into the bottle mouth 10', the top cover 3' is pressed down until the upper end 30' is completely sleeved on the bottle mouth 10'. In this process, the inner wall of the upper end 30' is attached to the bottle mouth 10' until the plug column 21' is completely embedded into the bottle mouth 10', the lower surface of the plug cap 20' is completely attached to the upper surface of the bottle mouth 10', and the lower surface of the bottom disc 31' is attached to the connection between the bottle neck 11' and the bottle body 12'. In this way, the sealing of the dual-chamber carton bottle 1' by the plug 2' is achieved, and no additional plug assembly needs to be introduced.

[0222] (5) The dual-chamber carton bottle 1' and the freeze-drying support are taken out of the freeze-drying machine.

[0223] The somatotropin freeze-dried preparation prepared in the dual-chamber carton bottle 1' through the freeze-drying method described above is sampled, appearance detected, moisture detected, and CCIT (vacuum decay method) detected, and the detection results are shown in Table 5:

[0224] [According to Rule 91 Correction 20.08.2025] Table 5 Appearance detection, moisture detection, and CCIT detection results of somatotropin freeze-dried preparation

[0225] FIG. 4A is an appearance diagram of the somatotropin freeze-dried preparation obtained through the freeze-drying process. As can be seen from Table 5 and FIG. 4A, the appearance detection result of the somatotropin freeze-dried preparation shows that the appearance is good, and the average moisture detection result is low; in addition, the sealing of the injection dual-chamber carton bottle packaging material in Examples 9-11 in the freeze-drying process is good, which can meet the sealing requirement of the freeze-dried preparation.

[0226] Example 13

[0227] An injection dual-chamber carton bottle packaging material, comprising a dual-chamber carton bottle 1' and a bottle cap assembly, the structure of the dual-chamber carton bottle 1' is the same as that of the dual-chamber carton bottle 1 of Example 9. The bottle cap assembly comprises a plug 2' and a top cover 3', the structure of the plug 2' is the same as that of the plug 2' of Example 9, and the structure of the top cover 3' is shown in FIG. 14B. The bottom disc 31' is adjusted to extend downward to additionally attach to at least a part of the bottle body 12'; the shape of the downwardly extending part of the bottom disc 31' is set as an octagonal prism. In addition, the maximum length of the protruding part 304' protruding from the inner wall of the upper end 30' is set as 0.25 mm, and other structures and parameters are the same as those of Example 9.

[0228] Example 14

[0229] The maximum length of the protrusion 304 protruding from the inner wall of the upper end 30 is replaced by 0.2 mm, and other structures and parameters are the same as those of Example 13. The compression plug and capping sealing test is performed on the bottle cap assembly, and it is found that the fit degree of the compression plug 2' and the cap 3' is high, and the compression plug 2' is not slipped off from the cap 3'; a larger pressure needs to be applied during the capping process, but it does not cause deformation and damage to part of the structure of the cap 3'; and the fit degree of the cap 3' and the bottle mouth 10' of the double-chamber carton bottle 1' is obviously improved and is not pulled out after a larger force is applied.

[0230] Example 15

[0231] The injection double-chamber carton bottle packaging material is used for the lyophilization process of the long-acting growth hormone, and the long-acting growth hormone lyophilized preparation is obtained. The injection double-chamber carton bottle packaging material is selected from 25 parts of the injection double-chamber carton bottle packaging material in Examples 13 and 14, and the steps of performing the lyophilization process and obtaining the long-acting growth hormone lyophilized preparation are as follows:

[0232] (1) Add a compression plug into each double-chamber carton bottle 1', and then fill the long-acting growth hormone to be lyophilized. The long-acting growth hormone contains 22.0 mg hGH / mL long-acting growth hormone, 10 mM succinic acid, 74.0 mg / mL trehalose dihydrate, and an appropriate amount of tromethamine to adjust the pH value of the solution to pH 5.0.

[0233] Place and fix the double-chamber carton bottle 1' on the lyophilization support. Among them, the lyophilization support is selected from a tray type lyophilization support, and the placement mode of the double-chamber carton bottle 1' in the lyophilization support is upright.

[0234] (2) After the compression plug 2' and the cap 3' in Examples 13-14 are pre-assembled and combined, they are placed at the bottle mouth 10' of the double-chamber carton bottle 1', and the pre-assembled and combined mode of the compression plug 2' and the cap 3' is the same as that of Example 12.

[0235] (3) The long-acting growth hormone to be lyophilized is respectively subjected to freezing, primary drying, secondary drying, and plate layer compression plug capping, and the specific operation method is the same as that of Example 12.

