High-concentration stable formula and preparation method of magnesium sulfate injection

Abstract

The invention relates to the technical field of pharmaceutical preparations, in particular to a high-concentration stable formula and a preparation method of magnesium sulfate injection, and the formula consists of high-purity magnesium sulfate, a compound stabilizer, a pH responsive carrier and water for injection. The preparation method comprises the following steps: preparing anhydrous magnesium sulfate of which the purity is greater than or equal to 99.99% by adopting a supercritical COdrying process; preparing ascorbic acid and EDTA (Ethylene Diamine Tetraacetic Acid) disodium loaded PLGA (Poly Lactic Acid-Glycolic Acid) microspheres as a compound stabilizer through a W / O emulsion method Constructing a pH responsive carrier containing polyacrylic acid by a double emulsion method; and finally, performing continuous membrane filtration, sterilization and filling. Through cooperation of the high-purity raw materials, the compound stabilizer, the pH-responsive carrier and the sterile process, the problems that an existing high-concentration magnesium sulfate injection is prone to crystallization, poor in stability, uncontrollable in release and high in impurity risk are solved, and the high-concentration magnesium sulfate injection is suitable for various scenes.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical preparation technology, and in particular to a high-concentration stable formulation and preparation method of magnesium sulfate injection. Background Technology

[0002] Magnesium sulfate injection is a key drug in the clinical treatment of eclampsia, premature birth, and other diseases, and the development of its high-concentration, stable formulation is of great significance. Current technologies for high-concentration magnesium sulfate solutions (such as 25% and 50%) suffer from the following core problems: 1. Insufficient physical stability: It is prone to crystallization at low temperatures, and the high osmotic pressure (such as 4060 mOsmol / L for a 50% solution) increases the risk of blockage in the infusion tubing; 2. Limitations in chemical stability: The pH range for adjustment is controversial (4.5-8.5), and the content decreases due to hydrolysis or oxidation during long-term storage; 3. Complex production process: The preparation of high-purity anhydrous magnesium sulfate requires high-precision equipment (such as spray drying), and stabilizers (such as triethanolamine) may introduce safety risks.

[0003] Therefore, based on the relevant technologies mentioned above, there is an urgent need to develop a high-concentration stable formulation and preparation method for magnesium sulfate injection. Summary of the Invention

[0004] In view of this, the purpose of this invention is to provide a high-concentration stable formulation and preparation method for magnesium sulfate injection, as there is an urgent need to provide a magnesium sulfate injection formulation and preparation method that takes into account high concentration, high stability and safety.

[0005] To achieve the above objectives, the present invention provides a high-concentration stable formulation and preparation method for magnesium sulfate injection.

[0006] A high-concentration stable formulation of magnesium sulfate injection is prepared from the following raw materials in parts by weight: 25-50 parts magnesium sulfate, 0.1-2 parts composite stabilizer, 0.5-3 parts pH-responsive carrier, and 50-75 parts water for injection.

[0007] A method for preparing a high-concentration, stable formulation of magnesium sulfate injection includes the following steps: Step S1. Preparation of high-purity raw materials: Anhydrous magnesium sulfate is prepared using a supercritical CO2 drying process; Step S2. Solution preparation: Step S201. Preparation of composite stabilizer; Step S202. Construction of pH-responsive vector; Step S3. Sterilization and filling: Continuous membrane filtration system.

[0008] Preferably, the supercritical CO2 drying process described in step S1 is as follows: Industrial-grade magnesium sulfate was dissolved in deionized water, heated to 80-90℃, and decolorized with activated carbon for 30 minutes. After filtration, it was dried with supercritical CO2 to obtain anhydrous magnesium sulfate with a purity ≥99.99%.

[0009] Preferably, the purity of the industrial-grade magnesium sulfate is ≥98%.

[0010] Preferably, the mass ratio of the industrial-grade magnesium sulfate to deionized water is 1:3.5-4.

[0011] Preferably, the amount of activated carbon used is 0.5%-1% of the amount of industrial-grade magnesium sulfate used.

[0012] The controlled ratio of industrial-grade magnesium sulfate to deionized water ensures that the magnesium sulfate is fully dissolved, avoids undissolved particles, and prevents excessive water from causing a burden on subsequent concentration.

[0013] Activated carbon decolorization can remove colored impurities from raw materials, such as organic residues, and reduce the interference of impurities on solution stability.

[0014] Preferably, the supercritical CO2 drying process is carried out at a temperature of 40-60℃, a pressure of 10-15MPa, and a CO2 flow rate of 5-10L / min.

[0015] Supercritical CO2 drying can remove moisture at low temperatures, avoiding the degradation of magnesium sulfate caused by high temperatures. It also avoids the hard agglomeration caused by traditional drying, resulting in highly dispersible and high-purity anhydrous magnesium sulfate, thus reducing the risk of crystallization or degradation caused by impurities from the source.

[0016] Preferably, the process for preparing the composite stabilizer in step S201 is as follows: Step S2011. Mix the oil phase and the water phase, and ultrasonically emulsify to form a W / O emulsion; Step S2012. Remove the organic solvent by vacuum distillation to obtain PLGA microspheres with supported stabilizer; Step S2013. Disperse the PLGA microspheres loaded with stabilizer in magnesium sulfate solution and adjust the pH to 6.5-7.5.

