A preparation process and quality control method for high-stability piracetam injection

Abstract

The present invention provides a preparation process and a quality control method for a high-stability piracetam injection, relating to the technical field of drug preparation. When preparing the piracetam injection, an innovative hydroxypropyl-sulfobutyl ether-β-cyclodextrin bifunctional inclusion technology is used to significantly improve the solubility of piracetam. Hydroxypropyl-sulfobutyl ether-β-cyclodextrin utilizes a hydroxypropyl group to improve the water solubility of cyclodextrin. The electrostatic and hydrophobic interactions of the sulfobutyl ether group enhance the inclusion affinity with piracetam, thereby increasing the solubility to more than 20 mg / mL. Polyglutamic acid surface modification technology imparts a surface potential of 25±3 mV to the microspheres, effectively reducing the sedimentation rate to less than 5%. Combined with a double spray-freeze drying technology, the porosity of the microspheres is controlled to be less than 5% and the residual moisture is ≤0.8%, thereby significantly improving the storage stability of the injection, achieving 12 months without precipitation, avoiding the use of organic solvents, improving the safety and clinical applicability of the injection, and significantly improving the solubility and storage stability of piracetam.

Description

Technical Field

[0001] The present 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] Piracetam is a nonsteroidal anti-inflammatory drug (NSAID) used to relieve pain associated with arthritis and other conditions. However, its solubility is poor, approximately 0.02 mg / mL, and its chemical stability is insufficient, resulting in precipitation and degradation during the preparation of injections. Existing technologies often rely on additives, co-solvents, or a single cyclodextrin, resulting in 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 China Publication No. "CN116139076A", a method for preparing piracetam injection and the piracetam injection prepared therefrom 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 prescribed amount of water for injection into a liquid preparation tank and cooling the mixture to 30-50°C; (2) adding weighed sodium acetate or a mixed sodium salt composed of sodium acetate and sodium chloride, stirring and dissolving the mixture uniformly; (3) adding weighed piracetam raw materials, stirring and dissolving the mixture uniformly; (4) adjusting the pH value of the mixed solution obtained in step (3) to 5.0-7.0 using acetic acid solution; (5) adding water for injection to the final volume, stirring and mixing the mixture 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:

[0006] Problem 1: Existing piracetam injections have extremely low solubility of approximately 0.02 mg / mL, making it difficult to prepare high-concentration stable solutions. Traditional methods rely on inhibitors or single cyclodextrins as solubilizers, but the solubility improvement is limited, usually below 5 mg / mL, and organic solvents are often required, increasing the risk of toxicity and hindering the actual preparation and use of piracetam injections.

[0007] Question 2: The existing piracetam injection is prone to degradation and precipitation during storage, and often shows a significant quality decline 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

[0008] Technical problems solved

[0009] In view of the deficiencies in the prior art, the present invention provides a preparation process and quality control method for a high-stability piracetam injection, which solves the following problems:

[0010] 1. The preparation of piracetam injection using a single solvent results in poor solubility, inadequate stability and safety of the finished product;

[0011] 2. 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.

[0012] Technical Solution

[0013] To achieve the above objectives, the present invention is implemented by the following technical solutions: a preparation process and quality control method of a high-stability piracetam injection, the preparation process comprising the following steps:

[0014] Sp1: Preparation of inclusion complex: 800 mg of hydroxypropyl-sulfobutyl ether-β-cyclodextrin was dissolved in 5 mL of phosphate buffered water for injection, 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, 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%;

[0015] 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, with the ratio of trehalose to polyglutamic acid being 5:1. 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 dispersion and form a microsphere precursor with a particle size of 200-300 nm and a polymer dispersion index of less than 0.3;

[0016] 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%;

[0017] Sp4: Freeze drying: The preliminary microspheres in Sp3 were freeze-dried in an environment of -50±1°C for 4 hours, with a vacuum degree of 0.1-0.2 mbar, and dried for 12 hours to obtain dry microspheres with a residual moisture content of ≤1.0%;

[0018] Sp5: Reconstitution of injection: 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 with an osmotic pressure of 270-310 mosm / kg and a pH of 7.0-7.5.

[0019] The above process significantly improves the solubility of piracetam to greater than 20 mg / mL and its storage stability, with no precipitation after 12 months of storage, through the dual-functional inclusion of hydroxypropyl-sulfobutyl ether-β-cyclodextrin, polyglutamic acid surface modification and double spray-freeze drying technology.

[0020] Preferably, when preparing the hydroxypropyl-sulfobutyl ether-β-cyclodextrin in 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.