[0236] (4) After the lyophilization process is completed, the double-chamber carton bottle 1' is subjected to nitrogen filling operation to maintain the low moisture content of the long-acting growth hormone lyophilized preparation, and then capping sealing. The capping sealing method is the same as that of Example 12.

[0237] (5) The double-chamber carton bottle 1' is taken out from the lyophilization machine, and the long-acting growth hormone lyophilized preparation in it is obtained.

[0238] The long-acting growth hormone lyophilized preparation prepared in the double-chamber carton bottle 1' by the above lyophilization method is sampled, appearance detected, moisture detected, and CCIT detected, and the detection results are shown in Table 6:

[0239] Table 6 Appearance test, moisture test and CCIT test results of the lyophilized preparations of Long-acting Growth Hormone

[0240] As can be seen from Table 6, the appearance test results of the lyophilized preparations of Long-acting Growth Hormone show that the appearance is good, and the average moisture test results are low; in addition, the sealing performance of the dual-chamber carton bottle packaging material in Example 13 and Example 14 in the lyophilization process is good, which can meet the sealing requirements of multiple preparations.

[0241] Example 16

[0242] A dual-chamber carton bottle packaging material for injection, comprising a dual-chamber carton bottle 1' and a bottle cap assembly, the bottle cap assembly comprising a top plug 2' and a top cap 3'. Wherein, a fitting part 306' is arranged on one side of the top disc opening of the top disc 300' close to the top plug 2', which uniformly recedes in the direction away from the top disc opening; in addition, four internal protrusions 310' are equidistantly arranged on the inner wall of the bottom disc 31' away from the upper end 30', and each internal protrusion 310' has a protrusion two-side opening 311' on the left and right sides thereof, as shown in FIGS. 14C and 15B, and other structures and parameters are the same as those of Example 13.

[0243] Example 17

[0244] The lyophilization process of Long-acting Growth Hormone was carried out using the dual-chamber carton bottle packaging material for injection, and the lyophilized preparation of Long-acting Growth Hormone was obtained. The dual-chamber carton bottle packaging material for injection was selected as 10 parts of the dual-chamber carton bottle packaging material for injection in Example 16, and the steps of carrying out the lyophilization process and obtaining the lyophilized preparation of Long-acting Growth Hormone were as follows:

[0245] (1) Add a middle plug into each dual-chamber carton bottle 1', and then fill the Long-acting Growth Hormone to be lyophilized. The Long-acting Growth Hormone comprises 22.0 mg hGH / mL Long-acting Growth Hormone, 10 mM succinic acid, 74.0 mg / mL trehalose dihydrate, and an appropriate amount of tromethamine to adjust the pH value of the solution to pH 5.0.

[0246] Place and fix the dual-chamber carton bottle 1' on the lyophilization support. Wherein, the lyophilization support is selected as a tray type lyophilization support, and the placement mode of the dual-chamber carton bottle 1' in the lyophilization support is upright.

[0247] (2) After the top plug 2' and the top cap 3' in Example 16 are pre-assembled and combined, they are placed at the bottle opening 10' of the dual-chamber carton bottle 1', and the pre-assembly and combination mode of the top plug 2' and the top cap 3' is the same as that of Example 12.

[0248] (3) The Long-acting Growth Hormone to be lyophilized is subjected to freezing, primary drying, secondary drying and plate layering and plug capping, respectively, and the specific operation method is the same as that of Example 12.

[0249] (4) After the freeze-drying process is completed, nitrogen is filled into the dual-chamber carton bottle 1' to maintain the low moisture content of the somatotropin freeze-dried preparation, and then the bottle is sealed by capping. The capping method is the same as that in Example 12.

[0250] (5) The dual-chamber carton bottle 1' is taken out of the freeze-dryer, and the somatotropin freeze-dried preparation in the dual-chamber carton bottle 1' is obtained.

[0251] The somatotropin freeze-dried preparation prepared in the dual-chamber carton bottle 1' through the above freeze-drying method is sampled, appearance tested, moisture tested, and CCIT tested, and the test results are shown in Table 7:

[0252] Table 7 Appearance test, moisture test, and CCIT test results of somatotropin freeze-dried preparation

[0253] FIG. 4B is an appearance diagram of the somatotropin freeze-dried preparation obtained through the freeze-drying process. As can be seen from Table 7 and FIG. 4B, the appearance test results of the somatotropin freeze-dried preparation show that the appearance is good, and the average moisture test results are low; in addition, the injection dual-chamber carton bottle packaging material in Example 16 has good sealing performance in the freeze-drying process, and can meet the sealing performance requirements of the preparation.

