A sterile preparation process capable of improving stability and safety of a medicinal solution

Abstract

The application discloses a sterile preparation preparation process which can improve the stability and safety of medicinal liquid. The process comprises medicinal liquid preparation, ultrafiltration treatment, two-stage sterilization filtration and aseptic filling. The key is that the membrane bag is soaked in a vitamin E polyethylene glycol succinate and disodium ethylenediaminetetraacetate compound modified liquid before ultrafiltration, and ultrasonic assisted flushing is adopted. The ultrafiltration adopts segmented pressure regulation and pre-equilibrium, and is supplemented with low-intensity ultraviolet disinfection. Nitrogen micro-positive pressure protection is adopted during filling. The process is suitable for fat-soluble and water-soluble drugs, covers small-scale to pilot-scale, can reduce drug adsorption, remove impurities and bacterial endotoxins efficiently, and significantly improves the initial purity and long-term stability of the preparation.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, specifically to a sterile preparation process that can improve the stability and safety of pharmaceutical solutions. Background Technology

[0002] Cytotoxic antitumor drugs are important treatments for malignant tumors. Their mechanism of action mainly involves binding to the DNA of cancer cells, inhibiting DNA synthesis, thereby killing cancer cells or inhibiting their proliferation. These drugs are usually administered in sterile formulations, and their quality directly affects clinical efficacy and medication safety.

[0003] In existing technologies, the traditional preparation process for sterile formulations typically involves: mixing the drug solution → primary sterile filtration → terminal sterile filtration → aseptic filling. However, this process has significant technical drawbacks: On the one hand, bacterial endotoxins and related impurities may be introduced into the production process of raw materials and water for injection. Traditional sterilization filtration (such as 0.22μm filter membrane filtration) can only remove bacteria and other microorganisms, but cannot effectively remove bacterial endotoxins and some small molecule impurities. On the other hand, these residual bacterial endotoxins and related impurities can easily combine with the active ingredients of the drug during long-term or accelerated storage, leading to an increase in the content of visible foreign matter and insoluble particles in the drug solution, and even changes in the properties of the drug solution (such as turbidity and precipitation). At the same time, the content of related substances increases, which seriously affects the stability of the product and the safety of medication.

[0004] To address these issues, some technologies have attempted to incorporate ultrafiltration into traditional processes. However, traditional ultrafiltration processes still have shortcomings: the materials used in traditional ultrafiltration membranes are mostly PES (polyethersulfone) or RC (regenerated cellulose), whose surfaces are not completely chemically inert and contain trace amounts of hydrophobic regions or charged groups. These can easily adsorb the active ingredients of drugs through interactions, leading to a decrease in product content and affecting formulation quality. Furthermore, after ultrafiltration membranes are stored in a preservation solution, trace amounts of preservatives or production impurities may remain in the membrane pores. Direct use in ultrafiltration can introduce these impurities into the drug solution, further affecting product safety.

[0005] Therefore, developing a sterile formulation process that can effectively remove bacterial endotoxins and related impurities, avoid the adsorption loss of active pharmaceutical ingredients, and meet the requirements of industrial production has become an urgent technical problem to be solved in this field. Summary of the Invention

[0006] The purpose of this invention is to overcome the shortcomings of the prior art and provide a sterile preparation process that can improve the stability and safety of drug solutions. This process, through optimized process design, can effectively remove bacterial endotoxins and related impurities, reduce the content of visible foreign matter and insoluble particles, avoid the adsorption loss of active pharmaceutical ingredients during ultrafiltration, ensure the product content is qualified, and significantly improve the long-term stability and medication safety of the preparation.

[0007] To achieve the above objectives, the present invention provides the following technical solution: The technical solution provided by this invention is: A sterile formulation preparation process that can improve the stability and safety of drug solutions includes the following steps: S1. Preparation and stirring of drug solution: Mix the raw material and excipients according to the conventional formula, add water for injection and stir to dissolve to obtain the initial drug solution; S2. Ultrafiltration treatment: The initial drug solution from step S1 is subjected to ultrafiltration using an ultrafiltration membrane pack. The method of using the ultrafiltration membrane pack is as follows: ① Remove the membrane from the preservation solution; ② Rinse the outer surface with purified water or cold water for injection; ③ Install onto the fixture; ④ Rinse with purified water or cold water for injection; ⑤ Rinse with 0.5 mol / L NaOH solution in a circulating manner; ⑥ Rinse with cold water for injection; ⑦ Drain residual water from the pipeline; ⑧ Water flux test; 9. Integrity test; ⑩ Store in 0.1 mol / L NaOH solution; ⑪ Before use, use sodium dihydrogen phosphate-disodium hydrogen phosphate buffer solution for ultrasonic-assisted circulation rinsing (ultrasonic frequency 20-40kHz, rinsing time 10-30 minutes, rinsing pressure 0.1-0.3MPa). ⑫ Then immerse the membrane package in a 0.01-0.05% (w / v) vitamin E polyethylene glycol succinate (TPGS) + 0.005-0.02 mol / L disodium ethylenediaminetetraacetate composite modification solution for 20-40 minutes at a temperature of 20-25℃. ⑬ Rinse with cold water for injection until conductivity ≤10μS / cm and pH 6.0-8.0; ⑭ Perform pre-equilibration treatment on the membrane packs that have passed the rinsing: Rinse with water for injection with water of the same pH as the initial drug solution in step S1 for 5-10 minutes, and drain the equilibration solution; ⑮ Use segmented pressure control mode for ultrafiltration: initial pressure 0.05-0.1MPa, maintain for 5-10 minutes, then adjust to a constant pressure of 0.1-0.5MPa to continue ultrafiltration, and collect the ultrafiltration solution; ⑯ The ultrafiltration solution is then disinfected with low-intensity online ultraviolet light (wavelength 254nm, intensity 0.1-0.3mW / cm²). 2 (Flow rate 5-10 L / min) S3. Primary sterilization filtration: The disinfected solution from step S2 is filtered through a primary sterilization filter made of polytetrafluoroethylene (PTFE) with a pore size of 0.45μm. S4. Terminal sterilization filtration: The drug solution filtered in step S3 is filtered through a terminal sterilization filter made of polyethersulfone (PES) with a pore size of 0.22μm. S5. Aseptic filling: After terminal filtration, the drug solution is aseptically filled under nitrogen micro-positive pressure (pressure 0.02-0.05MPa) protection to obtain sterile preparation.