[0021] Preferably, during the preparation of the inclusion complex of Sp1, 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 as an antioxidant during stirring to further improve the stability of the inclusion complex, and the inclusion efficiency is increased to 92-95%.

[0022] 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, the solution 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.

[0023] 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%.

[0024] 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%.

[0025] Preferably, when the polyglutamic acid surface of Sp2 is modified, the electrostatic adsorption efficiency of polyglutamic acid is enhanced by adding polyvinyl alcohol with a mass concentration of 0.01% as an auxiliary dispersant to the microsphere precursor solution; 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%.

[0026] 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.

[0027] Preferably, the quality control method of the preparation process comprises the following steps:

[0028] Sp1: Raw material acceptance: HPLC and LC / MS were used to test the purity of piracetam to be ≥99.5%, total impurities ≤0.5%, single impurities ≤0.1%, Karl Fischer method was used to determine the moisture content to be ≤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 to be 4500-5500Da;

[0029] Sp2: Preparation process monitoring: Online monitoring of the inclusion complex preparation temperature at 40±1°C, pH 7.2±0.1, dynamic light scattering detection of microsphere precursor particle size of 200-300nm, polymer dispersion index less than 0.3, and Karl Fischer method determination of microsphere moisture content ≤1.0% after freeze-drying;

[0030] Sp3: Final product testing: including physical and chemical testing, microsphere characteristics testing, biological testing and stability verification;

[0031] Physical and chemical testing: 95-105% piracetam content by HPLC, ≤1.0% total impurities by LC-MS; pH 7.0-7.5 by pH meter; osmotic pressure 270-310 mosm / kg by freezing point depression method;

[0032] Microsphere property testing: Dynamic light scattering determined the microsphere particle size to be 150-400 nm, with a polymer dispersion index of less than 0.2; Zeta potential was used to determine the surface potential of -20 to -30 mV; in vitro dissolution testing was conducted in a pH 7.4 phosphate buffer at 37°C and a rotation speed of 100 rpm, verifying that the release rate was ≥80% within 30 minutes.

[0033] Biological testing: membrane filtration method to test sterility, rabbit method to test the absence of pyrogen reaction;

[0034] Stability verification: Through accelerated tests and long-term tests, the experimental environment of the accelerated test was 40℃ / 75%RH and the experimental time was 6 months, and the experimental environment of the long-term test was 25℃ / 60%RH and the experimental time was 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.

[0035] The preparation process optimizes process parameters through machine learning algorithms. Based on historical data, inclusion efficiency, particle size, and porosity, a prediction model is established to dynamically adjust 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 consistency is improved to more than 98%.

[0036] Beneficial effects

[0037] The present invention provides a preparation process and quality control method for a high-stability piracetam injection, which has the following beneficial effects:

[0038] 1. The present invention adopts the innovative hydroxypropyl-sulfobutyl ether-β-cyclodextrin bifunctional inclusion technology in the preparation of 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 interactions of the sulfobutyl ether group, thereby increasing the solubility to more than 20 mg / mL, far exceeding the solubility effect of traditional amino acids or single cyclodextrins. At the same time, the polyglutamic acid surface modification technology gives the micro The surface potential of the sphere 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 no precipitation for 12 months. Compared with the defects of traditional injections that are easy to degrade and precipitate, 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.

[0039] 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 piracetam injection in the preparation, comprehensively monitors the quality of raw materials, intermediates and final products, and breaks through the limitations of 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, and uses machine learning algorithms to optimize process parameters. A prediction model is constructed based on historical data, and the ultrasonic frequency, spray drying temperature and freeze-drying vacuum degree are dynamically adjusted to achieve 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

[0040] Figure 1 is a flow chart of the preparation process of the present invention;

[0041] Figure 2 A diagram showing the steps of the quality control method for the preparation process of the present invention;

[0042] Figure 3 is a component structure diagram of the piracetam injection of the present invention;

[0043] Figure 4 It is a trend diagram of the preparation process parameters of the present invention. DETAILED DESCRIPTION

[0044] The following will clearly and completely describe the technical solutions in the embodiments of the present invention in conjunction with the accompanying drawings. 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 making creative efforts are within the scope of protection of the present invention. Specific embodiment one:

[0046] 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:

[0047] 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, and 20 mg of piracetam was added (the molar ratio of HP-SBECD to piracetam was 1:3). The mixture was stirred at 500±50 rpm for 2 hours. During the stirring process, the oxidative free radicals were reduced by the 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 the reaction was carried out 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, and 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, a phosphate buffer system was used to maintain pH stability. Nitrogen and antioxidants protected the activity of the drug, forming a stable complex solution, laying the foundation for subsequent microsphere preparation.

