Preparation process and quality control method of high-stability piracetam injection

Abstract

The invention provides a preparation process and a quality control method of a high-stability piracetam injection, and relates to the technical field of medicine preparation, when the piracetam injection is prepared, through an innovative hydroxypropyl-sulfobutyl ether-beta-cyclodextrin bifunctional inclusion technology, the solubility of piracetam is remarkably improved, and the stability of the piracetam injection is improved. According to the hydroxypropyl-sulfobutyl ether-beta-cyclodextrin, the water solubility of cyclodextrin is improved through a hydroxypropyl group, the inclusion affinity with piracetam is enhanced through the electrostatic and hydrophobic interaction of a sulfobutyl ether group, the solubility is improved to exceed 20 mg / mL, the surface potential of microspheres is endowed with-25 + / -3 mV through a polyglutamic acid surface modification technology, the sedimentation rate is effectively reduced to 5% or below, and the stability of the microspheres is improved. The porosity of the microspheres is controlled to be less than 5% and the residual moisture is controlled to be less than or equal to 0.8% by combining a double spraying-freeze drying technology, so that the storage stability of the injection is remarkably improved, no precipitation is realized for 12 months, the use of an organic solvent is avoided, the safety and clinical applicability of the injection are improved, and the solubility and storage stability of piracetam are remarkably improved.

Description

Technical Field

[0001] The invention relates to the technical field of drug preparation, and in particular to a preparation process and a quality control method of a high-stability piracetam injection. Background Art

[0002] Piroxicam is a nonsteroidal anti-inflammatory drug (NSAID) used to relieve arthritis and other related pain, but its solubility is poor, about 0.02 mg / mL, and its insufficient chemical stability leads to precipitation and degradation during the preparation of injection. Existing technologies mostly rely on dependency, co-solvents or single cyclodextrin, and have problems such as insufficient long-term storage stability or complex processes.

[0003] According to a piracetam composition injection disclosed in China with publication number "CN104069107B", each 1000 ml of injection contains: 200 g of piracetam, 55-100 g of vitamin C, 30-50 g of vitamin B6, and 9 g of sodium chloride. The present invention also discloses a method for preparing the piracetam composition injection. The injection of the present invention has the advantages of good solubility, high stability and high safety.

[0004] According to the Chinese publication number "CN116139076A", a method for preparing piracetam injection and the prepared piracetam injection are disclosed, belonging to the technical field of pharmaceutical preparation preparation. The method of the present invention comprises the following steps: (1) taking 70-80% (v / v) of the prescription amount of water for injection into a liquid preparation tank and cooling it to 30-50°C; (2) adding weighed sodium acetate or a mixed sodium salt composed of sodium acetate and sodium chloride, stirring and dissolving uniformly; (3) adding weighed piracetam raw materials, stirring and dissolving uniformly; (4) using acetic acid solution to adjust the pH value of the mixed solution obtained in step (3) to 5.0-7.0; (5) adding water for injection to make up to the final volume, stirring and mixing uniformly. The present invention effectively improves the stability of the piracetam injection product by effectively controlling the pH value range of the piracetam injection preparation and improving the order of adding process raw materials.

[0005] The above patent documents and prior art have the following technical problems when used: Problem 1: The existing piracetam injection is difficult to prepare a high-concentration stable solution due to the extremely low solubility of piracetam, about 0.02 mg / mL. Traditional methods rely on inhibitors or single cyclodextrin to assist in solution, but the solubility improvement is limited, usually below 5 mg / mL, and organic solvents are often added, which increases the risk of toxicity and is not conducive to the preparation and use of actual piracetam injection; Question 2: The existing piracetam injection is prone to degradation and precipitation during storage, and often shows a significant decline in quality within 6 months. In addition, the traditional process relies on manual adjustment of parameters, resulting in poor intermittent consistency of the prepared piracetam injection. Summary of the invention

[0006] Technical issues solved In view of the deficiencies in the prior art, the present invention provides a preparation process and quality control method of a high-stability piracetam injection, which solves the following problems: 1. The preparation of piracetam injection with a single solvent results in poor solubility, insufficient stability and safety of the finished product; 2. To address the problems of low quality control accuracy and insufficient batch consistency in the preparation of piracetam injection, as well as the easy degradation and precipitation of finished products during storage.

[0007] Technical Solution To achieve the above objectives, the present invention is implemented by the following technical scheme: a preparation process and quality control method of a high-stability piracetam injection, the preparation process comprising the following steps: Sp1: Preparation of inclusion complex: 800 mg of hydroxypropyl-sulfobutyl ether-β-cyclodextrin was dissolved in 5 mL of phosphate buffered water for injection at pH 7.2, heated to 40±1°C, 20 mg of piracetam was added, and the molar ratio of hydroxypropyl-sulfobutyl ether-β-cyclodextrin to piracetam was 1:3, stirred at 500±50 rpm for 2 hours to form a hydroxypropyl-sulfobutyl ether-β-cyclodextrin-piracetam inclusion complex solution with an inclusion efficiency of ≥90%; Sp2: Preparation of microsphere precursor: 50 mg of trehalose and 10 mg of polyglutamic acid were added to the inclusion complex solution prepared in Sp1, and the ratio of trehalose to polyglutamic acid was 5:1. Ultrasonic treatment was performed at a frequency of 40±1kHz, a power of 100±5W, and a time of 5±0.5min to optimize the dispersibility and form a microsphere precursor with a particle size of 200-300nm and a polymer dispersion index of less than 0.3; Sp3: Microsphere forming: The microsphere precursor solution in Sp2 was placed in a spray dryer with an inlet air temperature of 130 ± 2 °C, an outlet air temperature of 70 ± 2 °C, and a feed rate of 5 ± 0.5 mL / min to form preliminary microspheres with a porosity of less than 5%; Sp4: Freeze drying: freeze-dry the preliminary microspheres in Sp3, pre-freeze at -50±1℃ for 4 hours, vacuum degree 0.1-0.2mbar, dry for 12 hours, and obtain dry microspheres with residual moisture ≤1.0%; Sp5: Reconstitution of injection solution: The dried microspheres of Sp4 were suspended in 1 mL of water for injection and shaken at 100 rpm for 5 min to prepare a piracetam injection solution with an osmotic pressure of 270-310 mosm / kg and a pH of 7.0-7.5.

[0008] The above process significantly improves the solubility of piracetam to more than 20 mg / mL and the storage stability, with no precipitation after 12 months of storage, through the bifunctional inclusion of hydroxypropyl-sulfobutyl ether-β-cyclodextrin, polyglutamic acid surface modification and double spray-freeze drying technology.

[0009] Preferably, when preparing the hydroxypropyl-sulfobutyl ether-β-cyclodextrin in the Sp1, a hydroxypropylation reaction is first carried out under alkaline conditions of pH 10-11, 1,2-propylene oxide is added, and the reaction is carried out for 6 hours, followed by a sulfobutyl etheration reaction, 1,4-butane sultone is added, and the reaction is carried out for 4 hours. The final product is purified by dialysis and spray dried to obtain hydroxypropyl-sulfobutyl ether-β-cyclodextrin, ensuring that the degree of substitution of hydroxypropyl is 3-5 and the degree of substitution of sulfobutyl ether is 1-2.

[0010] Preferably, during the preparation of the Sp1 inclusion complex, nitrogen is used to protect the environment to reduce the oxidative degradation of piracetam, the nitrogen flow rate is controlled at 0.5-1 L / min, and ascorbic acid with a mass concentration of 0.1% is added during stirring as an antioxidant to further improve the stability of the inclusion complex, and the inclusion efficiency is increased to 92-95%.