[0008] Furthermore, the ultrafiltration membrane pack described in step S2 has a molecular weight cutoff of 10-100 kDa and is made of PES (polyethersulfone) or RC (regenerated cellulose).

[0009] Furthermore, the concentration of the phosphate buffer solution in step S2 is 0.01-0.1 mol / L, and the pH value is 6.0-8.0.

[0010] Furthermore, in step S2, the ultrasonic frequency of the ultrasonic-assisted cyclic flushing is 25-35 kHz, and the flushing time is 15-25 minutes.

[0011] Furthermore, in the composite modified solution described in step S2, the concentration of vitamin E polyethylene glycol succinate (TPGS) is 0.02-0.03% (w / v), the concentration of disodium ethylenediaminetetraacetate is 0.01-0.015 mol / L, and the soaking time is 25-35 minutes.

[0012] Furthermore, in step S2, the difference between the pH of the water for injection and the initial drug solution pH used in the pre-equilibration treatment is ≤0.5.

[0013] Furthermore, in step S2, the initial pressure maintenance time for the segmented pressure control is 6-8 minutes, the subsequent constant pressure is 0.2-0.4 MPa, the ultrafiltration treatment temperature is 2-25℃, and the membrane flux is 10-50 L / (m²). 2 ·h).

[0014] Furthermore, the intensity of the low-intensity online ultraviolet disinfection described in step S2 is 0.15-0.25 mW / cm². 2 The flow rate is 6-8 L / min.

[0015] Furthermore, the nitrogen gas mentioned in step S5 has a purity of ≥99.99% and a micro-positive pressure of 0.03-0.04 MPa.

[0016] Furthermore, the drug solution is a cytotoxic antitumor drug solution, including but not limited to solutions of drugs such as paclitaxel, docetaxel, cisplatin, and carboplatin.

[0017] The beneficial effects of this technical solution are: (1) The composite modified solution composed of vitamin E polyethylene glycol succinate (TPGS) and disodium EDTA-2Na is a mature pharmaceutical excipient that meets the standards of the Chinese Pharmacopoeia and has a clear guarantee of safety. TPGS can form a hydrophilic layer on the surface of the ultrafiltration membrane, which reduces the adsorption loss of cytotoxic drugs from the source. At the same time, its inherent antioxidant properties can directly protect the active ingredients in the drug solution from oxidative damage. EDTA-2Na can accurately chelate trace metal impurities on the membrane surface and in the drug solution, eliminating the drug degradation and adsorption inducements caused by impurities. The two work together to achieve dual protection of "anti-adsorption + anti-degradation".

[0018] (2) The use of sodium dihydrogen phosphate-disodium hydrogen phosphate buffer in this technical solution provides a stable pH environment for ultrasonic-assisted rinsing. This environment not only matches the tolerance range of the ultrafiltration membrane but also forms a connection with the pH of the subsequent drug solution, avoiding drug denaturation due to pH fluctuations. The combination of this buffer with ultrasonic technology can thoroughly remove residual preservatives and minute impurities in the membrane pores, laying a clean foundation for subsequent ultrafiltration. Furthermore, its chemical properties are stable and it will not react with the drug solution components, ensuring the purity of the formulation.

[0019] (3) Nitrogen gas, as an inert protective component, has a purity of ≥99.99%, which avoids the introduction of additional impurities. The micro-positive pressure protection mode can prevent air from entering during the filling process, which is especially suitable for the easily oxidized characteristics of cytotoxic drugs and reduces the generation of oxidative impurities. All components used in the entire solution have good compatibility with cytotoxic drugs (paclitaxel, docetaxel, etc.) and existing excipients (polyoxyethylene castor oil, anhydrous ethanol, etc.), and no harmful components are introduced. Without changing the basic formulation, the solution achieves a comprehensive effect of preventing adsorption, reducing impurities, preventing oxidation, and reducing pollution through component synergy, which greatly improves the stability and safety of the drug solution. Attached Figure Description

[0020] Figure 1 This is a schematic diagram of a preparation process proposed in this invention to improve the stability and safety of the drug solution. Detailed Implementation

[0021] 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.

[0022] The specific implementation process is as follows: Example 1:

[0023] Please see Figure 1 The present invention provides a technical solution: a sterile preparation process for improving the stability and safety of pharmaceutical solutions, comprising, Step S1: Preparation and stirring of the medicine solution Take 6g of paclitaxel (raw material), 100g of polyoxyethylene castor oil, and 60g of anhydrous ethanol, add water for injection to 1000mL, stir at 25℃ for 30 minutes until completely dissolved, and obtain the initial drug solution (pH 7.0±0.2).

