Filling process of novel aripiprazole double-cavity pre-filling injector

Abstract

The invention relates to the technical field of medicine packing materials, in particular to a filling process of a novel aripiprazole double-cavity pre-filling syringe, and a syringe barrel of the novel double-cavity pre-filling syringe is made of COP / COC materials; comprising the following steps of sterilization, middle plug placement, sterile filling, freeze drying, plug pressing and assembling, and a complete double-cavity pre-filled syringe is obtained.The filling process combines high strength and heat conduction uniformity of COP / COC materials, in-situ freeze-drying in the syringe is achieved, the step of powder transfer after freeze-drying of a traditional penicillin bottle is avoided, and the production efficiency is improved. According to the present invention, the sterile risk and the production cost are significantly reduced, the manufacturing process is simplified, the equipment complexity and the product loss are reduced, and the high dose accuracy and the yield are ensured.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical packaging technology, specifically to a filling process for a novel aripiprazole dual-chamber pre-filled syringe. Background Technology

[0002] In existing technologies, the release characteristics of long-acting aripiprazole formulations are closely related to their particle size distribution. According to data disclosed in relevant core patents (such as CN1870980B), the average particle size of aripiprazole needs to be controlled within 1-10 micrometers (preferably about 2.5 micrometers) to maintain stable blood drug concentrations for several weeks. However, traditional pre-filled injection systems mostly use borosilicate glass. To ensure smooth sliding of the piston and stopper within the glass cylinder wall, silicone oil must be sprayed onto the inner wall of the glass for siliconization treatment.

[0003] However, silicone oil systems have the following serious inherent drawbacks, especially when dealing with suspension formulations such as aripiprazole: Risks of Drug Aggregation and Altered Efficacy: Existing technologies (such as patent CN103327968A) clearly indicate that if aripiprazole lyophilized product comes into contact with silicone oil, the silicone oil will mix into the drug solution during reconstitution and resuspension, causing irreversible aggregation of aripiprazole particles. This aggregation leads to an increase in average particle size and a decrease in specific surface area, thereby significantly reducing the drug's dissolution rate in vivo. This causes the pharmacokinetic (PK) profile to deviate from expectations, affecting therapeutic efficacy and safety.

[0004] "Stick-slip" phenomenon: Glass syringes rely on silicone oil for lubrication, but uneven distribution or migration of silicone oil during long-term storage can lead to excessive starting force or pressure fluctuations during injection, affecting the accuracy of the dosage.

[0005] Process complexity: To avoid the influence of silicone oil on aripiprazole, original technologies (such as CN103327968A) have to adopt complex processes, such as designing special "cylindrical raised" drug blocks or leaving "gaps" between the drug block and the tube wall to physically reduce the contact between the drug and silicone oil. This increases manufacturing difficulty and supply chain risks.

[0006] Therefore, developing a novel filling process that fundamentally eliminates silicone oil interference, ensures aripiprazole particle size stability, and simplifies the manufacturing process is a pressing technical challenge that needs to be addressed in this field. Summary of the Invention

[0007] The purpose of this invention is to provide a filling process for a novel dual-chamber pre-filled syringe for aripiprazole. This process uses a perfluorinated / silicone-free COP / COC packaging system, which completely solves the problem of aripiprazole particle agglomeration caused by silicone oil through the characteristics of the material itself, ensuring that the particle size distribution and dissolution characteristics are consistent with or even better than those of the original formulation.

[0008] To achieve the above objectives, the technical solution provided by the present invention is as follows: A filling process for a novel aripiprazole dual-chamber pre-filled syringe, wherein the syringe barrel of the novel dual-chamber pre-filled syringe is made of COP / COC material; The filling process includes the following steps: S1. Sterilization: The syringe barrel made of COP / COC is pre-sterilized at high temperature. The excellent heat resistance and radiation resistance of this material are used to ensure the sterility level. S2, Insertion of the middle plug: Insert the middle plug without silicone oil coating into the syringe barrel and push it to the predetermined position to precisely divide the syringe into the upper chamber and the lower chamber; S3. Aseptic filling: The prepared aripiprazole suspension with a specific particle size distribution is aseptically filled into the upper chamber; S4. In-situ freeze drying: The filled syringe assembly is loaded into the cell and sent to the freeze dryer for in-situ freeze drying. During the freeze drying process, due to the low adsorption of COP / COC, the drug solution will not stick to the wall or creep due to the wall effect, thus forming a drug cake with a uniform structure. S5. Pressing the plug: After freeze-drying, the top plug is directly pressed in to seal the product under vacuum or inert gas protection. S6. Assembly: Fill the lower chamber with water for injection or a special solvent and insert the piston to obtain a complete double-chamber pre-filled syringe.

