Continuous ultrafiltration system for paclitaxel albumin nanoparticle preparation

Abstract

The utility model provides a paclitaxel albumin nanoparticle preparation continuous ultrafiltration system which comprises a first SPTFF ultrafiltration module, a constant-flow water replenishing device and a static mixer, and a three-way valve is arranged on a connecting pipeline of an inlet of the static mixer. The three-way valve is respectively connected with an inlet of the static mixer, an outlet of the first SPTFF ultrafiltration module and an outlet of the constant-flow water replenishing device; and an inlet of the second SPTFF ultrafiltration module is connected with an outlet of the static mixer. According to the continuous ultrafiltration system for the paclitaxel albumin nanoparticle preparation, provided by the utility model, the front-end feeding amount can be adjusted according to the production batch, and the original fixed process can be adjusted into a linear process within a registration range, so that the flexibility of the production process is improved; when the system is used for production, liquid medicine emulsified and homogenized at the front end can be subjected to ultrafiltration concentration and elution in real time to a subsequent process, and extra waiting is not needed; and moreover, the frequency of manually switching on and off the ultrafiltration system is reduced, and the risk of misoperation of personnel is reduced.

Description

Technical Field

[0001] The utility model belongs to the technical field of biological albumin, and in particular relates to a continuous ultrafiltration system for a paclitaxel albumin nanoparticle preparation. Background Art

[0002] Paclitaxel is a natural anticancer drug with a molecular formula of C 47 H 51 NO 14 , white crystalline powder, odorless, tasteless, insoluble in water, easily soluble in organic solvents such as methanol, acetonitrile, chloroform, acetone, etc. Up to now, the approved indications of 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, and the previous chemotherapy should include an anthracycline anticancer drug; Abraxane's indications approved by FDA and EMA include breast cancer, non-small cell lung cancer and pancreatic cancer; the indications approved in Japan include breast cancer, non-small cell lung cancer, gastric cancer and pancreatic cancer; the indications under development include ovarian cancer, etc.

[0003] Due to its physical properties, paclitaxel is insoluble in water but soluble in other organic solvents. At present, the processes of other companies in clinical application products use polyoxyethylene castor oil and ethanol as API solvents, which are highly allergenic and restrictive, causing many inconveniences to patients and doctors during use. Therefore, technicians have successfully developed a paclitaxel albumin nanoparticle preparation with higher bioavailability through process research and improvement: the improved process no longer uses highly allergenic polyoxyethylene castor oil, but only uses anhydrous ethanol to assist in dissolution, and in the later stage of production, the solvent ethanol used to dissolve the auxiliary raw materials is removed by reduced pressure evaporation or thin film evaporation, which greatly improves the safety of the product.

[0004] At present, the main method for removing organic solvents from liquid medicine is distillation. This method requires the liquid medicine itself to be heat-resistant, the boiling point of the organic solvent in the liquid medicine components needs to have a gradient, the organic solvent needs to be miscible with water, and it needs to be distilled out together with water vapor without destroying the original components. In summary: the existing method of removing organic solvents from solutions has high requirements on the properties of the liquid medicine itself, and is not suitable for the preparation and production of heat-sensitive drugs.

[0005] Chinese patent CN03108361 discloses a "method for preparing nanoparticles of paclitaxel and albumin", which shares a method for preparing nanoparticles of paclitaxel and albumin with anti-tumor properties. In this method, the mixture obtained by adding powdered paclitaxel to an aqueous solution of albumin and chloroform is subjected to high-pressure homogenization treatment, and then the solvent in the solution is removed by long-term rotary evaporation to achieve the requirements for preparing paclitaxel albumin nanoparticles.

[0006] According to the previous process, when paclitaxel albumin nanoparticles are prepared to the ultrafiltration stage, a long period of drug solution collection is required. The traditional ultrafiltration TFF tangential flow ultrafiltration can only be started after the liquid level in the collection tank at the front end of the ultrafiltration reaches the requirement. The drug solution collection needs to last about 3 hours.

