Freeze-drying method, freeze-drying preparation and injection of growth hormone

Abstract

The invention discloses a freeze-drying method of a product for pharmaceutical, cosmetic or medical beauty application, which comprises the following steps of: adding a middle plug into a double-cavity clamping type bottle, filling a product to be freeze-dried, and placing and fixing the double-cavity clamping type bottle on a freeze-drying bracket; the top plug is limited on a bottle opening of the double-cavity clamping bottle; performing freezing, primary drying and secondary drying on the to-be-freeze-dried product respectively; and the top plug is fixed by the top cover and the bottle opening is sealed. According to the freeze-drying method provided by the invention, high-quality freeze-drying parameters and freeze-drying operation can be provided, so that the top plug and the top cover are utilized to complete integrated plug pressing and cover sealing of the double-cavity cassette bottle, the obtained growth hormone freeze-drying preparation for the growth culture can keep higher quality, the use effect of the freeze-drying preparation is improved, and the storage time of the freeze-drying preparation is prolonged.

Description

DIVISION

[0001] This application is a divisional application of the case with the application number of 2024116862168, the application date of November 22, 2024, and the invention title of Freeze-drying method of lonapegsomatropin, freeze-dried preparation of lonapegsomatropin and injection. TECHNICAL FIELD

[0002] 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

[0003] 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. The double-chamber carton bottle packaging material can provide a better choice. The double-chamber carton bottle is divided into two chambers by a middle plug. The front chamber is used to store freeze-dried drugs, and the rear chamber is used to store reconstituting agents. When used, the reconstituting agent can flow into the front chamber through a bypass to reconstitute the freeze-dried drugs by pushing the bottom plug. After reconstitution, the bottom plug is continuously pushed to the top to complete the injection process.

[0004] Lonapegsomatropin, also known as somavert, 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 double-chamber carton bottle to store lonapegsomatropin and reconstituting agents separately, medical personnel can easily reconstitute freeze-dried lonapegsomatropin and administer it. 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 shelf stability of the active ingredients in lonapegsomatropin.

[0005] However, the conventional freeze-drying process needs to separately seal the double-chamber carton bottle after freeze-drying, which cannot complete the integrated operation of freeze-drying lonapegsomatropin and sealing the double-chamber carton bottle in the freeze-drying machine. 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 freeze-dried preparation of lonapegsomatropin has a good form, lower water content and a more suitable use method.

[0006] Therefore, there is an urgent need for a new lyophilization method of long-acting growth hormone to solve the above problems, improve lyophilization efficiency and product quality, fill the gap in the field of double-cavity carton bottles for long-acting growth hormone lyophilization technology, and further enhance the core competitiveness of finished preparations. SUMMARY

[0007] The present application aims to provide a solution that can overcome at least one of the above-mentioned deficiencies of the prior art.

[0008] According to an aspect of the present application, a lyophilization method of long-acting growth hormone is provided, which comprises: adding a middle plug into the double-cavity carton bottle, then pouring the long-acting growth hormone to be lyophilized into the double-cavity carton bottle; assembling the top plug with the top cover, and placing the top cover above the bottle opening of the double-cavity carton bottle; placing and fixing the double-cavity carton bottle 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-cavity carton bottle using the top cover to seal the double-cavity carton bottle and fix the top plug, and to make the top plug seal the bottle opening and the bottle neck of the double-cavity carton bottle.

[0009] The lyophilization method provided by the present application simultaneously presses the plug and the cover 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°C to -40°C; the temperature range for primary drying is -60°C to 0°C, and the temperature range for secondary drying is 15°C to 40°C; and the pressure range for primary drying and secondary drying is 0.02 mbar to 0.2 mbar, preferably the pressure for primary drying and secondary drying is 0.06 mbar, respectively.

[0012] In some embodiments of the present application, pressing the top plug into the double-cavity carton bottle using the top cover also includes: performing a nitrogen charging operation on the double-cavity carton bottle before pressing the top plug, to maintain a low moisture content of the long-acting growth hormone.

[0013] In some embodiments of the present application, a lyophilized preparation of Long-acting Growth Hormone is also provided, which is prepared according to any of the above lyophilization methods of Long-acting Growth Hormone. The lyophilized preparation of Long-acting Growth Hormone has high lyophilized mass and low moisture, and when used for treating growth hormone deficiency in children, it can be quickly reconstituted for injection and provides better growth effect for the user.

[0014] In some embodiments of the present application, an injection kit is also provided, which can include: a double-chamber carton bottle package for injection, a lyophilized preparation of Long-acting Growth Hormone, and a reconstitution agent. The double-chamber carton bottle package for injection can be used to reconstitute and inject the lyophilized preparation of Long-acting Growth Hormone.

[0015] In some embodiments of the present application, the double-chamber carton bottle package for injection can include: a double-chamber carton bottle and a bottle cap assembly, wherein the double-chamber carton bottle is used to hold 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 opening of the double-chamber carton bottle; the top cap is used to press and fix the top plug so that the top plug seals the bottle opening of the double-chamber carton bottle; and the double-chamber carton bottle is sealed; wherein the process of pressing and fixing the top plug with the top cap so that the top plug seals the bottle opening of the double-chamber carton bottle includes the following steps: The top plug is pre-assembled into the top cap; the top cap with the assembled top plug is placed above the bottle opening of the double-chamber 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 plug sealing and cap sealing by pressing the top plug, so as to improve the sealing efficiency of the double-chamber carton bottle in the lyophilization process, avoid the number of operation failures 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.

[0016] In some embodiments of the present application, the double-chamber carton bottle can include: an inner chamber, a bottle body, a bottle neck, and a bottle opening, the center of the bottle opening is provided with a bottle opening opening connected with the inner chamber, the inner diameter of the bottle opening opening is smaller than the inner diameter of the bottle opening and the bottle neck; the outer wall of one side of the bottle body has a bypass protrusion.

[0017] 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 any of the above lyophilization methods of Long-acting Growth Hormone or the lyophilized preparation of Long-acting Growth Hormone provided by the present application.

[0018] According to another aspect of the present application, another lyophilization method of Long-acting Growth Hormone is also provided, which includes: The double-cavity carton bottle is filled with a stopper, and then is filled with the long-acting growth hormone to be freeze-dried. The top cover is assembled with the top stopper, and is placed above the bottle mouth of the double-cavity carton bottle. The double-cavity carton bottle is placed and fixed on the customized freeze-drying support. The long-acting growth hormone to be freeze-dried is subjected to freezing, primary drying and secondary drying, respectively. The top cover is used to press the top stopper to be embedded with the double-cavity carton bottle, so as to seal the double-cavity carton bottle and fix the top stopper, and the top stopper seals the bottle mouth of the double-cavity carton bottle.

[0019] In some embodiments of the present application, the freeze-drying support is a stand-alone freeze-drying support or a tray-type freeze-drying support, preferably, the freeze-drying support is a tray-type freeze-drying support; and the double-cavity carton bottle is placed in the freeze-drying support in a right-up or upside-down manner, preferably, the double-cavity carton bottle is placed in the freeze-drying support in a right-up manner.

[0020] In some embodiments of the present application, the temperature range 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 0.02 mbar to 0.2 mbar, preferably, the pressure for primary drying and secondary drying is 0.06 mbar, respectively.

[0021] In some embodiments of the present application, the top cover is used to press the top stopper to be embedded with the double-cavity carton bottle, further comprising: before pressing the top stopper, the double-cavity carton bottle is subjected to nitrogen filling operation, so as to maintain the low moisture content of the long-acting growth hormone.

[0022] In some embodiments of the present application, another long-acting growth hormone freeze-dried preparation is further included, which is prepared by the freeze-drying method of another long-acting growth hormone according to any one of the above.

[0023] In some embodiments of the present application, an injection is further included, comprising: an injection double-cavity carton bottle package, a long-acting growth hormone freeze-dried preparation and a reconstitution agent, and the reconstitution and injection of the long-acting growth hormone freeze-dried preparation can also be completed by using the injection double-cavity carton bottle package.

[0024] In some embodiments of the present application, the injection double-cavity carton bottle package comprises: 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 long-acting growth hormone freeze-dried preparation and the reconstitution agent; the bottle cap assembly comprises a top stopper and a top cover; the top stopper seals the bottle mouth of the double-cavity carton bottle; the top cover is used to press and fix the top stopper, so that the top stopper seals the bottle mouth of the double-cavity carton bottle; and the double-cavity carton bottle is sealed; In some embodiments of the present application, the process of pressing and fixing the top cover to the top stopper, so that the top stopper seals the bottle mouth of the double-cavity carton bottle, comprises the following steps: the top stopper is pre-assembled into the top cover; the top cover with the assembled top stopper is placed above the bottle mouth of the double-cavity carton bottle, and the top cover is pressed downward.

[0025] In some embodiments of the present application, the double-chamber carton bottle 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, the inner diameter of the bottle mouth opening is smaller than the inner diameter of the bottle mouth and the bottle neck; the outer wall of one side of the bottle body has a bypass protrusion.

[0026] In some embodiments of the present application, the lyophilized preparation of long-acting growth hormone is prepared by another lyophilization method of long-acting growth hormone according to any one of the above or another lyophilized preparation of long-acting growth hormone provided by the present application.

[0027] Compared with the prior art, the present application has at least one of the following technical effects: 1. The present application provides an integrated sealing method for pressing and capping the double-chamber carton bottle package for injection in the lyophilization process of the preparation.

[0028] 2. The present application provides optimal lyophilization parameters and water removal operations for the lyophilization process of long-acting growth hormone, so that the long-acting growth hormone obtained by the lyophilization method maintains optimal quality and is convenient for efficient storage and use.

[0029] 3. The present application provides a high-quality long-acting growth hormone lyophilized preparation prepared by lyophilization, 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 preparation, helping the children to reach or approach normal height.