[0009] Preferably, the inner wall of the upper chamber of the syringe barrel is recessed inward to form a guide groove for the lysozyme to flow through.

[0010] Preferably, the drying process in step S4 is carried out by radiation heating or convection heating.

[0011] Preferably, the freeze-drying process in step S4 specifically includes: S41. Pre-freezing: After inserting the syringe assembly into the freeze dryer, adjust the temperature of the freeze dryer to -50℃~-40℃ and maintain it for 250-350 minutes. S42. Single drying: After pre-freezing, raise the temperature of the freeze dryer to -25℃ to -15℃ within 60 minutes, and at the same time adjust the pressure inside the freeze dryer to 0.2-0.4 mbar, and maintain it for 2500 min to 4000 min; S43. Secondary drying: After the primary drying is completed, the temperature of the freeze dryer is raised to 20℃~30℃ within 60 minutes, while the pressure inside the freeze dryer is 0.2-0.4mbar, and maintained for 250min-400min.

[0012] Preferably, during the drying process in step S42, the rate of increase of the internal pressure of the freeze dryer is monitored in real time. When the rate of increase of the internal pressure is less than 1 Pa / min, the drying process is stopped.

[0013] Preferably, in the secondary drying of step S43, the moisture content of the freeze-dried tablets is reduced to 1%-2% of the original moisture content.

[0014] Compared with the prior art, the beneficial effects of the present invention are as follows: 1. This invention uses COP / COC material, fundamentally eliminating the use of silicone oil. This avoids silicone oil-induced aripiprazole crystal aggregation, ensuring that the particle size of the reconstituted suspension is strictly maintained within the design range. This guarantees the stability of drug dissolution rate and in vivo bioavailability. Unlike the original patent, there is no need to avoid silicone oil risks through physical gaps. At the same time, the extremely low surface energy and naturally low coefficient of friction of COP / COC material, combined with high-precision injection molding process, achieves smooth sliding without the need for lubricants, eliminating the "stick-slip" phenomenon of glass syringes. This ensures a smooth injection feel and accurate dosage. Furthermore, the COP / COC surface has extremely low protein and drug adsorption, which, compared to glass surfaces, minimizes the residue of aripiprazole micropowder on the tube wall, improving the yield and dosage accuracy of this valuable drug.

[0015] 2. Combining the high strength and uniform thermal conductivity of COP / COC material, in-situ freeze-drying inside the syringe is achieved, avoiding the powder transfer step after freeze-drying in traditional vials. This significantly reduces sterility risks and production costs, simplifies the manufacturing process, reduces equipment complexity and product loss, and ensures high dosage accuracy and yield. Attached Figure Description

[0016] To more clearly illustrate the technical solutions of the embodiments of the present invention, the accompanying drawings used in the description of the embodiments will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0017] Figure 1 This is a cross-sectional view of the novel dual-chamber pre-filled syringe of the present invention.

[0018] The attached diagram lists the components represented by each number as follows: 1. Syringe barrel; 2. Middle plug; 3. Top plug; 4. Piston; 5. Flow guide groove Detailed Implementation

[0019] The technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0020] like Figure 1 As shown: Embodiment 1 provided by the present invention is as follows: A filling process for a novel aripiprazole dual-chamber pre-filled syringe is disclosed. The syringe barrel of the novel dual-chamber pre-filled syringe is made of COP / COC material. This polymer has a regular molecular structure and low surface energy, and has a naturally low coefficient of friction (the coefficient of friction is about 0.15-0.2, which is much lower than that of glass, which is 0.4-0.5). At the same time, the dimensional tolerances of the barrel, the middle stopper and the piston are controlled by high-precision injection molding (fitting clearance ≤0.02mm). When the middle stopper and the piston slide in the barrel, the contact surfaces fit tightly and the frictional resistance is uniform. Smooth sliding can be achieved without the need for additional silicone oil, thereby avoiding the risk of silicone oil contact with the drug from the source and ensuring the stability of the drug.