[0007] The drug solution needs to go through the process of first concentration → manual stop of the equipment to replenish water → first elution → manual stop of the equipment to replenish water → second elution → manual stop of the equipment to replenish water → third elution to finally obtain the paclitaxel albumin nanoparticle preparation of qualified quality. During the ultrafiltration process, the operator is required to manually stop the equipment three times according to the process range and replenish water. There is a lot of manual intervention and the operation is cumbersome, and there is a risk of human error.

[0008] In the preparation process of paclitaxel albumin nanoparticles, the drug solution is weighed and fed into the preparation tank, and then the components are mixed uniformly to form nanoparticles through a stirring emulsification homogenization process, and then transferred to a subsequent collection tank and TFF tangential flow ultrafiltration is started to remove ethanol. The above method requires interrupting production to carry out the ethanol removal process separately. There are three main disadvantages of interrupting production to carry out the ethanol removal process separately:

[0009] 1. Interrupting production and carrying out the ethanol removal process alone will extend the production time. Paclitaxel albumin nanoparticles are unstable during the preparation of the drug solution, which will have a certain impact on the quality of the product;

[0010] 2. Carrying out the above ethanol removal process will cause production interruption and discontinuity, which will have a certain impact on production efficiency;

[0011] 3. Pharmaceutical production is moving towards information-based, automated, and continuous production. The degree of automation in the above methods needs to be improved, and they cannot adapt to the future environment of intelligent and continuous manufacturing of products.

[0012] In summary, the disadvantages of the existing technology are mainly that the waiting time in the production process is long, the quality of paclitaxel albumin nanoparticle preparations is at risk; there are many human intervention operations, and there is a risk of human error. Utility Model Content

[0013] In view of this, the technical problem to be solved by the utility model is to provide a continuous ultrafiltration system for paclitaxel albumin nanoparticle preparation. The continuous ultrafiltration system provided by the utility model can ultrafilter, concentrate and elute the front-end emulsified and homogenized drug solution in real time to the subsequent process without the need for additional waiting, and reduces the frequency of manual switching of the ultrafiltration system, reducing the risk of human error operation.

[0014] The utility model provides a paclitaxel albumin nanoparticle preparation continuous ultrafiltration system, comprising:

[0015] The first SPTFF ultrafiltration module;

[0016] Constant flow water replenishment device;

[0017] A static mixer, wherein a three-way valve is provided on the connecting pipeline at the inlet of the static mixer, and the three-way valve is respectively connected to the inlet of the static mixer, the outlet of the first SPTFF ultrafiltration module and the outlet of the constant flow water replenishment device;

[0018] A second SPTFF ultrafiltration module having an inlet connected to the outlet of the static mixer.

[0019] Preferably, the volume of the first SPTFF ultrafiltration module is 40m 3 .

[0020] Preferably, the first SPTFF ultrafiltration module uses 5-stage ultrafiltration membrane packages in series, with a membrane package combination with a membrane area ratio of 3:2:2:1:1 from front to back, and a total membrane area of ​​40m 2 .

[0021] Preferably, the first SPTFF ultrafiltration module comprises a reflux valve for adjusting TMP control.

[0022] Preferably, the pump speed of the first SPTFF ultrafiltration module is 100-160 rpm, the inlet pressure is 9.0-11.0 psi, the reflux pressure is 0.5-1.0 psi, and the TMP is 3.0-5.0 psi.

[0023] Preferably, the volume of the second SPTFF ultrafiltration module is 40m 3 .

[0024] Preferably, the second SPTFF ultrafiltration module uses a 5-stage ultrafiltration membrane package in series, with a membrane package combination with a membrane area ratio of 3:2:2:1:1 from front to back, and a total membrane area of ​​40m 2 .

[0025] Preferably, the second SPTFF ultrafiltration module comprises a reflux valve for adjusting TMP control.

[0026] Preferably, the pump speed of the second SPTFF ultrafiltration module is 50-100 rpm, the inlet pressure is 9.0-13.0 psi, the reflux pressure is 2.0-6.0 psi, and the TMP is 5.0-9.0 psi.

[0027] Preferably, a pre-filter is also provided at the inlet end of the first SPTFF ultrafiltration module.

