Liquid preparation before freeze-drying of paclitaxel albumin as well as preparation method and freeze-drying method of liquid preparation

Abstract

The invention discloses a paclitaxel albumin liquid preparation before freeze-drying. The paclitaxel albumin liquid preparation is prepared from the following components in percentage by mass: 1.5 to 3.0 percent of paclitaxel, 15 to 30 percent of human serum albumin, 0 to 0.2 percent of absolute ethyl alcohol, 0 to 3 percent of water for injection, 1.22 to 1.61 percent of sodium caprylate, 1.82 to 2.36 percent of N-acetyl-L-tryptophan and 0 to 0.4 percent of pH (Potential of Hydrogen) regulator, the invention also provides a preparation method and a freeze-drying method of the paclitaxel albumin liquid preparation before freeze-drying. The freeze-dried powder injection is prepared through technical innovation, a brand new formula, low-temperature vacuum freeze-drying, inert gas filling and freeze-drying rate control, and the freeze-dried powder injection has the outstanding characteristics of good stability, more reliable quality safety and the like.

Description

Technical Field

[0001] The present invention relates to the technical field of drug freeze-dried powder, in particular to a paclitaxel albumin pre-freeze-dried liquid preparation and a preparation method and a freeze-drying method thereof. Background Art

[0002] Paclitaxel is a natural anticancer drug with a molecular formula of C47H51NO14. It is a white crystalline powder, odorless, tasteless, and insoluble in water, but easily soluble in organic solvents such as methanol, acetonitrile, chloroform, and acetone. Up to now, the approved indications for paclitaxel in China are metastatic breast cancer that has failed combined chemotherapy or breast cancer that has recurred within 6 months after adjuvant chemotherapy. Unless there are clinical contraindications, previous chemotherapy should include an anthracycline anticancer drug; Abraxane has been approved by the FDA and EMA for breast cancer, non-small cell lung cancer, and pancreatic cancer; Japan has approved indications for breast cancer, non-small cell lung cancer, gastric cancer, and pancreatic cancer; and the indications under development include ovarian cancer, etc. Traditional paclitaxel injections usually use polyoxyethylene castor oil and ethanol as API solvents, which are highly sensitizing and restrictive, causing many inconveniences in controlling the patient's condition. In addition, the injection itself is easily affected by visible foreign matter and related substances, resulting in poor stability, which is not conducive to long-term storage of samples and increases corporate costs.

[0003] CN101953806A discloses "a method for preparing nano-paclitaxel freeze-dried powder". The patent is characterized in that mannitol, glucose or lactic acid is added as an excipient to the paclitaxel preparation, the appearance quality of the product powder is significantly improved, the reconstitution is optimized, and the problem of poor appearance and long reconstitution time of paclitaxel albumin freeze-dried powder injection is solved. However, it is well known that everyone's physique is different, and sometimes severe lactose intolerance occurs. Lactose is an animal-derived excipient, which may come from the milk of animals with diseases such as mad cow disease. There are safety risks in using it for pharmaceutical production, especially injection.

[0004] CN102928321A discloses "an albumin-bound paclitaxel nanoparticle freeze-dried preparation and its preparation method". The invention provides an albumin-bound paclitaxel nanoparticle freeze-dried preparation, which can improve the stability and safety of paclitaxel, prolong the efficacy, and improve the targeting ability. The patent uses sterile paclitaxel (nanoscale) 0.1-2%, human serum albumin (nanoscale) 0.2-60%, surfactant 0.2-60%, oil phase 0.2-30%, freeze-dried skeleton 0.2-60%, pH regulator 0.1-5%, stabilizer 0.1-5% as the prescription ratio to ensure the bioavailability of the product. However, the oil phase mainly uses various phospholipids as excipients, and some phospholipids are animal-derived phospholipids, which may carry some pathogenic viruses or other allergenic substances, which is not conducive to product quality control and clinical use.