[0021] The filling process includes the following steps: S1. Sterilization: The syringe barrel made of COP / COC is pre-sterilized at high temperature. The excellent heat resistance and radiation resistance of this material are used to ensure the sterility level. S2, Insertion of the middle plug: Insert the middle plug without silicone oil coating into the syringe barrel and push it to the predetermined position to precisely divide the syringe into the upper chamber and the lower chamber; S3. Aseptic filling: The prepared aripiprazole suspension with a specific particle size distribution is aseptically filled into the upper chamber; S4. In-situ freeze drying: The filled syringe assembly is loaded into the cell and sent to the freeze dryer for in-situ freeze drying. During the freeze drying process, due to the low adsorption of COP / COC, the drug solution will not stick to the wall or creep due to the wall effect, thus forming a drug cake with a uniform structure. S5. Pressing the plug: After freeze-drying, the top plug is directly pressed in to seal the product under vacuum or inert gas protection. S6. Assembly: Fill the lower chamber with water for injection or a special solvent and insert the piston to obtain a complete double-chamber pre-filled syringe.

[0022] Specifically, the inner wall of the upper chamber of the syringe barrel is recessed inward to form a guide groove for the lysozyme to flow through.

[0023] As can be seen from the above description, the flow channel helps the lysozyme flow more smoothly during injection, ensuring thorough mixing of the drug and the lysozyme, improving the convenience and efficiency of drug administration, while reducing the risk of residual liquid. Furthermore, the COP / COC material provides sufficient strength to the cartridge, allowing the flow channel to be directly opened on the inner wall of the cartridge body, without having to make the cartridge body protrude before opening the channel as in existing technologies. This not only optimizes the appearance of the cartridge but also makes the cartridge body easier to manufacture as a whole.

[0024] Specifically, the drying process in step S4 is carried out by radiation heating or convection heating.

[0025] As described above, the heat output of both heating methods can be precisely controlled, strictly matching the temperature requirements of each stage of "pre-freezing - primary drying - secondary drying". Aripiprazole, which is sensitive to temperature, can always be kept within a safe temperature range, reducing the risk of degradation and ensuring stable efficacy. Simultaneously, radiant heating does not require contact with the syringe components, and convection heating allows for smooth airflow circulation between the tray / crate, both perfectly compatible with dedicated fixing devices. This avoids interference between the heating components and the fixing devices, ensuring a smooth connection between the "fixing-heating-freeze-drying" process and improving process compatibility and reliability. Furthermore, convection heating accelerates water vapor removal, and radiant heating rapidly provides sublimation heat. The combination or use of these two methods can appropriately shorten the total time for primary and secondary drying while ensuring drying quality, reducing equipment downtime, increasing production volume, and indirectly lowering production costs. It also avoids the potential risk of drug deterioration caused by excessively long drying cycles.

[0026] Specifically, the freeze-drying process in step S4 is as follows: S41. Pre-freezing: After inserting the syringe assembly into the freeze dryer, adjust the temperature of the freeze dryer to -50℃~-40℃ and maintain it for 250-350 minutes. S42. Single drying: After pre-freezing, raise the temperature of the freeze dryer to -25℃ to -15℃ within 60 minutes, and at the same time adjust the pressure inside the freeze dryer to 0.2-0.4 mbar, and maintain it for 2500 min to 4000 min; S43. Secondary drying: After the primary drying is completed, the temperature of the freeze dryer is raised to 20℃~30℃ within 60 minutes, while the pressure inside the freeze dryer is 0.2-0.4mbar, and maintained for 250min-400min.

[0027] As described above, in the freeze-drying process, the pre-freezing stage rapidly freezes the aripiprazole aqueous solution or suspension at -50℃ to -40℃ to form a uniform ice crystal structure, avoiding uneven drug concentration. A holding time of 250-350 minutes ensures complete freezing of the drug solution, laying the foundation for subsequent drying. In the primary drying stage, the temperature is steadily increased to -25℃ to -15℃ within 60 minutes to prevent sudden temperature rises from damaging the morphology of the freeze-dried tablets. Simultaneously, a low-pressure environment of 0.2-0.4 mbar accelerates ice crystal sublimation, and a holding time of 2500-4000 minutes ensures that most of the moisture is removed, reducing uneven porosity within the tablets and improving stability. In the secondary drying stage, the temperature is increased to 20℃ to 30℃ within 60 minutes. While maintaining low pressure, residual moisture in the tablets is further removed to prevent moisture absorption or degradation caused by low-temperature residual moisture, extending the drug's storage time. Furthermore, the aforementioned temperature control curve, combined with COP (Coefficient of Performance), is employed. The material has uniform thermal conductivity, and the resulting aripiprazole freeze-dried cake is loose and porous, with a short reconstitution time, and the particle size distribution after reconstitution remains highly consistent with the original solution before filling.