[0254] Example 18

[0255] An injection dual-chamber carton bottle packaging material includes a dual-chamber carton bottle 1' and a bottle cap assembly, and the bottle cap assembly includes a top plug 2" and a top cap 3" for sealing the dual-chamber carton bottle 1'. The top plug 2" is used to seal the bottle mouth 10' of the dual-chamber carton bottle 1'. The dual-chamber carton bottle 1' is sealed by the top plug 2" to the bottle mouth 10' through a pressing plug assembly, wherein the pressing plug assembly includes a pressing jig 51 and a holding jig 50, and the structure is shown in FIG. 21A. The top plug has a plug cap 20" and a plug column 21", and the plug column 21" needs to be completely embedded in the bottle mouth opening 100' in the center of the bottle mouth 10', and the lower surface of the plug cap 20" needs to be completely attached to the upper surface of the bottle mouth 10' to achieve sealing of the bottle mouth 10'.

[0256] For this bottle cap assembly, when the freeze-drying process is completed and the freeze-dried preparation needs to be airtight, the pressing plug assembly can be used to complete the sealing of the bottle mouth 10' by the top plug 2", and the top cap 3" is installed after the top plug 2" is fixed to further improve the airtightness of the dual-chamber carton bottle 1', specifically:

[0257] (1) Top plug sealing

[0258] Firstly, the upper and lower ends of the holding fixture 50 of the pressing assembly are both open, the inner wall of the holding fixture 50 is attached to the outer surface of the bottle mouth 10' and the bottle body 12', and the holding fixture 50 is pressed until it is completely attached to the upper end of the bottle body 12'. Since the holding fixture 50 is tightly attached to the bottle mouth 10' and the bottle body 12', it has a large friction, and thus the holding fixture 50 is not easy to fall off the double-cavity cartridge bottle 1'. In addition, the upper end of the holding fixture 50 protrudes from the bottle mouth 10'.

[0259] Next, the stopper 2" is placed in the holding fixture 50, specifically, the stopper 2" is placed on the protruding part 500 of the holding fixture 50, the protruding part 500 can hold the cap 20" to fix the position of the stopper 2", so that the plug column 21" is aligned with the bottle mouth opening 100', facilitating the embedding of the plug column 21" into the bottle mouth opening 100" when it moves downward. In particular, the number of protruding parts 500 is two, which are respectively arranged on both sides of the upper end of the holding fixture 50.

[0260] Then, the inner wall of the pressing fixture 51 of the pressing assembly is attached to the outer wall of the holding fixture 50 and slides downward, the lower end of the pressing fixture 51 is open, the upper surface is closed and the center is concave downward, the inner wall of the concave part is provided with a pressing column 510 which protrudes along the axis direction of the pressing fixture 51, during the downward sliding of the pressing fixture 51, the pressing column 510 can contact and apply downward pressure on the cap 20" to realize the movement of the stopper 2" as a whole to the bottle mouth 10", until the plug column 21" is completely embedded in the bottle mouth 10"; after the plug column 21" is completely embedded in the bottle mouth 10", the cap 20" can be clamped at the lower end of the protruding part 500, so that the protruding part 500 can further clamp the stopper 2" to avoid its falling off.

[0261] It should be noted that before the plug column 21" is completely embedded in the bottle mouth 10", the height of the holding fixture 50 protruding from the bottle mouth 10" is less than the height of the upper surface of the pressing fixture 51 protruding from the bottle mouth 10"; therefore, before the plug column 21" is completely embedded in the bottle mouth 10", the pressing fixture 51 cannot move downward due to the obstruction of the holding fixture 50, avoiding the incomplete embedding of the stopper 2" and the bottle mouth 10". In particular, the number of pressing columns 510 is two, which are respectively arranged on both sides of the inner wall of the concave part of the upper surface of the pressing fixture 51, to apply uniform downward pressure on the stopper 2".

[0262] Finally, the pressing fixture 51 and the holding fixture 50 are removed, the pressing assembly is only used to control the sealing of the stopper 2" to the bottle mouth 10", and thus it needs to be removed after the sealing is completed, so as to facilitate the subsequent capping.

[0263] (2) Top cover sealing

[0264] The top cover 3" is used to fix the top plug 2" and seal the bottle mouth 10' of the double-chambered carton bottle 1' through the top plug 2". The structure of the top cover 3" is shown in FIG. 21B, which includes a main body and a bottom disc 31", the main body has a top disc 300" at the center of the upper end of the top cover 3" and a thread 301" at the edge of the upper end of the top cover 3", and the bottom disc 31" is arranged above the main body, and the bottom disc 31" is open below; after the top plug 2" is completely embedded in the bottle mouth 10', the top cover 3" is pressed downward and sleeved on the bottle mouth 10', and in this process, the inner walls of the main body and the bottom disc 31" are attached to the bottle mouth 10' and the bottle neck 11'; therefore, after the top cover 3" is pressed until the bottom disc 31" is completely attached to the upper surface of the bottle body 12', the top cover 3" has a large friction with the double-chambered carton bottle 1', which can avoid falling off to improve the sealing performance of the double-chambered carton bottle 1'.