[0030] 4. The present application provides an injection, which can store long-acting growth hormone lyophilized preparation and reconstituting agent based on the double-chamber carton bottle package for injection and store them stably for a long time, and the long-acting growth hormone lyophilized preparation and the reconstituting agent can be quickly mixed and reconstituted when the injection is used, ensuring efficient and convenient use of the lyophilized preparation. BRIEF DESCRIPTION OF DRAWINGS

[0031] 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 accompanying drawings are provided to aid in the understanding of the present application and constitute a part of the specification, together with the detailed description, to explain the present application and do not limit the present application. In the drawings, the same reference numerals generally refer to the same components or steps.

[0032] Figure 1 The present application illustrates a schematic diagram of a lyophilization support.

[0033] Figure 2 The present application illustrates a lyophilization curve schematic diagram of long-acting growth hormone lyophilized preparation.

[0034] Figure 3The appearance of the lyophilized formulation of the somatotropin of the present application is shown.

[0035] Figure 4 The appearance of another lyophilized formulation of the somatotropin of the present application is shown.

[0036] Figure 5 The structure of the double chamber cartouche 1 and the stopper 2 of the present application is shown.

[0037] Figure 6A The structure of the cap 3 of the present application is shown.

[0038] Figure 6B Another structure of the cap 3 of the present application is shown.

[0039] Figure 7 Another structure of the stopper 2 and yet another structure of the cap 3 of the present application are shown.

[0040] Figure 8A The structure of the stopper positioning point 303 of the present application is shown.

[0041] Figure 8B Another structure of the stopper positioning point 303 of the present application is shown.

[0042] Figure 9 The structure of the upper end 30 of the present application is shown.

[0043] Figure 10 The structure of the maximum length of the protrusion 304 of the present application is shown.

[0044] Figure 11 The structure of the upper and lower cut angles of the protrusion 304 of the present application is shown.

[0045] Figure 12 The structure of the double chamber cartouche packaging assembly of the present application is shown.

[0046] Figure 13 The structure of the double chamber cartouche 1' and the stopper 2' of the present application is shown.

[0047] Figure 14A The structure of the cap 3' of the present application is shown.

[0048] Figure 14B Another structure of the cap 3' of the present application is shown.

[0049] Figure 15 Another structure of the stopper 2' and yet another structure of the cap 3' of the present application are shown.

[0050] Figure 16A The structure of the stopper positioning point 303' of the present application is shown.

[0051] Figure 16B Another structural diagram of the top plug positioning point 303' of the present application is shown.

[0052] Figure 17 A structural diagram of the upper end 30' of the present application is shown.

[0053] Figure 18 A structural diagram of the maximum length, upper cutting angle and lower cutting angle of the protrusion 304' of the present application is shown.

[0054] Figure 19 A structural diagram of the double-cavity carton bottle packaging material assembly of the present application is shown.

[0055] Explanation of Reference Signs 1 - Double-cavity carton bottle 2 - Top plug 3 - Top cover 4 - Sheath 1' - Double-cavity carton bottle 2' - Top plug 3' - Top cover 4' - Sheath 10 - Bottle mouth 11 - Bottle neck 12 - Bottle body 13 - Inner cavity 10' - Bottle mouth 11' - Bottle neck 12' - Bottle body 13' - Inner cavity 20 - Plug cap 21 - Plug column 22 - Sealing portion 20' - Plug cap 21' - Plug column 22' - Sealing portion 30 - Upper end 31 - Middle end 32 - Lower end 30' - Upper end 31' - Bottom disc 40' - Sheath main body 41' - Flange 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 310 - Convex ring 320 - Convex strip 321 - First notch 300' - Top disc 301' - Thread 302' - Opening 303' - Top plug positioning point 304' - Protrusion 321' - First notch 400' - Second notch DETAILED DESCRIPTION

[0056] As described above, the lyophilization method of long-acting growth hormone provided in the present application comprises: adding a middle plug into a double-cavity ampoule 1, and then pouring long-acting growth hormone to be lyophilized into the double-cavity ampoule 1; assembling a top plug 2 with a top cover 3, and placing the top cover 3 above a bottle opening 10 of the double-cavity ampoule 1, and placing and fixing the double-cavity ampoule 1 on a customized lyophilization support; respectively performing freezing, primary drying and secondary drying on the long-acting growth hormone to be lyophilized; and pressing the top plug 2 and the double-cavity ampoule 1 by using the top cover 3 to close the double-cavity ampoule 1 and fix the top plug 2, and to make the top plug 2 close the bottle opening 10 of the double-cavity ampoule 1.

[0057] In the present application, the middle plug added into the double-cavity ampoule 1 and the long-acting growth hormone to be lyophilized can be any type of middle plug for double-cavity ampoule and lyophilizable long-acting growth hormone added according to the size and configuration of the double-cavity ampoule 1. 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 present application. In the process of fixing the top plug 2 by using the top cover 3 and closing the bottle opening 10 of the double-cavity ampoule 1 through the top plug 2, the driving mode of the top cover 3 can be any driving mode that can be implemented in the lyophilization machine, such as mechanical pressing, air pressure driving, pneumatic clamp driving or spring pressing.

[0058] In the present application, the long-acting growth hormone to be lyophilized can be poured into the double-cavity ampoule 1 after adding the middle plug into the double-cavity ampoule 1, and in particular, the long-acting growth hormone to be lyophilized can be long-acting growth hormone to be lyophilized and stored for a short or long period of time in the inner cavity 13 of the double-cavity ampoule 1. The user can pour long-acting growth hormone solution into one of the inner cavities 13 of the double-cavity ampoule 1 to perform lyophilization by using the lyophilization method of the present application.

[0059] In the present application, the lyophilization support is a stand-alone lyophilization support or a tray-type lyophilization support. The present application provides a lyophilization support of a type selected from a stand-alone lyophilization support and a tray-type lyophilization support. Those skilled in the art can select the specific model, size and working parameters in the lyophilization machine of the lyophilization support according to the actual lyophilization requirements. Preferably, the lyophilization support used is a tray-type lyophilization support, which is easy to place a larger number of double-cavity ampoules 1.

[0060] In particular, the double-cavity ampoule 1 can be placed in the lyophilization support in an upright or inverted manner. Preferably, the double-cavity ampoule 1 is placed in the lyophilization support in an upright manner, which facilitates uniform distribution of heat in the double-cavity ampoule 1 and improves the efficiency of solvent sublimation. In addition, it can also reduce the degree of sedimentation and aggregation of long-acting growth hormone, so as to ensure uniform and stable appearance.

[0061] 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 ~ -40°C, and the somatotropin to be freeze-dried has a high freezing efficiency and maintains its own quality, so the freezing temperature is any one of -60°C ~ -40°C. Specifically, the temperature range for freezing the somatotropin in the double-cavity carton bottle 1 is -60°C ~ -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 ~ 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 ~ 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.

[0062] 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 ~ 0°C and 15°C ~ 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 ~ 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 ~ 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.

[0063] 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 nitrogen can also keep the position of the middle plug fixed in the double-chamber carton bottle.

[0064] 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.

[0065] This application also includes an injectable preparation comprising: a dual-chamber cartridge vial for injection, a lyophilized formulation of lop-P-growth hormone, and a reconstituter. It should be noted that the lyophilized formulation and reconstituter of lop-P-growth hormone can be any specification of lyophilized formulation and reconstituter of lop-P-growth hormone suitable for the dual-chamber cartridge vial for injection and the lyophilization process. Specifically, the lyophilized formulation of lop-P-growth hormone can be any lyophilized lop-P-growth hormone to be lyophilized that can be filled into the dual-chamber cartridge vial 1 of this application, prepared by the lyophilization method of this application, or it can be the lyophilized formulation of lop-P-growth hormone provided in this application.

[0066] Furthermore, the reconstitution solvent can be any reconstitution solvent that effectively reconstitutes any of the lyophilized lop-petroleum growth hormone preparations prepared above, such as sterile water for injection, which can rapidly reconstitute the lyophilized lop-petroleum growth hormone preparations provided in this application before administration.

[0067] In this application, the packaging material for a dual-chamber cartridge vial for injection includes: a dual-chamber cartridge vial 1 and a cap assembly, wherein the dual-chamber cartridge vial 1 is used to hold a lyophilized formulation of loppi growth hormone and a reconstitution solvent. The cap assembly includes a top stopper 2 and a top cap 3 for sealing the dual-chamber cartridge vial 1. The dual-chamber cartridge vial 1 is as follows... Figure 5 As shown, it can be placed in a freeze-drying rack used in existing freeze-drying processes, and the dual-chamber cartridge bottle packaging material can be fixed and placed upright or upside down in the freeze-drying rack and sheath; the cap assembly can be made of any material suitable for achieving the cap sealing function. The top stopper 2 is positioned within the top cover 3 to seal the bottle opening 10 of the dual-chamber cartridge bottle 1; the top cover 3 is used to press and fix the top stopper 2, so that the top stopper 2 seals the bottle opening 10 of the dual-chamber cartridge bottle 1, and seals the dual-chamber cartridge bottle 1; wherein, the process of pressing and fixing the top stopper 2 on the top cover 3 to seal the bottle opening 10 of the dual-chamber cartridge bottle 1 may include the following steps: The top plug 2 is pre-assembled into the top cap 3; and the top cap 3 with the top plug 2 pre-assembled is placed above the bottle mouth 10 of the double-chamber cartridge bottle 1, and the top cap 3 is pressed down to press the top plug 2. The top cap 3 can be pressed down by mechanical clamping, pneumatic drive, pneumatic clamp drive, or spring pressing, etc.