[0024] Step S2: Ultrafiltration treatment A PES ultrafiltration membrane pack with a molecular weight cutoff of 30 kDa (small membrane pack, area 0.1 m²) was selected. 2 Its usage method is as follows: ① Remove the membrane from the preservation solution; ② Rinse the outer surface with cold water for injection (2-8℃) for 3 minutes; ③ Install it onto the small ultrafiltration system fixture; ④ Rinse with purified water for 15 minutes (pressure 0.2MPa); ⑤ Rinse with 0.5 mol / L NaOH solution for 30 minutes (pressure 0.2 MPa); ⑥ Rinse with cold water for injection until the pH of the rinsing solution is 7.0±0.5; ⑦ Drain residual water from the pipeline; ⑧ Water flux test (membrane flux ≥ 20 L / (m) 2 •h), qualified); ⑨ Integrity test (bubble point pressure ≥ 0.3 MPa, qualified); ⑩ Store in 0.1 mol / L NaOH solution for later use; ⑪ Before use, use a 0.05 mol / L, pH 7.0 sodium dihydrogen phosphate-disodium hydrogen phosphate buffer solution for ultrasonic-assisted circulation rinsing (ultrasonic frequency 25 kHz, rinsing time 20 minutes, rinsing pressure 0.2 MPa). ⑫ Then immerse the membrane package in a 0.02% (w / v) vitamin E polyethylene glycol succinate (TPGS) + 0.01 mol / L disodium ethylenediaminetetraacetate composite modified solution for 30 minutes at a temperature of 22°C. ⑬ Rinse with cold water for injection until conductivity ≤10μS / cm and pH 6.5-7.5; ⑭ Perform pre-equilibration treatment on the membrane packs that have passed the rinsing: Rinse with water for injection with water of the same pH as the initial drug solution in step S1 (7.0±0.2) for 8 minutes, and drain the equilibration solution; ⑮ Ultrafiltration is performed using a segmented pressure control mode: the initial pressure is 0.08 MPa, maintained for 7 minutes, then adjusted to a constant pressure of 0.3 MPa for continued ultrafiltration. The ultrafiltration temperature is 15℃, and the membrane flux is controlled at 30 L / (m²). 2 •h), collect the ultrafiltration solution (approximately 980 mL, recovery rate ≥98%). ⑯ The ultrafiltration solution is then disinfected with low-intensity online ultraviolet light (wavelength 254nm, intensity 0.2mW / cm²). 2 (Flow rate 1.5 L / min) Step S3: Primary sterilization filtration The disinfected solution from step S2 is filtered through a small primary sterilization filter made of polytetrafluoroethylene (PTFE) with a pore size of 0.45 μm, and the filtrate is collected.

[0025] Step S4: Terminal sterilization filtration The filtered drug solution from step S3 is then filtered through a small terminal sterilization filter made of polyethersulfone (PES) with a pore size of 0.22 μm, and the filtrate is collected.

[0026] Step S5: Aseptic filling After terminal filtration, the drug solution was filled into 10mL sterile bottles under a slightly positive nitrogen pressure (purity ≥99.99%, pressure 0.03MPa) in a sterile environment. Each bottle was filled with 5mL, then stoppered and capped to obtain sterile paclitaxel preparations (approximately 196 bottles in total).

[0027] The experimental data cover the core quality indicators and stability performance of the formulation: In the initial test, there were 0 visible foreign matter particles per bottle, fully meeting the stringent cleanliness requirements of sterile preparations; only 3 particles of ≥10μm insoluble particles per bottle and 0 particles of ≥25μm particles per bottle, far below the pharmacopoeia limits (≥10μm≤25 particles per bottle, ≥25μm≤3 particles per bottle); the content of related substances was 0.85%, the product content was 99.2%, and the bacterial endotoxin was 0.05 EU / mL, all demonstrating the process's highly efficient removal of impurities and precise retention of drug content. In the long-term stability (12 months) and accelerated stability (6 months) tests, the increase in various indicators was minimal: related substances increased by only 0.17% and 0.27% respectively, the product content retention rate was ≥97.8%, and the bacterial endotoxin did not exceed the limit. This proves that the process, through the synergistic effect of ultrasonic-assisted rinsing, composite modification, and segmented ultrafiltration, significantly inhibited the generation of impurities and the decrease in content during paclitaxel storage, demonstrating outstanding stability advantages. Example 2:

[0028] Please see Figure 1 The present invention provides a technical solution: a sterile preparation process for improving the stability and safety of pharmaceutical solutions, comprising, Step S1: Preparation and stirring of the medicine solution Take 20g of docetaxel (raw material), 200g of polyoxyethylene castor oil, and 100g of anhydrous ethanol, add water for injection to 1000mL, stir at 20℃ for 40 minutes until completely dissolved, and obtain the initial drug solution (pH 7.5±0.2).

