Apparatus and method for continuous preparation of paclitaxel albumin nanoparticles

Abstract

This invention provides a method for the continuous preparation of paclitaxel albumin nanoparticles, comprising the following steps: A) Paclitaxel raw material is fed into an emulsification device at a first rate of 80-90 ml / min; albumin aqueous solution is fed into the emulsification device at a second rate of 3-4 L / min; B) Paclitaxel raw material and albumin aqueous solution are emulsified and sheared to complete drug loading, thus obtaining the nanoparticles. In this method, the paclitaxel organic solvent and human serum albumin aqueous solution are continuously introduced, allowing for continuous emulsification and shearing. The emulsification and shearing effect is consistent every minute, and the production batch size is only related to time. The batch size is determined by controlling the emulsification and shearing time, and the product uniformity is not affected by the batch size. This invention solves the problem that current paclitaxel nanoparticle preparation processes cannot achieve continuous manufacturing, improving system flexibility; and addresses the problems of batch dependence on equipment and difficulty in batch expansion.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical synthesis technology, and in particular to an apparatus and method for the continuous preparation of paclitaxel albumin nanoparticles. Background Technology

[0002] Paclitaxel possesses a unique antitumor mechanism, primarily acting on tubulin. Tubulin is a component of the cytoskeleton in all eukaryotic cells and a crucial part of the spindle apparatus during cell division. Paclitaxel increases tubulin content in cells by inducing and stabilizing tubulin polymerization and inhibiting its normal physiological depolymerization. During cell division, this increased tubulin leads to a reduction in spindle microtubules, preventing the formation of spindle fibers and the spindle apparatus. Consequently, cancer cell division is permanently arrested in the G2 and M phases, hindering replication and ultimately leading to apoptosis. Clinically, paclitaxel is used alone or in combination with other antitumor drugs, mainly for the treatment of breast cancer, ovarian cancer, non-small cell lung cancer, and pancreatic cancer.

[0003] Currently, there are four main types of taxane drugs: paclitaxel injection, docetaxel (docetaxel), liposomal paclitaxel (paclitaxel liposome for injection), and albumin-bound paclitaxel (paclitaxel for injection (Albumin Bound)). The first two are traditional paclitaxel formulations. Because taxane drugs are poorly soluble in water, paclitaxel and docetaxel use polyoxyethylene castor oil and Tween 80, respectively, as solubilizers to increase solubility. The blocking effect of the solvent on endocytosis and the toxicity of the solvent itself result in low bioavailability and tolerability of paclitaxel, requiring pre-treatment with anti-allergy medication and prolonged infusion time. Paclitaxel liposomes also require pre-treatment with dexamethasone and antihistamines before use. Albumin-bound paclitaxel (Nab-P) is a novel nano-formulation of paclitaxel and is internationally recognized as the most advanced paclitaxel formulation. This nanoparticles, synthesized by non-covalently binding endogenous human serum albumin to paclitaxel, completely overcome the water-insoluble drawback of paclitaxel, eliminating the need for polyoxyethylene castor oil or Tween 80 as a solubilizer. Since albumin is an endogenous natural product, it possesses advantages such as safety, non-toxicity, non-immunogenicity, biodegradability, and good biocompatibility. Albumin-bound paclitaxel, using human albumin as a carrier, leverages the unique advantages of particle size to fully utilize the efficient penetration and retention of nanoparticles, exhibiting an EPR passive targeting effect and offering advantages such as better efficacy, excellent water solubility, minimal toxicity, and targeted efficacy.