[0017] Preferably, the oil phase in step S2011 is prepared from PLGA and dichloromethane.

[0018] Preferably, the aqueous phase in step S2011 is prepared from ascorbic acid, disodium EDTA and deionized water.

[0019] Preferably, the mass ratio of the oil phase to the water phase in step S2011 is 5-10:1.

[0020] Preferably, the mass ratio of PLGA to dichloromethane in the oil phase in step S2011 is 1:10-20.

[0021] Preferably, the mass ratio of ascorbic acid, disodium EDTA, and deionized water in the aqueous phase in step S2011 is 1-2:1:20-50.

[0022] Preferably, the particle size of the PLGA microspheres loaded with the stabilizer in step S2012 is 50-100 nm.

[0023] PLGA microspheres with a particle size of 50-100nm serve as a carrier to load ascorbic acid and disodium EDTA, which inhibit the growth of magnesium sulfate crystals through steric hindrance, thus playing a role in physical stabilization.

[0024] Ascorbic acid can act as an antioxidant, preventing magnesium sulfate from being degraded by oxidation and playing a chemical stabilizing role.

[0025] Disodium EDTA is used to chelate Fe. 3+ and Ca 2+ It contains metal ions, which reduce the hydrolysis reaction catalyzed by metal ions and play a role in chemical stabilization.

[0026] The ratio of oil phase to water phase and the concentration of PLGA can be adjusted to control the microsphere size, ensuring uniform dispersion of microspheres and avoiding agglomeration and blockage.

[0027] Adjusting the pH to 6.5-7.5 can stabilize the acid-base environment of the magnesium sulfate solution and reduce degradation caused by pH fluctuations.

[0028] Preferably, the process of constructing the pH-responsive carrier in step S202 is as follows: Step S2021. Prepare pH-responsive microspheres using a two-emulsion method; Step S202. The release rate of pH-responsive microspheres differs by ≥3 times under pH conditions of 5.5-7.4, thus obtaining a pH-responsive carrier.

[0029] Preferably, the process for preparing pH-responsive microspheres using the dual emulsion method in step S2021 is as follows: Step S20211. Preparation of the internal aqueous phase: Prepare an aqueous solution of magnesium sulfate and polyacrylic acid; Step S20212. Preparation of the oil phase: Dissolve PLGA in dichloromethane; Step S20213. Preparation of external aqueous phase: Prepare an aqueous solution containing polyvinyl alcohol; Step S20214. Mix the inner aqueous phase, oil phase and outer aqueous phase at a mass ratio of 1:5-10:20-50 to obtain a pH-responsive carrier.

[0030] Preferably, the mass fraction of magnesium sulfate in the aqueous solution in step S20211 is 25%-50%.

[0031] Preferably, the mass fraction of polyacrylic acid in the aqueous solution in step S20211 is 0.5%-2%.

[0032] Preferably, the molecular weight of the polyacrylic acid in step S20211 is 5000 Da.

[0033] Preferably, the molecular weight of the PLGA in step S20212 is 20000 Da.

[0034] Preferably, the mass ratio of PLGA to dichloromethane in the oil phase in step S20212 is 1:10-20.

[0035] Preferably, the mass fraction of the polyvinyl alcohol aqueous solution in step S20213 is 1%-5%.

[0036] Preferably, the mass ratio of the internal aqueous phase, oil phase, and external aqueous phase is 1:5-10:20-50.

[0037] The high-concentration magnesium sulfate in the internal aqueous phase meets the core requirements of "high-concentration injection", while the polyacrylic acid with a molecular weight of 5000 Da provides pH responsiveness, protonating and shrinking under acidic conditions and ionizing and swelling under alkaline conditions.

[0038] PLGA with a molecular weight of 20,000 Da in the oil phase serves as the microsphere framework, controlling the drug release rate and being biodegradable to avoid toxic residues.

[0039] The external aqueous phase polyvinyl alcohol can stabilize the interface between the two emulsions, prevent leakage of the internal aqueous phase, and assist in the formation of microspheres.

[0040] The phase ratio ensures the integrity of the microsphere structure. The inner aqueous phase is encapsulated by the oil phase, and the oil phase is dispersed in the outer aqueous phase, which can achieve pH-responsive release, enabling rapid release from the acidic environment of the lesion site and slow release from normal tissue.

[0041] Preferably, the process of the continuous membrane filtration system in step S3 is as follows: Step S301. Cross-flow filtration technology is adopted, combined with ceramic membrane filtration for sterilization, with an impurity rejection rate ≥99.9%; Step S302. Dispense into glass ampoules or pre-filled syringes, sterilize by moist heat or radiation, and seal after cooling.

[0042] Cross-flow filtration combined with a ceramic membrane can efficiently remove tiny particles, bacteria, and residual impurities from the solution, avoiding the risk of vascular embolism during infusion. The sterilization process ensures the sterility of the injection solution, meeting clinical safety standards.

[0043] Synergistic preparation of high-purity raw materials and "composite stabilizer preparation": High-purity (≥99.99%) magnesium sulfate prepared by supercritical CO2 drying is almost free of impurities, avoiding competition between impurities (such as calcium salts and chlorides) and disodium EDTA for chelation sites, ensuring that disodium EDTA specifically chelates metal ions and enhances chemical stability; at the same time, it reduces the interference of impurities on the dispersibility of PLGA microspheres (impurities easily lead to microsphere aggregation), ensuring uniform dispersion of 50-100nm microspheres.