[0005] Therefore, how to provide a paclitaxel freeze-dried powder with good stability and more reliable quality and safety is a technical problem that needs to be solved urgently by those skilled in the art. Summary of the invention

[0006] In order to solve the above technical problems, the present invention provides a paclitaxel albumin pre-lyophilized liquid preparation and a preparation method and a lyophilization method thereof. The present invention adopts a new formula through technological innovation, and relies on low-temperature vacuum freezing and lyophilization, filling with inert gas and controlling the lyophilization rate to prepare a lyophilized powder injection, which has outstanding characteristics such as good stability and more reliable quality and safety.

[0007] The technical solution provided by the present invention is as follows: A paclitaxel albumin pre-lyophilized liquid preparation consists of the following components by mass percentage: 1.5-3.0% paclitaxel, 15-30% human serum albumin, 0-0.2% anhydrous ethanol, 0-3% water for injection, 1.22-1.61% sodium octanoate, 1.82-2.36% N-acetyl-L-tryptophan, and 0-0.4% pH regulator.

[0008] Preferably, the paclitaxel, human serum albumin, anhydrous ethanol, water for injection, sodium octanoate, N-acetyl-L-tryptophan and pH adjuster are all of pharmaceutical grade.

[0009] Preferably, the pH adjuster is sodium hydroxide and dilute hydrochloric acid.

[0010] A method for preparing the paclitaxel albumin pre-lyophilized liquid preparation as described above comprises the following steps: S101, first dissolving paclitaxel using anhydrous ethanol, and then respectively introducing the human albumin aqueous solution and the paclitaxel ethanol solution into an emulsifying disperser at a certain flow rate for high-speed shearing; S102, after the shearing is completed, the temperature is lowered to room temperature for dialysis; S103, after the dialysis is completed, sodium octanoate and N-acetyl L-tryptophan are first added as albumin stabilizers, and then a pH regulator is added to adjust the pH value of the entire solution; S104, final sterilization and filtration to complete the preparation of the drug solution, and obtain the paclitaxel albumin pre-lyophilized liquid preparation.

[0011] Preferably, in step S101, the flow rate of the human albumin aqueous solution is 3-4.5 L / min, and the flow rate of the paclitaxel ethanol solution is 70-100 ml / min.

[0012] Preferably, in step S101, the flow rate of the emulsifying disperser is controlled at 1000-5000 rpm.

[0013] Preferably, the pH value in step S103 is 6.4-7.4.

[0014] A freeze-drying method for a paclitaxel albumin pre-lyophilized liquid preparation as described above or a paclitaxel albumin pre-lyophilized liquid preparation prepared by the preparation method of the paclitaxel albumin pre-lyophilized liquid preparation as described above, comprising the following steps: S201, pre-freezing: Use a freeze dryer (vacuum freeze dryer) to cool the paclitaxel albumin solution to below -50°C and maintain for 0.5 to 3.5 hours for pre-freezing; S202, using the vacuum pump of the freeze dryer, start to evacuate the inside of the freeze dryer, and maintain the vacuum degree at no more than 40Pa; S203, slowly raising the oil temperature to 40° C. in a staged manner for 19 to 41 hours; S204, analytical drying: maintaining the oil temperature at 40°C, and controlling the vacuum of the freeze dryer to 0-5 Pa for 3-7 hours; S205, turning off the vacuum pump to stop the vacuum, and then performing negative pressure plugging on the paclitaxel albumin freeze-dried powder injection that has been freeze-dried and sublimated, and after confirming that the rubber plug is tightly pressed, transferring the paclitaxel albumin freeze-dried powder injection to the freeze dryer for capping.