[0004] Currently, among the albumin-bound paclitaxel products marketed in China, the preparation process of paclitaxel albumin nanoparticles involves mixing an albumin solution of a certain concentration with a paclitaxel organic solution of a certain concentration, followed by stirring and shearing. Then, through thin-film evaporation by controlling the jacket temperature of the mixing tank, a solution of paclitaxel bound to human serum albumin is obtained. This production process has the following drawbacks: 1. Thin-film evaporation requires a mixing tank of a certain volume depending on the batch size. When scaling up production, the batch size and tank volume cannot be increased proportionally. The tank size (including diameter and height) needs to be redesigned based on the batch size and the distribution of the drug solution within the tank, involving a huge workload of readjusting process parameters; 2. Continuous production cannot be achieved. When preparing paclitaxel albumin nanoparticles through thin-film evaporation, subsequent production can only continue after the thin-film evaporation step is completed.

[0005] Therefore, it is essential to provide a method for the continuous preparation of paclitaxel albumin nanoparticles. Summary of the Invention

[0006] In view of this, the technical problem to be solved by the present invention is to provide a method for the continuous preparation of paclitaxel albumin nanoparticles, which can realize the large-scale continuous preparation of paclitaxel albumin nanoparticles.

[0007] This invention provides an apparatus for the continuous preparation of paclitaxel albumin nanoparticles, comprising:

[0008] The outlets of the water for injection unit and the albumin storage unit are connected to the inlet of the insulation coil via a static mixer.

[0009] The outlet of the insulated coil is connected to the first inlet of the emulsifying device;

[0010] The outlet of the paclitaxel feedstock storage device is connected to the second inlet of the emulsification device;

[0011] The outlet of the emulsification device is connected to the inlet of the collection device.

[0012] The preferred emulsification device is an inline shear disperser.

[0013] This invention provides a method for the continuous preparation of paclitaxel albumin nanoparticles, comprising the following steps:

[0014] A) Paclitaxel feedstock is fed to the emulsification unit at a first rate of 80-90 ml / min;

[0015] The albumin aqueous solution is fed to the emulsification device at a second rate of 3-4 L / min.

[0016] B) Paclitaxel raw material and albumin aqueous solution are emulsified and sheared to complete drug loading, thus obtaining the drug.

[0017] Preferably, the rotation speed of the emulsification shearing in step B) is 2000~3000 r / min.

[0018] Preferably, the conveying temperature of the paclitaxel raw material is 20~30℃.

[0019] Preferably, the albumin aqueous solution is transported at a temperature of 60~70℃.

[0020] Preferably, the first rate is 82~88 ml / min.

[0021] Preferably, the second speed is 3.2~3.8 L / min.

[0022] Preferably, the mass concentration of paclitaxel in the paclitaxel feedstock solution is 20-30 mg / g.

[0023] Preferably, the albumin concentration in the albumin aqueous solution is 5-6 mg / g.

[0024] The average particle size of the paclitaxel albumin nanoparticles is less than 200 nm, with less than 50 nm and less than 5% having a particle size greater than 350 nm.

[0025] Compared with existing technologies, this invention provides a method for the continuous preparation of paclitaxel albumin nanoparticles, comprising the following steps: A) Paclitaxel raw material is fed into an emulsification device at a first speed of 80-90 ml / min; albumin aqueous solution is fed into the emulsification device at a second speed of 3-4 L / min; B) Paclitaxel raw material and albumin aqueous solution are emulsified and sheared to complete drug loading, thus obtaining the nanoparticles. In this method, the paclitaxel organic solvent and human serum albumin aqueous solution are continuously introduced, allowing for continuous emulsification and shearing. The emulsification and shearing effect is consistent every minute, and the production batch size is only related to time. The batch size is determined by controlling the emulsification and shearing time, and the product uniformity is not affected by the batch size. This invention solves the problem that current paclitaxel nanoparticle preparation processes cannot achieve continuous manufacturing, improving system flexibility; it solves the problems of batch dependence on equipment and difficulty in batch expansion; and it improves the uniformity of nanoparticle preparation processes, especially in large-scale production. Attached Figure Description

[0026] Figure 1 This is a schematic diagram of the apparatus for the continuous preparation of paclitaxel albumin nanoparticles according to the present invention. Detailed Implementation

[0027] This invention provides an apparatus and method for the continuous preparation of paclitaxel albumin nanoparticles. Those skilled in the art can refer to the content of this document and appropriately modify the process parameters to achieve the desired result. It should be particularly noted that all similar substitutions and modifications are obvious to those skilled in the art and fall within the scope of protection of this invention. The method and application of this invention have been described through preferred embodiments. Those skilled in the art can obviously modify or appropriately change and combine the method and application described herein without departing from the content, spirit, and scope of this invention to realize and apply the technology of this invention.