[0044] Synergistic effect of high-purity raw material preparation and "pH-responsive carrier construction": High-purity magnesium sulfate reduces impurity ions in the internal aqueous phase, avoiding impurities from affecting the pH response sensitivity of polyacrylic acid (impurities may disrupt the ionization balance of polyacrylic acid carboxyl groups), and ensuring that the release rate of microspheres is stable (≥3 times) in an environment of pH 5.5-7.4.

[0045] High-purity raw material preparation and "membrane filtration sterilization" work together: Supercritical drying removes most impurities, reducing the "impurity load" of membrane filtration, allowing the ceramic membrane to focus on retaining tiny particles and bacteria, improving filtration efficiency (avoiding impurities clogging the membrane pores), and ensuring that the retention rate is stable at ≥99.9%.

[0046] Both the composite stabilizer and the pH-responsive carrier use PLGA as the core carrier (PLGA microspheres in the composite stabilizer and PLGA as the oil phase skeleton in the pH-responsive carrier). PLGA has consistent biocompatibility and degradability, avoiding compatibility issues caused by different carrier materials. At the same time, PLGA stabilizes magnesium sulfate in both systems through steric hindrance (the composite stabilizer inhibits crystallization, and the pH-responsive carrier controls release), forming a dual guarantee of "physical stability + release regulation".

[0047] Synergistic stability and release of the composite stabilizer and pH-responsive carrier: The composite stabilizer ensures the stability of magnesium sulfate during storage through ascorbic acid (antioxidant), disodium EDTA (chelation), and PLGA microspheres (anti-crystallization); the pH-responsive carrier, through the pH responsiveness of polyacrylic acid, precisely releases stable magnesium sulfate after administration (avoiding local crystallization caused by concentration fluctuations during release), achieving full-cycle protection of "storage stability - controllable release".

[0048] The synergy between "pH-responsive carrier" and "membrane filtration sterilization": The microsphere size of the pH-responsive carrier (controlled by the ratio of the two emulsions) matches the pore size of the ceramic membrane (0.1-0.2μm): The microsphere size is much smaller than the membrane pore size (50-100nm vs 0.1-0.2μm), allowing it to pass through the membrane without being trapped. At the same time, the membrane filtration removes free impurities (such as unencapsulated magnesium sulfate particles and residual solvents), ensuring that the final injection solution contains only structurally intact pH-responsive microspheres and avoiding impurities from interfering with release performance.

[0049] End-to-end collaboration: Achieving "high concentration - high stability - precise release - sterile safety": High concentration foundation: The high concentration design of 25%-50% magnesium sulfate in the internal aqueous phase, combined with the preparation of high-purity raw materials (avoiding impurities that limit solubility), lays the foundation for "high-concentration injection". Stability assurance: The composite stabilizer (anti-crystallization and anti-degradation) works synergistically with high-purity raw materials (reducing impurity interference) to solve the core problems of easy crystallization and degradation of high-concentration magnesium sulfate; Precise release: Based on stability, the pH-responsive carrier achieves targeted release to the lesion site (reducing systemic toxicity) through the synergistic effect of polyacrylic acid and PLGA. Aseptic and safe: The continuous membrane filtration and sterilization process removes all impurities and microorganisms while retaining the active ingredients, ensuring safe clinical use.

[0050] This invention addresses four major pain points of existing high-concentration magnesium sulfate injections: "easy crystallization, poor stability, uncontrollable release, and impurity risk," through a synergistic chain of technologies: "high-purity raw materials reduce interference → composite stabilizers ensure stability → pH-responsive carriers control release → membrane filtration ensures sterility." The various technologies do not work independently, but rather through a positive feedback loop of "improved raw material purity → enhanced stabilizer efficiency → optimized carrier performance → improved sterilization safety," ultimately achieving the clinical requirements of "long-term stability at 25%-50% high concentrations (≥12 months storage at 4-40℃), precise pH-responsive release, and sterility without impurities," making it suitable for various scenarios.

[0051] The beneficial effects of this invention are: This invention provides a high-concentration stable formulation and preparation method for magnesium sulfate injection. The preparation method provided by this invention can significantly improve the physical stability of magnesium sulfate injection: the high-purity magnesium sulfate prepared by supercritical CO2 drying reduces impurity "crystal nuclei", and combined with the steric hindrance effect of 50-100nm PLGA microspheres, the crystallization rate of the injection is ≤2.1% after 6 months of storage at 4℃, and the proportion of ≥1μm particles is ≤0.5%, effectively avoiding the risk of blockage in infusion lines.

[0052] The preparation method provided by this invention can enhance the chemical stability of magnesium sulfate injection: the ascorbic acid oxidation and EDTA disodium chelation of metal ions in the composite stabilizer, together with the precise control of pH 6.5-7.5, make the content decrease rate ≤1.5% after 3 months of accelerated testing and the pH fluctuation ≤0.5 after 6 months, thus solving the problem of degradation during long-term storage.

[0053] The formulation provided by this invention can achieve pH-responsive targeted release: polyacrylic acid (5000Da) and PLGA (20000Da) in the pH-responsive carrier work synergistically to achieve a release rate of 82%-86% at the lesion site (pH5.5) in 24 hours, compared to only 24%-27% in normal tissue (pH7.4), with a release rate difference of 3.2-3.5 times (no difference in the prior art), reducing systemic toxicity, especially reducing the incidence of hypermagnesemia in patients with renal insufficiency (only 4.0%-5.0%, compared to 16%-22% in the prior art).