[0011] Preferably, the ultrasonic treatment of Sp2 adopts an intermittent mode, which is turned on every 30 seconds, closed after 15 seconds, and cycled 10 times. The solution temperature is maintained at ≤45°C by a temperature control device to avoid local overheating. After treatment, centrifugation is performed at a speed of 5000 rpm for 5 minutes to remove trace insoluble matter and ensure the clarity and uniformity of the precursor.

[0012] Preferably, during the spray drying process of Sp3, the sprayer is equipped with a dual-fluid nozzle, the air flow pressure is 0.3-0.5 MPa, the spray angle is 45°, the microsphere formation is monitored by an online particle size analyzer, and the feed rate is adjusted in real time to ensure that the microsphere particle size distribution is 150-400 nm and the recovery rate is ≥85%.

[0013] Preferably, during the freeze-drying process of Sp4, a programmed temperature rising strategy is adopted. After pre-freezing, the temperature is raised to -20°C at 0.5°C / min and maintained for 6 hours, and then raised to 10°C at 0.3°C / min and maintained for 4 hours. The temperature of the microspheres is monitored by an infrared thermometer to ensure that there is no collapse during the freeze-drying process and the residual moisture of the microspheres is ≤0.8%.

[0014] Preferably, when the polyglutamic acid surface of Sp2 is modified, polyvinyl alcohol with a mass concentration of 0.01% is added to the microsphere precursor solution as an auxiliary dispersant to enhance the electrostatic adsorption efficiency of polyglutamic acid; the surface potential of the modified microspheres is measured by a Zeta potential meter and optimized to -25±3mV, reducing the sedimentation rate during storage of the injection solution to less than 5%.

[0015] Preferably, during the reconstitution process of the Sp5 injection solution, the water for injection is pre-filtered through a 0.22 μm filter membrane and nitrogen is introduced for deoxygenation, and the oxygen content is controlled at ≤1 ppm. After reconstitution, high-speed centrifugation is performed at a speed of 8000 rpm for 3 minutes to remove trace bubbles and ensure that the clarity of the injection solution meets the pharmacopoeia standards.

[0016] Preferably, the quality control method of the preparation process comprises the following steps: Sp1: Raw material acceptance: HPLC and LC / MS were used to detect the purity of piracetam ≥ 99.5%, total impurities ≤ 0.5%, single impurities ≤ 0.1%, Karl Fischer method was used to determine the moisture content ≤ 0.5%, nuclear magnetic resonance was used to determine the degree of substitution of hydroxypropyl-sulfobutyl ether-β-cyclodextrin, and gel permeation chromatography was used to determine the molecular weight of polyglutamic acid 4500-5500Da; Sp2: Preparation process monitoring: online monitoring of the inclusion complex preparation temperature of 40±1℃, pH7.2±0.1, dynamic light scattering detection of microsphere precursor particle size of 200-300nm, polymer dispersion index less than 0.3, Karl Fischer method determination of microsphere moisture content after freeze drying ≤1.0%; Sp3: Final product testing: including physical and chemical testing, microsphere property testing, biological testing and stability verification; Physical and chemical testing: 95-105% piracetam content determined by HPLC, ≤1.0% total impurities determined by LC-MS; pH 7.0-7.5 determined by pH meter; 270-310mosm / kg osmotic pressure determined by freezing point depression method; Microsphere characteristic detection: Dynamic light scattering determined the microsphere particle size to be 150-400nm, and the polymer dispersion index to be less than 0.2; Zeta potential instrument determined the surface potential to be -20 to -30mV; in vitro dissolution test, the environment was pH 7.4 phosphate buffer, the temperature was 37°C, the rotation speed was 100rpm, and the release rate was verified to be ≥80% in 30min; Biological testing: membrane filtration method to test sterility, rabbit method to test the absence of pyrogenic reaction; Stability verification: Through accelerated tests and long-term tests, in which the experimental environment of the accelerated test is 40℃ / 75%RH and the experimental time is 6 months, and the experimental environment of the long-term test is 25℃ / 60%RH and the experimental time is 12 months, it is confirmed that the content decreases by ≤5%, there is no precipitation, and there is no significant change in particle size and surface potential.

[0017] The preparation process optimizes process parameters through machine learning algorithms, establishes a prediction model based on historical data, inclusion efficiency, particle size, and porosity, and dynamically adjusts the ultrasonic frequency in the range of 38-42kHz, the spray drying inlet temperature in the range of 128-132°C, and the freeze-drying vacuum in the range of 0.08-0.22mbar, and the batch-to-batch consistency is improved to more than 98%.

[0018] Beneficial Effects The present invention provides a preparation process and quality control method of a high-stability piracetam injection, which has the following beneficial effects: 1. The present invention adopts the innovative hydroxypropyl-sulfobutyl ether-β-cyclodextrin bifunctional inclusion technology when preparing piracetam injection, which significantly improves the solubility of piracetam and solves the problem of poor water solubility of piracetam in the traditional method. Hydroxypropyl-sulfobutyl ether-β-cyclodextrin uses the hydroxypropyl group to improve the water solubility of cyclodextrin, and at the same time enhances the inclusion affinity with piracetam through the electrostatic and hydrophobic interaction of the sulfobutyl ether group, so that the solubility is increased to more than 20 mg / mL, which is far superior to the solubilizing effect of traditional amino acids or single cyclodextrin. At the same time, the polyglutamic acid surface modification technology gives the micro The sphere surface potential is -25±3mV, which effectively reduces the sedimentation rate to below 5%. Combined with the double spray-freeze drying technology, the porosity of the microspheres is controlled to be less than 5% and the residual moisture is ≤0.8%, which significantly improves the storage stability of the injection and achieves the goal of 12 months without precipitation. Compared with the defects of easy degradation and precipitation of traditional injections, it solves the limitation of low solubility and avoids the use of organic solvents, thereby improving the safety and clinical applicability of the injection. It provides an innovative solution for the preparation of high-concentration piracetam injection and significantly improves the solubility and storage stability of piracetam.

[0019] 2. The present invention introduces advanced technologies such as liquid chromatography-mass spectrometry, nuclear magnetic resonance, dynamic light scattering and Zeta potential detection in the quality control of the preparation of piracetam injection, comprehensively monitors the quality of raw materials, intermediates and final products, and breaks through the limitations of the sensitivity and accuracy of traditional detection methods. Liquid chromatography-mass spectrometry can accurately identify piracetam impurities, nuclear magnetic resonance quantitatively analyzes the degree of substitution of hydroxypropyl-sulfobutyl ether-β-cyclodextrin, dynamic light scattering and Zeta potential detection ensure the consistency of microsphere particle size and surface potential, optimizes process parameters using machine learning algorithms, constructs prediction models based on historical data, dynamically adjusts ultrasonic frequency, spray drying temperature and freeze-drying vacuum, and achieves batch-to-batch consistency of more than 98%, surpassing the traditional process adjustment method that relies on manual experience. Data-driven intelligent optimization not only improves production efficiency and product quality stability, but also ensures quality control and process optimization during the preparation of piracetam injection to improve product consistency, providing an innovative solution for industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0020] Figure 1 is a flow chart of the preparation process of the present invention; Figure 2 A quality control method step diagram for the preparation process of the present invention; Figure 3 The component structure diagram of the piracetam injection of the present invention; Figure 4 It is a variation trend diagram of the preparation process parameters of the present invention. DETAILED DESCRIPTION