[0068] In this application, the dual-cavity cartridge bottle 1 includes: an inner cavity 13, a bottle body 12, a neck 11, and a bottle mouth 10. The bottle mouth 10 has a centrally located opening 100 connected to the inner cavity 13, and the inner diameter of the opening 100 is smaller than the inner diameters of the bottle mouth 10 and the neck 11. One side of the outer wall of the bottle body 12 has a bypass protrusion 120. Those skilled in the art will understand that the dimensions of the inner cavity 13, bottle body 12, neck 11, and bottle mouth 10 of the dual-cavity cartridge bottle 1 can be adjusted to fit the size range of commonly used freeze-drying supports. For example, changing the vertical length of one or more parts of the dual-cavity cartridge bottle 1 or changing the radial length of one or more parts of the dual-cavity cartridge bottle 1 does not depart from the scope of protection of this application.

[0069] 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 attached to the upper surface of the bottle opening 10 to achieve 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, 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.

[0070] In the present application, the top cap 3 as shown in Figure 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 attached to the bottle opening 20, the bottle neck 21 and at least a part of the bottle body 22; when the top cap 3 is directed 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 attached above the plug cap 20 to fix 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 the double-chamber carton bottle.

[0071] It should be noted that the shape of the lower end 32 of the top cap 3 can be cylindrical or prismatic, as shown in Figure 6B , the length in the vertical direction can be adjusted, so the lower end 32 can be attached to a small part of the bottle body 12, or to most parts or the entire bottle body 12 to achieve better sealing performance and to meet 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 mutual fixing effect; in particular, the convex strip 320 can also be removed. The shape of the lower end 32 can be cylindrical or prismatic to avoid the top cap 3 from slipping off or sliding relative to the double-chamber carton bottle 1 under the action of rotational centrifugal force, which affects the sealing performance.

[0072] In particular, the length of the middle end 31 of the top cap 3 in the direction of the bottle neck 11 and the bottle body 12 can be adjusted, and the convex ring 310 can be adjusted to be attached to the lower part of the upper end 30 to adapt to the sealing requirements of the double-chamber carton bottle 1 for different degrees of gasket attachment of the top cap 3, for example, the length of the top cap 3 in the direction of the bottle body 12 or the volume of the top cap 3 needs to be reduced to meet the size requirements of the double-chamber carton bottle 1 and the top cap 3 in the freeze-drying process. In particular, the center of the top disc 300 has a top disc opening, and the circumferential lower edge to the upper edge of the top disc opening can have an inclination angle βThe 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 planar.

[0073] In the present application, as shown in Figure 7 The top plug 2 can further comprise a sealing portion 22 protruding above the plug cap 20, which can be inserted into the top disc opening. When the top plug 2 is fully inserted into the bottle mouth 10, i.e. the double-chambered cartridge bottle 1 is fully pressurized, the sealing portion 22 is inserted into the top disc opening and partially protrudes longitudinally out of 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. During 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 into and embedded in the top disc opening from the circumferential lower edge of the top disc opening.

[0074] Therefore, during 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 of which closely fits the circumferential outer edge of the top disc opening and finally partially protrudes out of the upper edge of the top disc opening. By adjusting the radial length of the sealing portion L , the radial length of the sealing portion can be made longer to improve the close fit between the edge portion of the sealing portion and the circumferential outer edge of the top disc opening, thereby further preventing the top plug 2 from slipping out of the top disc 300. In addition, by adjusting the size of the sealing portion β , the circumferential lower edge of the top disc opening and the sealing portion 22 can have a closer fit with the circumferential upper edge of the top disc opening, so that the top disc opening closely surrounds and fixes the sealing portion 22.

[0075] In some embodiments, the radial length of the sealing portion 22 L may be 2.0 mm - 5.0 mm, in particular, the radial length of the sealing portion 22 L may 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 of the sealing portion 22 L may be 3.0 mm - 4.0 mm, in particular, the radial length of the sealing portion 22 Lmay 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 may be 0°, 1°, 2°, 3°, 4°, 5°, 6°, 7°, 8°, 9°, or 10°, etc.

[0076] 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.

[0077] By making the radial length of the sealing portion 22 L 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 whole top plug 2 does not slip off. Preferably, the radial length of the sealing portion 22 is set to be β 0°, when the top disc opening does not have an inclination angle in the vertical direction, it can already provide good fixation of the sealing portion 22, and also avoid excessive resistance when the sealing portion 22 is inserted into the top disc opening; in another case, when the top disc opening needs to have a certain size of inclination angle in the vertical direction to improve the limiting effect of the top disc 300 on the top plug 2, the inclination angle can also be set to be βThe radial length of the sealing portion 22 can be adjusted according to the actual sealing condition of the bottle cap assembly, based on the above-mentioned size reference, to adjust the fitting and fixing degree of the sealing portion 22 and the top disc 300. L the inclination angle β and / or the circumferential lower edge opening length of the top disc opening, etc.

[0078] In particular, the diameter of the cap 20 of the stopper 2 can be slightly smaller than the inner diameter of the top cover 3. The stopper 2 can be tightly fixed with the bottle opening 100 through the cooperation of the stopper positioning point 303 and the cap 20, to achieve sealing. In this case, the diameter of the cap 20 is 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 Figure 9 When the stopper 2 is pressed by the top cover 3, the compressed volume of the cap 20 extends to the gap part 200 reserved around the cap 20, so that the cap 20 does not protrude upwardly to the top disc opening in the middle due to compression, avoiding affecting injection.

[0079] In some embodiments, the diameter of the plug cap 20 can range from 5.0 mm - 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 - 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.

[0080] In some embodiments, the diameter of the upper end 30 of the top cover 3 can range from 5.0 mm - 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 - 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.

[0081] 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 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 removed seal of the double-chambered cartridge 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 appropriate gap part 200 can be provided by appropriately adjusting the size relationship between the diameter of the plug cap 20 and the diameter of the upper end 30.

[0082] By inserting and fitting the sealing part 22 into the top disc opening during the pre-assembly of the stopper 2, and limiting the plug cap 20 by cooperating with the stopper positioning point 303, the stopper 2 can be stably fixed in the top cover 3. Therefore, the mechanical processes performed on the top cover 3 during the freeze-drying process, such as shaking and hanging, will not affect the fixation of the stopper 2 in the top cover 3, thereby avoiding the stopper 2 from falling off the top cover 3 before the capping operation, and ensuring the capping qualification rate after the freeze-drying is completed; the configuration of the gap part 200 of the plug cap 20 can also avoid the occurrence of coring when the plug cap 20 is used with the injection needle, thereby ensuring the normal use of the growth hormone lyophilized preparation.

[0083] In the present application, the upper end 30 of the top cover 3 also has a stopper positioning point 303, as shown in Figure 8A , Figure 8B The stopper 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 stopper 2 fitted with the bottle mouth 10. Specifically, the stopper positioning point 303 extends radially along the upper end 30 and is uniformly spaced around the inner wall of the stopper positioning point 303, and the shape of the stopper positioning point 303 can be cylindrical or prismatic, and in addition, the number and the spacing length / arc of the plurality of stopper positioning points 303 can be adjusted to maintain the optimal fixation of the stopper 2.

[0084] In this application, the number of top stopper positioning points 303 is four or five or more. Specifically, the number of top stopper positioning points 303 can be even to maintain a symmetrical arrangement along the center of the upper end 30, providing a more stable fixing function for the top stopper 2. Preferably, the number of top stopper positioning points 303 is four or eight to provide a relatively stable fixing function for the top stopper 2; more preferably, the number of top stopper positioning points 303 is eight to provide the most stable fixing function for the top stopper 2. The top stopper positioning points 303 can also be used to position the top stopper 2 before it is pressed into the bottle neck 10. The top stopper 2 is limited by the top stopper positioning points 303 to prevent it from sliding off the bottle neck 10 on its own.

[0085] In this application, the upper end 30 of the top cover 3 is further provided with a protrusion 304 protruding in the direction of the axis of the top cover 3 on its inner wall, such as Figure 10 As shown, the top cap 3 can be limited on the bottle neck 10 by the protrusion 304 before capping, so that sublimated solvent, such as water, in the inner cavity 13 can be discharged through the opening 302; therefore, the protrusion 304 helps to provide gas exchange and sublimated water discharge for the dual-cavity cartridge bottle 1 during freeze-drying. Those skilled in the art will understand that the protrusion 304 does not hinder the movement of the top stopper 2 during the insertion of the top stopper 2 into the bottle neck 10. Since the protrusion 304 is evenly distributed on the inner wall of the upper end 30, and the top plate 300 can apply pressure evenly to the entire surface of the cap 20 pre-assembled into the upper end 30 when capping, the top stopper 2 can be stably and horizontally inserted into the bottle neck 10.

[0086] In this application, the number of protrusions 304 is two or three or more; preferably, the maximum length of the protrusions 304 protruding towards the axis of the top cover 3 is ( D ) can be 0.10 mm, 0.11 mm, 0.12 mm, 0.13 mm, 0.14 mm, 0.15 mm, 0.16mm, 0.17 mm, 0.18 mm, 0.19 mm, 0.20 mm, 0.21 mm, 0.22 mm, 0.23 mm, 0.24 mm, 0.25 mm, 0.26 mm, 0.27 mm, 0.28 mm, 0.29 mm or 0.30 mm. Specifically, D It can be 0.15 mm to 0.30 mm; more preferably, D The thickness can be 0.20 mm to 0.28 mm, which prevents the top cover from deforming due to excessive pressure during sealing, and ensures good sealing performance and prevents slippage after sealing; more preferably, D The thickness can be 0.23 mm to 0.28 mm, which can prevent deformation due to pressure when the top cover is pressed down, and the top cover has good sealing performance after pressing down, making it less prone to slippage. It should be noted that when the material of the protruding part 304 is different... DThe value is adjustable to achieve optimal positioning of the top cap 3 before capping and optimal improvement in the fit between the upper end 30 and the dual-chamber cartridge bottle 1. Preferably, when the outer diameter of the bottle mouth 10 is 7.3 mm, D The diameter can be 0.23 mm, 0.25 mm or 0.28 mm, and the protrusion 304 can provide optimal stability after the top cover 3 is pressed in.