[0054] The preparation method provided by this invention can improve safety and production efficiency: supercritical drying combined with continuous membrane filtration (ceramic membrane rejection rate ≥99.9%) ensures that the number of particles ≥0.5μm is ≤28 / mL (compared to 120-180 / mL in the prior art), meeting the sterility requirements; the process energy consumption is reduced by 30% compared with traditional spray drying, and the production capacity is increased by 50%, combining safety and economy.

[0055] In summary, this invention achieves "long-term stability, precise release, and safe and controllable" high-concentration magnesium sulfate injection through the synergy of the entire technology chain, making it suitable for various scenarios and with broad application prospects. Detailed Implementation

[0056] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described in detail below with reference to specific embodiments.

[0057] Example 1: A method for preparing a high-concentration stable formulation of magnesium sulfate injection, comprising the following steps: S1. Preparation of high-purity raw materials: Anhydrous magnesium sulfate was prepared by supercritical CO2 drying process: 10 parts of industrial grade magnesium sulfate with a purity ≥98% were dissolved in 35 parts of deionized water, heated to 80℃, 0.05 parts of activated carbon were added for decolorization for 30 min, filtered, and then dried by supercritical CO2 at a temperature of 40℃, a pressure of 10MPa, and a CO2 flow rate of 5L / min to obtain anhydrous magnesium sulfate with a purity ≥99.99%; S2. Solution preparation: PLGA and dichloromethane are mixed at a mass ratio of 1:10 to obtain an oil phase. Ascorbic acid, disodium EDTA, and deionized water are mixed at a mass ratio of 1:1:20 to obtain an aqueous phase. The oil phase and aqueous phase are mixed at a mass ratio of 5:1 and ultrasonically emulsified to form a W / O emulsion. The organic solvent is removed by vacuum distillation to obtain PLGA microspheres with a particle size of 50-100 nm loaded with stabilizer. The PLGA microspheres with stabilizer are dispersed in magnesium sulfate solution and the pH is adjusted to 6.5-7.5. S3. Construction of pH-responsive carrier: Preparation of internal aqueous phase: Prepare an aqueous solution of magnesium sulfate and polyacrylic acid, wherein the mass fraction of magnesium sulfate is 25%, the mass fraction of polyacrylic acid is 0.5%, and the molecular weight of polyacrylic acid is 5000 Da; S4. Preparation of oil phase: Dissolve PLGA in dichloromethane, wherein the mass ratio of PLGA to dichloromethane is 1:10, and the molecular weight of PLGA is 20000 Da; S5. Preparation of external aqueous phase: Prepare an aqueous solution containing polyvinyl alcohol, wherein the mass fraction of the aqueous solution of polyvinyl alcohol is 1%; S6. Mix the internal aqueous phase, oil phase and external aqueous phase at a mass ratio of 1:5:20 to obtain pH-responsive microspheres; S7. Take 25 parts of high-purity anhydrous magnesium sulfate, add 50 parts of water for injection, stir to dissolve and form a magnesium sulfate base solution, add 0.1 parts of composite stabilizer to the base solution, stir to disperse the microspheres evenly, add 0.5 parts of pH-responsive carrier, stir to mix, adjust the pH of the solution to 6.5-7.5, and obtain the initial product of magnesium sulfate injection. S8. Sterilization and filling: Continuous membrane filtration system: adopts cross-flow filtration technology, combined with 0.1-0.2μm ceramic membrane filtration for sterilization, with an impurity rejection rate of ≥99.9%. It is dispensed into glass ampoules or pre-filled syringes, sterilized by moist heat at 121℃ for 15min, and sealed after cooling to obtain a high-concentration and stable formulation of magnesium sulfate injection.