[0048] 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 dispersion and form microsphere precursors with a particle size of 200-300 nm and a polymer dispersion index (PDI) of less than 0.3. Ultrasonic treatment was performed in intermittent mode, with an interval of 30 seconds, and then 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 for 5min, to remove trace insoluble matter and ensure the clarity and uniformity of the precursor. When modifying the surface of polyglutamic acid (PGA), by adding 0.01% (w / v) polyvinyl alcohol (PVA) as an auxiliary dispersant to the microsphere precursor solution, the electrostatic adsorption efficiency of PGA is enhanced, and the surface of the microspheres is negatively charged, which can be measured by a Zeta potential instrument. The surface potential of the modified microspheres is measured by a Zeta potential instrument and optimized to -25±3mV, reducing the sedimentation rate of the injection solution during storage to less than 5%. Trehalose protects the microsphere structure, PGA modification adds weight to reduce sedimentation, and PVA optimizes dispersibility. Combined with spraying and centrifugation technology, a high-quality precursor is formed, providing a uniform and stable raw material for microsphere molding;

[0049] Sp3: Microsphere forming: The microsphere precursor solution in Sp2 is 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±0.5mL / 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%. Microspheres are quickly formed by drying, dual nozzles and online monitoring ensure consistency, and low-temperature air outlet and air pressure control provide structurally stable intermediates for subsequent freeze drying;

[0050] 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 rising 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 extended the storage stability and provided high-quality dry microspheres for re-dissolution.

[0051] Sp5: Reconstitution of injection: 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 with an osmotic pressure of 270-310 mosm / kg and a pH of 7.0-7.5. During the reconstitution of the injection, 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 met the pharmacopoeial standards.

[0052] 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 dual spray-freeze drying technology, while ensuring that the process can be industrialized to meet clinical needs. Specific embodiment two:

[0054] like Figures 1 to 4 As shown, based on the content in the above specific embodiments, the following contents are further disclosed:

[0055] To ensure the quality, safety, and efficacy 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. This method combines advanced testing technology and data-driven process optimization to comprehensively monitor and guarantee product quality. The quality control method for the preparation process includes the following steps:

[0056] Sp1: Raw material acceptance: Piracetam purity ≥ 99.5%, total impurities ≤ 0.5%, single impurities ≤ 0.1%, Karl Fischer method for water ≤ 0.5%, nuclear magnetic resonance (NMR) for hydroxypropyl-sulfobutyl ether-β-cyclodextrin substitution, gel permeation chromatography (GPC) for PGA molecular weight 4500-5500Da, the main raw materials Piracetam (API), hydroxypropyl-sulfobutyl ether-β-cyclodextrin (HP-SBECD) and polyglutamic acid (PGA) are tested. Piracetam acceptance adopts high performance liquid chromatography (HPLC) and liquid chromatography-mass spectrometry (LC-MS) technology, with detection purity requirements ≥ 99.5%, total impurities ≤ 0. 5%, single impurity ≤ 0.1%, and the water content is ≤ 0.5% by Karl Fischer titration; the operation process is: randomly sample 3 portions from each batch of raw materials, each 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 substitution degree, requiring hydroxypropyl substitution degree 3-5, sulfobutyl ether substitution degree 1-2, the operation process is: sample 0.5g, dissolve in heavy water (D2O), run 1 H-NMR calculates the degree of substitution by integrating characteristic peaks to ensure that its inclusion performance meets the standards. The molecular weight of PGA is determined by gel permeation chromatography (GPC) for acceptance, with a requirement of 4500-5500 Da. The operating procedure is as follows: 0.5 g of sample is prepared into a 1 mg / mL solution, and the molecular weight distribution is analyzed by GPC to ensure its function as a stabilizer. HPLC, LC-MS, NMR, and GPC are used 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 issues, thereby ensuring process reliability and repeatability.