[0021] The following will be combined with the drawings in the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention. Specific embodiment one: like Figures 1 to 4 As shown, a preparation process and quality control method of a high-stability piracetam injection, the preparation process comprises the following steps: Sp1: Preparation of inclusion complex: 800 mg of hydroxypropyl-sulfobutyl ether-β-cyclodextrin (HP-SBECD) was dissolved in 5 mL of phosphate buffered water for injection at pH 7.2, heated to 40±1°C, 20 mg of piracetam (HP-SBECD to piracetam molar ratio 1:3) was added, and stirred at 500±50 rpm for 2 hours. During the stirring process, the oxidative free radicals were reduced by an oxidant to form a hydroxypropyl-sulfobutyl ether-β-cyclodextrin-piracetam inclusion complex solution with an inclusion efficiency of ≥90%. When preparing hydroxypropyl-sulfobutyl ether-β-cyclodextrin (HP-SBECD), a hydroxypropylation reaction was first carried out under alkaline conditions of pH 10-11, 1,2-propylene oxide was added, and the reaction was carried out for 6 hours, followed by a sulfobutylation reaction. 1,4-Butane sultone was added and reacted for 4 hours. The final product was purified by dialysis and spray dried to obtain hydroxypropyl-sulfobutyl ether-β-cyclodextrin, ensuring that the degree of substitution of hydroxypropyl was 3-5 and the degree of substitution of sulfobutyl ether was 1-2. During the preparation of the inclusion complex, nitrogen was used to protect the environment to reduce the oxidative degradation of piracetam. The nitrogen flow rate was controlled at 0.5-1L / min. 0.1% (w / v) ascorbic acid was added as an antioxidant during stirring to further improve the stability of the inclusion complex. The inclusion efficiency was increased to 92-95%. The solubility of piracetam was significantly improved by inclusion of hydroxypropyl-sulfobutyl ether-β-cyclodextrin. At the same time, the phosphate buffer system was used to maintain pH stability. Nitrogen and antioxidants protected the activity of the drug to form a stable complex solution, laying the foundation for the subsequent microsphere preparation. Sp2: Preparation of microsphere precursor: 50 mg of trehalose and 10 mg of polyglutamic acid (PGA, molecular weight 4500-5500 Da, trehalose to PGA ratio 5:1) were added to the inclusion complex solution prepared in Sp1. Ultrasonic treatment was performed at a frequency of 40±1 kHz, a power of 100±5 W, and a time of 5±0.5 min to optimize the dispersibility and form a microsphere precursor with a particle size of 200-300 nm and a polymer dispersion index (PDI) of less than 0.3. The ultrasonic treatment was performed in intermittent mode, which was turned on every 30 seconds and turned off after 15 seconds. The cycle was repeated 10 times. The solution temperature was maintained at ≤45°C by a temperature control device to avoid local overheating. After treatment, the solution was centrifuged at a speed of 500. 0rpm, time is 5min, trace insoluble matter is removed, the clarity and uniformity of the precursor are ensured, and when polyglutamic acid (PGA) is modified on the surface, 0.01% (w / v) polyvinyl alcohol (PVA) is added to the microsphere precursor solution as an auxiliary dispersant to enhance the electrostatic adsorption efficiency of PGA, so that the surface of the microspheres is negatively charged, which can be measured by a Zeta potential meter. The surface potential of the modified microspheres is measured by a Zeta potential meter and optimized to -25±3mV, reducing the sedimentation rate of the injection solution during storage to less than 5%. Trehalose is used to protect the microsphere structure, PGA modification is used to give a load to reduce sedimentation, and PVA is used to optimize dispersibility. A high-quality precursor is formed by combining spraying and centrifugation technology to provide uniform and stable raw materials for microsphere molding; Sp3: Microsphere forming: The microsphere precursor solution in Sp2 is placed in a spray dryer with an inlet air temperature of 130±2℃, an outlet air temperature of 70±2℃, and a feed rate of 5±0.5mL / min to form preliminary microspheres with a porosity of less than 5%. During the spray drying process, the sprayer is equipped with a dual-fluid nozzle, an air flow pressure of 0.3-0.5MPa, and a spray angle of 45°. The microsphere formation is monitored by an online particle size analyzer, and the feed rate is adjusted in real time to ensure that the microsphere particle size distribution is 150-400nm and the recovery rate is ≥85%. The microspheres are quickly formed by drying, and the dual nozzles and online monitoring ensure consistency. The low-temperature air outlet and air pressure control provide a structurally stable intermediate for subsequent freeze drying; Sp4: Freeze drying: The preliminary microspheres in Sp3 were freeze dried, pre-frozen at -50±1℃ for 4 hours, vacuum degree 0.1-0.2mbar, and dried for 12 hours to obtain dry microspheres with residual moisture ≤1.0%. During the freeze drying process, a programmed temperature increase strategy was adopted. After pre-freezing, the temperature was raised to -20℃ at 0.5℃ / min and maintained for 6 hours, and then raised to 10℃ at 0.3℃ / min and maintained for 4 hours. The temperature of the microspheres was monitored by an infrared thermometer to ensure that there was no collapse during the freeze drying process. The residual moisture of the microspheres was ≤0.8%. Freeze drying was used to avoid moisture and maintain the morphology of the microspheres. Low residual moisture prolonged storage stability and provided high-quality dry microspheres for reconstitution. Sp5: Reconstitution of injection solution: The dried microspheres of Sp4 were suspended in 1 mL of water for injection and oscillated at 100 rpm for 5 min to prepare a piracetam injection solution with an osmotic pressure of 270-310 mosm / kg and a pH of 7.0-7.5. During the reconstitution of the injection solution, the water for injection was pre-filtered through a 0.22 μm filter membrane and nitrogen was introduced for deoxygenation. The oxygen content was controlled at ≤1 ppm. After reconstitution, high-speed centrifugation was performed at a speed of 8000 rpm for 3 min to remove trace bubbles and ensure that the clarity of the injection solution met the pharmacopoeia standards.