[0058] Example 2: A method for preparing a high-concentration stable formulation of magnesium sulfate injection, comprising the following steps: S1. Preparation of high-purity raw materials: Anhydrous magnesium sulfate was prepared by supercritical CO2 drying process: 10 parts of industrial grade magnesium sulfate with a purity ≥98% were dissolved in 37 parts of deionized water, heated to 83℃, 0.07 parts of activated carbon were added for decolorization for 30 min, filtered, and then dried by supercritical CO2. The temperature of supercritical CO2 drying was 45℃, the pressure was 12MPa, and the CO2 flow rate was 7L / min, to obtain anhydrous magnesium sulfate with a purity ≥99.99%; S2. Solution preparation: PLGA and dichloromethane were mixed at a mass ratio of 1:13 to obtain an oil phase. Ascorbic acid, disodium EDTA, and deionized water were mixed at a mass ratio of 1.3:1:30 to obtain an aqueous phase. The oil phase and aqueous phase were mixed at a mass ratio of 7:1 and ultrasonically emulsified to form a W / O emulsion. The organic solvent was removed by vacuum distillation to obtain PLGA microspheres with a particle size of 50-100 nm loaded with stabilizer. The PLGA microspheres with stabilizer were dispersed in magnesium sulfate solution and the pH was adjusted to 6.5-7.5. S3. Construction of pH-responsive carrier: Preparation of internal aqueous phase: Prepare an aqueous solution of magnesium sulfate and polyacrylic acid, wherein the mass fraction of magnesium sulfate is 30%, the mass fraction of polyacrylic acid is 1%, and the molecular weight of polyacrylic acid is 5000 Da; S4. Preparation of oil phase: Dissolve PLGA in dichloromethane, wherein the mass ratio of PLGA to dichloromethane is 1:13, and the molecular weight of PLGA is 20000 Da; S5. Preparation of external aqueous phase: Prepare an aqueous solution containing polyvinyl alcohol, wherein the mass fraction of the aqueous solution of polyvinyl alcohol is 2%; S6. Mix the internal aqueous phase, oil phase and external aqueous phase at a mass ratio of 1:7:30 to obtain pH-responsive microspheres; S7. Take 30 parts of high-purity anhydrous magnesium sulfate, add 60 parts of water for injection, stir to dissolve and form a magnesium sulfate base solution, add 1 part of composite stabilizer to the base solution, stir to make the microspheres uniformly dispersed, add 1.5 parts of pH-responsive carrier, stir to mix, adjust the pH of the solution to 6.5-7.5, and obtain the initial product of magnesium sulfate injection. S8. Sterilization and filling: Continuous membrane filtration system: adopts cross-flow filtration technology, combined with 0.1-0.2μm ceramic membrane filtration for sterilization, with an impurity rejection rate of ≥99.9%. It is dispensed into glass ampoules or pre-filled syringes, sterilized by moist heat at 121℃ for 15min, and sealed after cooling to obtain a high-concentration and stable formulation of magnesium sulfate injection.

[0059] Example 3: A method for preparing a high-concentration stable formulation of magnesium sulfate injection, comprising the following steps: S1. Preparation of high-purity raw materials: Anhydrous magnesium sulfate was prepared by supercritical CO2 drying process: 10 parts of industrial grade magnesium sulfate with a purity ≥98% were dissolved in 39 parts of deionized water, heated to 87℃, 0.09 parts of activated carbon were added for decolorization for 30 min, filtered, and then dried by supercritical CO2 at a temperature of 50℃, a pressure of 14MPa, and a CO2 flow rate of 9L / min to obtain anhydrous magnesium sulfate with a purity ≥99.99%; S2. Solution preparation: PLGA and dichloromethane were mixed at a mass ratio of 1:16 to obtain an oil phase. Ascorbic acid, disodium EDTA, and deionized water were mixed at a mass ratio of 1.6:1:40 to obtain an aqueous phase. The oil phase and aqueous phase were mixed at a mass ratio of 9:1 and ultrasonically emulsified to form a W / O emulsion. The organic solvent was removed by vacuum distillation to obtain PLGA microspheres with a particle size of 50-100 nm loaded with stabilizer. The PLGA microspheres with stabilizer were dispersed in magnesium sulfate solution and the pH was adjusted to 6.5-7.5. S3. Construction of pH-responsive carrier: Preparation of internal aqueous phase: Prepare an aqueous solution of magnesium sulfate and polyacrylic acid, wherein the mass fraction of magnesium sulfate is 40%, the mass fraction of polyacrylic acid is 1.5%, and the molecular weight of polyacrylic acid is 5000 Da; S4. Preparation of oil phase: Dissolve PLGA in dichloromethane, wherein the mass ratio of PLGA to dichloromethane is 1:17, and the molecular weight of PLGA is 20000 Da; S5. Preparation of external aqueous phase: Prepare an aqueous solution containing polyvinyl alcohol, wherein the mass fraction of the aqueous solution of polyvinyl alcohol is 4%; S6. Mix the internal aqueous phase, oil phase and external aqueous phase at a mass ratio of 1:9:40 to obtain pH-responsive microspheres; S7. Take 40 parts of high-purity anhydrous magnesium sulfate, add 70 parts of water for injection, stir to dissolve and form a magnesium sulfate base solution, add 1.3 parts of composite stabilizer to the base solution, stir to make the microspheres uniformly dispersed, add 2 parts of pH-responsive carrier, stir to mix, adjust the pH of the solution to 6.5-7.5, and obtain the initial product of magnesium sulfate injection. S8. Sterilization and filling: Continuous membrane filtration system: adopts cross-flow filtration technology, combined with 0.1-0.2μm ceramic membrane filtration for sterilization, with an impurity rejection rate of ≥99.9%. It is dispensed into glass ampoules or pre-filled syringes, sterilized by moist heat at 121℃ for 15min, and sealed after cooling to obtain a high-concentration and stable formulation of magnesium sulfate injection.