[0057] Sp2: Preparation process monitoring: Online monitoring of the inclusion complex preparation temperature of 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 microsphere moisture ≤1.0% after freeze-drying; in the inclusion complex preparation stage, 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, sample 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; in the microsphere precursor preparation stage, 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°, and measure the particle size distribution and uniformity to 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 the titrator and titrate to the endpoint to calculate the moisture content to ensure that the dryness of the microspheres meets the stability requirements. By real-time monitoring of key parameters such as temperature, pH, and stirring speed, combined with detection methods such as DLS and ultraviolet spectrophotometry, the quality status of the intermediate products in the preparation process can be dynamically grasped, and 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-to-batch differences;

[0058] Sp3: Final product testing: This includes physical and chemical testing, microsphere property testing, biological testing, and stability verification. Multi-dimensional testing technology is used to comprehensively evaluate the physical and chemical properties, microsphere performance, safety, and stability of the injection to ensure that the product meets pharmacopoeia and clinical requirements. The specific contents are as follows:

[0059] Physical and chemical testing: HPLC determination of piracetam content 95-105%, LC-MS determination of total impurities ≤1.0%; pH meter determination of pH 7.0-7.5; freezing point depression method determination of osmotic pressure 270-310mosm / kg. Physical and chemical testing includes HPLC determination of piracetam content (required 95-105% labeled amount). The operation procedure is to take three samples, each 1mL, and use HPLC (C18 column, mobile phase methanol-water 70:30, 333nm) to measure 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 operation procedure is to scan the range of m / z 50-500 to quantify the impurity peak; pH is measured using a pH meter (7.0-7.5) and the freezing point depression method is used to measure the osmotic pressure (270-310mosm / kg). The operation procedure is to use a calibrated pH meter and osmotic pressure meter to measure the samples respectively to ensure that the physical and chemical properties meet the standards.

[0060] Microsphere characteristic testing: DLS measured the microsphere particle size to be 150-400 nm, with a PDI of less than 0.2; a Zeta potential meter measured the surface potential to be -20 to -30 mV; an in vitro dissolution test (pH 7.4 phosphate buffer, 37°C, 100 rpm) was performed to verify that the release rate was ≥80% in 30 minutes. The microsphere characteristic testing included using DLS to measure the microsphere particle size (150-400 nm, PDI <0.2). The operation procedure was to take a 1 mL sample and place it on the DLS instrument for measurement; using a Zeta potential meter to measure the surface potential (-20 to -30 mV). The operation procedure was to measure the sample potential value to evaluate stability; an in vitro dissolution test (pH 7.4 phosphate buffer, 37°C, 100 rpm) was performed, taking three samples of 1 mL each, and using HPLC to measure the release rate in 30 minutes to ensure drug release performance.

[0061] Biological testing: sterility is tested by membrane filtration, and the absence of pyrogen is tested by rabbit assay. Biological testing includes testing sterility by membrane filtration, where the sample is filtered, cultured, and observed for bacterial growth; and testing pyrogens by rabbit assay, where the sample is injected, where the rabbit's body temperature is monitored for abnormal temperature rise.

[0062] Stability verification: Through accelerated testing (40℃ / 75%RH, 6 months) and long-term testing (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 testing (40℃ / 75%RH, 6 months) and long-term testing (25℃ / 60%RH, 12 months). Sampling was conducted every 3 months to test piracetam content (decrease ≤5%), impurities, particle size, surface potential and appearance (no precipitation). The operation process was to take samples at predetermined time points and verify using the above-mentioned test methods;

[0063] The preparation process uses a machine learning algorithm to optimize the process parameters, establishes a prediction model based on historical data (inclusion efficiency, particle size, porosity), and dynamically adjusts the ultrasonic frequency (38-42kHz), spray drying inlet temperature (128-132℃) and freeze-drying vacuum (0.08-0.22mbar). The batch consistency is improved to more than 98%. In order to improve the stability and batch consistency of the preparation process, a machine learning algorithm is used to optimize the process parameters, and a prediction model is established based on historical data (such as inclusion efficiency, particle size, porosity). The input parameters include ultrasonic frequency (38-42kHz), spray drying inlet temperature (128-132℃) and freeze-drying vacuum (0.08-0.22mbar). The mist drying inlet air temperature (128-132°C) and freeze-drying vacuum degree (0.08-0.22mbar) are input into the model through real-time data acquisition (such as online sensors monitoring temperature and particle size). 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. Ultimately, through multiple iterative optimizations, the batch consistency is improved to over 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.

[0064] This quality control method ensures a high-quality starting point through raw material acceptance, guarantees process stability through preparation process monitoring, comprehensively verifies product quality through final product testing, and combines machine learning optimization to improve batch consistency, ensuring the quality, safety and efficacy of high-stability piracetam injection, and has the potential for industrial production and clinical application. Specific embodiment three:

[0066] like Figures 1 to 4 As shown, based on the content in the above specific embodiments, the following contents are further disclosed:

[0067] 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:

[0068] Experimental purpose: To verify the feasibility and stability of the preparation process in the technical solution, evaluate the effectiveness of the quality control method in the technical solution, compare the differences in key performance indicators between the technical solution and the existing technical solution, and prove its superiority;