[0023] The above process significantly improves the solubility (solubility greater than 20 mg / mL) and storage stability (no precipitation for 12 months) of piracetam through the dual-functional inclusion of hydroxypropyl-sulfobutyl ether-β-cyclodextrin, PGA surface modification and double spray-freeze drying technology, and ensures that the process can be industrialized to meet clinical needs. Specific embodiment 2: like Figures 1 to 4 As shown, according to the contents in the above specific embodiments, the following contents are further disclosed: To ensure the quality, safety and effectiveness of high-stability piracetam injection, this quality control method comprehensively monitors and guarantees product quality through three core steps: raw material acceptance, preparation process monitoring and final product testing, combined with advanced testing technology and data-driven process optimization. The quality control method of the preparation process includes the following steps: Sp1: Raw material acceptance: High performance liquid chromatography (HPLC) and liquid chromatography-mass spectrometry (LC-MS) are used to detect the purity of piracetam ≥99.5%, total impurities ≤0.5%, single impurities ≤0.1%, Karl Fischer method to determine the moisture content ≤0.5%, nuclear magnetic resonance (NMR) to determine the degree of substitution of hydroxypropyl-sulfobutyl ether-β-cyclodextrin, gel permeation chromatography (GPC) to determine the molecular weight of PGA 4500-5500Da, the main raw materials piracetam (API), hydroxypropyl-sulfobutyl ether-β-cyclodextrin (HP-SBECD) and polyglutamic acid (PGA) are tested. The acceptance of piracetam adopts high performance liquid chromatography (HPLC) and liquid chromatography-mass spectrometry (LC-MS) technology, and the detection purity requirement is ≥99.5%, total impurities ≤0.5%, single impurities ≤0.1%, Karl Fischer method to determine the moisture content ≤0.5%, nuclear magnetic resonance (NMR) to determine the degree of substitution of hydroxypropyl-sulfobutyl ether-β-cyclodextrin, gel permeation chromatography (GPC) to determine the molecular weight of PGA 4500-5500Da. ≤0.5%, single impurity ≤0.1%, and the water content is ≤0.5% by Karl Fischer titration; the operation process is as follows: randomly sample 3 portions from each batch of raw materials, each of which is about 1g, and use HPLC (equipped with C18 column, mobile phase is methanol-water 70:30, detection wavelength 333nm) to calculate the purity by the main peak area; use LC-MS (mass spectrometry scanning range m / z50-500) to identify and quantify the type and content of impurities; use Karl Fischer titrator to determine the water content to ensure that the results meet the requirements. The acceptance of hydroxypropyl-sulfobutyl ether-β-cyclodextrin uses nuclear magnetic resonance (NMR) technology to determine the degree of substitution, requiring hydroxypropyl substitution degree 3-5, sulfobutyl ether substitution degree 1-2, and the operation process is as follows: sample 0.5g, dissolve in heavy water (D 2 O), run ¹H-NMR, calculate the degree of substitution by integrating the characteristic peaks to ensure that its inclusion performance meets the standards, and the molecular weight of PGA is determined by gel permeation chromatography (GPC), which is required to be 4500-5500Da. The operation process is: take 0.5g of sample, prepare it into a 1mg / mL solution, analyze the molecular weight distribution by GPC to ensure its function as a stabilizer, and use HPLC, LC-MS, NMR and GPC and other technical means to comprehensively evaluate the purity, impurities, structure and molecular weight of the raw materials to prevent preparation failure or product quality degradation due to raw material quality problems, and ensure the reliability and repeatability of the process; Sp2: Preparation process monitoring: Online monitoring of the preparation temperature of the inclusion complex at 40±1℃, pH7.2±0.1, dynamic light scattering (DLS) detection of microsphere precursor particle size of 200-300nm, polymer dispersion index (PDI) less than 0.3, Karl Fischer method determination of freeze-dried microsphere moisture ≤1.0%; During the preparation of the inclusion complex, use online monitoring equipment to record the temperature (controlled at 40±1℃), pH (7.2±0.1) and stirring speed (500±50rpm) in real time, record data every 15min, take a sample of 5mL after stirring for 2 hours, and use ultraviolet spectrophotometry (detection wavelength 333nm) to determine the inclusion efficiency, which is required to be ≥90%. If it does not meet the standard, extend the stirring time to 3 hours and retest to ensure that piracetam and hydroxypropyl-sulfobutyl ether-β-cyclodextrin are fully included; During the preparation of the microsphere precursor, after ultrasonic treatment Take 1 mL of sample and use dynamic light scattering (DLS) to detect the particle size (required to be 200-300 nm) and polymer dispersion index (PDI<0.3). The operation process is as follows: place the sample in the DLS instrument, set the scattering angle to 173°, measure the particle size distribution and uniformity, and ensure that the precursor is suitable for subsequent microsphere formation; in the freeze-drying stage, take 3 samples after drying, and use Karl Fischer titration to determine the residual moisture of the microspheres, which is required to be ≤1.0%. The operation process is as follows: place the sample in a titrator, titrate to the endpoint to calculate the moisture content, and ensure that the dryness of the microspheres meets the stability requirements. By real-time monitoring of key parameters such as temperature, pH, stirring speed, and combining detection methods such as DLS and ultraviolet spectrophotometry, the quality status of the intermediate products in the preparation process can be dynamically grasped, and the process parameters can be adjusted in time (such as extending the stirring time or adjusting the ultrasonic power) to ensure process stability and avoid batch differences; Sp3: Final product testing: including physical and chemical testing, microsphere property testing, biological testing and stability verification of the product. Through multi-dimensional testing technology, the physical and chemical properties, microsphere performance, safety and stability of the injection are comprehensively evaluated to ensure that the product meets the pharmacopoeia and clinical requirements. The specific contents are as follows: Physical and chemical testing: HPLC determination of piracetam content 95-105%, LC-MS determination of total impurities ≤1.0%; pH meter determination of pH7.0-7.5; freezing point depression method determination of osmotic pressure 270-310mosm / kg. Physical and chemical testing includes the use of HPLC to determine the content of piracetam (required to be 95-105% of the labeled amount). The operating procedure is to take 3 samples, each of 1mL, and use HPLC (C18 column, mobile phase methanol-water 70:30, 333nm) to determine the main peak area to calculate the content; LC-MS is used to detect related substances (total impurities ≤1.0%, single impurity ≤0.5%). The operating procedure is to scan the range of m / z50-500 and quantify the impurity peak; pH meter is used to determine pH (7.0-7.5) and freezing point depression method is used to determine osmotic pressure (270-310mosm / kg). The operating procedure is to use calibrated pH meter and osmotic pressure meter to measure samples respectively to ensure that the physical and chemical properties meet the standards; Microsphere characteristic detection: DLS determines the microsphere particle size to be 150-400nm, and the PDI is less than 0.2; the Zeta potential instrument determines the surface potential to be -20 to -30mV; the in vitro dissolution test (pH7.4 phosphate buffer, 37°C, 100rpm) verifies that the release is ≥80% in 30min. The microsphere characteristic detection includes using DLS to determine the microsphere particle size (150-400nm, PDI<0.2), and the operation procedure is to take a sample of 1mL and place it in the DLS instrument for measurement; the surface potential is measured using a Zeta potential instrument (-20 to -30mV), and the operation procedure is to measure the sample potential value to evaluate stability; an in vitro dissolution test (pH7.4 phosphate buffer, 37°C, 100rpm) is performed, and 3 samples of 1mL are taken, and the release amount in 30min is determined by HPLC to be ≥80% to ensure drug release performance; Biological testing: Membrane filtration method to test sterility, rabbit method to test the absence of pyrogenic reaction; Biological testing includes using membrane filtration method to test sterility, the operation process is to filter the sample and then culture it to observe the growth of no colonies; using rabbit method to test pyrogens, the operation process is to monitor the rabbit body temperature after injecting the sample and see if there is any abnormal increase; Stability verification: Through accelerated tests (40℃ / 75%RH, 6 months) and long-term tests (25℃ / 60%RH, 12 months), it was confirmed that the content decreased by ≤5%, there was no precipitation, and there was no significant change in particle size and surface potential. Stability verification was carried out through accelerated tests (40℃ / 75%RH, 6 months) and long-term tests (25℃ / 60%RH, 12 months). Samples were taken every 3 months to test the piracetam content (decreased by ≤5%), impurities, particle size, surface potential and appearance (no precipitation). The operating procedure was to take samples at predetermined time points and verify using the above-mentioned test methods; The preparation process uses machine learning algorithms to optimize process parameters, establishes a prediction model based on historical data (such as inclusion efficiency, particle size, and porosity), and dynamically adjusts the ultrasonic frequency (38-42kHz), spray drying inlet temperature (128-132°C), and freeze-drying vacuum (0.08-0.22mbar). The batch-to-batch consistency is improved to more than 98%. In order to improve the stability and batch-to-batch consistency of the preparation process, a machine learning algorithm is used to optimize process parameters, and a prediction model is established based on historical data (such as inclusion efficiency, particle size, and porosity). The input parameters include ultrasonic frequency (38-42kHz), spray drying inlet temperature (128-132°C), and freeze-drying vacuum (0.08-0.22mbar). The mist drying inlet air temperature (128-132℃) and freeze drying vacuum degree (0.08-0.22mbar) are input into the model through real-time data collection (such as online sensors monitoring temperature and particle size), and the parameters are dynamically adjusted and fed back to the process equipment. For example, if the particle size is too large, the ultrasonic frequency is increased to 42kHz; if the moisture content is too high, the vacuum degree is reduced to 0.08mbar. Finally, through multiple iterative optimizations, the batch consistency is improved to more than 98%. The function of this optimization is to use data-driven technology to achieve precise control of process parameters, reduce human intervention and errors, and improve production efficiency and product quality stability.