[0015] Preferably, the staged heating method in step S203 is specifically as follows: S2031, raising the oil temperature to -10°C at a rate of 10-40°C / hour for 1-4 hours; S2032, raising the oil temperature to 0°C at a rate of 1.25-2.5°C / hour for 4-8 hours; S2033, raising the oil temperature to 10°C at a rate of 1.25-2.5°C / hour for 4-8 hours; S2034, raising the oil temperature to 15°C at a rate of 0.7-1.7°C / hour for 3-7 hours; S2035, raising the oil temperature to 20°C at a rate of 0.7-1.7°C / hour for 3-7 hours; S2036, raising the oil temperature to 25°C at a rate of 1°C / hour for 3 to 5 hours; S2037. Raise the oil temperature to 40°C at a rate of 15°C / hour for 1 to 2 hours.

[0016] The present invention adopts a staged heating method to help release the moisture in the product. The sublimation process of the solid accelerates the sublimation rate by absorbing heat. Under the premise of ensuring that the product quality is controllable, the fastest freeze-drying rate can be guaranteed.

[0017] The present invention has the following advantages over the prior art: The present invention aims at the problem that paclitaxel albumin has toxicity caused by traditional processes and is difficult to store due to traditional dosage forms during traditional production, storage and use. The present invention readjusts the production formula and preparation process, and uses vacuum freeze-drying technology to prepare paclitaxel albumin lyophilized powder injection from a pre-lyophilized liquid preparation of paclitaxel albumin, which can effectively increase the safety of the product and the stability of the drug, and its quality and safety are significantly improved compared with previous preparations of the same type. DETAILED DESCRIPTION

[0018] In order to enable those skilled in the art to better understand the technical solutions in the present invention, the technical solutions in the embodiments of the present invention are clearly and completely described below. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in the field without creative work are within the scope of protection of the present invention.

[0019] Embodiment 1: A paclitaxel albumin pre-lyophilized liquid preparation consists of the following components by mass percentage: 1.5% paclitaxel, 15% human serum albumin, 0.2% anhydrous ethanol, 3% water for injection, 1.22% sodium octanoate, 1.82% N-acetyl-L-tryptophan, and 0.2% pH regulator.

[0020] A method for preparing the above-mentioned paclitaxel albumin pre-lyophilized liquid preparation comprises the following steps: S101, dissolving paclitaxel with anhydrous ethanol, and then introducing the human albumin aqueous solution and the paclitaxel ethanol solution into an MHD2000 / 4 emulsifier at flow rates of 3 L / min and 70 ml / min, respectively, for high-speed shearing, and the flow rate of the emulsifier was controlled at 1000 rpm; S102, after the shearing is completed, the temperature is lowered to room temperature for dialysis; S103, after the dialysis is completed, sodium octanoate and N-acetyl L-tryptophan are first added as albumin stabilizers, and then a pH regulator is added to adjust the pH value of the entire solution; S104, final sterilization and filtration to complete the preparation of the drug solution, and obtain the paclitaxel albumin pre-lyophilized liquid preparation.

[0021] A freeze-drying method for the above-mentioned paclitaxel albumin pre-freeze-dried liquid preparation comprises the following steps: S201, pre-freezing: lower the product temperature to below -50°C and maintain for 0.5 hours for pre-freezing; S202, start evacuating, and keep the vacuum degree at 12Pa; S203, raising the oil temperature to 40°C in a staged manner, and maintaining 40°C for 1 hour; S204, analytical drying: maintaining the oil temperature at 40°C, and controlling the vacuum of the freeze dryer to 5Pa for 3 hours; S205, turning off the vacuum pump to stop the vacuum, and then performing negative pressure plugging on the paclitaxel albumin freeze-dried powder injection that has been freeze-dried and sublimated, and after confirming that the rubber plug is tightly pressed, transferring the paclitaxel albumin freeze-dried powder injection to the freeze dryer for capping.

[0022] In this embodiment, the method of stage heating in step S203 is specifically as follows: S2031, raising the oil temperature to -10°C at a rate of 40°C / hour for 1 hour; S2032, raise the oil temperature to 0°C at a rate of 2.5°C / hour for 4 hours; S2033, raising the oil temperature to 10°C at a rate of 2.5°C / hour for 4 hours; S2034, raising the oil temperature to 15°C at a rate of 1.7°C / hour for 3 hours; S2035, raising the oil temperature to 20°C at a rate of 1.7°C / hour for 3 hours; S2036, raising the oil temperature to 25°C at a rate of 1°C / hour for 5 hours; S2037. Raise the oil temperature to 40°C at a rate of 15°C / hour for 1 hour.