[0069] The experimental materials are as follows: Piracetam, hydroxypropyl-sulfobutyl ether-β-cyclodextrin (HP-SBECD), trehalose, polyglutamic acid (PGA), polyvinyl alcohol (PVA), ascorbic acid, phosphate buffered saline, and water for injection;

[0070] Control material: cosolvent used in the prior art solution (such as β-cyclodextrin);

[0071] 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;

[0072] The preparation process of the present application scheme was verified as follows: piracetam was mixed with hydroxypropyl-sulfobutyl ether-β-cyclodextrin in a molar ratio of 1:2, phosphate buffered saline (pH 7.0) was added, and the mixture was stirred for 4 hours; the inclusion efficiency was determined by ultraviolet spectrophotometry; trehalose (5% w / v), PGA (0.5% w / v), and PVA (1% w / v) were added to the inclusion complex solution, ultrasonically treated (500W, 10 min), and centrifuged to remove unincluded substances, and the particle size and polydispersity index (PDI) were determined by DLS; the microsphere precursor solution was passed through a spray dryer (inlet air temperature 150°C, outlet air temperature 80°C) to prepare microspheres, and the microsphere particle size was monitored by an online particle size analyzer; the microspheres were placed in a freeze dryer (-50°C, 48 hours), and the residual moisture was determined by the Karl Fischer method; the dried microspheres were re-dissolved in water for injection (piracetam concentration of 10 mg / mL), and the pH and osmotic pressure were determined;

[0073] The quality control validation 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 (300 rpm) 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 measured after freeze-drying; physical and chemical testing: pH, osmotic pressure; microsphere characteristics: particle size, zeta potential; biological testing: in vitro dissolution; stability: precipitation is observed after storage at 25°C for 12 months; test indicators: solubility (mg / mL); storage stability (no precipitation for 12 months); batch consistency (content uniformity); in vitro dissolution rate (percentage released in 30 minutes);

[0074] Preparation of control sample: The prior art uses β-cyclodextrin (1:2 molar ratio) to prepare piracetam injection. The formula of piracetam injection is as follows: piracetam and β-cyclodextrin are used as cosolvents, phosphate is used as a pH adjuster, and water for injection is used as the solvent. 160 mg of β-cyclodextrin is dissolved in 5 mL of phosphate buffered water for injection (pH 6.5), heated to 50°C, and 20 mg of piracetam is added (molar ratio 1:2). The solution is 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.

[0075] Experimental data record: parameter detection was performed on the injection prepared in this application and the prior art. 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:

[0076] Table 1 Preparation process parameters

[0077]

[0078] Table 2 Quality control test results

[0079]

[0080] Table 3 Performance comparison

[0081]

[0082] The experimental analysis is as follows:

[0083] 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.

[0084] Quality control: high purity of raw materials and few impurities; the surface potential of microspheres is more negative (-25mV), which enhances dispersibility;

[0085] Improved performance: Solubility increased to >20 mg / mL (compared to 5-10 mg / mL with existing technology), no precipitation after 12 months of storage, 98% batch consistency, and faster in vitro dissolution rate (≥80%).

[0086] Experiments have proved that the technical solution is superior to existing technologies in preparation process, quality control and performance, providing a reliable basis for the development of piracetam injection. Specific embodiment four:

[0088] like Figures 1 to 4 As shown, based on the content in the above specific embodiments, the following contents are further disclosed:

[0089] 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:

[0090] Case 1: Production of clinical piracetam injection for the treatment of acute arthritis pain:

[0091] Piracetam, a nonsteroidal anti-inflammatory drug (NSAID), is widely used to treat the severe pain associated with acute arthritis. However, the low solubility (approximately 0.02 mg / mL) and poor storage stability (prone to precipitation within 6 months) of traditional piracetam injections limit their use in emergency settings. A pharmaceutical company is using this technology to produce a highly stable piracetam injection for rapid analgesia in patients with acute arthritis. The goal is to increase the solubility to greater than 20 mg / mL, achieve 12 months of storage stability without precipitation, and ensure rapid release to meet acute treatment needs.