[0025] This quality control method ensures a high-quality starting point through raw material acceptance, ensures process stability through preparation process monitoring, comprehensively verifies product quality through final product testing, and improves batch consistency through machine learning optimization, thereby ensuring the quality, safety and effectiveness of high-stability piracetam injection, and has the potential for industrial production and clinical application. Specific embodiment three: like Figures 1 to 4 As shown, according to the contents in the above specific embodiments, the following contents are further disclosed: In order to further verify the effects of the preparation process and quality control method in the above-mentioned specific embodiment 1 and specific embodiment 2, the following experiments were designed for verification: Experimental purpose: To verify the feasibility and stability of the preparation process in the technical solution, to evaluate the effectiveness of the quality control method in the technical solution, to compare the differences between the technical solution and the existing technical solution in key performance indicators, and to prove its superiority; The experimental materials are as follows: Piroxicam, hydroxypropyl-sulfobutyl ether-β-cyclodextrin (HP-SBECD), trehalose, polyglutamic acid (PGA), polyvinyl alcohol (PVA), ascorbic acid, phosphate buffered saline, and water for injection; Control material: cosolvent used in the prior art solution (such as β-cyclodextrin); Experimental equipment: high performance liquid chromatography (HPLC), liquid chromatography-mass spectrometry (LC-MS), nuclear magnetic resonance (NMR), gel permeation chromatography (GPC), dynamic light scattering (DLS), Zeta potential meter, spray dryer, freeze dryer, pH meter, osmometer, ultrasonic processor, centrifuge, constant temperature oscillator; The preparation process of the present application scheme is verified as follows: Piracetam and hydroxypropyl-sulfobutyl ether-β-cyclodextrin are mixed in a molar ratio of 1:2, phosphate buffered saline solution (pH 7.0) is added, and stirred for 4 hours; the inclusion efficiency is determined by ultraviolet spectrophotometry; trehalose (5% w / v), PGA (0.5% w / v) and PVA (1% w / v) are added to the inclusion complex solution, ultrasonic treatment (500W, 10min), centrifugation is performed to remove unincluded substances, and the particle size and polydispersity index (PDI) are determined by DLS; the microsphere precursor solution is passed through a spray dryer (inlet air temperature 150°C, outlet air temperature 80°C) to prepare microspheres, and the microsphere particle size is monitored by an online particle size analyzer; the microspheres are placed in a freeze dryer (-50°C, 48 hours), and the residual moisture is determined by the Karl Fischer method; the dried microspheres are re-dissolved in water for injection (10 mg / mL piracetam concentration), and the pH and osmotic pressure are determined; The quality control verification of this application scheme is as follows: HPLC is used to detect the purity of piracetam, LC-MS and NMR are used to verify the structure of hydroxypropyl-sulfobutyl ether-β-cyclodextrin, and GPC is used to determine the molecular weight of PGA; the temperature (25±2°C), pH (7.0±0.2) and stirring speed (300rpm) during the inclusion process are recorded online; DLS is used to detect the particle size and PDI of the microsphere precursor; the moisture content of the microspheres is determined after freeze-drying; physical and chemical tests: pH, osmotic pressure; microsphere characteristics: particle size, Zeta potential; biological tests: in vitro dissolution; stability: storage at 25°C for 12 months to observe precipitation; test indicators: solubility (mg / mL); storage stability (no precipitation for 12 months); batch-to-batch consistency (content uniformity); in vitro dissolution rate (30min release percentage); Preparation of control sample: The prior art uses β-cyclodextrin (1:2 molar ratio) to prepare piracetam injection. The formula of piracetam injection is: piracetam and β-cyclodextrin are cosolvents, phosphate is a pH adjuster, and water for injection is prepared as a solvent. 160 mg of β-CD is dissolved in 5 mL of phosphate buffered water for injection (pH 6.5), heated to 50°C, 20 mg of piracetam (molar ratio 1:2) is added, stirred for 3 hours (300 rpm), filtered through a 0.45 μm filter membrane to remove insoluble matter, and a clear solution is obtained. The pH is adjusted to 6.5-7.0, and water for injection is added to the target concentration (20 mg / mL) to obtain the prepared piracetam injection; Experimental data recording: parameter detection was performed on the injection prepared in the present application and the prior art, and all key parameters and test results were recorded in a table. The average value of three parallel experiments was taken, as shown in Tables 1, 2 and 3 below: Table 1 Preparation process parameters Table 2 Quality control test results Table 3 Performance comparison The experimental analysis is as follows: Preparation process: The inclusion efficiency of the technical solution (92-95%) is significantly higher than that of the existing technology (70-80%), indicating that hydroxypropyl-sulfobutyl ether-β-cyclodextrin is superior to β-cyclodextrin, the microspheres have smaller and more uniform particle size (PDI < 0.3), low residual moisture (≤ 0.8%), and better process stability.

[0027] Quality control: high purity of raw materials, less impurities; the surface potential of microspheres is more negative (-25mV), which enhances dispersibility; Improved performance: Solubility increased to >20 mg / mL (5-10 mg / mL with existing technology), no precipitation after 12 months of storage, batch consistency of 98%, and faster in vitro dissolution rate (≥80%).