[0028] This invention provides an apparatus for the continuous preparation of paclitaxel albumin nanoparticles, comprising:

[0029] The outlets of the water for injection unit and the albumin storage unit are connected to the inlet of the insulation coil via a static mixer.

[0030] The outlet of the insulated coil is connected to the first inlet of the emulsifying device;

[0031] The outlet of the paclitaxel feedstock storage device is connected to the second inlet of the emulsification device;

[0032] The outlet of the emulsification device is connected to the inlet of the collection device.

[0033] In one preferred embodiment of the present invention, the apparatus for continuously preparing paclitaxel albumin nanoparticles is specifically as follows: Figure 1 As shown, Figure 1 This is a schematic diagram of the apparatus for the continuous preparation of paclitaxel albumin nanoparticles according to the present invention. It includes: 1 a water for injection tank; 2 an albumin storage tank; 3 a static mixer; 4 a paclitaxel storage tank; 5 an insulated coil; 6 a pipeline shear disperser; and 7 a collection device.

[0034] The apparatus for continuous preparation of paclitaxel albumin nanoparticles provided by this invention includes a water-for-injection device. Preferably, the water-for-injection device of this invention is a water-for-injection tank.

[0035] The outlets of the water for injection unit and the albumin storage unit are connected to the inlet of the insulated coil via a static mixer.

[0036] The albumin storage device is preferably an albumin storage tank.

[0037] The outlet of the insulated coil is connected to the first inlet of the emulsifying device.

[0038] The emulsification device described in this invention is preferably a pipeline shear disperser.

[0039] The outlet of the paclitaxel feedstock storage device is connected to the second inlet of the emulsification device.

[0040] Preferably, this invention adds pumps before the outlet of the water for injection device, the albumin storage device, and the paclitaxel raw material storage device. These pumps allow albumin and paclitaxel raw materials to continuously enter the emulsification device, where they are emulsified, and then collected in the collection device.

[0041] The outlet of the emulsification device is connected to the inlet of the collection device.

[0042] This invention addresses the problems of continuous manufacturing in the preparation process of paclitaxel nanoparticles and the inability to adapt to products with large batch variations. The aforementioned device solves these technical problems.

[0043] In production using the scheme of this invention, the materials in the paclitaxel raw material tank, albumin excipient tank, and water for injection tank decrease as they are conveyed out by the peristaltic pump, and materials can be added at any time according to the production batch. The insulated coil and emulsifier do not store the drug solution; the human serum albumin completes incubation during its flow within the insulated coil. Therefore, the insulated coil acts as a drug solution pipeline and does not affect the product production batch. The drug solution, after emulsification and shearing in the emulsifier, is temporarily stored in the collection tank along with the equipment. The emulsifier does not affect the product production batch. Therefore, if it is necessary to increase the production batch, only the volume of the collection tank needs to be adjusted, without requiring major modifications to the entire solution preparation system. This scheme has low area requirements for the solution preparation function areas and can adapt to a wide range of product batches.

[0044] This invention provides a method for the continuous preparation of paclitaxel albumin nanoparticles, comprising the following steps:

[0045] A) Paclitaxel feedstock is fed to the emulsification unit at a first rate of 80-90 ml / min;

[0046] The albumin aqueous solution is fed to the emulsification device at a second rate of 3-4 L / min.

[0047] B) Paclitaxel raw material and albumin aqueous solution are emulsified and sheared to complete drug loading, thus obtaining the drug.