[0092] Implementation process:

[0093] 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), and PGA (molecular weight 4500-5500Da). Use HPLC, LC-MS, NMR, and GPC to test the quality of the raw materials to ensure that they meet the requirements of the technical plan;

[0094] 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, added with 20 mg of piracetam, stirred at 500 rpm for 2 hours, added with 0.1% ascorbic acid and nitrogen protection (0.5-1 L / min), the inclusion efficiency reached 92-95%; 50 mg of trehalose, 10 mg of PGA (ratio 5:1) and 0.01% of PVA were added, ultrasonicated (40 kHz, 100 W, 5 min, intermittent mode), centrifuged (5000 rpm, 5 min), and formed into a particle size of 200 The microsphere precursor had a diameter of -300 nm and a PDI <0.3, with a surface potential of -25 ± 3 mV. The product was spray-dried (inlet air temperature 130 ± 2°C, outlet air temperature 70 ± 2°C, feed rate 5 mL / min) to form microspheres with a porosity <5%, a particle size of 150-400 nm, and a recovery rate ≥85%. The product was freeze-dried (pre-freezing at -50°C for 4 hours, 0.1-0.2 mbar, programmed temperature) to a residual moisture content of ≤0.8%. The microspheres were then reconstituted in 1 mL of deoxygenated water for injection (oxygen content ≤1 ppm) and shaken at 100 rpm for 5 min. The pH was 7.0-7.5, and the osmotic pressure was 270-310 mosm / kg.

[0095] Quality control: HPLC analysis of piracetam purity of 99.6%, total impurities of 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 for particle size, and Karl Fischer for moisture; HPLC analysis of content of 95-105%, LC-MS analysis of total impurities ≤1.0%, DLS analysis of particle size, zeta potential of -20 to -30 mV, in vitro dissolution of ≥80% in 30 minutes, and sterility and pyrogen-free tests.

[0096] Clinical trial: A small-scale clinical trial was conducted in which 50 patients with acute arthritis were intravenously injected with this injection (20 mg / mL, once a day for 7 consecutive days). The analgesic effect and adverse reactions were recorded. The data are shown in Table 4 below:

[0097] Table 4

[0098]

[0099] The piracetam injection produced by this technical solution has shown significant advantages in clinical applications. The solubility has been increased to 20.5 mg / mL, more than four times 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, PDI 0.25), with a surface potential of -26.5 mV and a sedimentation rate of only 3.8%, ensuring the clarity and stability of the injection. There is no precipitation for 12 months, far exceeding the traditional solution (precipitation after 6 months). The in vitro dissolution rate reaches 82.4%, and the analgesic onset time is shortened to 15 minutes. 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.

[0100] Case 2: Large-scale industrial production of piracetam injection for the treatment of rheumatic diseases:

[0101] Patients with rheumatic diseases require long-term use of piracetam injection to relieve joint pain and inflammation. However, traditional preparations suffer from poor batch-to-batch consistency (typically <90%) and insufficient storage stability, limiting large-scale production and market supply. A large pharmaceutical company has adopted this technical solution to establish an industrial production line for piracetam injection for the treatment of rheumatic diseases. The goal is to achieve batch consistency ≥98%, storage stability without precipitation for 12 months, and quality control to ensure product compliance with pharmacopoeial standards.

[0102] Implementation process:

[0103] Production line design: Based on the technical solution, we configure automated equipment, including high-precision stirred reactors, ultrasonic processors, spray drying towers, freeze dryers, and aseptic filling lines;

[0104] 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 was performed (40kHz, 100W, 5min, intermittent mode), and centrifuged 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°C, outlet air temperature 70±2°C, feed rate 5L / h), two-fluid nozzle, particle size 150-400nm, recovery rate ≥85%; freeze drying (-50°C, 4-hour prefreeze, 0.1-0.2mbar, programmed temperature), residual moisture ≤0.8%; microspheres were reconstituted in water for injection (oxygen content ≤1ppm), shaken at 100rpm, and aseptically filled; pH 7.0-7.5, osmotic pressure 270-310mosm / kg;

[0105] Quality Control and Optimization: Raw Material Acceptance: HPLC and LC-MS testing for 99.7% purity of piracetam and 0.2% total impurities; NMR and GPC verification of hydroxypropyl-sulfobutyl ether-β-cyclodextrin (HP-SBECD) and PGA; Process Monitoring: Online sensors monitor temperature, pH, and particle size, and Karl Fischer method is used to measure moisture; Final Testing: HPLC for content, LC-MS for impurities, DLS, zeta potential, dissolution testing, sterility, and pyrogen testing;

[0106] Process optimization: A machine learning algorithm dynamically adjusts ultrasonic frequency (38-42kHz) and spray temperature (128-132°C) based on inclusion efficiency, particle size, and porosity data, achieving 98% batch consistency.