[0028] Specifically, during the drying process in step S42, the rate of increase of the internal pressure of the freeze dryer is monitored in real time. When the rate of increase of the internal pressure is less than 1 Pa / min, the drying process is stopped.

[0029] As can be seen from the above description, by real-time monitoring of the pressure rise rate inside the freeze dryer, and using "pressure rise rate less than 1 Pa / min" as the endpoint of one drying cycle, this judgment standard is more accurate and objective compared to the traditional experience-based judgment method: when the pressure rise rate is less than 1 Pa / min, it indicates that the sublimation of ice crystals inside the freeze-dried tablets is basically complete. Stopping the drying cycle at this point can avoid tablet embrittlement and degradation of active ingredients caused by over-drying, and can also prevent tablets from absorbing moisture and deteriorating due to incomplete drying, thus ensuring that the quality of freeze-dried tablets is stable and controllable.

[0030] Specifically, in the secondary drying process of step S43, the moisture content of the freeze-dried tablets is reduced to 1%-2% of the original moisture content.

[0031] As can be seen from the above description: on the one hand, extremely low moisture content can inhibit the occurrence of drug degradation reactions, greatly improve the long-term stability of aripiprazole, and ensure that the efficacy of the drug remains unchanged within the shelf life; on the other hand, a moisture content of 1%-2% can prevent the tablets from becoming brittle and fragile due to excessive dehydration, ensuring the integrity of the tablets during storage and transportation, while not affecting the dissolution rate during use.

[0032] The specific filling process of the novel aripiprazole dual-lumen pre-filled syringe of the present invention is as follows: Sterilization process: High-temperature pre-sterilization (usually using 121℃ saturated steam sterilization for 30 minutes) kills microorganisms and endotoxins in the syringe barrel, laying the foundation for subsequent aseptic operations and ensuring that aripiprazole solution is not contaminated during filling.

[0033] Insertion of the middle stopper and separation of the chamber: The middle stopper is inserted into the sterilized cylinder and pushed to the predetermined position. The sealing structure of the middle stopper (such as a butyl rubber sealing ring) is used to separate the inside of the cylinder into an independent upper chamber (drug chamber) and a lower chamber (solvent chamber), so as to achieve physical isolation between the drug and the lysozyme and avoid premature dissolution of the drug during storage, which would lead to a decrease in stability.

[0034] Aseptic filling and in-situ freeze-drying: Aseptic filling technology (such as a peristaltic pump + sterile filling needle, operated in a Class A clean area) is used to inject aripiprazole aqueous solution or suspension into the upper chamber to ensure the sterility of the drug solution; then the syringe assembly is loaded into a special tray / nest (keeping it vertical to prevent the drug solution from tilting and overflowing) and sent into the freeze dryer. The freeze dryer completes pre-freezing, primary drying and secondary drying in stages by controlling the temperature and pressure of the chamber, specifically: Pre-freezing stage: Rapidly cool down to -45℃ and maintain it to allow the water in the liquid to freeze evenly in the form of ice crystals, avoiding the formation of large ice crystals due to slow freezing speed (large ice crystals will damage the formulation skeleton and cause the product to collapse after drying). First drying stage: Under a vacuum of 0.3 mbar, the temperature is slowly raised to -20°C. Energy is transferred to the syringe by radiation heat transfer, causing the ice crystals to sublimate directly (skipping the liquid stage) into water vapor. The water vapor is captured by the condenser of the freeze dryer (condensed into ice), thus removing the free water. The sublimation of the free water is determined by detecting the pressure rise rate (<1 Pa / min), ensuring thorough drying.

[0035] Secondary drying stage: The temperature is further increased to 25°C, and energy is provided in a vacuum environment to desorb the tightly bound water in the drug solid matrix into water vapor and remove it, reducing the residual moisture to 1%-2% and inhibiting the drug degradation reaction.