[0028] Experiments have proved that the technical solution is superior to the existing technology in terms of preparation process, quality control and performance, providing a reliable basis for the development of piracetam injection. Specific embodiment four: like Figures 1 to 4 As shown, according to the contents in the above specific embodiments, the following contents are further disclosed: In order to further illustrate the feasibility of the technical solution of this application in actual use, the following application case contents are further disclosed: Case 1: Production of clinical piracetam injection for the treatment of acute arthritis pain: Piracetam, as a nonsteroidal anti-inflammatory drug (NSAID), is widely used to treat severe pain caused by acute arthritis. However, the low solubility (about 0.02 mg / mL) and poor storage stability (easy to precipitate within 6 months) of traditional piracetam injection limit its application in emergency scenarios. A pharmaceutical company adopts this technical solution to produce high-stability piracetam injection for rapid analgesic treatment of patients with acute arthritis. The goal is to increase the solubility to more than 20 mg / mL, the storage stability to 12 months without precipitation, and ensure rapid release to meet the needs of acute treatment; Implementation process: Raw material preparation and acceptance: Purchase high-purity piracetam (purity ≥ 99.5%), hydroxypropyl-sulfobutyl ether-β-cyclodextrin (hydroxypropyl substitution degree 3-5, sulfobutyl ether substitution degree 1-2), PGA (molecular weight 4500-5500Da), and use HPLC, LC-MS, NMR and GPC to test the quality of raw materials to ensure that they meet the requirements of the technical plan; Preparation process: 800 mg of hydroxypropyl-sulfobutyl ether-β-cyclodextrin (HP-SBECD) was dissolved in 5 mL of pH 7.2 phosphate buffered water for injection, heated to 40 ± 1 °C, 20 mg of piracetam was added, stirred at 500 rpm for 2 hours, 0.1% ascorbic acid and nitrogen protection (0.5-1 L / min) were added, and the inclusion efficiency reached 92-95%; 50 mg of trehalose, 10 mg of PGA (ratio 5:1) and 0.01% of PVA were added, ultrasonic treatment (40 kHz, 100 W, 5 min, intermittent mode), centrifugation (5000 rpm, 5 min), and a particle size of 200 was formed. -300nm, PDI<0.3 microsphere precursor, surface potential -25±3mV; spray drying (inlet air temperature 130±2℃, outlet air temperature 70±2℃, feed rate 5mL / min), forming microspheres with porosity <5%, particle size 150-400nm, recovery rate ≥85%; freeze drying (-50℃ prefreezing for 4 hours, 0.1-0.2mbar, programmed temperature rise), residual moisture ≤0.8%; microspheres were re-dissolved in 1mL deoxygenated water for injection (oxygen content ≤1ppm), oscillated at 100rpm for 5min, pH7.0-7.5, osmotic pressure 270-310mosm / kg; Quality control: HPLC detected the purity of piracetam to be 99.6%, and the total impurities to be 0.3%; NMR confirmed the degree of substitution of hydroxypropyl-sulfobutyl ether-β-cyclodextrin (HP-SBECD); GPC verified the molecular weight of PGA; online monitoring of temperature and pH, DLS detected the particle size, and Karl Fischer method measured the moisture; HPLC measured the content to be 95-105%, LC-MS measured the total impurities to be ≤1.0%, DLS measured the particle size, Zeta potential -20 to -30mV, in vitro dissolution 30min ≥80%, and the sterility and pyrogen-free tests were qualified; Clinical trial: A small-scale clinical trial was conducted to intravenously inject the injection (20 mg / mL, once a day for 7 consecutive days) into 50 patients with acute arthritis. The analgesic effect and adverse reactions were recorded. The data are shown in Table 4 below: Table 4 The piracetam injection produced by this technical solution has shown significant advantages in clinical applications. The solubility is increased to 20.5 mg / mL, which is more than 4 times higher than that of the traditional solution (4.8 mg / mL), meeting the needs of high-concentration injection. The microspheres are small and uniform in size (220 nm, PDI0.25), with a surface potential of -26.5 mV and a sedimentation rate of only 3.8%, ensuring that the injection is clear and stable, with no precipitation for 12 months, far exceeding the traditional solution (precipitation after 6 months). The in vitro dissolution rate is 82.4%, the analgesic onset time is shortened to 15 minutes, and the patient's pain score (VAS) decreases by 70% within 30 minutes. The efficacy is significant, the adverse reaction rate is as low as 4%, and the safety is better than the traditional solution. This case verifies the feasibility of hydroxypropyl-sulfobutyl ether-β-cyclodextrin (HP-SBECD) inclusion, PGA modification and double drying technology, providing an efficient and stable injection preparation for the treatment of acute arthritis.

[0030] Case 2: Large-scale industrial production of piracetam injection for the treatment of rheumatic diseases: Rheumatic disease patients need to use piracetam injection for a long time to relieve joint pain and inflammation, but traditional preparations have poor batch consistency (usually <90%) and insufficient storage stability, which limits large-scale production and market supply. A large pharmaceutical company adopts this technical solution to establish an industrial production line to produce piracetam injection for the treatment of rheumatic disease, with the goal of achieving batch consistency ≥ 98%, storage stability of 12 months without precipitation, and ensuring that the product meets the pharmacopoeia standards through quality control; Implementation process: Production line design: Based on the technical solution, automated equipment is configured, including high-precision stirred reactors, ultrasonic processors, spray drying towers, freeze dryers and aseptic filling lines; Preparation process: In a 50L reactor, 8kg of hydroxypropyl-sulfobutyl ether-β-cyclodextrin (HP-SBECD) was dissolved in 50L of pH 7.2 phosphate buffer, 40±1°C, 0.2kg of piracetam was added, and the mixture was stirred at 500rpm for 2 hours under nitrogen protection (0.5L / min), 0.1% ascorbic acid, and the inclusion efficiency was 92-95%; 0.5kg of trehalose, 0.1kg of PGA (ratio 5:1), and 0.01% of PVA were added, and ultrasonic treatment (40kHz, 100W, 5min, intermittent mode) was performed, and centrifugation was performed at 5000rpm. The particle size was 2 00-300nm, PDI<0.3, surface potential -25±3mV; industrial spray drying tower (inlet air temperature 130±2℃, outlet air temperature 70±2℃, feed rate 5L / h), dual-fluid nozzle, particle size 150-400nm, recovery rate ≥85%; freeze drying (-50℃, 4 hours pre-freezing, 0.1-0.2mbar, programmed temperature rise), residual moisture ≤0.8%; microspheres are re-dissolved in water for injection (oxygen content ≤1ppm), 100rpm shaking, sterile filling, pH7.0-7.5, osmotic pressure 270-310mosm / kg; Quality control and optimization: Raw material acceptance: HPLC and LC-MS test the purity of piracetam to be 99.7% and the total impurities to be 0.2%; NMR and GPC verify hydroxypropyl-sulfobutyl ether-β-cyclodextrin (HP-SBECD) and PGA; Process monitoring: Online sensors monitor temperature, pH, particle size, and Karl Fischer method measures moisture; Final testing: HPLC measures content, LC-MS measures impurities, DLS, Zeta potential, dissolution test, sterility and pyrogen test; Process optimization: The machine learning algorithm dynamically adjusts the ultrasonic frequency (38-42kHz) and spray temperature (128-132°C) based on the inclusion efficiency, particle size, and porosity data, and the batch consistency reaches 98%; The injection with the production specification of 20 mg / mL and 1 mL / vial was tracked for clinical use effects, and the statistical data results were recorded as shown in Table 5 below: Table 5 This technical solution has shown excellent performance in industrial production, with a solubility of 21.2 mg / mL, nearly 4 times higher than the traditional solution (5.3 mg / mL), supporting the production of high-concentration preparations, microsphere particle size of 210 nm, PDI0.22, surface potential -27.2 mV, sedimentation rate of only 3.2%, and no precipitation after storage for 12 months, solving the problem of poor stability of traditional solutions. Machine learning optimization has achieved batch consistency of 98.5%, far exceeding the traditional solution (88.7%), and increased production efficiency by 20%. Clinical feedback shows that patients' VAS scores decreased by 75% after use, with high satisfaction, which is significantly improved compared with the traditional solution (55%). Quality control uses LC-MS, DLS and other technologies to ensure low impurities and stable microsphere performance. The product meets the pharmacopoeia standards. This case verifies the feasibility of the technical solution in industrial production and provides high-quality injection for the treatment of rheumatism. Specific embodiment five: like Figures 1 to 4 As shown, according to the contents in the above specific embodiments, the following contents are further disclosed: In order to further verify the effect of the present application when used by actual patients, verify the stability of the present application when used and the reaction during application, the following application contents are further disclosed: Case 1: Rapid analgesia for a patient with acute arthritis: Patient background: Zhang, male, 45 years old, construction worker, weighing 70kg, suffered from acute knee arthritis due to strenuous exercise, manifested by swelling and severe pain in the right knee joint, visual analogue scale (VAS) score of 8 points, limited movement, imaging examination showed inflammation of joint soft tissue, no bone injury, and required rapid analgesia to resume work ability; Treatment options include: Ratio and content of injection: Formula (per 1mL): Piracetam 20mg, Hydroxypropyl-sulfobutyl ether-β-cyclodextrin (HP-SBECD) 800mg, Trehalose 50mg, PGA10mg, PVA0.1mg, Ascorbic acid 1mg, Phosphate buffered saline (pH7.2), Water for injection added to 1mL; Single dose: 20mg (1mL, concentration 20mg / mL), once a day, intravenous injection; Treatment course: 5 consecutive days; Administration: intravenous injection (5 mL / min) to ensure that the drug quickly enters the blood circulation and achieves analgesic effect. The injection solution has a pH of 7.0-7.5 and an osmotic pressure of 270-310 mosm / kg to ensure injection safety. Auxiliary treatment: local ice compress, rest, avoid strenuous exercise; Efficacy observation: Observation indicators: VAS score, degree of joint swelling (measurement of knee joint circumference), adverse reactions; Observation time points: before treatment, the first day of treatment (30 minutes after injection), the third day, and the fifth day; Results: 30 minutes after treatment, the VAS score dropped to 4 points, on the 3rd day it dropped to 2 points, and on the 5th day it dropped to 0 points. The joint swelling subsided significantly, and the patient resumed normal walking. The only adverse reaction was mild discomfort at the injection site (incidence 2%). The observation indicators are shown in Table 6: Table 6 In this case, the high solubility of the injection (20.5 mg / mL) ensured the rapid dissolution and absorption of a single dose of 20 mg. The hydroxypropyl-sulfobutyl ether-β-cyclodextrin (HP-SBECD) inclusion technology (inclusion efficiency 93.2%) improved the bioavailability of piracetam. The in vitro dissolution test showed a 30-min release rate of 82.4%, which was consistent with the rapid analgesic effect (VAS decreased by 50% in 30 min). PGA modification (surface potential -26.5 mV) reduced the sedimentation rate to 3.8%, ensuring that the injection was clear and free of precipitation, suitable for acute treatment. The low adverse reaction rate (2%) was due to ascorbic acid and nitrogen protection (total impurities ≤1.0%), which improved safety. This case verified the application value of the technical solution in rapid analgesia of acute arthritis.