[0107] The injection was produced with a specification of 20 mg / mL and 1 mL / vial. The clinical effects were tracked and the statistical data were recorded as shown in Table 5 below:

[0108] Table 5

[0109]

[0110] This technical solution has demonstrated excellent performance in industrial production, with a solubility of 21.2 mg / mL, nearly four times higher than the traditional solution (5.3 mg / mL), supporting the production of high-concentration preparations. The microspheres have a particle size of 210 nm, a PDI of 0.22, a surface potential of -27.2 mV, and a sedimentation rate of only 3.2%. There is no precipitation after 12 months of storage, which solves 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, a significant improvement over the traditional solution (55%). Quality control uses technologies such as LC-MS and DLS to ensure low impurities and stable microsphere performance. The product meets pharmacopoeia standards. This case verifies the feasibility of the technical solution in industrial production and provides high-quality injection for the treatment of rheumatic diseases. Specific embodiment five:

[0112] like Figures 1 to 4 As shown, based on the content in the above specific embodiments, the following contents are further disclosed:

[0113] To further verify the effectiveness of this application when used on actual patients, and to verify the stability and response of this application when used, the following application contents are further disclosed:

[0114] Case 1: Rapid analgesia for a patient with acute arthritis:

[0115] Patient Background: Mr. Zhang, a 45-year-old male construction worker weighing 70 kg, developed acute knee arthritis due to strenuous exercise. He presented with right knee swelling and severe pain, a visual analogue scale (VAS) score of 8, and limited mobility. Radiographic examinations showed soft tissue inflammation in the joint but no bone damage. He required rapid analgesia to resume work ability.

[0116] Treatment options include:

[0117] Injection ratio and content: Formula (per 1 mL): Piracetam 20 mg, Hydroxypropyl-sulfobutyl ether-β-cyclodextrin (HP-SBECD) 800 mg, Trehalose 50 mg, PGA 10 mg, PVA 0.1 mg, Ascorbic acid 1 mg, Phosphate buffer saline (pH 7.2), Water for injection to 1 mL; Single dose: 20 mg (1 mL, concentration 20 mg / mL), once daily, intravenous injection; Treatment course: 5 consecutive days;

[0118] Administration: Intravenous injection (5 mL / min) ensures rapid entry of the drug into the bloodstream to achieve analgesic effects. The injection solution has a pH of 7.0-7.5 and an osmotic pressure of 270-310 mosm / kg to ensure injection safety.

[0119] Auxiliary treatment: local ice compress, rest, avoid strenuous exercise;

[0120] Efficacy observation: Observation indicators: VAS score, degree of joint swelling (knee joint circumference measurement), adverse reactions; Observation time points: before treatment, on the first day of treatment (30 minutes after injection), on the third day, and on the fifth day;

[0121] Results: 30 minutes after treatment, the VAS score dropped to 4 points, on the third day it dropped to 2 points, and on the fifth 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 rate 2%). The observation indicators are shown in Table 6:

[0122] Table 6

[0123]

[0124] In this case, the high solubility of the injection (20.5 mg / mL) ensured the rapid dissolution and absorption of a single 20 mg dose. 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%, consistent with the rapid analgesic effect (30-min VAS decrease of 50%). 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.

[0125] Case 2: Long-term treatment of a patient with chronic rheumatoid arthritis:

[0126] Patient background: Ms. Li, a 60-year-old female retired teacher, weighing 55 kg, had been diagnosed with chronic rheumatoid arthritis for 5 years. She experienced morning stiffness and pain in both finger joints and knees, a VAS score of 6, a positive rheumatoid factor (RF), and elevated C-reactive protein (CRP) (35 mg / L). She required long-term anti-inflammatory and analgesic treatment to improve her quality of life.

[0127] Treatment options include:

[0128] Injection ratio and content: Formula (per 1 mL): Piracetam 20 mg, Hydroxypropyl-sulfobutyl ether-β-cyclodextrin (HP-SBECD) 800 mg, Trehalose 50 mg, PGA 10 mg, PVA 0.1 mg, Ascorbic acid 1 mg, Phosphate buffer (pH 7.2), water for injection to 1 mL, 10 mg (0.5 mL, diluted to 5 mL of normal saline), twice a week, intravenous injection, for 8 consecutive weeks, then adjusted to once a week according to the condition;

[0129] Administration: Intravenous drip (10 mL / min), diluted to reduce local irritation. The injection solution has a pH of 7.0-7.5 and an osmotic pressure of 270-310 mosm / kg to ensure safety for long-term use.