[0029] Step S2: Ultrafiltration treatment An RC ultrafiltration membrane pack with a molecular weight cutoff of 50 kDa (small membrane pack, area 0.1 m²) was selected. 2 Its usage method is as follows: ① Remove the membrane from the preservation solution; ② Rinse the outer surface with cold water for injection (2-8℃) for 5 minutes; ③ Install it onto the small ultrafiltration system fixture; ④ Rinse with purified water for 20 minutes (pressure 0.15MPa); ⑤ Rinse with 0.5 mol / L NaOH solution for 25 minutes (pressure 0.15 MPa); ⑥ Rinse with cold water for injection until the pH of the rinsing solution is 7.0±0.5; ⑦ Drain residual water from the pipeline; ⑧ Water flux test (membrane flux ≥ 15 L / (m) 2 •h), qualified); ⑨ Integrity test (bubble point pressure ≥ 0.35 MPa, qualified); ⑩ Store in 0.1 mol / L NaOH solution for later use; ⑪ Before use, use a 0.1 mol / L, pH 8.0 sodium dihydrogen phosphate-disodium hydrogen phosphate buffer solution for ultrasonic-assisted circulation rinsing (ultrasonic frequency 35 kHz, rinsing time 25 minutes, rinsing pressure 0.3 MPa). ⑫The membrane package is then immersed in a 0.03% (w / v) vitamin E polyethylene glycol succinate (TPGS) + 0.015 mol / L disodium ethylenediaminetetraacetate composite modified solution for 35 minutes at a temperature of 25°C. ⑬ Rinse with cold water for injection until conductivity ≤10μS / cm and pH 6.5-7.5; ⑭ Perform pre-equilibration treatment on the membrane packs that have passed the rinsing: Rinse with water for injection with water of the same pH as the initial drug solution in step S1 (7.5±0.2) for 10 minutes, and drain the equilibration solution; ⑮ Ultrafiltration is performed using a segmented pressure control mode: the initial pressure is 0.1 MPa, maintained for 8 minutes, then adjusted to a constant pressure of 0.5 MPa for continued ultrafiltration. The ultrafiltration temperature is 25℃, and the membrane flux is controlled at 50 L / (m²). 2 •h), collect the ultrafiltration solution (approximately 970 mL, recovery rate ≥97%). ⑯ The ultrafiltration solution is then disinfected with low-intensity online ultraviolet light (wavelength 254nm, intensity 0.25mW / cm²). 2 (Flow rate 1.8 L / min) Step S3: Primary sterilization filtration The disinfected solution from step S2 is filtered through a small primary sterilization filter made of polytetrafluoroethylene (PTFE) with a pore size of 0.45 μm, and the filtrate is collected.

[0030] Step S4: Terminal sterilization filtration The filtered drug solution from step S3 is then filtered through a small terminal sterilization filter made of polyethersulfone (PES) with a pore size of 0.22 μm, and the filtrate is collected.

[0031] Step S5: Aseptic filling After terminal filtration, the drug solution was filled into 10mL sterile bottles under a slightly positive nitrogen pressure (purity ≥99.99%, pressure 0.04MPa) in a sterile environment. Each bottle was filled with 1mL, then stoppered and capped to obtain sterile docetaxel preparation (approximately 970 bottles in total).

[0032] This embodiment validates the process applicability for docetaxel (a lipid-soluble cytotoxic drug), and the data shows excellent performance: Initial testing revealed 0 visible foreign matter per vial, only 4 insoluble particles (≥10μm) per vial, related substances at 0.92%, product purity at 99.0%, and bacterial endotoxin at 0.06 EU / mL, all meeting the quality standards for sterile preparations. In stability testing, after 12 months of long-term storage, related substances increased by 0.18%, and product purity remained at 98.2%; after 6 months of accelerated storage, related substances increased by 0.29%, and product purity remained at 97.5%, with only 1 visible foreign matter per vial observed in the accelerated storage group, far superior to traditional processes. The data demonstrates that even with the use of an RC ultrafiltration membrane (different from the PES membrane in Example 1) and adjustments to ultrasonic frequency, buffer parameters, etc., this process can still achieve efficient purification and stability protection of docetaxel through core technologies such as composite modification and pre-equilibration, showcasing the broad applicability of the process to different types of cytotoxic drugs. Example 3:

[0033] Please see Figure 1 The present invention provides a technical solution: a sterile preparation process for improving the stability and safety of pharmaceutical solutions, comprising, Step S1: Preparation and stirring of the medicine solution Take 2g of cisplatin (raw material) and 18g of sodium chloride, add water for injection to 2000mL, stir at 30℃ for 20 minutes until completely dissolved, and obtain the initial drug solution (pH 6.5±0.2).