[0087] In this application, the shape of the protrusion 304 can be trapezoidal, semi-circular, semi-elliptical, or rectangular. Preferably, the shape of the protrusion 304 is trapezoidal. When the shape of the protrusion 304 is preferably a trapezoid with its short side close to the bottle mouth 10, the upper end 30 fits more tightly with the bottle mouth 10, and the top cover 3 can fit very stably on the dual-chamber cartridge bottle 1 to maintain good airtightness.

[0088] When the protrusion 304 is trapezoidal in shape, it is preferable that the upper chamfer of the surface of the protrusion 304 facing the axis of the top cover 3 and its side surface is ( θ It can be any angle between 0° and 90°, such as Figure 19 As shown. More preferably, θ It can be 30°~45°, specifically, θ The angles 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 When the angle is less than 30°, the effect of the protrusion 304 in improving the tightness of the fit between the top cap 3 and the bottle mouth 10 may be significantly weakened; when θ When the angle 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 is preferable to... θ Any angle between 30° and 45°; more preferably, θ The angle can be 30°, so that the protrusion 304 can provide a good fit between the top cap 3 and the bottle mouth 10, without adversely hindering the capping process.

[0089] Furthermore, when the protrusion 304 is trapezoidal in shape, it is even more preferable that the lower chamfer of the surface of the protrusion 304 facing the axis of the top cover 3 and its side surface ( α () can be any angle between 0° and 90°, since the pressure during the capping process is mainly determined by θ The magnitude of the influence, therefore, when α and θ When the values ​​are the same, the protrusion 304 can have a stable axisymmetric structure, which is not easily deformed or damaged during the capping process or storage. Therefore, this application is further preferred. α30°, to improve the efficiency and deformation resistance of the protrusion 304, and more preferably, the protrusion 304 has a height of 5-10 mm, and a width of 2-5 mm. θ , α 30°, so that the top cover 3 will not be structurally damaged due to excessive force during capping, and the top cover 3 can be highly tightly attached to the double-chamber carton bottle 1, which also improves the efficiency and accuracy of capping the double-chamber carton bottle 1.

[0090] 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 combined with a sheath to further form an injection double-chamber carton bottle packaging material assembly, which includes an injection double-chamber carton bottle packaging material and a sheath 4 used in combination 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.

[0091] Specifically, the sheath 4 of the present application is an open-top octagonal prism, and its structure is shown in Figure 12 After the double-chamber carton bottle 1 completes the freeze-drying process and is sealed by the top cover 3, the double-chamber carton bottle 1 can be pressed into the sheath to provide effective storage protection. In this process, the lower end 32 of the top cover 3 can be attached to 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, so that the sheath can stably protect the entire packaging material.

[0092] In the present application, the lower end 32 is cylindrical or octagonal, and can preferably be octagonal, and is fixedly assembled with the sheath 4 used to store the double-chamber carton bottle 1 by interference fit; specifically, the lower end 32 near the upper outer edge of the middle end 31 has a first notch 321, the top end of the sheath 4 is stretched and limited on the first notch 321, and the top cover 3 and the sheath 4 are forced towards each other and clamped in the middle. By this interference fit of the lower end 32 and the sheath 4, when the double-chamber carton bottle 1 is placed in the sheath 4, the top cover 3 and the top plug 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, to ensure the high-quality storage of the somatotropin freeze-dried preparation.

[0093] Specifically, in some embodiments, the lyophilized preparation of long-acting growth hormone is reconstituted in water in the double-chambered vial 1 and administered by injection through a needle, such as a microfine needle (MFN), the hub of which has 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-chambered vial 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-chambered vial packaging assembly can be kept from rotating during screwing / dismounting of the injection needle, so as to avoid idle rotation during screwing / dismounting of the sterile injection needle and improve the use efficiency of the lyophilized preparation of long-acting growth hormone.

[0094] The present application also provides another lyophilization method of long-acting growth hormone, which is used in cooperation with a double-chambered vial 1' having a longer neck and a corresponding stopper 2' and cap 3'. Specifically, the lyophilization method comprises: adding a stopper to the double-chambered vial 1', and then pouring the long-acting growth hormone to be lyophilized into the double-chambered vial 1'; assembling the stopper 2' and the cap 3', and placing them above the mouth 10' of the double-chambered vial 1'; placing and fixing the double-chambered vial 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-chambered vial 1' together using the cap 3' to seal the double-chambered vial 1' and fix the stopper 2', and make the stopper 2' seal the mouth 10' of the double-chambered vial 1'.

[0095] In the lyophilization method, the stopper added to the double-chambered vial 1' and the long-acting growth hormone to be lyophilized can also be any size of stopper for double-chambered vial and lyophilizable long-acting growth hormone with a suitable content that are suitable for the size and structure of the double-chambered vial 1'. The freezing, primary drying, and secondary drying operations can be performed in a lyophilization machine that can accommodate the lyophilization support used in the lyophilization method. During the process of fixing the stopper 2' using the cap 3' and sealing the mouth 10' of the double-chambered vial 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.

[0096] In the present application, the long-acting growth hormone to be lyophilized can be poured into the double-chambered vial 1' after adding a stopper to the double-chambered vial 1'. Specifically, the long-acting growth hormone to be lyophilized can be long-acting growth hormone that is added to the inner chamber 13' of the double-chambered vial 1' for lyophilization and short-term / long-term storage. Users can select any long-acting growth hormone solution to be lyophilized and pour it into one of the inner chambers 13' of the double-chambered vial 1' to lyophilize using the lyophilization method of the present application.

[0097] In the present application, the freeze-drying support is a stand-alone freeze-drying support or a tray freeze-drying support. The present application sets the type of freeze-drying support used in the freeze-drying method as a stand-alone freeze-drying support or a tray freeze-drying support. The person skilled in the art can select and adjust the specific model, size and working parameters of the freeze-drying support in the freeze-drying machine according to the actual application. The present application only gives a preferred freeze-drying method for recombinant growth hormone. Preferably, the freeze-drying support is a tray freeze-drying support, which is easy to place a larger number of double-chamber ampoules 1'.

[0098] In particular, the double-chamber ampoule 1' is placed in the freeze-drying support in an upright or inverted manner. Preferably, the double-chamber ampoule 1' is placed in the freeze-drying support in an upright manner, which is conducive to the uniform distribution of heat in the double-chamber ampoule 1', improves the solvent, such as water sublimation efficiency, and in addition, can reduce the degree of sedimentation and aggregation of the recombinant growth hormone, and keep the appearance of the recombinant growth hormone uniform and stable.

[0099] In the present application, the temperature range for freezing the long-acting growth hormone in the double-cavity carton bottle 1' can be a temperature range suitable for freeze-drying the long-acting growth hormone, and the freezing temperature is generally -60°C to -40°C, and the growth hormone to be freeze-dried has a high freezing efficiency and maintains its own quality, so the freezing temperature is any temperature value in the range of -60°C to -40°C. Specifically, the temperature range for freezing the long-acting growth hormone 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.

[0100] 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°C to 0°C and 15°C to 40°C, 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 0.02 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.

[0101] In the present application, the use of the top cover 3' to press the top plug 2' and the double-cavity carton bottle 1' into a fit also includes: before pressing the top plug 2', the double-cavity carton bottle 1' is subjected to a nitrogen filling 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 a nitrogen filling 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, and on the other hand, the 1 standard atmosphere nitrogen can also make the position of the plug in the double-cavity carton bottle fixed.

[0102] In the present application, it also includes a Lonapeen freeze-dried preparation 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 implemented in the freeze-drying process of the Lonapeen in the freeze-drying method of the present application are changed, such as the temperature and pressure of the first drying, after pouring the same kind of Lonapeen to be freeze-dried, different quality or different properties of Lonapeen freeze-dried preparations can also be produced by the other freeze-drying method, such as obtaining different water content, different solid form of Lonapeen freeze-dried preparations, etc.

[0103] 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 which can be filled into the double-cavity carton bottle 1' of the present application and which 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.

[0104] 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.

[0105] 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 Figure 13 It should be noted that the double-cavity carton bottle package material for injection can include 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.

[0106] 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 include the following steps: 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.

[0107] In the present application, the double-cavity carton 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 carton 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 carton bottle 1', changing the radial length of one or more parts of the double-cavity carton bottle 1', etc., all of which do not deviate from the protection scope of the present application.

[0108] 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.

[0109] In the present application, the top cover 3' comprises an upper end 30' and a bottom disc 31' as shown in Figure 14A ; 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 carton 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.

[0110] 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 top cover 3' in the lyophilization process, etc. The shape of the bottom disc 31' can be set as a cylinder or a multi-prism, as shown in Figure 14B , to avoid the top cover 3' slipping off or relative sliding with the double-cavity carton bottle 1' under the action of rotational centrifugal force, which affects the sealing performance.

[0111] Specifically, the center of the top plate 300' also has a top plate opening, and the perimeter of the top plate opening from its lower edge to its upper edge may have an angle of inclination in the vertical direction. β’ The circumferential upper edge of the top plate opening has a larger opening length than the circumferential lower edge; the circumferential edge surface of the top plate opening can be a curved surface or a plane.

[0112] In this application, the top plug 2' may further include: a sealing portion 22' protruding above the plug cap 20', such as... Figure 15 As shown, the sealing portion 22' can be inserted into the opening of the top plate. When the top stopper 2' is fully embedded in the bottle mouth 10', that is, when the double-chamber cartridge bottle 1' is stopped, its sealing portion 22' is embedded in the opening of the top plate and partially protrudes longitudinally from the opening of the top plate. Those skilled in the art will understand that the size of the sealing portion 22' can be slightly larger than the opening size of the lower periphery of the top plate opening. During the process of pre-assembling the top stopper 2' into the top cap 3', the top stopper 2' needs to be fixed by the upper end 30', and the surface of the sealing portion 22' can undergo slight deformation to insert into and embed itself in the opening of the top plate from the lower periphery of the top plate opening.