[0032] Case 2: Long-term treatment of a patient with chronic rheumatoid arthritis: Patient background: Ms. Li, female, 60 years old, retired teacher, weight 55kg, diagnosed with chronic rheumatoid arthritis for 5 years, morning stiffness and pain in both finger joints and knee joints, VAS score 6 points, positive rheumatoid factor (RF), elevated C-reactive protein (CRP) (35mg / L), requiring long-term anti-inflammatory and analgesic treatment to improve quality of life; Treatment options include: Ratio and content of injection: Formula (per 1mL): piracetam 20mg, hydroxypropyl-sulfobutyl ether-β-cyclodextrin (HP-SBECD) 800mg, trehalose 50mg, PGA10mg, PVA0.1mg, ascorbic acid 1mg, phosphate buffered saline (pH7.2), water for injection is added to 1mL, 10mg (0.5mL, diluted to 5mL normal saline), twice a week, intravenous injection, for 8 consecutive weeks, and then adjusted to once a week according to the condition; Administration: intravenous drip (10 mL / min), diluted and administered to reduce local irritation, injection pH 7.0-7.5, osmotic pressure 270-310 mosm / kg, to ensure safety for long-term use; Adjunctive treatment: oral methotrexate (7.5 mg / week), physical rehabilitation training; Efficacy observation: Observation indicators: VAS score, morning stiffness time (min), CRP level, adverse reactions; Observation time points: before treatment, 2nd week, 4th week, 8th week of treatment; Results: In the second week, VAS dropped to 4 points, and morning stiffness time was shortened to 15 minutes; in the fourth week, VAS dropped to 2 points, and CRP dropped to 15 mg / L; in the eighth week, VAS was 1 point, and CRP dropped to 8 mg / L. The patient's joint function was significantly improved, and the adverse reaction was 1 mild dizziness (incidence 2%). The data are shown in Table 7: Table 7 This case aims at the long-term treatment needs of chronic rheumatoid arthritis. A lower dose (10 mg / time) is used to reduce the risk of drug accumulation. Hydroxypropyl-sulfobutyl ether-β-cyclodextrin (HP-SBECD) inclusion (solubility 21.2 mg / mL) ensures that low doses still have efficient anti-inflammatory effects. PGA modification (sedimentation rate 3.2%) and double drying (residual moisture 0.6%) ensure that the injection solution is precipitated-free for 12 months, making it suitable for long-term storage and use. The in vitro dissolution rate of 84.6% supports the sustained release of the drug. The 77% decrease in CRP reflects the effective control of inflammation. Quality control (LC-MS detection of total impurities ≤1.0%) ensures drug purity. Dilution and dripping reduce the adverse reaction rate to 2%. This case verifies the stability and safety of the technical solution in the long-term treatment of chronic diseases.

[0033] Case 3: Postoperative pain management: Patient background: Mr. Wang, male, 35 years old, programmer, weighing 80 kg, underwent internal fixation surgery for right tibia due to fracture. He had obvious pain on the first day after surgery, with a VAS score of 7 points and local swelling. He needed short-term strong analgesia to promote postoperative recovery and reduce the use of opioids. Treatment options include: Ratio and content of injection: Formula (per 1mL): piracetam 20mg, hydroxypropyl-sulfobutyl ether-β-cyclodextrin (HP-SBECD) 800mg, trehalose 50mg, PGA10mg, PVA0.1mg, ascorbic acid 1mg, phosphate buffered saline (pH7.2), water for injection added to 1mL; single dose: 30mg (1.5mL, diluted to 10mL normal saline), once a day, intravenous injection; for 3 consecutive days, then transition to oral NSAID; Administration: intravenous drip (15 mL / min), diluted to ensure comfort; injection pH 7.0-7.5, osmotic pressure 270-310 mosm / kg, suitable for postoperative patients; Adjuvant treatment: local cold compress, analgesic pump (oral ibuprofen); Efficacy observation: Observation indicators: VAS score, degree of swelling (circumference of affected limb), amount of opioids used, adverse reactions; Observation time points: before treatment, the first day of treatment (1 hour after injection), the second day, and the third day; Results: On the first day, the VAS dropped to 3 points in 1 hour, and the swelling was reduced; on the second day, the VAS dropped to 1 point, and the opioid dosage was reduced by 50%; on the third day, the VAS was 0, the circumference of the affected limb returned to normal, and there was no adverse reaction. The observation data are shown in Table 8 below: Table 8 This case targeted the high-dose requirement (30 mg / time) for postoperative pain. The high solubility (21.2 mg / mL) and rapid release properties (in vitro dissolution 84.6%) of the injection were utilized to reduce the VAS score by 57% within 1 hour, effectively controlling acute pain. Hydroxypropyl-sulfobutyl ether-β-cyclodextrin (HP-SBECD) inclusion (inclusion efficiency 94.1%) and PGA modification (surface potential -27.2 mV) ensured rapid drug absorption and stability of the injection. Double drying (residual moisture 0.6%) supported short-term storage without precipitation. Quality control (DLS particle size 210 nm, PDI 0.22) ensured product consistency. The amount of opioids was reduced by 100%, reducing the risk of addiction. The absence of adverse reactions reflected the high safety of the injection (sterility and qualified pyrogen tests). This case verified the efficiency and safety of the technical solution in postoperative pain management.

[0034] The VAS score is a measurement tool used to assess pain intensity, usually represented by a 10 cm (100 mm) straight line, with the ends of the line marked as "no pain" and "worst pain". According to the patient's own pain perception, a point is marked on the straight line, and the distance from the marked point to the "no pain" end (in centimeters or millimeters) is the VAS score, with a score range of 0-10 (or 0-100), 0 points (0 mm): completely painless; 10 points (100 mm): unbearable worst pain; In the case, the VAS score is in units of 0-10. According to the above patient understanding and records, the scoring criteria are shown in Table 9 below; Table 9 VAS scoring method: Use a scoring card marked with a 10-cm straight line, with "no pain (0)" marked on the left end and "worst pain (10)" marked on the right end. Divide the area below the straight line into 10 equal distances (0-10), each 1 cm apart. Provide a pen and ruler. The patient marks the pain location on the straight line with a pen, and the doctor uses a ruler to measure the distance from the marked point to the "no pain" end (accurate to 0.1 cm). Use an electronic VAS scoring tool in the hospital information system. The patient selects the pain location by sliding the bar or clicking, and the system automatically records the score.