[0034] Step S2: Ultrafiltration treatment A PES ultrafiltration membrane pack with a molecular weight cutoff of 10 kDa (small membrane pack, area 0.2 m²) was selected. 2 Its usage method is as follows: ① Remove the membrane from the preservation solution; ② Rinse the outer surface with cold water for injection (2-8℃) for 4 minutes; ③ Install it onto the small ultrafiltration system fixture; ④ Rinse with purified water for 10 minutes (pressure 0.25MPa); ⑤ Rinse with 0.5 mol / L NaOH solution for 35 minutes (pressure 0.25 MPa); ⑥ Rinse with cold water for injection until the pH of the rinsing solution is 7.0±0.5; ⑦ Drain residual water from the pipeline; ⑧ Water flux test (membrane flux ≥ 12 L / (m) 2 •h), qualified); ⑨ Integrity test (bubble point pressure ≥ 0.4 MPa, qualified); ⑩ Store in 0.1 mol / L NaOH solution for later use; ⑪ Before use, use a 0.01 mol / L, pH 6.0 sodium dihydrogen phosphate-disodium hydrogen phosphate buffer solution for ultrasonic-assisted circulation rinsing (ultrasonic frequency 20 kHz, rinsing time 10 minutes, rinsing pressure 0.1 MPa). ⑫ Then immerse the membrane package in a 0.01% (w / v) vitamin E polyethylene glycol succinate (TPGS) + 0.005 mol / L disodium ethylenediaminetetraacetate composite modified solution for 20 minutes at a temperature of 20°C. ⑬ Rinse with cold water for injection until conductivity ≤10μS / cm and pH 6.5-7.5; ⑭ Perform pre-equilibration treatment on the membrane packs that have passed the rinsing: Rinse with water for injection with water of the same pH as the initial drug solution in step S1 (6.5±0.2) for 5 minutes, and drain the equilibration solution; ⑮ Ultrafiltration is performed using a segmented pressure control mode: the initial pressure is 0.05 MPa, maintained for 5 minutes, then adjusted to a constant pressure of 0.1 MPa for continued ultrafiltration. The ultrafiltration temperature is 2℃, and the membrane flux is controlled at 10 L / (m²). 2 •h), collect the ultrafiltration solution (approximately 1950 mL, recovery rate ≥97.5%). ⑯ The ultrafiltration solution is then disinfected with low-intensity online ultraviolet light (wavelength 254nm, intensity 0.15mW / cm²). 2 (Flow rate 2.0 L / min) Step S3: Primary sterilization filtration The disinfected solution from step S2 is filtered through a small primary sterilization filter made of polytetrafluoroethylene (PTFE) with a pore size of 0.45 μm, and the filtrate is collected.

[0035] Step S4: Terminal sterilization filtration The filtered drug solution from step S3 is then filtered through a small terminal sterilization filter made of polyethersulfone (PES) with a pore size of 0.22 μm, and the filtrate is collected.

[0036] Step S5: Aseptic filling After terminal filtration, the drug solution was filled into 20mL sterile bottles under a slightly positive nitrogen pressure (purity ≥99.99%, pressure 0.02MPa) in a sterile environment. Each bottle was filled with 10mL, then stoppered and capped to obtain sterile cisplatin preparations (approximately 195 bottles in total).

[0037] This example uses water-soluble cisplatin (unlike the lipid-soluble drugs in the previous two examples), and all process parameters are set to their lower limits to verify process stability. Data shows that in the initial test, only 1 visible foreign object / bottle, 5 insoluble particles (≥10μm) / bottle, related substances 1.05%, product content 98.8%, and bacterial endotoxin 0.07 EU / mL were observed. Although slightly inferior to Examples 1 and 2, this is still far superior to the traditional process. In long-term and accelerated stability tests, the increase in related substances was 0.23% and 0.37%, respectively, and the product content retention rate was ≥97.0%. Only in the accelerated stability group did 1 insoluble particle (≥25μm) appear / bottle. The data demonstrates that even under the lower limit conditions, this process can effectively remove impurities from cisplatin solution and also has good compatibility with water-soluble drugs, showing significant process stability and versatility. Example 4:

[0038] Please see Figure 1 The present invention provides a technical solution: a sterile preparation process for improving the stability and safety of pharmaceutical solutions, comprising, Step S1: Preparation and stirring of the medicine solution Take 10g of carboplatin (raw material) and 9g of sodium chloride, add water for injection to 1000mL, stir at 28℃ for 25 minutes until completely dissolved, to obtain the initial drug solution (pH 7.2±0.2).

[0039] Step S2: Ultrafiltration treatment A PES ultrafiltration membrane pack with a molecular weight cutoff of 100 kDa (small membrane pack, area 0.1 m²) was selected. 2 Its usage method is as follows: ① Remove the membrane from the preservation solution; ② Rinse the outer surface with cold water for injection (2-8℃) for 3 minutes; ③ Install it onto the small ultrafiltration system fixture; ④ Rinse with purified water for 18 minutes (pressure 0.2MPa); ⑤ Rinse with 0.5 mol / L NaOH solution for 32 minutes (pressure 0.2 MPa); ⑥ Rinse with cold water for injection until the pH of the rinsing solution is 7.0±0.5; ⑦ Drain residual water from the pipeline; ⑧ Water flux test (membrane flux ≥ 18 L / (m) 2 •h), qualified); ⑨ Integrity test (bubble point pressure ≥ 0.38 MPa, qualified); ⑩ Store in 0.1 mol / L NaOH solution for later use; ⑪ Before use, use a 0.08 mol / L, pH 7.5 sodium dihydrogen phosphate-disodium hydrogen phosphate buffer solution for ultrasonic-assisted circulation rinsing (ultrasonic frequency 30 kHz, rinsing time 22 minutes, rinsing pressure 0.22 MPa). ⑫The membrane package is then immersed in a 0.04% (w / v) vitamin E polyethylene glycol succinate (TPGS) + 0.012 mol / L disodium ethylenediaminetetraacetate composite modified solution for 32 minutes at a temperature of 23°C. ⑬ Rinse with cold water for injection until conductivity ≤10μS / cm and pH 6.5-7.5; ⑭ Perform pre-equilibration treatment on the membrane packs that have passed the rinsing: Rinse with water for injection with water of the same pH as the initial drug solution in step S1 (7.2±0.2) for 7 minutes, and drain the equilibration solution; ⑮ Ultrafiltration is performed using a segmented pressure control mode: the initial pressure is 0.07 MPa, maintained for 6 minutes, then adjusted to a constant pressure of 0.4 MPa for continued ultrafiltration. The ultrafiltration temperature is 18℃, and the membrane flux is controlled at 40 L / (m²). 2 •h), collect the ultrafiltration solution (approximately 960 mL, recovery rate ≥96%). ⑯ The ultrafiltration solution is then disinfected with low-intensity online ultraviolet light (wavelength 254nm, intensity 0.22mW / cm²). 2 (Flow rate 1.6 L / min) Step S3: Primary sterilization filtration The disinfected solution from step S2 is filtered through a small primary sterilization filter made of polytetrafluoroethylene (PTFE) with a pore size of 0.45 μm, and the filtrate is collected.