[0023] Embodiment 2: A paclitaxel albumin pre-lyophilized liquid preparation consists of the following components by mass percentage: 3.0% paclitaxel, 30% human serum albumin, 0.2% anhydrous ethanol, 2% water for injection, 1.61% sodium octanoate, 2.36% N-acetyl-L-tryptophan, and 0.4% pH regulator.

[0024] A method for preparing the above-mentioned paclitaxel albumin pre-lyophilized liquid preparation comprises the following steps: S101, dissolving paclitaxel with anhydrous ethanol, and then introducing the human albumin aqueous solution and the paclitaxel ethanol solution into an MHD2000 / 4 emulsifier at flow rates of 4.5 L / min and 100 ml / min, respectively, for high-speed shearing, and the flow rate of the emulsifier was controlled at 1000 rpm; S102, after the shearing is completed, the temperature is lowered to room temperature for dialysis; S103, after the dialysis is completed, sodium octanoate and N-acetyl L-tryptophan are first added as albumin stabilizers, and then a pH regulator is added to adjust the pH value of the entire solution; S104, final sterilization and filtration to complete the preparation of the drug solution, and obtain the paclitaxel albumin pre-lyophilized liquid preparation.

[0025] A freeze-drying method for the above-mentioned paclitaxel albumin pre-freeze-dried liquid preparation comprises the following steps: S201, pre-freezing: lower the product temperature to below -50°C and maintain for 0.5 hours for pre-freezing; S202, start vacuuming and maintain the vacuum degree at 40Pa; S203, raising the oil temperature to 40°C in a staged manner, and maintaining 40°C for 1 hour; S204, analytical drying: maintaining the oil temperature at 40°C, and controlling the vacuum of the freeze dryer to 5Pa for 3 hours; S205, turning off the vacuum pump to stop the vacuum, and then performing negative pressure plugging on the paclitaxel albumin freeze-dried powder injection that has been freeze-dried and sublimated, and after confirming that the rubber plug is tightly pressed, transferring the paclitaxel albumin freeze-dried powder injection to the freeze dryer for capping.

[0026] In this embodiment, the method of stage heating in step S203 is specifically as follows: S2031, raising the oil temperature to -10°C at a rate of 40°C / hour for 1 hour; S2032, raise the oil temperature to 0°C at a rate of 2.5°C / hour for 4 hours; S2033, raising the oil temperature to 10°C at a rate of 2.5°C / hour for 4 hours; S2034, raising the oil temperature to 15°C at a rate of 1.7°C / hour for 3 hours; S2035, raising the oil temperature to 20°C at a rate of 1.7°C / hour for 3 hours; S2036, raising the oil temperature to 25°C at a rate of 1°C / hour for 5 hours; S2037. Raise the oil temperature to 40°C at a rate of 15°C / hour for 1 hour.

[0027] Embodiment 3: A paclitaxel albumin pre-lyophilized liquid preparation consists of the following components by mass percentage: 2.0% paclitaxel, 20% human serum albumin, 0.1% anhydrous ethanol, 1.5% water for injection, 1.5% sodium octanoate, 2.0% N-acetyl-L-tryptophan, and 0.3% pH regulator.

[0028] A method for preparing the above-mentioned paclitaxel albumin pre-lyophilized liquid preparation comprises the following steps: S101, dissolving paclitaxel with anhydrous ethanol, and then introducing the human albumin aqueous solution and the paclitaxel ethanol solution into an MHD2000 / 4 emulsifier at flow rates of 3 L / min and 70 ml / min, respectively, for high-speed shearing, and the flow rate of the emulsifier was controlled at 1000 rpm; S102, after the shearing is completed, the temperature is lowered to room temperature for dialysis; S103, after the dialysis is completed, sodium octanoate and N-acetyl L-tryptophan are first added as albumin stabilizers, and then a pH regulator is added to adjust the pH value of the entire solution; S104, final sterilization and filtration to complete the preparation of the drug solution, and obtain the paclitaxel albumin pre-lyophilized liquid preparation.