[0113] Therefore, during the pre-assembly of the top plug 2' into the top cover 3', the sealing portion 22' can be embedded into the top plate opening, with its edge portion tightly fitting the circumferential outer edge of the top plate opening, and ultimately partially protruding from the upper edge of the top plate opening. Alternatively, the radial length of the sealing portion 22' can be adjusted. L’ This allows for a longer radial length, improving the tightness of the fit between its edge portion and the circumferential outer edge of the top plate opening, further preventing the top plug 2' from slipping out of the top plate 300'. Additionally, adjustments can be made... β’ The size of the top plate opening and the circumferential lower edge of the top plate opening and the sealing part 22' have a tighter fit relative to the circumferential upper edge of the top plate opening, so that the top plate opening tightly surrounds the fixed sealing part 22'.

[0114] In some implementations, the radial length of the sealing portion 22' L’ It can be 2.0 mm - 5.0 mm, specifically, the radial length of the sealing portion 22'. L’ The diameter 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 of the sealing portion 22' is... L’may be 3.0 mm - 4.0 mm, in particular, the radial length of the sealing portion 22' L’ may be preferably 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’ may be 0°, 1°, 2°, 3°, 4°, 5°, 6°, 7°, 8°, 9° or 10°, etc.

[0115] 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 be preferably 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.

[0116] by making the radial length of the sealing portion 22' L’ slightly larger than the circumferential lower edge opening length of the top disc opening, the sealing portion 22' is more closely fitted with the circumferential lower edge of the top disc opening, and the top disc opening is effective in fitting and fixing 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, the radial length of the sealing portion 22' β’ is 0°, when the top disc opening has no inclination angle in the vertical direction, it can provide good fixation for the sealing portion 22', 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 at a certain size of inclination angle in the vertical direction to improve the limiting effect of the top disc 300' on the top plug 2, the inclination angle β’The radial length of the sealing portion 22' is 5°, so as to improve the fixing degree of the sealing portion 22' without affecting the insertion and embedding of the sealing portion 22' into the opening of the top disc. The radial length of the sealing portion 22' can be adjusted according to the actual operation of the bottle cap assembly in the growth hormone lyophilization process, based on the above parameter benchmark L’ , the inclination angle β’ , and the circumferential lower edge opening length of the opening of the top disc, so as to adjust the fixing degree of the sealing portion 22' and the top disc 300'.

[0117] 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'. Due to the cooperation between the top plug positioning point 303' and the 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 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 cap 20' and the inner wall of the upper end 30', as shown in Figure 17 . 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 upward into the opening of the top disc due to pressure.

[0118] In some embodiments, the diameter of the plug cap 20’ can range from 5.0 mm - 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 - 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.

[0119] In some embodiments, the diameter of the upper end 30' of the top cover 3' can range from 5.0 mm - 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 - 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.

[0120] 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 the 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 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', 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 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, 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 of the double-cavity cartridge bottle 1', and / or the cooperation with the syringe for use. For example, the stability of the pre-assembly of the top plug 2' can be adjusted by appropriately adjusting the diameter of the plug cap 20'; the more tightly sealed or more easily removed seal of the double-cavity cartridge 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 pressure on 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.

[0121] 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 are applied to the top cover 3', such as shaking, hanging, etc., 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 avoiding the core taking when the plug cap 20' is used with the injection needle, thereby ensuring the efficient use of the lyophilized somatropin preparation.

[0122] In the present application, the upper end 30' of the top cover 3' also has a top plug positioning point 303', as shown in Figure 16A , Figure 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 annularly spaced, and the shape of the top plug positioning point 303' can be cylindrical or prismatic, and in addition, the number and the spacing length / arc of the plurality of top plug positioning points 303' can be adjusted to maintain the optimal fixation of the top plug 2'.

[0123] In this application, the number of top stopper positioning points 303' is four or five or more. Specifically, the number of top stopper positioning points 303' can be even to maintain their symmetrical arrangement along the center of the upper end 30', providing a more stable fixing function for the top stopper 2'. Preferably, the number of top stopper positioning points 303' is four or eight to provide a relatively stable fixing function for the top stopper 2'; more preferably, the number of top stopper positioning points 303' is eight to provide the most stable fixing function for the top stopper 2'. The top stopper positioning points 303' can also be used for positioning the top stopper 2' before it is pressed into the bottle neck 10', limiting the top stopper 2' and preventing it from sliding off the bottle neck 10' on its own.

[0124] In this application, the upper end 30' of the top cap 3' is further provided with a protrusion 304' protruding in the direction of the axis of the top cap 3' on its inner wall. The top cap 3' can be limited on the bottle mouth 10' by the protrusion 304' before capping, so that the sublimated water in the inner cavity 13' can be discharged through the opening 302'. Therefore, the provision of the protrusion 304' helps to provide gas exchange and water discharge for the dual-chamber cartridge bottle 1'. Those skilled in the art will understand that the protrusion 304' will not hinder the movement of the top stopper 2' during the process of the top stopper 2' being inserted into the bottle mouth 10'. Since the protrusion 304' is evenly distributed on the inner wall of the upper end 30', and the top plate 300' can evenly apply pressure to the entire surface of the cap 20' pre-assembled into the upper end 30' when the top plate is capped, the top stopper 2' can be stably and horizontally inserted into the bottle mouth 10'.

[0125] In this application, the number of protrusions 304' is two or three or more; preferably, the maximum length of the protrusions 304' protruding in the direction of the axis of the top cover 3' is ( D’ ) can be 0.10 mm, 0.11 mm, 0.12 mm, 0.13 mm, 0.14 mm, 0.15mm, 0.16 mm, 0.17 mm, 0.18 mm, 0.19 mm, 0.20 mm, 0.21 mm, 0.22 mm, 0.23 mm, 0.24 mm, 0.25 mm, 0.26 mm, 0.27 mm, 0.28 mm, 0.29 mm or 0.30 mm. Specifically, D’ It can be 0.15 mm to 0.30 mm; more preferably, D’ The thickness can be 0.20 mm to 0.28 mm, which prevents the top cover from deforming due to excessive pressure during sealing, and ensures good sealing performance and prevents slippage after sealing; more preferably, D’0.23 mm~0.28mm, which can avoid deformation of the top cover 3' caused by pressure during capping, and the top cover 3' has good sealing performance after capping and is not easy to slip off. It should be noted that when the material of the protruding part 304' is different, D’ The value of the protruding part 304' can be adjusted to achieve optimal limiting of the top cover 3' before capping and 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’ 0.23 mm, 0.25 mm or 0.28 mm, so that the protruding part 304' can provide the most stable fixation for the top cover 3'.

[0126] In the present application, the shape of the protruding part 304' can be trapezoidal, semicircular, semi-elliptical or rectangular, preferably the shape of the protruding part 304' is trapezoidal. When the shape of the protruding part 304' is trapezoidal, 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.

[0127] When the shape of the protruding part 304' is trapezoidal, the face of the protruding part 304' towards the axis direction of the top cover 3' and the upper cutting angle of its side face θ' can be any angle between 0°~90°, as shown in Figure 18 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 protruding part 304' may have a significant weakening effect on improving the fit tightness of the top cover 3' and the bottle mouth 10'; when θ' is greater than 45°, the protruding part 304' may have a significant hindering effect on 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 between 30°~45°; more preferably, θ' can be 30°, so that the protruding part 304' can provide better fit effect of the top cover 3' and the bottle mouth 10' and not adversely hinder the capping process.

[0128] In addition, when the shape of the protruding part 304' is trapezoidal, it is further preferred that the face of the protruding part 304' towards the axis direction of the top cover 3' and the lower cutting angle of its side face α’ can also be any angle between 0°-90°. Since the size of the pressure during the capping process is mainly affected by the size of the protruding part 304', when θ' is greater than 45°, the protruding part 304' may have a significant hindering effect on the capping process, causing the top cover 3' to deform or even be damaged during the capping process. Therefore, it can be preferred that α’With θ' The convex portion 304' can have the most stable axisymmetric structure when having the same value, and is not prone to deformation or damage during capping or storage. Therefore, the present application further preferably has α’ It can be 30° to improve the use efficiency and deformation resistance of the convex portion 304'. More preferably, the convex portion 304' has an angle of 30° with the horizontal plane, which can improve the capping efficiency and precision of the double-chamber carton bottle 1' in the process of recombinant human growth hormone lyophilization. θ' , α’ Both are 30°, which will not cause structural damage to the top cover 3' during the capping process of the top cover 3', while also maintaining the close fit of the top cover 3' and the double-chamber carton bottle 1', and can improve the capping efficiency and precision of the double-chamber carton bottle 1' in the process of recombinant human growth hormone lyophilization.

[0129] The present application also proposes another injection double-chamber carton bottle packaging material, which includes the above-mentioned another bottle cap assembly and double-chamber carton bottle 1', and proposes another injection double-chamber carton bottle packaging material assembly, which includes the above-mentioned another injection double-chamber carton bottle packaging material and the sheath 4' used therewith, as shown in Figure 19 It is 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' formed and / or maintained by any combination proposed in the present application.

[0130] The bottom disc 31' has a first notch 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 on the first notch 321' of the bottom disc 31', the top cover 3' and the sheath 4' achieve interference fit, and the top plug 2' and the double-chamber carton bottle 1' are clamped in the middle by the opposite force. 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 double-chamber carton bottle packaging material is placed in the sheath 4', the top cover 3' and the top plug 2' therein are more tightly fixed with the bottle mouth 10', effectively avoiding air leakage, rotation, falling off, etc.