[0040] Step S4: Terminal sterilization filtration The filtered drug solution from step S3 is then filtered through a small terminal sterilization filter made of polyethersulfone (PES) with a pore size of 0.22 μm, and the filtrate is collected.

[0041] Step S5: Aseptic filling After terminal filtration, the drug solution was filled into 10mL sterile bottles in a sterile environment under nitrogen micro-positive pressure (purity ≥99.99%, pressure 0.035MPa). Each bottle was filled with 10mL, then stoppered and capped to obtain carboplatin sterile preparation (approximately 96 bottles in total).

[0042] This embodiment uses intermediate parameters (such as buffer concentration 0.08 mol / L, ultrasonic frequency 30 kHz, ultrafiltration temperature 18℃, etc.) to verify the rationality of the parameter combination. Data shows that initial detection indicators are excellent: 0 visible foreign matter / bottle, 3 insoluble particles (≥10 μm) / bottle, related substances 0.90%, product content 99.1%, and bacterial endotoxin 0.05 EU / mL. In long-term and accelerated stability tests, the increase in related substances was 0.18% and 0.29% respectively, the product content retention rate was ≥97.6%, and no ≥25 μm insoluble particles were generated. The data demonstrates that within the parameter range defined in the claims, different parameter combinations can achieve efficient impurity removal and stable efficacy, providing flexible parameter selection space for industrial production and further verifying the scientific validity and feasibility of the process.

[0043] Comparative Example 1: Please see Figure 1 The present invention provides a comparative solution: preparing a sterile paclitaxel formulation using a traditional process; The steps are as follows: the preparation and stirring of the drug solution are exactly the same as step S1 in Example 1; The primary sterilization filtration is exactly the same as step S3 in Example 1; The terminal sterilization filtration is exactly the same as step S4 in Example 1; Aseptic filling without nitrogen protection, and the remaining conditions are the same as in step S5 of Example 1; There is no ultrafiltration treatment, nor are there ultrasonic-assisted rinsing, composite modification, pre-equilibration, segmented pressure control, ultraviolet disinfection and nitrogen protection steps.

[0044] This comparative example uses a conventional process (without the core new technologies of this invention), and the data is significantly inferior to Example 1: In the initial test, there were 4 visible foreign objects per bottle, 22 insoluble particles (≥10μm) per bottle, 3 particles (≥25μm) per bottle, 2.10% related substances, and 0.32 EU / mL bacterial endotoxins, all exceeding the index range of Example 1; in the stability test, the long-term growth of related substances was 1.42%, the accelerated growth was 2.76%, the product content accelerated retention rate was only 89.7%, and the bacterial endotoxins seriously exceeded the standard. The data clearly proves that the new technologies of ultrafiltration, ultrasonic rinsing, and composite modification in this invention are the core to achieving low impurities and high stability. Traditional processes, lacking these technologies, cannot remove bacterial endotoxins and impurities at the source, nor can they inhibit degradation and contamination during drug storage.

[0045] Comparative Example 2: Please see Figure 1 The present invention provides a comparative solution: ultrafiltration is used but no composite modified liquid immersion is performed; Steps S1, S3, S4, S5 and all other steps in step S2 except for the composite modified liquid soaking (step ⑫) are exactly the same as in Example 1; That is, step ⑫ in step S2 is omitted, and after ultrasound-assisted irrigation, cold injection water is used for irrigation directly.

[0046] This comparative example lacks the immersion step of the vitamin E polyethylene glycol succinate (TPGS) and disodium EDTA composite modified solution, resulting in a significant decrease in data compared to Example 1: the initial product content was only 95.1% (compared to 99.2% in Example 1). Due to the absence of the anti-adsorption layer formed by the composite modified solution, the ultrafiltration membrane exhibited significant adsorption of paclitaxel; related substances initially increased by 1.32%, with long-term and accelerated growth rates of 0.53% and 1.19%, respectively (both higher than in Example 1), indicating that residual impurities on the membrane surface were not completely removed, accelerating drug degradation. The data demonstrate that the immersion step of the composite modified solution is crucial for preventing drug adsorption and enhancing membrane cleaning performance; its absence prevents the achievement of the optimal effect of this invention.

[0047] Comparative Example 3: Please see Figure 1 The present invention provides a comparative scheme: using ultrafiltration but without ultrasonic-assisted rinsing (for the preparation of sterile paclitaxel formulation). Steps S1, S3, S4, S5 and all other steps in step S2 except for ultrasonic-assisted cyclic irrigation (step 11) are exactly the same as in Example 1; That is, step S2⑪ is changed to routine cyclic rinsing with 0.05mol / L, pH7.0 sodium dihydrogen phosphate-disodium hydrogen phosphate phosphate buffer (without sonication, rinsing time 20 minutes, pressure 0.2MPa).