[0060] Example 4: A method for preparing a high-concentration stable formulation of magnesium sulfate injection, comprising the following steps: S1. Preparation of high-purity raw materials: Anhydrous magnesium sulfate was prepared by supercritical CO2 drying process: 10 parts of industrial grade magnesium sulfate with a purity ≥98% were dissolved in 40 parts of deionized water, heated to 90℃, 0.1 parts of activated carbon were added for decolorization for 30 min, filtered, and then dried by supercritical CO2 at a temperature of 60℃, a pressure of 15MPa, and a CO2 flow rate of 10L / min to obtain anhydrous magnesium sulfate with a purity ≥99.99%; S2. Solution preparation: PLGA and dichloromethane are mixed at a mass ratio of 1:20 to obtain an oil phase. Ascorbic acid, disodium EDTA, and deionized water are mixed at a mass ratio of 2:1:50 to obtain an aqueous phase. The oil phase and aqueous phase are mixed at a mass ratio of 10:1 and ultrasonically emulsified to form a W / O emulsion. The organic solvent is removed by vacuum distillation to obtain PLGA microspheres with a particle size of 50-100 nm loaded with stabilizer. The PLGA microspheres with stabilizer are dispersed in magnesium sulfate solution and the pH is adjusted to 6.5-7.5. S3. Construction of pH-responsive carrier: Preparation of internal aqueous phase: Prepare an aqueous solution of magnesium sulfate and polyacrylic acid, wherein the mass fraction of magnesium sulfate is 50%, the mass fraction of polyacrylic acid is 2%, and the molecular weight of polyacrylic acid is 5000 Da; S4. Preparation of oil phase: Dissolve PLGA in dichloromethane, wherein the mass ratio of PLGA to dichloromethane is 1:20, and the molecular weight of PLGA is 20000 Da; S5. Preparation of external aqueous phase: Prepare an aqueous solution containing polyvinyl alcohol, wherein the mass fraction of the aqueous solution of polyvinyl alcohol is 5%; S6. Mix the internal aqueous phase, oil phase and external aqueous phase at a mass ratio of 1:10:50 to obtain pH-responsive microspheres; S7. Take 50 parts of high-purity anhydrous magnesium sulfate, add 75 parts of water for injection, stir to dissolve and form a magnesium sulfate basic solution, add 2 parts of composite stabilizer to the basic solution, stir to disperse the microspheres evenly, add 3 parts of pH-responsive carrier, stir to mix, adjust the pH of the solution to 6.5-7.5, and obtain the initial product of magnesium sulfate injection. S8. Sterilization and filling: Continuous membrane filtration system: adopts cross-flow filtration technology, combined with 0.1-0.2μm ceramic membrane filtration for sterilization, with an impurity rejection rate of ≥99.9%. It is dispensed into glass ampoules or pre-filled syringes, sterilized by moist heat at 121℃ for 15min, and sealed after cooling to obtain a high-concentration and stable formulation of magnesium sulfate injection.

[0061] Comparative Example 1: Commercially available 25% magnesium sulfate injection solution (without composite stabilizers and pH-responsive carriers) was used. Technical solution: Raw materials: Industrial grade magnesium sulfate (95% purity), unpurified; Formulation: 25% magnesium sulfate, 75% water for injection, no stabilizer; Process: Traditional dissolution-filtration-sterilization, without supercritical drying or PLGA microspheres.

[0062] Comparative Example 2: Composite stabilizer formulation lacking PLGA microspheres The formulation in Example 1 of this patent removes PLGA microspheres and contains only ascorbic acid + disodium EDTA (mass ratio 1:1).

[0063] Technical solution: Formulation: 30% magnesium sulfate, 0.5% ascorbic acid, 0.5% disodium EDTA, 69% water for injection; Process: Omit PLGA microsphere preparation, directly dissolve the stabilizer.

[0064] Comparative Example 3: Anhydrous magnesium sulfate prepared by conventional spray drying process: Anhydrous magnesium sulfate (98% purity) was prepared by spray drying (120℃).

[0065] Technical solution: Raw materials: industrial grade magnesium sulfate (purity 95%), spray drying temperature 120℃; Formula: 50% magnesium sulfate, 50% water for injection, containing a small amount of impurities (Ca²⁺ 0.1%).

[0066] Comparative Example 4: PLGA microspheres without pH responsiveness (lacking polyacrylic acid): The formulation of Example 1 in this patent removes polyacrylic acid, and the microspheres contain only PLGA and magnesium sulfate.

[0067] Technical solution: Internal aqueous phase: 30% magnesium sulfate, no polyacrylic acid; Microsphere release: There is no difference in release rate between pH 5.5 and pH 7.4 environments (both are 50% / 24h).

[0068] Performance testing: 1. Physical stability test: Low-temperature crystallization rate: The sample was stored at 4℃ for 6 months, and the crystal particles were observed under a microscope. The proportion of the crystallized area was calculated (crystallization rate = crystallized area / total observed area × 100%). Particle size distribution: The particle size in the solution was determined using a laser particle size analyzer (such as Malvern Mastersizer 3000) (with a focus on the proportion of particles ≥1μm to assess the risk of clogging).

[0069] 2. Chemical stability test: Accelerated test for content change: The sample was stored at 40℃ and 75% relative humidity for 3 months. The magnesium sulfate content was determined by high performance liquid chromatography (HPLC), and the content decrease rate was calculated (decrease rate = (initial content - content after 3 months) / initial content × 100%). pH stability: The pH of the solution was measured monthly during storage using a pH meter (accuracy ±0.01), and the pH fluctuation range was recorded.

[0070] 3. pH-responsive release performance test: The magnesium sulfate release rate over 24 hours was determined by dialysis in buffer solutions at pH 5.5 (simulating inflammation / lesion site) and pH 7.4 (simulating normal blood) (release rate = 24-hour release amount / total load × 100%), and the difference in release rate was calculated (difference = pH 5.5 release rate / pH 7.4 release rate).

[0071] 4. Safety and purity testing: 0.5μm particle count: The number of particles ≥0.5μm in each milliliter of solution was determined by a light-obscured particle counter according to the method in the Chinese Pharmacopoeia. Risk of hypermagnesemia: Samples (dose 1 g / kg) were injected intravenously into animals with renal insufficiency (rats), and blood magnesium concentration was measured 24 h later. The incidence of blood magnesium > 5 mmol / L (toxic threshold) was calculated.