[0028] Compared with the prior art, the utility model provides a paclitaxel albumin nanoparticle preparation continuous ultrafiltration system, including: a first SPTFF ultrafiltration module; a constant flow water replenishment device; a static mixer, a three-way valve is provided at the connecting pipeline of the inlet of the static mixer, and the three-way valve is respectively connected to the inlet of the static mixer, the outlet of the first SPTFF ultrafiltration module and the outlet of the constant flow water replenishment device; a second SPTFF ultrafiltration module whose inlet is connected to the outlet of the static mixer. The paclitaxel albumin nanoparticle preparation continuous ultrafiltration system provided by the utility model can adjust the front-end feed amount according to the production batch, and can adjust the original fixed process to a linear process within the registration range, thereby increasing the flexibility of the production process; using the system for production, the front-end emulsified and homogenized liquid can be ultrafiltered, concentrated and eluted to the subsequent process in real time without additional waiting; and the system reduces the frequency of manual switching of the ultrafiltration system, and reduces the risk of personnel misoperation. The system can perfectly connect paclitaxel (albumin-bound) for injection in series, and there is no waiting time between each section, and all sections are continuously operated, thereby improving production efficiency. BRIEF DESCRIPTION OF THE DRAWINGS

[0029] Figure 1 This is a schematic structural diagram of a continuous ultrafiltration system for a paclitaxel albumin nanoparticle preparation provided by the utility model. DETAILED DESCRIPTION

[0030] The utility model provides a paclitaxel albumin nanoparticle preparation continuous ultrafiltration system, comprising:

[0031] The first SPTFF ultrafiltration module;

[0032] Constant flow water replenishment device;

[0033] A static mixer, wherein a three-way valve is provided on the connecting pipeline at the inlet of the static mixer, and the three-way valve is respectively connected to the inlet of the static mixer, the outlet of the first SPTFF ultrafiltration module and the outlet of the constant flow water replenishment device;

[0034] A second SPTFF ultrafiltration module having an inlet connected to the outlet of the static mixer.

[0035] See also Figure 1 , Figure 1 This is a schematic structural diagram of a continuous ultrafiltration system for a paclitaxel albumin nanoparticle preparation provided by the utility model.

[0036] The utility model provides a paclitaxel albumin nanoparticle preparation continuous ultrafiltration system comprising a first SPTFF ultrafiltration module, wherein the inlet of the first SPTFF ultrafiltration module is connected to a drug delivery system of the paclitaxel albumin nanoparticle preparation liquid after front-end emulsification and homogenization.

[0037] Preferably, in order to improve the concentration effect of the drug solution in the first SPTFF ultrafiltration module, a pre-filter is also provided at the inlet end of the first SPTFF ultrafiltration module, and the pre-filter is arranged between the inlet of the first SPTFF ultrafiltration module and the outlet of the drug delivery system, and is used to pre-filter the paclitaxel albumin nanoparticle preparation drug solution after the front-stage emulsification and homogenization before entering the first SPTFF ultrafiltration module.

[0038] In the present invention, the volume of the first SPTFF ultrafiltration module is 40m 3 .

[0039] The first SPTFF ultrafiltration module uses a 5-stage ultrafiltration membrane package in series, with a membrane package combination with a membrane area ratio of 3:2:2:1:1 from front to back, and a total membrane area of ​​40m 2 .

[0040] In some specific embodiments of the present invention, the first SPTFF ultrafiltration module includes a reflux valve for adjusting TMP control. Preferably, the pump speed of the first SPTFF ultrafiltration module is 100-160 rpm, which can be 100, 110, 120, 130, 140, 150, 160, or any value between 100-160 rpm; the inlet pressure is 9.0-11.0 psi, which can be 9, 9.5, 10, 10.5, 11, or any value between 9.0-11.0 psi; the reflux pressure is 0.5-1.0 psi, which can be 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, or any value between 0.5-1.0 psi; TMP is 3.0-5.0 psi, which can be 3.0, 3.5, 4.0, 4.5, 5.0, or any value between 3.0-5.0 psi.

[0041] In the utility model, the paclitaxel albumin nanoparticle preparation continuous ultrafiltration system further comprises a constant flow water replenishing device, and the constant flow water replenishing device is used to replenish water for injection.