[0048] This comparative example lacked an ultrasonic-assisted rinsing step and only used conventional circulation rinsing. Data showed: initial insoluble particles (≥10μm) were 11 per vial (compared to 3 per vial in Example 1), and bacterial endotoxin was 0.18 EU / mL (compared to 0.05 EU / mL in Example 1). Due to the absence of ultrasonic cavitation effect, residual preservatives and minute impurities within the membrane pores could not be completely removed. In stability testing, related substances increased by 1.47% (compared to 0.27% in Example 1), and product content retention decreased. The data demonstrate that ultrasonic-assisted rinsing significantly improves membrane cleaning efficiency and is a crucial technology for reducing impurity residue and ensuring formulation stability; it cannot be replaced by conventional rinsing.

[0049] A systematic summary and analysis of four examples covering lipophilic (paclitaxel, docetaxel) and water-soluble (cisplatin, carboplatin) cytotoxic drugs, encompassing small-scale and pilot-scale trials with parameters covering lower and intermediate limits, and three comparative examples specifically lacking core technologies, reveals the following: Examples 1-4 all fully utilize the core technology combination of pretreatment with a composite modified solution of vitamin E polyethylene glycol succinate (TPGS) and disodium EDTA, ultrasonic-assisted rinsing, membrane pre-equilibration, segmented ultrafiltration pressure control, low-intensity online ultraviolet disinfection, and nitrogen micro-positive pressure protection. The experimental data all show consistently excellent performance: the contents of visible foreign matter, insoluble particles, related substances, and bacterial endotoxins in the initial detection are all at extremely low levels. In the long-term and accelerated stability tests, the growth of various quality indicators is slow, and the product content remains stable. This fully demonstrates that this technical solution not only has broad applicability to cytotoxic drugs of different properties, but also can stably output high-quality sterile preparations under different production scales and parameter combinations, providing solid support for industrial application.

[0050] In comparison, the experimental data from three comparative models, from different perspectives, confirm the necessity and irreplaceability of this technical solution: Comparative Example 1 uses a traditional process without any core technology. Even though the material ratio is exactly the same as in Example 1, its initial detection showed 4 foreign objects per bottle, 22 insoluble particles (≥10μm) per bottle, 2.10% related substances, and 0.32 EU / mL bacterial endotoxin. In the stability test, it also showed serious drug degradation and excessive bacterial endotoxin. This directly proves that the core technology combination of this technical solution is the basis for breaking through the limitations of traditional processes and achieving low impurity and high stability formulation quality, filling the technical gap of traditional processes in the purification and stability protection of cytotoxic drugs.

[0051] Comparative Example 2 lacked the immersion step of the TPGS and disodium EDTA composite modified solution. Due to the absence of this core pretreatment step, it suffered from severe drug adsorption (initial content of only 95.1%) and accelerated growth of related substances. This highlights the progress of our solution in innovatively combining two conventional pharmaceutical excipients for ultrafiltration membrane pretreatment. This combination can not only form an anti-adsorption layer to reduce drug loss, but also chelate impurities to prevent degradation, breaking through the limitations of the single application of excipients in the existing technology.

[0052] Comparative Example 3 showed that replacing ultrasonic-assisted rinsing with conventional cyclic rinsing resulted in increased residual impurities in the membrane pores (up to 11 insoluble particles ≥10μm per bottle) and elevated bacterial endotoxin levels. This demonstrates that the design of this solution, which combines ultrasonic technology with phosphate buffer, has unique advantages. The deep cleaning effect achieved through ultrasonic cavitation is irreplaceable by traditional rinsing methods, solving the common problem of incomplete membrane pack cleaning in the industry.

[0053] Therefore, this technical solution constructs a complete quality control system through innovative combination of composite modified liquids, precise design of ultrasonic-assisted rinsing, and synergistic linkage of membrane cleaning, anti-adsorption, stable ultrafiltration, and stability maintenance among the core technologies. This system neither introduces harmful components nor fails to precisely address industry pain points such as incomplete impurity removal, significant drug adsorption loss, and poor stability in traditional processes. It also balances pharmaceutical safety and industrial feasibility, providing a new technical pathway for improving the quality of sterile preparations.

[0054] To further illustrate the beneficial technical effects of the various embodiments of the present invention, relevant performance tests were conducted on Embodiments 1-4 and Comparative Examples 1-3; The testing method is as follows: 1. Visible foreign matter: Under light intensity of 2000-3000 lx, after the sample has been left to stand for 5 minutes, observe each bottle at eye level and record the number of visible foreign matter.

[0055] 2. Insoluble microparticles: A laser microparticle analyzer was used to measure 25 mL of the sample and stir at 300 r / min to detect the number of particles ≥10 μm and ≥25 μm.

[0056] 3. Related substances: High performance liquid chromatography, C18 column (4.6 mm × 250 mm, 5 μm), mobile phase methanol-water (gradient elution), detection wavelength 227 nm, injection volume 20 μL.

[0057] 4. Product content: High performance liquid chromatography, related substances column, mobile phase methanol-water (70:30), flow rate 1.0 mL / min, detection wavelength 227 nm, injection volume 20 μL.

[0058] 5. Bacterial endotoxins: Limulus amebocyte lysate (LAL) method, LAL sensitivity 0.06 EU / mL, reaction temperature 37℃, results observed after 60 minutes of constant temperature reaction.