[0072] The results are shown in Table 1-2 below: Table 1 Summary of performance test results for Examples 1-4 Table 2 Summary of performance test results for Comparative Examples 1-4 Data Analysis: (I) Physical stability: Synergistic effect of PLGA microspheres and high-purity raw materials: Examples 1-4: Crystallinity ≤2.1%, and particle size ≥1μm ≤0.5%, significantly better than the comparative example. The core reason is: High-purity magnesium sulfate (≥99.99%) prepared by supercritical CO2 drying is almost free of impurities, thus avoiding impurities acting as "crystal nuclei" to induce crystallization; 50-100nm PLGA microspheres inhibit the growth of magnesium sulfate crystals through steric hindrance, while uniform dispersion prevents particle agglomeration.

[0073] Comparative Example 1 (commercially available): without PLGA microspheres and high-purity raw materials, impurities (such as calcium salts) act as crystal nuclei, resulting in a crystallization rate as high as 35% and severe particle agglomeration (≥1μm particles account for 8.5%). Comparative Example 2 (without PLGA): Ascorbic acid + disodium EDTA alone could not inhibit crystallization (crystallization rate 18%). Due to the lack of steric hindrance from PLGA, the stabilizer was prone to agglomeration to form large particles (≥1μm particles accounted for 5.2%).

[0074] (II) Chemical stability: Synergistic effect of composite stabilizers and pH regulation: Examples 1-4: Content decrease rate ≤1.5%, pH fluctuation ≤0.5 (6 months), excellent stability. The key is: Ascorbic acid provides antioxidant benefits, while disodium EDTA chelates metal ions, inhibiting the hydrolysis / oxidation of magnesium sulfate. PLGA microspheres work synergistically with a pH 6.5-7.5 buffer system to reduce the impact of acid-base fluctuations on chemical stability.

[0075] Comparative Examples 1-3: In the absence of composite stabilizers or high-purity raw materials, impurities (such as Fe³⁺) undergo catalytic hydrolysis, resulting in a decrease in content of 3.5%-4.2% and pH fluctuations of 1.3-1.5 (comparative example 1 increased from 5.5 to 6.8).

[0076] (III) pH-responsive release: Synergistic effect of polyacrylic acid and PLGA: Examples 1-4: The release rate at pH 5.5 (82%-86%) is 3.2-3.5 times that at pH 7.4 (24%-27%), meeting the requirement of "rapid release at lesion sites and slow release from normal tissues". The core mechanism is: polyacrylic acid (5000Da) protonates and shrinks at pH 5.5 (acidic), causing the pores of PLGA microspheres to open; at pH 7.4 (neutral), the carboxyl groups ionize and swell, blocking the pores and achieving release regulation.

[0077] Comparative Examples 1-3: No pH-responsive carrier, no difference in release rate (release difference ≈ 1.0), unable to target drug delivery; Comparative Example 4 (without polyacrylic acid): PLGA microspheres alone lacked pH response function, with a release difference of 1.0, indicating a loss of targeting.

[0078] (iv) Safety: Collaborative assurance of the entire process: Examples 1-4: ≥0.5μm particle count ≤28 particles / mL, hypermagnesemia incidence ≤5.0%, significantly better safety than the control group. The reason is: Supercritical drying + continuous membrane filtration (ceramic membrane) for dual impurity removal, resulting in extremely low particle count; pH-responsive release reduces drug accumulation in normal tissues and lowers the risk of blood magnesium poisoning.

[0079] Comparative Example 1 (commercially available): Traditional processes produce more impurities (180 particles / mL) and lack targeted release, with a hypermagnesemia incidence rate of 22%; Comparative Example 3 (spray drying): High temperature activated impurities (such as Ca²⁺), with a particle count of 150 particles / mL and an incidence of hypermagnesemia of 18%.

[0080] in conclusion: Examples 1-4 address four major pain points of existing technologies through a synergistic end-to-end process: high-purity raw materials (supercritical drying) → composite stabilizer (PLGA microspheres loaded with ascorbic acid / EDTA) → pH-responsive carrier (polyacrylic acid + PLGA) → membrane filtration sterilization. 1. Physical stability: PLGA microspheres + high-purity raw materials reduce the crystallization rate from 35% to ≤2.1%; 2. Chemical stability: The combination of composite stabilizer and pH adjustment reduced the content decrease rate from 4.2% to ≤1.5%; 3. Targeted release: Polyacrylic acid achieves pH response, increasing the release difference from 1.0 to 3.2-3.5 times; 4. Safety: The end-to-end impurity removal process reduces the number of particles by 85% and lowers the risk of hypermagnesemia by 77%.

[0081] Those skilled in the art should understand that the discussion of any of the above embodiments is merely exemplary and is not intended to imply that the scope of the invention is limited to these examples; within the framework of the invention, the technical features of the above embodiments or different embodiments can also be combined, the steps can be implemented in any order, and there are many other variations of the different aspects of the invention as described above, which are not provided in detail for the sake of brevity.

[0082] This invention is intended to cover all such substitutions, modifications, and variations that fall within the broad scope of the appended claims. Therefore, any omissions, modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of this invention should be included within the scope of protection of this invention.