[0042] The paclitaxel albumin nanoparticle preparation continuous ultrafiltration system also includes a static mixer, and a three-way valve is provided on the connecting pipe at the inlet of the static mixer, and the three-way valve is respectively connected to the inlet of the static mixer, the outlet of the first SPTFF ultrafiltration module and the outlet of the constant flow water replenishment device.

[0043] The water for injection in the constant flow water replenishment device is mixed with the concentrated drug solution in the first SPTFF ultrafiltration module in the static mixer.

[0044] In the utility model, in order to accurately control the mixing amount of injection water and liquid medicine, a first flow meter is arranged between the first SPTFF ultrafiltration module and the tee of the static mixer; a second flow meter is arranged between the constant flow water replenishment device and the tee of the static mixer.

[0045] The paclitaxel albumin nanoparticle preparation continuous ultrafiltration system further comprises a second SPTFF ultrafiltration module whose inlet is connected to the outlet of the static mixer.

[0046] In the present invention, the volume of the second SPTFF ultrafiltration module is 40m 3 .

[0047] The second SPTFF ultrafiltration module uses a 5-stage ultrafiltration membrane package in series, with a membrane package combination with a membrane area ratio of 3:2:2:1:1 from front to back, and a total membrane area of ​​40m 2 .

[0048] In some specific embodiments of the present invention, the second SPTFF ultrafiltration module includes a reflux valve for adjusting TMP control. Preferably, the pump speed of the second SPTFF ultrafiltration module is 50-100 rpm, which can be 50, 60, 70, 80, 90, 100, or any value between 50-100 rpm; the inlet pressure is 9.0-13.0 psi, which can be 9, 10, 11, 12, 13, or any value between 9.0-13.0 psi; the reflux pressure is 2.0-6.0 psi, which can be 2.0, 3.0, 4.0, 5.0, 6.0, or any value between 2.0-6.0 psi, and the TMP is 5.0-9.0 psi, which can be 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, or any value between 5.0-9.0 psi.

[0049] In the second SPTFF ultrafiltration module, the solvent in the drug solution is eluted.

[0050] The paclitaxel albumin nanoparticle preparation continuous ultrafiltration system provided by the utility model increases the contact area between the drug solution and the membrane package by changing the flow channel of the original TFF tangential flow ultrafiltration process, and achieves the original ultrafiltration process The first concentration multiple is achieved by controlling the transmembrane pressure, the inlet end pressure, and the permeate end pressure during the ultrafiltration process, and the concentrated drug solution is transported to the rear end at a constant flow rate. After the drug solution after the front-end emulsification and homogenization enters the first SPTFF ultrafiltration module directly without waiting to complete the first concentration, a set of constant flow water replenishment devices, a static mixer for auxiliary drug solution mixing, and a second SPTFF ultrafiltration module are added according to the ultrafiltration rear end delivery flow rate, and the effect of improving the previous multiple ultrafiltration elutions is achieved through one water replenishment and then elution, that is, the drug solution produced after one water replenishment and elution is the drug solution after the end of the previous ultrafiltration process.

[0051] In the present invention, the first SPTFF ultrafiltration membrane group uses a 5-stage ultrafiltration membrane package in series, with a membrane package combination with a membrane area ratio of 3:2:2:1:1 from front to back, and a total membrane area of ​​40m 2 . Adjust the reflux valve for TMP control, and wait until the system pressure reading stabilizes after adjustment. The first SPTFF ultrafiltration membrane group can achieve the concentration requirements of the drug solution when the pump speed is 100-160rpm and the TMP is 3.0-5.0psi, and the specific concentration multiple is about 12-13 times. Then, using the same process method, the second SPTFF ultrafiltration membrane group can achieve a concentration multiple of 10 times when the pump speed is 50-100rpm and the TMP is 5.0-9.0psi. Based on the determination process of the first SPTFF process parameters, the second SPTFF ultrafiltration module process is determined synchronously.

[0052] The utility model provides a continuous ultrafiltration system that can adapt to the front-end linear process and save preparation time, which has the following advantages:

[0053] 1. The system can adjust the front-end feeding amount according to the production batch, and can adjust the original fixed process to a linear process within the registration range to increase the flexibility of the production process;

[0054] 2. The system can be used for production, and the front-end emulsified and homogenized liquid can be ultrafiltered, concentrated and eluted to the subsequent process in real time without additional waiting;

[0055] 3. The continuous ultrafiltration system reduces the frequency of manual switching of the ultrafiltration system and reduces the risk of human error.