[0131] In the present application, the bottom disc 31' is in the shape of a cylinder or an octagonal prism, and the sheath 4' includes a sheath body 40' and a flange 41'. When the top cover 3' and the sheath 4' are interference fit, the top cover 3' and the double-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 double-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 cover 3', the top cover 3' is driven to rotate together with the double-chamber carton bottle 1' due to the force. 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', and when a lyophilized preparation is used, the injection needle needs to be screwed / detached, the top cover 3' may drive the entire double-chamber carton bottle 1' to rotate together, thereby making the injection needle idle and unable to be fixed / unfixed with / from the top cover 3'.

[0132] Therefore, the shape of the bottom disc 31' of the bottle cap assembly configured with the packaging assembly is an octagonal prism, and the shape of the sheath body 40' is 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 Figure 19 Thus, the bypass protrusion 120' of the double-chamber carton bottle 1' of the packaging assembly can be limited to the octagonal vertex of the inner wall of the sheath 4' (B'-B'), and the bottle body 12' will generate a large friction force with the inner wall of the bottom disc 31' during the capping process; when the top cap 3' is subjected to external force from, for example, a syringe needle, the bottom disc 31' and the inner wall of the sheath 4' are in interference fit and fixed to each other (A'-A'), so that the top cap 3' will not slip or slide relative to the double-chamber carton bottle 1', further stabilizing the whole packaging assembly and avoiding the impact on the airtightness of the double-chamber carton bottle 1' and improving the use efficiency.

[0133] 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 notch 400', which is pressed and buckled on the flange 41' to make the sheath body 40' and the flange 41' in interference fit 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 assembly.

[0134] Specifically, in some embodiments, the other kind of lyophilized somatropin preparation described above is reconstituted in the double-chamber carton bottle 1' and injected into children through a syringe needle, and the needle seat of the syringe needle has a threaded structure. When the syringe needle is installed on the top cap 3' for somatropin injection or removed from the top cap 3', the threaded structure of the needle seat is engaged or removed from the threads 301' of the top cap 3' by rotation. In this process, the bottom disc 31' of the top cap 3' is fixed by the octagonal inner wall of the sheath 4' to prevent rotation, and the bypass protrusion 120' of the double-chamber carton bottle 1' is also fixed by the vertex of the inner wall of the sheath 4' to prevent rotation. Therefore, by selecting the octagonal shape of the bottom disc 31' and cooperating with the sheath 4', the double-chamber carton bottle packaging assembly can be prevented from being affected by the rotation of the syringe needle during screwing / removal of the syringe needle, so as to avoid idling during screwing / removal of the sterile syringe needle and improve the use efficiency of the double-chamber carton bottle packaging assembly.

[0135] The two kinds of lyophilized somatropin preparations provided by the present application as described above are any one of the lyophilized somatropin preparations prepared according to any one of the lyophilization methods provided by the present application or any one of the two kinds of lyophilized somatropin preparations provided by the present application. It can be understood that these lyophilized somatropin preparations can all be used in the field of growth hormone. The various lyophilized somatropin preparations 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.

[0136] Examples The materials used in the experiments and the experimental methods are generally and / or specifically described in this application. The reagents or instruments not specified by the manufacturer are all conventional reagent products that can be obtained commercially.

[0137] Example 1 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 as shown in the figure. 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 sealed through the top plug. Specifically, Figure 6A First, the top plug 2 is positioned inside the top cap 3 through 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. 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 through 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 in the center, a thread 301 and an opening 302 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 below the middle end 31. The lower end 32 is open; 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. 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 wall of the middle end 31 and the lower end 32 is fitted with the bottle body 12.

[0138] The top disc 300 is a hollow cylindrical structure with a shortened middle part. During the process of pressing the top cap 3 downward by external force, the top plug 2 is pressed into the bottle opening 10 through the lower surface of the top disc 300, so that the top plug 2 is further embedded into the bottle opening 10 until the plug column 21 with a diameter slightly larger than the inner diameter of the bottle opening is completely embedded into the bottle opening 10 under the action of pressure, and the lower surface of the plug cap 20 is completely fitted with the upper surface of the bottle opening 10, so as to seal the double-cavity carton bottle 1 by using the top plug 2. No additional plug pressing device is needed to participate in the sealing, which reduces the additional process and time required for sealing the double-cavity carton bottle 1, and also avoids the influence of inaccurate sealing on the production efficiency of the freeze-drying process.

[0139] In particular, when the top cap 3 is arranged to press the top plug 2 to be completely embedded in the bottle opening 10, the upper surface inner wall of the middle end 31 can also be completely fitted with the upper surface of the bottle body 12; therefore, while the top cap 3 seals the bottle opening 100 by using the top plug 2, the top cap 3 also seals the top plug 2 embedded in the bottle opening, and seals the bottle opening 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.

[0140]

[0141] ​The diameter of the upper end 30 is 7.3 mm, leaving a gap 200 between the upper end 30 and the plug cap 20 with a diameter of 7.0 mm; the upper end 30 also has a stopper positioning point 303, as shown in Figure 6A As shown in Figure 5 The stopper positioning point 303 is located below the top disc 300 and protrudes from the inner wall of the upper end 30 towards the axis of the cap 3. After the stopper 2 is fully inserted into the bottle mouth 10, the stopper positioning point 303 is in contact with the plug cap 20, and the plug cap 20 is pressed by the stopper positioning point 303 towards the axis of the cap 3, thereby increasing the friction between the plug cap 20 and the inner wall of the upper end 30, preventing the stopper 2 from loosening or slipping out of the cap 3 during the pre-assembly process due to loose fitting. The number of stopper positioning points 303 is four, evenly distributed on the inner wall of the upper end 30.

[0142] The upper end 30 also has a protrusion 304, as shown in FIG. 6, which is arranged below the stopper positioning point 303 and protrudes from the inner wall of the upper end 30 towards the axis of the cap 3. After the stopper 2 is fully inserted into the bottle mouth 10, the protrusion 304 is in contact with the outer wall of the bottle mouth 10, and the bottle mouth 10 is pressed by the protrusion 304 towards the axis of the cap 3, thereby increasing the friction between the bottle mouth 10 and the inner wall of the upper end 30, preventing the cap 3 from slipping off after sealing due to loose fitting, and improving the sealing performance of the double-chamber card-type bottle 1. The maximum length of the protrusion 304 protruding from the inner wall of the upper end 30 is set to 0.23 mm, and the shape of the protrusion 304 is set to trapezoidal with a number of two, distributed on both sides of the inner wall of the upper end 30, and the upper cutting angle is 30°.

[0143] 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 fitting degree of the cap 3 and the bottle body 22 after the cap 3 is fitted with the double-chamber card-type bottle 1, further improving the stability of the fitting of the cap 3 and the double-chamber card-type bottle 1.

[0144] The bottle cap assembly was subjected to pressure plug and pressure cap sealing test, and it was found that the fitting degree of the stopper 2 and the cap 3 was high, and the stopper 2 did not slip out of the cap 3; a certain pressure was required during the pressure cap process, but it did not cause deformation and damage to part of the structure of the cap 3; the fitting degree of the cap 3 and the bottle mouth 10 of the double-chamber card-type bottle 1 was significantly improved and was not pulled out after a larger force was applied.

[0145] Example 2 The maximum length of the protruding portion 304 protruding from the inner wall of the upper end 30 is replaced by 0.25 mm, and other structures and parameters are the same as in Example 1. The bottle cap assembly is subjected to compression plug and capping sealing test, and it is found that the fit of the top plug 2 and the top cap 3 is high, and the top plug 2 does not slip off from the top cap 3. After replacing the maximum length of the protruding portion 304 protruding from the inner wall of the upper end 30 by 0.25 mm, a certain pressure needs to be applied during the capping 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 bottle mouth 10 of the double-cavity carton bottle 1 is also significantly improved, and it is not pulled out after a larger force is applied.

[0146] Example 3 The maximum length of the protruding portion 304 protruding from the inner wall of the upper end 30 is replaced by 0.28 mm, and other structures and parameters are the same as in Example 1. The bottle cap assembly is subjected to compression plug and capping sealing test, and it is found that the fit of the top plug 2 and the top cap 3 is high, and the top plug 2 does not slip off from the top cap 3. After replacing the maximum length of the protruding portion 304 protruding from the inner wall of the upper end 30 by 0.28 mm, a certain pressure needs to be applied during the capping 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 bottle mouth 10 of the double-cavity carton bottle 1 is also significantly improved, and it is not pulled out after a larger force is applied.

[0147] Example 4 The injection double-cavity carton bottle packaging material is used for the lyophilization process of Lonapegsomatropin, and the lyophilized Lonapegsomatropin preparation is obtained. The injection double-cavity carton packaging material in Example 1-Example 3 is selected for 20 parts, and the steps of the lyophilization process and the lyophilized preparation are as follows: (1) Add a plug to each double-cavity carton bottle 1, and then fill the Lonapegsomatropin to be lyophilized. The Lonapegsomatropin includes two types, wherein the first type of Lonapegsomatropin contains: 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 contains: 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. The double-cavity carton bottle 1 is placed and fixed on a lyophilization support, wherein the lyophilization support is selected as a tray type lyophilization support, as shown in FIG. 1, and the double-cavity carton bottle 1 is placed in the lyophilization support in an upright manner. Figure 1

[0148] ​(2) The top plug 2 and the top cover 3 in Examples 1-3 are pre-assembled and combined, and placed at the bottle mouth 10 of the double-cavity 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; the bottle mouth 10 is aligned with the opening of the lower end 32, and the top plug 2 is naturally placed at the bottle mouth 10 as a whole.