[0029] A freeze-drying method for the above-mentioned paclitaxel albumin pre-freeze-dried liquid preparation comprises the following steps: S201, pre-freezing: lower the product temperature to below -50°C and maintain for 0.5 hours for pre-freezing; S202, start evacuating, and keep the vacuum degree at 12Pa; S203, raising the oil temperature to 40°C in a staged manner, and maintaining 40°C for 1 hour; S204, analytical drying: maintaining the oil temperature at 40°C, and controlling the vacuum of the freeze dryer to 5Pa for 3 hours; S205, turning off the vacuum pump to stop the vacuum, and then performing negative pressure plugging on the paclitaxel albumin freeze-dried powder injection that has been freeze-dried and sublimated, and after confirming that the rubber plug is tightly pressed, transferring the paclitaxel albumin freeze-dried powder injection to the freeze dryer for capping.

[0030] In this embodiment, the method of stage heating in step S203 is specifically as follows: S2031, raising the oil temperature to -10°C at a rate of 10°C / hour for 4 hours; S2032, raising the oil temperature to 0°C at a rate of 1.25°C / hour for 8 hours; S2033, raising the oil temperature to 10°C at a rate of 1.25°C / hour for 8 hours; S2034, raising the oil temperature to 15°C at a rate of 0.7°C / hour for 7 hours; S2035, raising the oil temperature to 20°C at a rate of 0.7°C / hour for 7 hours; S2036, raising the oil temperature to 25°C at a rate of 1°C / hour for 5 hours; S2037. Raise the oil temperature to 40°C at a rate of 15°C / hour for 1 hour.

[0031] Embodiment 4: A paclitaxel albumin pre-lyophilized liquid preparation consists of the following components by mass percentage: 3.0% paclitaxel, 25% human serum albumin, 0.2% anhydrous ethanol, 3% water for injection, 1.6% sodium octanoate, 2.3% N-acetyl-L-tryptophan, and 0.4% pH regulator.

[0032] A method for preparing the above-mentioned paclitaxel albumin pre-lyophilized liquid preparation comprises the following steps: S101, dissolving paclitaxel with anhydrous ethanol, and then introducing the human albumin aqueous solution and the paclitaxel ethanol solution into an MHD2000 / 4 emulsifier at flow rates of 5 L / min and 100 ml / min, respectively, for high-speed shearing, and the flow rate of the emulsifier was controlled at 5000 rpm; S102, after the shearing is completed, the temperature is lowered to room temperature for dialysis; S103, after the dialysis is completed, sodium octanoate and N-acetyl L-tryptophan are first added as albumin stabilizers, and then a pH regulator is added to adjust the pH value of the entire solution; S104, final sterilization and filtration to complete the preparation of the drug solution, and obtain the paclitaxel albumin pre-lyophilized liquid preparation.

[0033] A freeze-drying method for the above-mentioned paclitaxel albumin pre-freeze-dried liquid preparation comprises the following steps: S201, pre-freezing: lower the product temperature to below -50°C and maintain for 0.5 hours for pre-freezing; S202, start vacuuming and maintain the vacuum degree at 40Pa; S203, raising the oil temperature to 40°C in a staged manner, and maintaining 40°C for 1 hour; S204, analytical drying: maintaining the oil temperature at 40°C, and controlling the vacuum of the freeze dryer to 5Pa for 3 hours; S205, turning off the vacuum pump to stop the vacuum, and then performing negative pressure plugging on the paclitaxel albumin freeze-dried powder injection that has been freeze-dried and sublimated, and after confirming that the rubber plug is tightly pressed, transferring the paclitaxel albumin freeze-dried powder injection to the freeze dryer for capping.