[0056] 4. This system can perfectly connect paclitaxel for injection (albumin-bound), and there is no waiting time between each process section. All process sections run continuously, which improves production efficiency.

[0057] At the same time, the utility model also provides a method for continuous ultrafiltration of paclitaxel albumin nanoparticle preparation, comprising the following steps:

[0058] A) The drug solution after the front-stage emulsification and homogenization directly enters the first SPTFF ultrafiltration module to complete the first concentration to obtain the concentrated drug solution;

[0059] B) The concentrated drug solution is mixed with water provided by a constant flow water replenishing device in a static mixer, and then enters a second SPTFF ultrafiltration module to obtain a paclitaxel albumin nanoparticle preparation.

[0060] Specifically, the utility model firstly allows the drug solution after the front-stage emulsification and homogenization to directly enter the first SPTFF ultrafiltration module to complete the first concentration, wherein the drug solution after the front-stage emulsification and homogenization completes the first concentration multiple of 12 to 13 times.

[0061] Then, the concentrated liquid medicine is mixed with water provided by a constant flow water replenishing device in a static mixer to obtain a mixed liquid, so that the volume ratio of the concentrated liquid medicine to water reaches about 1:21.

[0062] Next, the mixed solution enters the second SPTFF ultrafiltration module to obtain a paclitaxel albumin nanoparticle preparation.

[0063] Among them, the concentration multiple of the obtained paclitaxel albumin nanoparticle preparation is 10 times;

[0064] The pump speed of the first SPTFF ultrafiltration module is 100-160 rpm, which can be 100, 110, 120, 130, 140, 150, 160, or any value between 100 and 160 rpm; the inlet pressure is 9.0-11.0 psi, which can be 9, 9.5, 10, 10.5, 11, or any value between 9.0 and 11.0 psi; the reflux pressure is 0.5-1.0 psi, which can be 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, or any value between 0.5 and 1.0 psi; TMP is 3.0-5.0 psi, which can be 3.0, 3.5, 4.0, 4.5, 5.0, or any value between 3.0 and 5.0 psi.

[0065] Based on the process of determining the first-stage SPTFF process parameters, the second-stage SPTFF ultrafiltration module process is simultaneously determined.

[0066] The pump speed of the second SPTFF ultrafiltration module is 50-100 rpm, which can be 50, 60, 70, 80, 90, 100, or any value between 50 and 100 rpm; the inlet pressure is 9.0-13.0 psi, which can be 9, 10, 11, 12, 13, or any value between 9.0 and 13.0 psi; the reflux pressure is 2.0-6.0 psi, which can be 2.0, 3.0, 4.0, 5.0, 6.0, or any value between 2.0 and 6.0 psi, and the TMP is 5.0-9.0 psi, which can be 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, or any value between 5.0 and 9.0 psi.

[0067] In the present invention, the production time of step A) and step B) is 3 to 4 hours.

[0068] In the utility model, after the front-stage emulsification and homogenization, the medicinal liquid directly enters the first SPTFF ultrafiltration module to complete the first concentration without waiting. Then, a set of constant-flow water replenishment device, a static mixer for auxiliary medicinal liquid mixing and a second SPTFF ultrafiltration module are added according to the ultrafiltration rear-end delivery flow rate. Through one water replenishment and then elution, the effect of improving the previous multiple ultrafiltration elutions is achieved, that is, the medicinal liquid produced after one water replenishment and elution is the improved medicinal liquid after the end of the previous ultrafiltration section.

[0069] The utility model provides a method for continuous ultrafiltration of paclitaxel albumin nanoparticle preparations, which changes from the previous method of collecting the front-end drug solution and temporarily storing it to a certain amount before carrying out subsequent production to a method of simultaneously carrying out multiple processes. In addition, the utility model greatly reduces the intervention of personnel in the operation of the equipment preparation program, basically realizes the prototype of continuous drug manufacturing, and reduces the risk of personnel intervention.