[0149] (3) The freeze-drying process of the prepared long-acting growth hormone is carried out by freezing, primary drying, secondary drying and lamination of the freeze-dried plug and cover, and the specific operation process is shown in Table 1: Table 1 Freeze-drying process and parameter setting of the prepared long-acting growth hormone

[0150] Atm is 1 standard atmosphere. In the freeze-drying process, the freeze-drying curve of the prepared long-acting growth hormone is shown in Figure 2 The injection double-cavity carton bottle package material after unloading from the box has a low water content and a good appearance of the prepared long-acting growth hormone freeze-dried preparation.

[0151] (4) After the freeze-drying process is completed, nitrogen is filled into the double-cavity carton bottle 1 to maintain the low water content of the freeze-dried preparation, and then the plug and cover are pressed and sealed synchronously. Specifically, After the freeze-drying is completed, the top cover 3 is pressed downward to press the top plug 2 to fit into the bottle mouth 10 of the double-cavity carton bottle 1, and at the same time, the top cover 3 is pressed downward until the upper end 30 is completely fitted on the bottle mouth 10, and in this process, the inner wall of the upper end 30 is in contact with the bottle mouth 10, and the inner walls of the middle end 31 and the lower end 32 are in contact with the bottle body 12, until the plug column 21 is completely fitted into the bottle mouth 10, and the lower surface of the plug cap 20 is completely in contact with the upper surface of the bottle mouth 10, so as to realize the sealing of the double-cavity carton bottle 1 by the top plug 2, without the need to introduce additional plug pressing components.

[0152] (5) The double-cavity carton bottle 1 is taken out of the freeze-drying machine, and the final long-acting growth hormone freeze-dried preparation is obtained.

[0153] The appearance and moisture of the long-acting growth hormone freeze-dried preparation prepared in the double-cavity carton bottle 1 by the above freeze-drying method are detected, and the detection results are shown in Table 2: Table 2 Appearance and moisture detection results of the freeze-dried preparation

[0154] As shown in Table 2, the appearance detection results of the long-acting growth hormone freeze-dried preparation show that the appearance is good, and the average moisture detection results of 6 times are low, and the freeze-drying effect is good.

[0155] In addition, the freeze-drying machine plate lamination cover operation (without adding freeze-drying samples) was carried out on the three double-chamber injection vial packaging materials in Examples 1-3, and the CCIT (vacuum decay method) test was carried out on the packaging materials after lamination. The results showed that the sealing properties of the three packaging materials were good.

[0156] In summary, using the packaging materials in Examples 1-3 to complete the above freeze-drying process can meet the requirements of the freeze-drying process and sealing of Longpe growth hormone. The Longpe growth hormone freeze-dried preparation obtained by the above freeze-drying method can meet the appearance and moisture requirements.

[0157] Example 5 The structure of the top cover 3 of the bottle cap assembly in Example 1 was adjusted to reduce the volume of the top cover 3, as shown in Figure 6B Specifically, the length of the top cover 3 extending along the neck 11 and the bottle body 12 in Example 2 was shortened, the length of the middle end 31 was shortened, the position of the convex ring 310 relative to the neck 11 and the bottle body 12 was further moved upward, and the lower part of the upper end 30 was attached. In addition, the convex strip 320 of the lower end 32 was removed, and the non-convex strip part of the lower end 32 was extended downward along the bottle body 12, the lower end 32 was shortened radially near the upper part of the middle end 31, and the first convex notch 321 was formed.

[0158] 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 a part of the bottle body 12 of the double-chamber carton bottle 1, and the structure of the adjusted top cover 3 is the same as that of the top cover 3 in Example 10 except for the middle end 31 and the lower end 32. The number of top plug positioning points 303 is 8, which are evenly distributed on the inner wall of the upper end 30.

[0159] The bottle cap assembly was tested for plug pressing and lamination sealing, and it was found that the top plug 2 had a high degree of fit with the top cover 3, and the top plug 2 did not slip out of the top cover 3; a large pressure was required during the lamination process, but no deformation or damage to part of the structure of the top cover 3 occurred; the fit of the top cover 3 with the bottle mouth 10 of the double-chamber carton bottle 1 was significantly improved, and it was not pulled out after a large force was applied.

[0160] Example 6 The maximum length of the convex 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 in Example 5. The bottle cap assembly was tested for plug pressing and lamination sealing, and it was found that the top plug 2 had a high degree of fit with the top cover 3, and the top plug 2 did not slip out of the top cover 3; a large pressure was required during the lamination process, but no deformation or damage to part of the structure of the top cover 3 occurred; the fit of the top cover 3 with the bottle mouth 10 of the double-chamber carton bottle 1 was significantly improved, and it was not pulled out after a large force was applied.

[0161] Example 7 The maximum length of the protrusion 304 protruding from the inner wall of the upper end 30 is replaced by 0.28 mm, and other structures and parameters are the same as those of Example 5. The compression plug and capping sealing test is performed on the bottle cap assembly, and it is found that the fit degree of the plug 2 and the cap 3 is high, and the 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; the fit degree of the cap 3 and the bottle mouth 10 of the double-cavity carton bottle 1 is obviously improved, and it is not pulled out after a larger force is applied.

[0162] Example 8 The injection double-cavity carton bottle packaging material is used for the lyophilization process of the long-acting growth hormone, and the lyophilized preparation of the long-acting growth hormone is obtained. The injection double-cavity carton packaging material is selected from the injection double-cavity carton packaging materials in Examples 5-7, each 25 parts, and the steps of the lyophilization process and the lyophilized preparation of the long-acting growth hormone are as follows: (1) Add the plug into each double-cavity 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 to pH 5.0. The double-cavity carton bottle 2 is placed and fixed on the lyophilization support, wherein the lyophilization support is selected from a tray type lyophilization support, as shown in FIG. 1, and the placement mode of the double-cavity carton bottle 1 in the lyophilization support is upright. Figure 1

[0163] (2) After the plug 2 and the cap 3 in Examples 5-8 are pre-assembled and combined, they are placed at the bottle mouth 10 of the double-cavity carton bottle 1. The pre-assembled and combined mode of the plug 2 and the cap 3 is the same as that of Example 4.

[0164] (3) The lyophilization process of the long-acting growth hormone to be lyophilized is carried out, including freezing, primary drying, secondary drying, and plate layer compression plug capping. The specific operation method is the same as that of Example 4.

[0165] (4) After the lyophilization process is completed, the double-cavity 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 is performed. The capping sealing method is the same as that of Example 4.

[0166] (5) The double-cavity carton bottle 4 is taken out from the lyophilization machine, and the final long-acting growth hormone lyophilized preparation is obtained.

[0167] The appearance detection and moisture detection of the long-acting growth hormone lyophilized preparation prepared by the above lyophilization method in the double-cavity carton bottle 4 are carried out, and the detection results are shown in Table 3: Table 3 Appearance detection, moisture detection, and CCIT detection results of the lyophilized preparation

[0168] ​As can be seen from Table 3, the appearance test results of the lyophilized preparations of Longpe growth hormone show good appearance, and the average moisture test results are low. In addition, the injection double-chamber carton bottle packaging material in Examples 5-7 has good sealing performance in the lyophilization process, which can meet the sealing performance requirements of the lyophilized preparations.

[0169] Example 9 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 Figure 13 , which comprises a bottle mouth 10', a bottle neck 11', a bottle body 12' and an inner cavity 13'. The bottle cap assembly comprises a top plug 2' and a top cap 3'. The structure of the top plug 2' is shown in Figure 9 , and the structure of the top cap 3' is shown in Figure 14A . The top cap 3' seals the bottle mouth 10' by using the top plug 2', and simultaneously caps the bottle mouth 10' of the double-chamber carton bottle 1'.

[0170] The top cap 3' comprises an upper end 30' and a bottom disc 31'. The upper end 30' has a central top disc 300', an edge thread 301' and an opening 302' of the lower outer wall. The bottom disc 31' is open at the bottom, and has a cavity inwardly arranged from the opening. After the pre-assembled top plug 2' is fitted into the upper end 30' of the top cap 3', the top cap 3' is pressed downward 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 process of pressing the top cap 3' as a whole, the top disc 300' simultaneously presses the top plug 2', so that the top plug 2' is embedded in the bottle mouth 10'. Therefore, the top cap 3' can also be used for simultaneous sealing and capping without the participation of an additional plug pressing assembly or in multiple steps, which reduces the time required for the sealing process of the double-chamber carton bottle 1' and avoids sealing failure.

[0171] The upper end 30' has eight uniformly distributed top plug positioning points 303', which 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 cap 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', and the cap 20' is pressed by the top plug positioning points 303' toward the axis of the top cap 3'. The frictional resistance between the cap 20' and the inner wall of the upper end 30' is increased, which prevents the top plug 2' from slipping out of or jumping out of the top cap 3', thereby avoiding sealing failure.

[0172] The upper end 30' also has a protrusion 304' arranged below the stopper positioning point 303' and protruding from the inner wall of the upper end 30' towards the axis of the top cover 3'. Before the stopper 2' is embedded in the bottle mouth 10', the protrusion 304' is placed on the bottle mouth to ensure that the sublimated moisture can be discharged from the opening 302'; after the stopper 2' is embedded in the bottle mouth 10', the protrusion 304' is in contact with the outer wall of the bottle mouth 10', so that the bottle mouth 10' is pressed by the protrusion 304' towards the axis of the top cover 3', thereby increasing the friction between the bottle mouth 10' and the inner wall of the upper end 30' to prevent the top cover 3' from slipping off or popping out of the bottle mouth 10'.

[0173] The maximum length of the protrusion 304' protruding from the inner wall of the upper end 30' is 0.23 mm, and the shape of the protrusion 304' is trapezoidal.

[0174] Example 10 A double-chamber carton bottle package for injection includes a double-chamber carton bottle 1' and a bottle cap assembly, and the bottle cap assembly includes a stopper 2' and a top cover 3'. Among them, the maximum length of the protrusion 304' protruding from the inner wall of the upper end 30' is replaced with 0.25 mm, and the other structures and parameters are the same as those of Example 9.