[0048] The method for continuous preparation of paclitaxel albumin nanoparticles provided by the present invention first involves feeding paclitaxel raw material to an emulsification device at a first speed.

[0049] The mass concentration of paclitaxel in the paclitaxel feedstock solution is 20-30 mg / g.

[0050] Specifically, the first speed is 80~90ml / min; preferably, the first speed is 82~88ml / min; more preferably, the first speed is 83~87ml / min.

[0051] The albumin aqueous solution is delivered to the emulsification device at a second rate. The mass concentration of albumin in the albumin aqueous solution is 5-6 mg / g.

[0052] Specifically, the second speed is 3~4 L / min; preferably, the second speed is 3.2~3.8 L / min; more preferably, the second speed is 3.3~3.7 L / min.

[0053] Human serum albumin and water for injection flow together into an insulated coil to complete the incubation of human serum albumin.

[0054] Start the peristaltic pumps at the outlets of the paclitaxel raw material tank, excipient tank, and water for injection tank to deliver the materials to the emulsifier at a certain speed for emulsification and shearing to complete the loading of human serum albumin.

[0055] The average particle size of the paclitaxel albumin nanoparticles prepared by this invention is less than 200 nm, with less than 50 nm and less than 5% having a particle size greater than 350 nm.

[0056] This invention provides a method for the continuous preparation of paclitaxel albumin nanoparticles, comprising the following steps: A) Paclitaxel raw material is fed into an emulsification device at a first speed of 80-90 ml / min; albumin aqueous solution is fed into the emulsification device at a second speed of 3-4 L / min; B) Paclitaxel raw material and albumin aqueous solution are emulsified and sheared to complete drug loading, thus obtaining the nanoparticles. In this method, the paclitaxel organic solvent and human serum albumin aqueous solution are continuously introduced, allowing for continuous emulsification and shearing. The emulsification and shearing effect is consistent every minute, and the production batch size is only related to time. The batch size is determined by controlling the emulsification and shearing time, and the product uniformity is not affected by the batch size. This invention solves the problem that current paclitaxel nanoparticle preparation processes cannot achieve continuous manufacturing, improving system flexibility; it solves the problems of batch dependence on equipment and difficulty in batch expansion; and it improves the uniformity of nanoparticle preparation processes, especially in large-scale production.

[0057] To further illustrate the present invention, the following describes in detail, with reference to embodiments, an apparatus and method for the continuous preparation of paclitaxel albumin nanoparticles provided by the present invention.

[0058] Example 1

[0059] Assemble according to the apparatus described in this invention:

[0060] The outlets of the water for injection unit and the albumin storage unit are connected to the inlet of the insulated coil via a static mixer; the outlet of the insulated coil is connected to the first inlet of the inline shear disperser; the outlet of the paclitaxel raw material storage unit is connected to the second inlet of the inline shear disperser; and the outlet of the emulsification unit is connected to the inlet of the collection unit.

[0061] Example 2

[0062] According to the connection device in Example 1, paclitaxel organic solvent is continuously fed into the emulsifier at a flow rate of 82 ml / min, while human serum albumin aqueous solution is continuously fed into the emulsifier at a flow rate of 3.2 L / min and a temperature of about 60°C. The emulsifier is then controlled to continuously emulsify and shear at a speed of 3000 r / min to complete drug loading and produce paclitaxel albumin nanoparticles that meet the quality standard particle size and particle size distribution. The nanoparticles are then collected in a collection tank. The particle size distribution of the collected drug solution is as follows: average particle size 120 nm, particles smaller than 50 nm 1%, and particles larger than 350 nm 0.5%.