[0070] In order to further understand the present invention, the paclitaxel albumin nanoparticle preparation continuous ultrafiltration system provided by the present invention is described below in conjunction with the examples. The protection scope of the present invention is not limited by the following examples.

[0071] Example 1

[0072] This embodiment provides a paclitaxel albumin nanoparticle preparation continuous ultrafiltration system, comprising:

[0073] The first SPTFF ultrafiltration module;

[0074] Constant flow water replenishment device;

[0075] A static mixer, wherein a three-way valve is provided on the connecting pipeline at the inlet of the static mixer, and the three-way valve is respectively connected to the inlet of the static mixer, the outlet of the first SPTFF ultrafiltration module and the outlet of the constant flow water replenishment device;

[0076] A second SPTFF ultrafiltration module having an inlet connected to the outlet of the static mixer.

[0077] Among them, the volume of the first SPTFF ultrafiltration module is 40m 3 The first SPTFF ultrafiltration module uses 5-stage ultrafiltration membrane packages in series, with a membrane package combination with a membrane area ratio of 3:2:2:1:1 from front to back, and a total membrane area of ​​40m 2 .

[0078] The first SPTFF ultrafiltration module includes a reflux valve for adjusting TMP control. The pump speed of the first SPTFF ultrafiltration module is 120 rpm, the inlet pressure is 10.0 psi, the reflux pressure is 0.8 psi, and the TMP is 4.1 psi.

[0079] The volume of the second SPTFF ultrafiltration module is 40m3 The second SPTFF ultrafiltration module uses a 5-stage ultrafiltration membrane package in series, with a membrane package combination with a membrane area ratio of 3:2:2:1:1 from front to back, and a total membrane area of ​​40m 2 .

[0080] The second SPTFF ultrafiltration module includes a reflux valve for adjusting TMP control. The pump speed of the second SPTFF ultrafiltration module is 70 rpm, the inlet pressure is 10 psi, the reflux pressure is 3 psi, and the TMP is 6 psi.

[0081] The first SPTFF ultrafiltration membrane group can achieve the concentration requirement of the drug solution when the pump speed is 120rpm and the TMP is 4.1psi, and the specific concentration multiple is about 12 to 13 times. Then, using the same process method, the second SPTFF ultrafiltration membrane group can achieve a concentration multiple of 10 times when the pump speed is 70rpm and the TMP is 6psi.

[0082] The water for injection in the constant flow water replenishment device is mixed with the concentrated drug solution in the first SPTFF ultrafiltration module in a static mixer, and the volume ratio of the concentrated drug solution to water is 1:21.

[0083] A pre-filter is also provided at the inlet end of the first SPTFF ultrafiltration module.

[0084] Comparative Example

[0085] When the preparation of paclitaxel albumin nanoparticles reaches the ultrafiltration stage, a long period of drug solution collection is required. The traditional ultrafiltration TFF tangential flow ultrafiltration can only be started after the liquid level in the collection tank at the front end of the ultrafiltration reaches the requirement. The drug solution collection needs to last about 3 hours.

[0086] The drug solution needs to go through the process of first concentration → manual stop of the equipment to replenish water → first elution → manual stop of the equipment to replenish water → second elution → manual stop of the equipment to replenish water → third elution to finally obtain the paclitaxel albumin nanoparticle preparation of qualified quality. During the ultrafiltration process, the operator needs to manually stop the equipment three times according to the process range and replenish water.

[0087] The above process route and parameters were used to produce albumin paclitaxel nanoparticles. The key quality attributes of the produced drug solution were tested by sampling and compared with the quality indicators before improvement to ensure that the continuous ultrafiltration mode would not affect the key CQA of the product. The comparison results are shown in Table 1:

[0088] Table 1

[0089]

[0090] In Table 1, the concentrate before improvement (1), the concentrate before improvement (2) and the concentrate before improvement (3) respectively represent three parallel tests conducted using the process of the comparative example.

[0091] SPTFF concentrate (1), SPTFF concentrate (2), and SPTFF concentrate (2) represent three parallel experiments conducted using the process of the embodiment.

[0092] It can be seen from the data in the table that the quality of the drug solution after improving the ultrafiltration module is basically consistent with the control ratio before improvement, both meet the product quality standards, the production time is shortened by about 1 hour, and the temporary storage time of the drug solution is greatly shortened, which can better ensure product stability.