[0175] Example 11 A double-chamber carton bottle package for injection includes a double-chamber carton bottle 1' and a bottle cap assembly, and the bottle cap assembly includes a stopper 2' and a top cover 3'. Among them, the maximum length of the protrusion 304' protruding from the inner wall of the upper end 30' is replaced with 0.28 mm, and the other structures and parameters are the same as those of Example 9.

[0176] Example 12 The double-chamber carton bottle package for injection is used to carry out a lyophilization process of recombinant human growth hormone, and a lyophilized recombinant human growth hormone preparation is obtained. The double-chamber carton bottle package for injection is selected from the double-chamber carton bottle package for injection in Examples 9-11, each 20 parts, and the steps of carrying out a lyophilization process and obtaining a lyophilized recombinant human growth hormone preparation are as follows: (1) Add a stopper to each double-chamber carton bottle 1' of the double-chamber carton bottle package for injection, then fill the recombinant human growth hormone to be lyophilized, and place and fix the double-chamber carton bottle 1' on a lyophilization support. Among them, 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. Figure 1

[0177] ​(2) The top plug 2' and the top cover 3' in Example 9-Example 11 are pre-assembled and combined respectively, and placed at the bottle mouth 10' of the double-cavity carton bottle 1', without capping. Specifically, the top cover 3' is limited to the bottle mouth 10' by the support of the protrusion 303', and 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'.

[0178] 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.

[0179] (3) The to-be-frozen somatropin is frozen, primary dried, secondary dried and plate laminated and capped respectively, and the specific operation process is shown in Table 1: Table 4 Freezing process and parameter setting of to-be-frozen drug solution

[0180] Wherein, Atm refers to 1 standard atmosphere.

[0181] (4) After the freezing process is completed, nitrogen filling operation is performed on the double-cavity carton bottle 1' to maintain the low moisture content of the somatropin freeze-dried preparation, and then the cap is sealed. Specifically, After the freeze-drying is completed, the top cover 3' is pushed downward to press the top plug 2' so that the top plug 2' is embedded into the bottle mouth 10' of the double-cavity carton bottle 1'. At the same time when the top plug 2' is embedded into the bottle mouth 10', the top cover 3' is pressed downward 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 in contact with 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 in contact with the upper surface of the bottle mouth 10', and the lower surface of the bottom disc 31' is in contact with the connection between the bottle neck 11' and the bottle body 12'. In this way, the sealing of the double-cavity carton bottle 1' by the top plug 2' is achieved, and no additional plug pressing assembly needs to be introduced.

[0182] (5) The double-cavity carton bottle 1' and the freeze-drying support are taken out of the freeze-drying machine.

[0183] The somatropin freeze-dried preparation prepared in the double-cavity carton bottle 1' by the above-mentioned freeze-drying method is sampled, appearance detected, moisture detected and CCIT (vacuum decay method) detected, and the detection results are shown in Table 2: Table 5 Appearance detection, moisture detection and CCIT detection results of freeze-dried preparation

[0184] Figure 4is the appearance chart of the lyophilized preparation of Long-acting Growth Hormone obtained by the lyophilization process. The appearance of the lyophilized preparation of Long-acting Growth Hormone is good, and the average moisture content is low, as shown in Table 5 and Figure 4 The appearance test results of the lyophilized preparation of Long-acting Growth Hormone show that the appearance is good, and the average moisture content is low. In addition, the sealing performance of the dual-chamber carton bottle package material in Examples 9-11 is good in the lyophilization process, which can meet the sealing requirements of the lyophilized preparation.

[0185] Example 13 A dual-chamber carton bottle package material for injection includes 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 in Example 9. The bottle cap assembly includes a top plug 2' and a top cap 3'. The structure of the top plug 2' is the same as that of the top plug 2' in Example 9, and the structure of the top cap 3' is as shown in Figure 14B The bottom disc 31' is adjusted to extend downward to additionally fit at least a portion of the bottle body 12'. The shape of the downwardly extending portion of the bottom disc 31' is set as an octagonal prism. In addition, the maximum length of the protrusion 304' protruding from the inner wall of the upper end 30' is set as 0.25 mm. The other structures and parameters are the same as those in Example 9.

[0186] Example 14 The lyophilization process of Long-acting Growth Hormone is carried out by using the dual-chamber carton bottle package material for injection, and the lyophilized preparation of Long-acting Growth Hormone is obtained. The dual-chamber carton bottle package material for injection is selected as 25 parts of the dual-chamber carton bottle package material for injection in Example 13. The steps of the lyophilization process and the obtaining of the lyophilized preparation of Long-acting Growth Hormone are as follows: (1) Add a center plug into each dual-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.

[0187] Place and fix the dual-chamber carton bottle 1' on the lyophilization support. 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.

[0188] (2) After the pre-assembled combination of the top plug 2' and the top cap 3' in Example 13, place it at the bottle mouth 10' of the dual-chamber carton bottle 1'. The pre-assembled combination mode of the top plug 2' and the top cap 3' is the same as that in Example 12.

[0189] (3) Freeze, primary dry, secondary dry, and plate layering and plug capping of the Long-acting Growth Hormone to be lyophilized are carried out respectively. The specific operation method is the same as that in Example 12.

[0190] (4) After the freeze-drying process, nitrogen was filled into the dual-chamber carton bottle 1' to maintain the low moisture content of the somatropin freeze-dried preparation, and then the bottle was sealed by capping. The capping method was the same as that of Example 12.

[0191] (5) The dual-chamber carton bottle 1' was taken out of the freeze-dryer to obtain the somatropin freeze-dried preparation therein.

[0192] The somatropin freeze-dried preparation prepared in the dual-chamber carton bottle 1' via the above freeze-drying method was sampled, appearance tested, moisture tested, and CCIT tested, and the test results are shown in Table 3: Table 6 Appearance test, moisture test, and CCIT test results of freeze-dried preparations

[0193] As shown in Table 6, the appearance test result of the somatropin freeze-dried preparation showed that the appearance was good, and the average moisture test result was low. In addition, the injection dual-chamber carton bottle packaging material in Example 13 had good sealing performance in the freeze-drying process, and could meet the sealing requirements of multiple preparations.

Claims

1. A freeze-drying method for cyclophosphamide growth hormone, comprising: Add the middle stopper to the double-chamber cartridge, and then fill it with the lyophilized cyclophosphamide growth hormone. After assembling the top stopper and top cap, place them above the mouth of the dual-chamber cartridge bottle, and then place and fix the dual-chamber cartridge bottle on the customized freeze-drying bracket. The lyophilized growth hormone was subjected to freezing, primary drying, and secondary drying processes, respectively. The top cap is used to press the top stopper into the dual-chamber cartridge bottle to seal the dual-chamber cartridge bottle and fix the top stopper, so that the top stopper seals the bottle opening of the dual-chamber cartridge bottle.

2. The freeze-drying method according to claim 1, wherein, The freeze-drying support is either a freestanding freeze-drying support or a tray-type freeze-drying support; preferably, the freeze-drying support is a tray-type freeze-drying support; and The dual-chamber cartridge bottle is placed upright or upside down in the freeze-drying support. Preferably, the dual-chamber cartridge bottle is placed upright in the freeze-drying support.

3. The freeze-drying method according to claim 1, wherein, The temperature range set for freezing the cyclophosphamide growth hormone in the dual-chamber cartridge is -60℃ to -40℃. The temperature range for the first drying stage is -60℃ to 0℃, and the temperature range for the second drying stage is 15℃ to 40℃; and The pressure range for primary and secondary drying is 0.02 mbar to 0.2 mbar, preferably 0.06 mbar for both.

4. The freeze-drying method according to claim 1, wherein, Using the top cap to press the top stopper into the dual-chamber cartridge bottle further includes: The dual-chamber vial is purged with nitrogen before the top stopper is pressed to maintain a low moisture content in the lonpe growth hormone.

5. A lyophilized formulation of cyclophosphamide growth hormone, prepared by the lyophilization method according to any one of claims 1-4.

6. An injectable preparation comprising: Packaging materials for double-chamber cartridge vials for injection, lyophilized formulations of lonpec growth hormone, and reconstituted solutions.

7. The injectable formulation according to claim 6, wherein, The injection dual-chamber cartridge vial packaging material includes: a dual-chamber cartridge vial and a cap assembly, wherein... The dual-chamber cartridge bottle is used to hold the lyophilized formulation of the cyclophosphamide growth hormone and the reconstituted solvent. The bottle cap assembly includes the top stopper and the top cap; The top plug seals the mouth of the dual-chamber cartridge bottle; The top cap is used to press and fix the top plug, so that the top plug seals the bottle opening of the dual-chamber cartridge bottle; and to seal the dual-chamber cartridge bottle; The process of pressing and fixing the top plug with the top cap to seal the bottle opening of the dual-chamber cartridge includes the following steps: The top plug is pre-assembled into the top cover; Place the top cap, which is already fitted with the top plug, above the mouth of the dual-chamber cartridge bottle and press the top cap down.

8. The injectable formulation according to claim 7, wherein, The dual-cavity cartridge bottle includes: an inner cavity, a bottle body, the bottle neck, and the bottle mouth, wherein the bottle mouth has a bottle mouth opening at its center that connects to the inner cavity, and the inner diameter of the bottle mouth opening is smaller than the inner diameter of the bottle mouth and the inner diameter of the bottle neck; The outer wall of one side of the bottle has a bypass protrusion.

9. The injectable formulation according to claim 6, wherein, The lyophilized form of lopenafil growth hormone is a lyophilized form of lopenafil growth hormone prepared by the lyophilization method according to any one of claims 1-4 or the lyophilized form of lopenafil growth hormone according to claim 5.

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