[0063] Example 3

[0064] According to the connection device in Example 1, paclitaxel organic solvent is continuously fed into the emulsifier at a flow rate of 85 ml / min, while human serum albumin aqueous solution is continuously fed into the emulsifier at a flow rate of 3.5 L / min and a temperature of about 65°C. The emulsifier is then controlled to rotate at 2500 r / min to continuously emulsify and shear, completing drug loading and producing paclitaxel albumin nanoparticles that meet the quality standard particle size and particle size distribution. The nanoparticles are then collected in a collection tank. The particle size distribution of the collected drug solution is as follows: average particle size 143 nm, particles smaller than 50 nm account for 1%, and particles larger than 350 nm account for 2%.

[0065] Example 4

[0066] Following the connection device of Example 1, paclitaxel organic solvent was continuously fed into the emulsifier at a rate of 88 ml / min, while human serum albumin aqueous solution was continuously fed into the emulsifier at a flow rate of 3.8 L / min and a temperature of approximately 70°C. The emulsifier was then continuously sputtered at 2000 rpm to complete the emulsification and shearing process, thus completing the drug loading and producing paclitaxel albumin nanoparticles that met the quality standard particle size and particle size distribution. These nanoparticles were then collected in a collection tank. The particle size distribution of the collected drug solution was as follows: average particle size 167 nm, particles smaller than 50 nm accounting for 1%, and particles larger than 350 nm accounting for 3%.

[0067] Comparative Example 1

[0068] Following the connection device of Example 1, paclitaxel organic solvent was continuously fed into the emulsifier at a rate of 75 ml / min, while human serum albumin aqueous solution was continuously fed into the emulsifier at a flow rate of 2.5 L / min and a temperature of approximately 50°C. The emulsifier was then continuously sputtered at 3500 rpm to complete the emulsification and shearing process, thus completing the drug loading and producing paclitaxel albumin nanoparticles that met the quality standard particle size and particle size distribution. These nanoparticles were then collected in a collection tank. The particle size distribution of the collected drug solution was as follows: average particle size 85 nm, 10% of particles smaller than 50 nm, and 1% of particles larger than 350 nm.

[0069] Comparative Example 2

[0070] Following the connection device of Example 1, paclitaxel organic solvent was continuously fed into the emulsifier at a rate of 100 ml / min, while human serum albumin aqueous solution was continuously fed into the emulsifier at a flow rate of 5 L / min and a temperature of approximately 80°C. The emulsifier was then continuously sputtered at 1800 r / min to complete the emulsification and shearing process, thus completing the drug loading and producing paclitaxel albumin nanoparticles that met the quality standard particle size and particle size distribution. These nanoparticles were then collected in a collection tank. The particle size distribution of the collected drug solution was as follows: average particle size 290 nm, 1% of particles smaller than 50 nm, and 9% of particles larger than 350 nm.

[0071] The above description is only a preferred embodiment of the present invention. It should be noted that for those skilled in the art, several improvements and modifications can be made without departing from the principle of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. A method of continuously preparing paclitaxel albumin nanoparticles, characterized in that, It comprises the following steps: A) paclitaxel raw material is delivered to the emulsification device at a first speed; the first speed is 80-90 ml / min; An albumin aqueous solution is delivered to the emulsification device at a second speed; the second speed is 3-4 L / min; the delivery temperature of the albumin aqueous solution is 60-70 ℃; B) the paclitaxel raw material and the albumin aqueous solution are emulsified and sheared to complete drug loading, and the paclitaxel albumin nanoparticle is obtained; the rotation speed of the emulsification and shearing is 2000-3000 r / min.

2. The method of claim 1, wherein, The delivery temperature of the paclitaxel raw material is 20-30 ℃.

3. The method of claim 2, wherein, The mass concentration of paclitaxel in the paclitaxel raw material solution is 20-30 mg / g.

4. The method of claim 1, wherein, The mass concentration of albumin in the albumin aqueous solution is 5-6 mg / g; The average particle size of the paclitaxel albumin nanoparticle is within 200 nm, the particle size of less than 50 nm is ≤5%, and the particle size of greater than 350 nm is ≤5%.

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