[0036] Stopping and Assembly: After lyophilization, the top stopper is pressed into the upper chamber opening using the movable plate (stopping device) of the lyophilizer in a vacuum or inert gas (nitrogen) environment to achieve an airtight packaging (to prevent air and moisture from entering and causing drug deterioration); then the lysozyme is injected into the lower chamber, the piston is inserted and sealed to form a complete double-chamber pre-filled syringe. When using a dual-chamber pre-filled syringe, pushing the piston allows the lysozyme to flow through the guide groove of the syringe barrel into the upper chamber to dissolve the drug, thus completing the drug delivery.

[0037] In this invention, unless otherwise explicitly specified and limited, the terms "installation," "setting," "connection," "fixing," "screw connection," etc., should be interpreted broadly. For example, they can refer to a fixed connection, a detachable connection, or an integral part; they can refer to a mechanical connection or an electrical connection; they can refer to a direct connection or an indirect connection through an intermediate medium; they can refer to the internal connection of two components or the interaction between two components. Unless otherwise explicitly limited, those skilled in the art can understand the specific meaning of the above terms in this invention according to the specific circumstances.

[0038] Although embodiments of the invention have been shown and described, it will be understood by those skilled in the art that variations may be made to these embodiments without departing from the principles and spirit of the invention, the scope of which is defined by the appended claims and their equivalents.

Claims

1. A process for filling of Aripiprazole in a novel dual chamber prefilled syringe characterized by: The syringe barrel (1) of the new double-chamber prefilled syringe is made of COP / COC material; The filling process comprises the following steps: S1, sterilization: the COP / COC syringe barrel (1) is pre-sterilized at high temperature, and the excellent heat and radiation resistance of the material ensures the sterile level; S2, middle plug placement: the middle plug (2) without silicone oil coating is loaded into the syringe barrel (1) and pushed to the predetermined position, which accurately separates the syringe into an upper chamber and a lower chamber; S3, aseptic filling: the prepared aripiprazole suspension with a specific particle size distribution is aseptically filled into the upper chamber; S4, in-situ freeze-drying: the filled syringe assembly is loaded into a nest cylinder and sent into a freeze dryer for in-situ freeze-drying. During the freeze-drying process, due to the low adsorption of COP / COC, the drug solution will not hang on the wall or climb due to wall effect, thereby forming a uniform drug cake; S5, compression plug: after freeze-drying, the top plug (3) is directly pressed in under vacuum or inert gas protection for sealing; S6, assembly: water for injection or special solvent is filled in the lower chamber, and the piston (4) is loaded to obtain a complete double-chamber prefilled syringe.

2. A process for filling of Aripiprazole in new dual chamber prefilled syringe as claimed in claim 1, wherein: The inner wall of the upper chamber of the syringe barrel (1) is inwardly recessed to form a flow guide groove (5) for the flow of solenoid.

3. The aripiprazole new type dual chamber prefilled syringe filling process according to claim 1, characterized in that: The drying process in step S4 is carried out by radiation heating or convection heating.

4. The aripiprazole new type dual chamber prefilled syringe filling process as claimed in claim 1 wherein: The freeze-drying process in step S4 is as follows: S41, pre-freezing: after the syringe assembly is sent into the freeze dryer, the temperature of the freeze dryer is adjusted to -50℃ to -40℃ and maintained for 250-350 min; S42, primary drying: after pre-freezing is completed, the temperature of the freeze dryer is raised to -25℃ to -15℃ within 60 min, and the pressure in the freeze dryer is adjusted to 0.2-0.4 mbar, and maintained for 2500-4000 min; S43, secondary drying: after primary drying is completed, the temperature of the freeze dryer is raised to 20-30℃ within 60 min, and the pressure in the freeze dryer is 0.2-0.4 mbar, and maintained for 250-400 min.

5. The aripiprazole new type dual chamber prefilled syringe filling process according to claim 4, characterized in that: During the primary drying process in step S42, the rising rate of the internal pressure of the freeze dryer is detected in real time, and when the rising rate of the internal pressure is less than 1 Pa / min, the primary drying is stopped.

6. The aripiprazole new type dual chamber prefilled syringe filling process as claimed in claim 4 wherein: In the secondary drying of step S43, the moisture of the freeze-dried tablet is reduced to 1-2% of the original moisture.

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