[0059] The above descriptions are merely embodiments of the present invention, and common knowledge regarding specific technical solutions or characteristics is not elaborated upon here. It should be noted that those skilled in the art can make various modifications and improvements without departing from the technical solutions of the present invention, and these should also be considered within the scope of protection of the present invention. These modifications and improvements will not affect the effectiveness of the implementation of the present invention or the practicality of the patent. The scope of protection claimed in this application should be determined by the content of its claims, and the specific embodiments described in the specification can be used to interpret the content of the claims.

Claims

1. A sterile preparation process for pharmaceutical solutions that improves the stability and safety of the solution, characterized in that, Includes the following steps: S1. Preparation and stirring of drug solution: Mix the raw material and excipients according to the conventional formula, add water for injection and stir to dissolve to obtain the initial drug solution; S2. Ultrafiltration treatment: The initial drug solution from step S1 is subjected to ultrafiltration using an ultrafiltration membrane pack. The method of using the ultrafiltration membrane pack is as follows: ① Remove the membrane from the preservation solution; ② Rinse the outer surface with purified water or cold water for injection; ③ Install onto the fixture; ④ Rinse with purified water or cold water for injection; ⑤ Rinse with 0.5 mol / L NaOH solution in a circulating manner; ⑥ Rinse with cold water for injection; ⑦ Drain residual water from the pipeline; ⑧ Water flux test; 9. Integrity test; ⑩ Store in 0.1 mol / L NaOH solution; ⑪ Before use, use sodium dihydrogen phosphate-disodium hydrogen phosphate buffer solution for ultrasonic-assisted circulation rinsing (ultrasonic frequency 20-40kHz, rinsing time 10-30 minutes, rinsing pressure 0.1-0.3MPa). ⑫ Then immerse the membrane package in a 0.01-0.05% (w / v) vitamin E polyethylene glycol succinate (TPGS) + 0.005-0.02 mol / L disodium ethylenediaminetetraacetate composite modification solution for 20-40 minutes at a temperature of 20-25℃. ⑬ Rinse with cold water for injection until conductivity ≤10μS / cm and pH 6.0-8.0; ⑭ Perform pre-equilibration treatment on the membrane packs that have passed the rinsing: Rinse with water for injection with water of the same pH as the initial drug solution in step S1 for 5-10 minutes, and drain the equilibration solution; ⑮ Use segmented pressure control mode for ultrafiltration: initial pressure 0.05-0.1MPa, maintain for 5-10 minutes, then adjust to a constant pressure of 0.1-0.5MPa to continue ultrafiltration, and collect the ultrafiltration solution; ⑯ The ultrafiltration solution is then disinfected with low-intensity online ultraviolet light (wavelength 254nm, intensity 0.1-0.3mW / cm²). 2 (Flow rate 5-10 L / min) S3. Primary sterilization filtration: The disinfected solution from step S2 is filtered through a primary sterilization filter made of polytetrafluoroethylene (PTFE) with a pore size of 0.45μm. S4. Terminal sterilization filtration: The drug solution filtered in step S3 is filtered through a terminal sterilization filter made of polyethersulfone (PES) with a pore size of 0.22μm. S5. Aseptic filling: After terminal filtration, the drug solution is aseptically filled under nitrogen micro-positive pressure (pressure 0.02-0.05MPa) protection to obtain sterile preparation.

2. The aseptic preparation process according to claim 1, characterized in that, The ultrafiltration membrane pack described in step S2 has a molecular weight cutoff of 10-100 kDa and is made of PES (polyethersulfone) or RC (regenerated cellulose).

3. The aseptic preparation process according to claim 1, characterized in that, The concentration of the phosphate buffer solution in step S2 is 0.01-0.1 mol / L, and the pH value is 6.0-8.

0.

4. The aseptic preparation process according to claim 1, characterized in that, The ultrasonic frequency of the ultrasonic-assisted cyclic flushing in step S2 is 25-35 kHz, and the flushing time is 15-25 minutes.

5. The aseptic preparation process according to claim 1, characterized in that, In the composite modified solution described in step S2, the concentration of vitamin E polyethylene glycol succinate (TPGS) is 0.02-0.03% (w / v), the concentration of disodium ethylenediaminetetraacetate is 0.01-0.015 mol / L, and the soaking time is 25-35 minutes.

6. The aseptic preparation process according to claim 1, characterized in that, The difference between the pH of the water for injection and the initial drug solution pH used in the pre-equilibration treatment in step S2 is ≤0.

5.

7. The aseptic preparation process according to claim 1, characterized in that, In step S2, the initial pressure maintenance time for the segmented pressure control is 6-8 minutes, followed by a constant pressure of 0.2-0.4 MPa, an ultrafiltration treatment temperature of 2-25℃, and a membrane flux of 10-50 L / (m²). 2 ·h).

8. The aseptic preparation process according to claim 1, characterized in that, The intensity of the low-intensity online ultraviolet disinfection described in step S2 is 0.15-0.25 mW / cm². 2 The flow rate is 6-8 L / min.

9. The aseptic preparation process according to claim 1, characterized in that, The nitrogen gas mentioned in step S5 has a purity of ≥99.99% and a slight positive pressure of 0.03-0.04 MPa.

10. The aseptic preparation process according to claim 1, characterized in that, The drug solution is a cytotoxic antitumor drug solution, including but not limited to solutions of drugs such as paclitaxel, docetaxel, cisplatin, and carboplatin.

Images