[0034] In this embodiment, the method of stage heating in step S203 is specifically as follows: S2031, raising the oil temperature to -10°C at a rate of 10°C / hour for 4 hours; S2032, raising the oil temperature to 0°C at a rate of 1.25°C / hour for 8 hours; S2033, raising the oil temperature to 10°C at a rate of 1.25°C / hour for 8 hours; S2034, raising the oil temperature to 15°C at a rate of 0.7°C / hour for 7 hours; S2035, raising the oil temperature to 20°C at a rate of 0.7°C / hour for 7 hours; S2036, raising the oil temperature to 25°C at a rate of 1°C / hour for 5 hours; S2037. Raise the oil temperature to 40°C at a rate of 15°C / hour for 1 hour.

[0035] Comparative Example 1: A paclitaxel albumin pre-lyophilized liquid preparation consists of the following components by mass percentage: 2.5-4.0% paclitaxel, 25-40% human serum albumin, 0.4% anhydrous ethanol, 0-3% water for injection, 1.69-2.16% sodium octanoate, 2.12-2.97% N-acetyl-L-tryptophan, and 0-0.4% pH regulator.

[0036] A method for preparing the above-mentioned paclitaxel albumin pre-lyophilized liquid preparation comprises the following steps: S101, dissolving paclitaxel with anhydrous ethanol, and then introducing the human albumin aqueous solution and the paclitaxel ethanol solution into an MHD2000 / 4 emulsifier at flow rates of 3 L / min and 70 ml / min, respectively, for high-speed shearing, and the flow rate of the emulsifier was controlled at 5000 rpm; S102, after the shearing is completed, the temperature is lowered to room temperature for dialysis; S103, after the dialysis is completed, sodium octanoate and N-acetyl L-tryptophan are first added as albumin stabilizers, and then a pH regulator is added to adjust the pH value of the entire solution; S104, final sterilization and filtration to complete the preparation of the drug solution, and obtain the paclitaxel albumin pre-lyophilized liquid preparation.

[0037] A freeze-drying method for the above-mentioned paclitaxel albumin pre-freeze-dried liquid preparation comprises the following steps: S201, pre-freezing: lower the product temperature to below -50°C and maintain for 0.5 hours for pre-freezing; S202, start evacuating, and keep the vacuum degree at 12Pa; S203, raising the oil temperature to 40°C in a staged manner, and maintaining 40°C for 1 hour; S204, analytical drying: maintaining the oil temperature at 40°C, and controlling the vacuum of the freeze dryer to 5Pa for 3 hours; S205, turning off the vacuum pump to stop the vacuum, and then performing negative pressure plugging on the paclitaxel albumin freeze-dried powder injection that has been freeze-dried and sublimated, and after confirming that the rubber plug is tightly pressed, transferring the paclitaxel albumin freeze-dried powder injection to the freeze dryer for capping.

[0038] In this embodiment, the method of stage heating in step S203 is specifically as follows: S2031, raise the oil temperature to -10°C for 1 hour; S2032, raise the oil temperature to 0°C for 2 hours; S2033, raise the oil temperature to 10°C for 2 hours; S2034, raise the oil temperature to 15°C for 1.5 hours; S2035, raising the oil temperature to 20°C for 1.5 hours; S2036, raising the oil temperature to 25°C for 2 hours; S2037. Raise the oil temperature to 40°C for 1 hour.

[0039] Comparative Example 2: A paclitaxel albumin pre-lyophilized liquid preparation consists of the following components by mass percentage: 0.5-1.5% paclitaxel, 5-15% human serum albumin, 0.1% anhydrous ethanol, 0-3% water for injection, 0.82-1.16% sodium octanoate, 1.23-1.76% N-acetyl-L-tryptophan, and 0-0.4% pH regulator.