[0035] It should be noted that, in this article, relational terms such as first and second, etc. are only used to distinguish one entity or operation from another entity or operation, and do not necessarily require or imply any such actual relationship or order between these entities or operations. Moreover, the terms "include", "comprise" or any other variants thereof are intended to cover non-exclusive inclusion, so that a process, method, article or device including a series of elements includes not only those elements, but also other elements not explicitly listed, or also includes elements inherent to such process, method, article or device. In the absence of further restrictions, the elements defined by the statement "comprising a reference structure" do not exclude the existence of other identical elements in the process, method, article or device including the elements.

[0036] Although embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that various changes, modifications, substitutions and variations may be made to the embodiments without departing from the principles and spirit of the present invention, and that the scope of the present invention is defined by the appended claims and their equivalents.

Claims

1. A preparation process of a high-stability piracetam injection, characterized in that: The preparation process comprises the following steps: Sp1: Preparation of inclusion complex: 800 mg of hydroxypropyl-sulfobutyl ether-β-cyclodextrin was dissolved in 5 mL of phosphate buffered water for injection at pH 7.2, heated to 40±1°C, 20 mg of piracetam was added, and stirred at 500±50 rpm for 2 hours to form a hydroxypropyl-sulfobutyl ether-β-cyclodextrin-piracetam inclusion complex solution with an inclusion efficiency of ≥90%; Sp2: Preparation of microsphere precursor: 50 mg of trehalose and 10 mg of polyglutamic acid were added to the inclusion complex solution prepared in Sp1, and ultrasonic treatment was performed at a frequency of 40 ± 1 kHz, a power of 100 ± 5 W, and a time of 5 ± 0.5 min to form a microsphere precursor with a particle size of 200-300 nm and a polymer dispersion index of less than 0.3; Sp3: Microsphere forming: The microsphere precursor solution in Sp2 was placed in a spray dryer with an inlet air temperature of 130 ± 2 °C, an outlet air temperature of 70 ± 2 °C, and a feed rate of 5 ± 0.5 mL / min to form preliminary microspheres with a porosity of less than 5%; Sp4: Freeze drying: freeze-dry the preliminary microspheres in Sp3, pre-freeze at -50±1℃ for 4 hours, vacuum degree 0.1-0.2mbar, dry for 12 hours, and obtain dry microspheres with residual moisture ≤1.0%; Sp5: Reconstitution of injection solution: The dried microspheres of Sp4 were suspended in 1 mL of water for injection and shaken at 100 rpm for 5 min to prepare a piracetam injection solution with an osmotic pressure of 270-310 mosm / kg and a pH of 7.0-7.

5.

2. The preparation process of a high-stability piracetam injection according to claim 1, characterized in that: When preparing the hydroxypropyl-sulfobutyl ether-β-cyclodextrin in the Sp1, a hydroxypropylation reaction is first carried out under alkaline conditions of pH 10-11, 1,2-propylene oxide is added, and the reaction is carried out for 6 hours, followed by a sulfobutylation reaction, 1,4-butane sultone is added, and the reaction is carried out for 4 hours. The final product is purified by dialysis and spray-dried to obtain hydroxypropyl-sulfobutyl ether-β-cyclodextrin, ensuring that the degree of substitution of hydroxypropyl is 3-5 and the degree of substitution of sulfobutyl ether is 1-2.

3. The preparation process of a high-stability piracetam injection according to claim 1, characterized in that: During the preparation of the Sp1 inclusion complex, nitrogen was used to protect the environment to reduce the oxidative degradation of piracetam, the nitrogen flow rate was controlled at 0.5-1 L / min, and ascorbic acid with a mass concentration of 0.1% was added as an antioxidant during the stirring process.

4. The preparation process of a high-stability piracetam injection according to claim 1, characterized in that: The ultrasonic treatment of Sp2 adopts an intermittent mode, which is turned on every 30 seconds, closed after 15 seconds, and cycled 10 times. The solution temperature is maintained at ≤45°C by a temperature control device. After treatment, it is centrifuged at a speed of 5000 rpm for 5 minutes to remove trace insoluble matter and ensure the clarity and uniformity of the precursor.

5. The preparation process of a high-stability piracetam injection according to claim 1, characterized in that: During the spray drying process of Sp3, the sprayer is equipped with a dual-fluid nozzle, the air flow pressure is 0.3-0.5 MPa, the spray angle is 45°, the microsphere formation is monitored by an online particle size analyzer, and the feed rate is adjusted in real time to make the microsphere particle size distribution in the range of 150-400 nm.

6. The preparation process of a high-stability piracetam injection according to claim 1, characterized in that: During the freeze-drying process of Sp4, a programmed temperature increase strategy was adopted. After pre-freezing, the temperature was increased to -20°C at 0.5°C / min and maintained for 6 hours, and then increased to 10°C at 0.3°C / min and maintained for 4 hours. The temperature of the microspheres was monitored by an infrared thermometer. There was no collapse during the freeze-drying process, and the residual moisture of the microspheres was ≤0.8%.

7. The preparation process of a high-stability piracetam injection according to claim 1, characterized in that: When the polyglutamic acid surface of Sp2 is modified, polyvinyl alcohol with a mass concentration of 0.01% is added to the microsphere precursor solution as an auxiliary dispersant. The surface potential of the modified microspheres is measured by a Zeta potential meter and optimized to -25±3mV.

8. The preparation process of a high-stability piracetam injection according to claim 1, characterized in that: During the reconstitution of the Sp5 injection solution, the injection water was pre-filtered through a 0.22 μm filter membrane and nitrogen was introduced for deoxygenation, and the oxygen content was controlled at ≤1 ppm. After reconstitution, high-speed centrifugation was performed at a speed of 8000 rpm for 3 minutes to remove trace bubbles.

9. The preparation process of the high-stability piracetam injection according to any one of claims 1 to 8, characterized in that: The quality control method of the preparation process comprises the following steps: Sp1: Raw material acceptance: HPLC and LC-MS were used to detect the purity of piracetam ≥ 99.5%, total impurities ≤ 0.5%, single impurities ≤ 0.1%, Karl Fischer method was used to determine the moisture content ≤ 0.5%, nuclear magnetic resonance was used to determine the degree of substitution of hydroxypropyl-sulfobutyl ether-β-cyclodextrin, and gel permeation chromatography was used to determine the molecular weight of PGA 4500-5500Da; Sp2: Preparation process monitoring: online monitoring of the inclusion complex preparation temperature of 40±1℃, pH7.2±0.1, dynamic light scattering detection of microsphere precursor particle size of 200-300nm, polymer dispersion index less than 0.3, Karl Fischer method determination of microsphere moisture content after freeze drying ≤1.0%; Sp3: Final product testing: including physical and chemical testing, microsphere property testing, biological testing and stability verification; Physical and chemical testing: 95-105% piracetam content determined by HPLC, ≤1.0% total impurities determined by LC-MS; pH 7.0-7.5 determined by pH meter, 270-310mosm / kg osmotic pressure determined by freezing point depression method; Microsphere characteristic detection: Dynamic light scattering determined the microsphere particle size to be 150-400nm, and the polymer dispersion index was less than 0.2; Zeta potential instrument determined the surface potential to be -20 to -30mV, and in vitro dissolution test verified that the release was ≥80% in 30min; Biological testing: membrane filtration method to test sterility, rabbit method to test the absence of pyrogenic reaction; Stability verification: Through accelerated tests and long-term tests, it was confirmed that the content decreased by ≤5%, there was no precipitation, and there was no significant change in particle size and surface potential.

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