[0093] Comparative Example 2

[0094] During the parameter exploration process, the pump speed of the first SPTFF ultrafiltration module was controlled at 100-160 rpm, the inlet pressure = 11.0-13.0 psi, the reflux pressure = 6.3-8.0 psi, and TMP = 0-2.0 psi to concentrate the drug solution. The same concentration parameters as those of the SPTFF in Example were used for ultrafiltration concentration. The drug solution concentrated within the above process range was sampled and tested. The test results showed that the paclitaxel content and the human serum albumin content were both lower than the product quality requirements.

[0095] Comparative Example 3

[0096] Referring to the concentration process of Comparative Example 2, the first SPTFF ultrafiltration module reduced the pump speed to 60-100 rpm, the inlet pressure was controlled at 7.0-10.0 psi, the reflux pressure was 4.0-5.5 psi, and TMP was 1.2-3.0 psi for concentration. The concentrated drug solution within the above process range was sampled and tested. The test results showed that the paclitaxel content, human serum albumin content, residual solvent, etc. were all higher than the product quality requirements.

[0097] The paclitaxel albumin nanoparticle preparation continuous ultrafiltration system provided by the utility model changes the production mode from the previous method of collecting the front-end drug solution and temporarily storing it to a certain amount before carrying out subsequent production to the simultaneous implementation of multiple processes. In addition, the utility model greatly reduces the intervention of personnel in the operation of the equipment preparation program, basically realizes the prototype of continuous drug manufacturing, and reduces the risk of personnel intervention.

[0098] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principle of the present invention. These improvements and modifications should also be regarded as the protection scope of the present invention.

Claims

1. A paclitaxel albumin nanoparticle preparation continuous ultrafiltration system, characterized in that: include: The first SPTFF ultrafiltration module; Constant flow water replenishment device; A static mixer, wherein a three-way valve is provided on the connecting pipeline at the inlet of the static mixer, and the three-way valve is respectively connected to the inlet of the static mixer, the outlet of the first SPTFF ultrafiltration module and the outlet of the constant flow water replenishment device; A second SPTFF ultrafiltration module having an inlet connected to the outlet of the static mixer.

2. The continuous ultrafiltration system according to claim 1, characterized in that: The volume of the first SPTFF ultrafiltration module is 40m 3 .

3. The continuous ultrafiltration system according to claim 1, characterized in that: The first SPTFF ultrafiltration module uses a 5-stage ultrafiltration membrane package in series, with a membrane package combination with a membrane area ratio of 3:2:2:1:1 from front to back, and a total membrane area of ​​40m 2 .

4. The continuous ultrafiltration system according to claim 1, characterized in that The first SPTFF ultrafiltration module includes a reflux end valve for adjusting TMP control.

5. The continuous ultrafiltration system according to claim 4, characterized in that: The pump speed of the first SPTFF ultrafiltration module is 100-160 rpm, the inlet pressure is 9.0-11.0 psi, the reflux pressure is 0.5-1.0 psi, and the TMP is 3.0-5.0 psi.

6. The continuous ultrafiltration system according to claim 1, characterized in that: The volume of the second SPTFF ultrafiltration module is 40m 3 .

7. The continuous ultrafiltration system according to claim 1, characterized in that: The second SPTFF ultrafiltration module uses a 5-stage ultrafiltration membrane package in series, with a membrane package combination with a membrane area ratio of 3:2:2:1:1 from front to back, and a total membrane area of ​​40m 2 .

8. The continuous ultrafiltration system according to claim 1, characterized in that: The second SPTFF ultrafiltration module includes a reflux end valve for adjusting TMP control.

9. The continuous ultrafiltration system according to claim 8, characterized in that: The pump speed of the second SPTFF ultrafiltration module is 50-100 rpm, the inlet pressure is 9.0-13.0 psi, the reflux pressure is 2.0-6.0 psi, and the TMP is 5.0-9.0 psi.

10. The continuous ultrafiltration system according to claim 1, characterized in that: A pre-filter is also provided at the inlet end of the first SPTFF ultrafiltration module.

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