Claims

1. A high-concentration, stable formulation of magnesium sulfate injection, characterized in that, It is prepared from the following raw materials in parts by weight: 25-50 parts of high-purity magnesium sulfate, 0.1-2 parts of composite stabilizer, 0.5-3 parts of pH-responsive carrier, and 50-75 parts of water for injection; The preparation method of the high-concentration stable formulation of the magnesium sulfate injection includes the following steps: Step S1. Preparation of high-purity raw materials: Anhydrous magnesium sulfate is prepared using a supercritical CO2 drying process; Step S2. Solution preparation: Step S201. Preparation of composite stabilizer; Step S202. Construction of pH-responsive vector; Step S3. Sterilization and filling: Continuous membrane filtration system.

2. The method for preparing a high-concentration stable formulation of magnesium sulfate injection according to claim 1, characterized in that, The supercritical CO2 drying process described in step S1 is as follows: Industrial-grade magnesium sulfate was dissolved in deionized water, heated to 80-90℃, and decolorized with activated carbon for 30 minutes. After filtration, it was dried with supercritical CO2 to obtain anhydrous magnesium sulfate with a purity ≥99.99%.

3. The method for preparing a high-concentration stable formulation of magnesium sulfate injection according to claim 2, characterized in that, The purity of the industrial-grade magnesium sulfate is ≥98%; The mass ratio of industrial-grade magnesium sulfate to deionized water is 1:3.5-4; The amount of activated carbon used is 0.5%-1% of the amount of industrial-grade magnesium sulfate used.

4. The method for preparing a high-concentration stable formulation of magnesium sulfate injection according to claim 1, characterized in that, The supercritical CO2 drying process is carried out at a temperature of 40-60℃, a pressure of 10-15MPa, and a CO2 flow rate of 5-10L / min.

5. The method for preparing a high-concentration stable formulation of magnesium sulfate injection according to claim 1, characterized in that, The process for preparing the composite stabilizer in step S201 is as follows: Step S2011. Mix the oil phase and the water phase, and ultrasonically emulsify to form a W / O emulsion; Step S2012. Remove the organic solvent by vacuum distillation to obtain PLGA microspheres with supported stabilizer; Step S2013. Disperse the PLGA microspheres loaded with stabilizer in magnesium sulfate solution and adjust the pH to 6.5-7.

5.

6. The method for preparing a high-concentration stable formulation of magnesium sulfate injection according to claim 5, characterized in that, The oil phase mentioned in step S2011 is prepared from PLGA and dichloromethane; The aqueous phase mentioned in step S2011 is prepared from ascorbic acid, disodium EDTA and deionized water; The mass ratio of the oil phase to the water phase in step S2011 is 5-10:1; In step S2011, the mass ratio of PLGA to dichloromethane in the oil phase is 1:10-20; In step S2011, the mass ratio of ascorbic acid, disodium EDTA, and deionized water in the aqueous phase is 1-2:1:20-50. The particle size of the PLGA microspheres with the stabilizer loaded in step S2012 is 50-100 nm.

7. The method for preparing a high-concentration stable formulation of magnesium sulfate injection according to claim 1, characterized in that, The process of constructing the pH-responsive vector in step S202 is as follows: Step S2021. Prepare pH-responsive microspheres using a two-emulsion method; Step S202. The release rate of pH-responsive microspheres differs by ≥3 times under pH conditions of 5.5-7.4, thus obtaining a pH-responsive carrier.

8. The method for preparing a high-concentration stable formulation of magnesium sulfate injection according to claim 7, characterized in that, The process for preparing pH-responsive microspheres using the dual emulsion method described in step S2021 is as follows: Step S20211. Preparation of the internal aqueous phase: Prepare an aqueous solution of magnesium sulfate and polyacrylic acid; Step S20212. Preparation of the oil phase: Dissolve PLGA in dichloromethane; Step S20213. Preparation of external aqueous phase: Prepare an aqueous solution containing polyvinyl alcohol; Step S20214. Mix the internal aqueous phase, oil phase and external aqueous phase at a mass ratio of 1:5-10:20-50 to obtain pH-responsive microspheres.

9. The method for preparing a high-concentration stable formulation of magnesium sulfate injection according to claim 8, characterized in that, The mass fraction of magnesium sulfate in the aqueous solution described in step S20211 is 25%-50%; The mass fraction of polyacrylic acid in the aqueous solution described in step S20211 is 0.5%-2%; The molecular weight of the polyacrylic acid mentioned in step S20211 is 5000 Da; The molecular weight of the PLGA mentioned in step S20212 is 20000 Da; In step S20212, the mass ratio of PLGA to dichloromethane in the oil phase is 1:10-20; The mass fraction of the polyvinyl alcohol aqueous solution in step S20213 is 1%-5%; The mass ratio of the internal aqueous phase, oil phase, and external aqueous phase is 1:5-10:20-50.

10. The method for preparing a high-concentration stable formulation of magnesium sulfate injection according to claim 1, characterized in that, The process of the continuous membrane filtration system described in step S3 is as follows: Step S301. Cross-flow filtration technology is adopted, combined with ceramic membrane filtration for sterilization, with an impurity rejection rate ≥99.9%; Step S302. Dispense into glass ampoules or pre-filled syringes, sterilize by moist heat or radiation, and seal after cooling.

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