[0040] A method for preparing the above-mentioned paclitaxel albumin pre-lyophilized liquid preparation comprises the following steps: S101, dissolving paclitaxel with anhydrous ethanol, and then introducing the human albumin aqueous solution and the paclitaxel ethanol solution into an MHD2000 / 4 emulsifier at flow rates of 5 L / min and 100 ml / min, respectively, for high-speed shearing, and the flow rate of the emulsifier was controlled at 5000 rpm; S102, after the shearing is completed, the temperature is lowered to room temperature for dialysis; S103, after the dialysis is completed, sodium octanoate and N-acetyl L-tryptophan are first added as albumin stabilizers, and then a pH regulator is added to adjust the pH value of the entire solution; S104, final sterilization and filtration to complete the preparation of the drug solution, and obtain the paclitaxel albumin pre-lyophilized liquid preparation.

[0041] A freeze-drying method for the above-mentioned paclitaxel albumin pre-freeze-dried liquid preparation comprises the following steps: S201, pre-freezing: lower the product temperature to below -50°C and maintain for 0.5 hours for pre-freezing; S202, start evacuating, and keep the vacuum degree at 8Pa; S203, raising the oil temperature to 40°C in a staged manner, and maintaining 40°C for 1 hour; S204, analytical drying: maintaining the oil temperature at 40°C, and controlling the vacuum of the freeze dryer to 5Pa for 3 hours; S205, turning off the vacuum pump to stop the vacuum, and then performing negative pressure plugging on the paclitaxel albumin freeze-dried powder injection that has been freeze-dried and sublimated, and after confirming that the rubber plug is tightly pressed, transferring the paclitaxel albumin freeze-dried powder injection to the freeze dryer for capping.

[0042] In this embodiment, the method of stage heating in step S203 is specifically as follows: S2031, raising the oil temperature to -10°C at a rate of 10°C / hour for 4 hours; S2032, raising the oil temperature to 0°C at a rate of 1.25°C / hour for 8 hours; S2033, raising the oil temperature to 10°C at a rate of 1.25°C / hour for 8 hours; S2034, raising the oil temperature to 15°C at a rate of 0.7°C / hour for 7 hours; S2035, raising the oil temperature to 20°C at a rate of 0.7°C / hour for 7 hours; S2036, raising the oil temperature to 25°C at a rate of 1°C / hour for 5 hours; S2037. Raise the oil temperature to 40°C at a rate of 15°C / hour for 1 hour.

[0043] The paclitaxel albumin freeze-dried powder injection finally prepared in the above Examples 1-4 and Comparative Examples 1-2 was subjected to 100% appearance inspection by light, residual solvent was tested by GC chromatograph, and water content was tested by Karl Fischer method. The test results are shown in Table 1 below. The water content standard of paclitaxel albumin freeze-dried powder injection in this industry is: ≤3%, and the residual solvent standard is: ≤0.075%.

[0044] Table 1 Test results of appearance, residual solvent and moisture

[0045] It can be seen from Table 1 above that the key quality attributes of the freeze-drying process: the appearance, residual solvents and moisture of the samples all meet the quality requirements, and qualified paclitaxel albumin freeze-dried powder injection can be produced by the processes of Examples 1 to 4. From the results of the control example, it can be seen that the product produced by the process parameters of the control example does not meet the quality requirements and cannot produce qualified products.

[0046] The above description of the disclosed embodiments enables one skilled in the art to implement or use the present invention. Various modifications to these embodiments will be apparent to one skilled in the art, and the general principles defined herein may be implemented in other embodiments without departing from the spirit or scope of the present invention. Therefore, the present invention will not be limited to the embodiments shown herein, but rather to the widest scope consistent with the principles and novel features disclosed herein.

Claims

1. A paclitaxel albumin pre-lyophilized liquid preparation, characterized in that: The composition is composed of the following components by mass percentage: paclitaxel 1.5-3.0%, human serum albumin 15-30%, anhydrous ethanol 0-0.2%, water for injection 0-3%, sodium octanoate 1.22-1.61%, N-acetyl-L-tryptophan 1.82-2.36%, and pH adjuster 0-0.4%.