[0265] In addition, the top disc 300" has a double-layer structure, the upper layer is a hollow cylinder, and the lower layer is a cylinder with an inner diameter equal to the inner diameter of the hollow part of the upper layer; after the bottom disc 31" is completely attached to the upper surface of the bottle body 12', the top disc 300" can hold the top plug 2" embedded in the bottle mouth 10' through the lower layer, so as to prevent the top plug 2" from falling out of the bottle mouth 10', and improve the sealing performance of the double-chambered carton bottle 1'.

[0266] In summary, the freeze-drying method for providing the long-acting growth hormone is used in combination with the double-chambered carton bottle packaging material for preparing the long-acting growth hormone freeze-dried preparation, which has regular freeze-drying curve parameters, good appearance and low moisture content, high stability for storage; the packaging material has good sealing performance after freeze-drying, providing a high-purity and sterile storage environment. Therefore, the long-acting growth hormone freeze-dried preparation obtained by the freeze-drying method of the above-mentioned embodiments can provide efficient support for GHD patients and growth hormone demand groups.

Claims

1. A lyophilization method of long-acting growth hormone, comprising: adding a middle plug into a double-chambered vial, and then pouring the long-acting growth hormone to be lyophilized into the double-chambered vial; assembling a top plug with a top cover, and placing the top cover above the bottle mouth of the double-chambered vial, and placing and fixing the double-chambered vial on a customized lyophilization support; freezing, primary drying and secondary drying the long-acting growth hormone to be lyophilized, respectively; pressing the top plug into the double-chambered vial with the top cover to seal the double-chambered vial and fix the top plug, and to make the top plug seal the bottle mouth of the double-chambered vial.

2. The lyophilization method of claim 1, wherein: the lyophilization support is a stand-alone lyophilization support or a tray-type lyophilization support, preferably, the lyophilization support is a tray-type lyophilization support; and the double-chambered vial is placed in the lyophilization support in an upright or inverted manner, preferably, the double-chambered vial is placed in the lyophilization support in an upright manner.

3. The lyophilization method of claim 1, wherein: the temperature range for freezing the long-acting growth hormone in the double-chambered vial is -60℃ to -40℃; the temperature range for primary drying is -60℃ to 0℃, and the temperature range for secondary drying is 15℃ to 40℃; and the pressure range for primary drying and secondary drying is 0.02mbar to 0.2mbar, preferably, the pressure for primary drying and secondary drying is 0.06mbar, respectively.

4. The lyophilization method of claim 1, wherein: pressing the top plug into the double-chambered vial with the top cover further comprises: nitrogen charging the double-chambered vial to maintain low moisture content of the long-acting growth hormone before pressing the top plug.

5. A lyophilized preparation of long-acting growth hormone, prepared by the lyophilization method of any one of claims 1-4.

6. A syringe comprising: A double-chambered vial package for injection, a lyophilized preparation of long-acting growth hormone, and a reconstitution agent.

7. The injection of claim 6, wherein: the double-chambered vial package for injection comprises a double-chambered vial and a cap assembly, wherein: the double-chambered vial is used to hold the lyophilized preparation of long-acting growth hormone and the reconstitution agent; the cap assembly comprises the top plug and the top cover; the top plug seals the bottle mouth of the double-chambered vial; the top cover is used to press and fix the top plug so that the top plug seals the bottle mouth of the double-chambered vial; and to seal the double-chambered vial; wherein the process of pressing and fixing the top plug with the top cover so that the top plug seals the bottle mouth of the double-chambered vial comprises the following steps: pre-assembling the top plug into the top cover; placing the top cover with the assembled top plug above the bottle mouth of the double-chambered vial, and pressing the top cover downward.

8. The injection of claim 7, wherein: the double-chambered vial comprises an inner chamber, a bottle body, a bottle neck, and a bottle mouth, wherein the center of the bottle mouth is provided with a bottle mouth opening connected with the inner chamber, and the inner diameter of the bottle mouth opening is smaller than the inner diameter of the bottle mouth and the bottle neck; one side of the outer wall of the bottle body has a bypass protrusion.

9. The injection according to claim 6, wherein, the Lonapeenod lyophilized preparation is a Lonapeenod lyophilized preparation prepared according to the lyophilization method of any one of claims 1 to 4 or the Lonapeenod lyophilized preparation of claim 5.

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