2. The paclitaxel albumin pre-lyophilized liquid preparation according to claim 1, characterized in that: The paclitaxel, human serum albumin, anhydrous ethanol, water for injection, sodium octanoate, N-acetyl-L-tryptophan and pH regulator are all of pharmaceutical grade.

3. The paclitaxel albumin pre-lyophilized liquid preparation according to claim 1, characterized in that: The pH regulator is sodium hydroxide and dilute hydrochloric acid.

4. A method for preparing a paclitaxel albumin pre-lyophilized liquid preparation according to any one of claims 1 to 3, characterized in that: The steps are as follows: S101, first dissolving paclitaxel using anhydrous ethanol, and then respectively introducing the human albumin aqueous solution and the paclitaxel ethanol solution into an emulsifying disperser at a certain flow rate for high-speed shearing; S102, after the shearing is completed, the temperature is lowered to room temperature for dialysis; S103, after the dialysis is completed, sodium octanoate and N-acetyl L-tryptophan are first added as albumin stabilizers, and then a pH regulator is added to adjust the pH value of the entire solution; S104, final sterilization and filtration to complete the preparation of the drug solution, and obtain the paclitaxel albumin pre-lyophilized liquid preparation.

5. The method for preparing the paclitaxel albumin pre-lyophilized liquid preparation according to claim 4, characterized in that: In step S101, the flow rate of the human albumin aqueous solution is 3-4.5 L / min, and the flow rate of the paclitaxel ethanol solution is 70-100 ml / min.

6. The method for preparing the paclitaxel albumin pre-lyophilized liquid preparation according to claim 4, characterized in that: In step S101, the flow rate of the emulsifying disperser is controlled at 1000-5000 rpm.

7. The method for preparing the paclitaxel albumin pre-lyophilized liquid preparation according to claim 4, characterized in that: The pH value in step S103 is 6.4-7.

4.

8. A freeze-drying method for a paclitaxel albumin pre-freeze-dried liquid preparation prepared by the preparation method of the paclitaxel albumin pre-freeze-dried liquid preparation according to any one of claims 1 to 3 or any one of claims 4 to 7, characterized in that: The steps are as follows: S201, pre-freezing: using a freeze dryer to cool the paclitaxel albumin solution to below -50°C, and maintaining the temperature for 0.5 to 3.5 hours for pre-freezing; S202, using the vacuum pump of the freeze dryer, start to evacuate the inside of the freeze dryer, and maintain the vacuum degree at no more than 40Pa; S203, slowly raising the oil temperature to 40° C. in a staged manner for 19 to 41 hours; S204, analytical drying: maintaining the oil temperature at 40°C, and controlling the vacuum of the freeze dryer to 0-5 Pa for 3-7 hours; S205, turning off the vacuum pump to stop the vacuum, and then performing negative pressure plugging on the paclitaxel albumin freeze-dried powder injection that has been freeze-dried and sublimated, and after confirming that the rubber plug is tightly pressed, transferring the paclitaxel albumin freeze-dried powder injection to the freeze dryer for capping.

9. The freeze-drying method of the paclitaxel albumin pre-freeze-dried liquid preparation according to claim 8, characterized in that: The specific method of stage heating in step S203 is: S2031, raising the oil temperature to -10°C at a rate of 10-40°C / hour for 1-4 hours; S2032, raising the oil temperature to 0°C at a rate of 1.25-2.5°C / hour for 4-8 hours; S2033, raising the oil temperature to 10°C at a rate of 1.25-2.5°C / hour for 4-8 hours; S2034, raising the oil temperature to 15°C at a rate of 0.7-1.7°C / hour for 3-7 hours; S2035, raising the oil temperature to 20°C at a rate of 0.7-1.7°C / hour for 3-7 hours; S2036, raising the oil temperature to 25°C at a rate of 1°C / hour for 3 to 5 hours; S2037. Raise the oil temperature to 40°C at a rate of 15°C / hour for 1 to 2 hours.

Images