[0130] Adjunctive treatment: oral methotrexate (7.5 mg / week), physical rehabilitation training;

[0131] Efficacy observation: Observation indicators: VAS score, morning stiffness time (min), CRP level, adverse reactions; Observation time points: before treatment, 2nd week, 4th week, and 8th week of treatment;

[0132] Results: In the second week, the VAS dropped to 4 points, and the morning stiffness duration was shortened to 15 minutes; in the fourth week, the VAS dropped to 2 points, and the CRP dropped to 15 mg / L; in the eighth week, the VAS was 1 point, and the CRP dropped to 8 mg / L. The patient's joint function improved significantly, and the adverse reaction was one mild dizziness (incidence rate 2%). The data are shown in Table 7:

[0133] Table 7

[0134]

[0135] This case addresses the long-term treatment needs of chronic rheumatoid arthritis and uses a lower dose (10 mg / time) 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 a highly effective anti-inflammatory effect. PGA modification (sedimentation rate 3.2%) and double drying (residual moisture 0.6%) ensure that the injection is precipitation-free for 12 months, making it suitable for long-term storage and use. The in vitro dissolution rate of 84.6% supports sustained drug release, and a 77% decrease in CRP reflects effective control of inflammation. Quality control (LC-MS detection of total impurities ≤1.0%) ensures drug purity, and diluted infusion reduces 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.

[0136] Case 3: Postoperative pain management:

[0137] Patient Background: Mr. Wang, a 35-year-old male programmer weighing 80 kg, underwent internal fixation of the right tibia for a fracture. He experienced significant pain on the first postoperative day, with a VAS score of 7 and local swelling. He required short-term intensive analgesia to promote postoperative recovery and reduce opioid use.

[0138] Treatment options include:

[0139] Injection ratio and content: Formula (per 1 mL): Piracetam 20 mg, Hydroxypropyl-sulfobutyl ether-β-cyclodextrin (HP-SBECD) 800 mg, Trehalose 50 mg, PGA 10 mg, PVA 0.1 mg, Ascorbic acid 1 mg, Phosphate buffer saline (pH 7.2), Water for injection added to 1 mL; Single dose: 30 mg (1.5 mL, diluted to 10 mL of normal saline), once daily, intravenous injection; for 3 consecutive days, then transition to oral NSAIDs;

[0140] Administration: Intravenous drip (15 mL / min), diluted for comfort; injection solution pH 7.0-7.5, osmotic pressure 270-310 mosm / kg, suitable for postoperative patients;

[0141] Adjuvant treatment: local cold compress, analgesia pump (oral ibuprofen);

[0142] Efficacy observation: Observation indicators: VAS score, swelling degree (circumference of affected limb), opioid usage, adverse reactions; Observation time points: before treatment, on the first day of treatment (1 hour after injection), the second day, and the third day;

[0143] Results: On the first day, the VAS dropped to 3 points within 1 hour, and the swelling was relieved. 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, and the circumference of the affected limb returned to normal. There were no adverse reactions. The observation data are shown in Table 8:

[0144] Table 8

[0145]

[0146] This case addresses the high-dose requirement (30 mg / time) for postoperative pain. The high solubility (21.2 mg / mL) and rapid release properties (84.6% in vitro dissolution) 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 injection stability. 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 opioid dosage was reduced by 100%, reducing the risk of addiction. The absence of adverse reactions reflected the high safety of the injection (sterility and pyrogen testing were qualified). This case validated the efficiency and safety of the technical solution in postoperative pain management.

[0147] The VAS score is a measurement tool used to assess pain intensity. It is usually represented by a 10-cm (100-mm) straight line with the ends marked as "no pain" and "worst pain" respectively. The patient marks a point on the line based on their own pain perception. The distance from the marked point to the "no pain" end (in centimeters or millimeters) is the VAS score. The score range is 0-10 (or 0-100). 0 points (0 mm): completely painless; 10 points (100 mm): unbearable and most disgusting pain. In the case, the VAS score is based on 0-10 points. Based on the patient's understanding and record, the scoring criteria are shown in Table 9.

[0148] Table 9

[0149]

[0150] 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. The line is divided into 10 equal distances (0-10), each 1 cm apart. Provide a pen and ruler. The patient uses a pen to mark the pain location on the line. 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.

[0151] It should be noted that, in this document, relational terms such as first and second, etc., are used only to distinguish one entity or operation from another entity or operation, and do not necessarily require or imply any actual relationship or order between these entities or operations. Moreover, the terms "comprises," "comprising," or any other variants thereof are intended to cover non-exclusive inclusion, such that a process, method, article, or device comprising a series of elements includes not only those elements, but also other elements not explicitly listed, or elements inherent to such process, method, article, or device. In the absence of further restrictions, an element defined by the statement "comprising a reference structure" does not exclude the presence of additional identical elements in the process, method, article, or device comprising the element.

[0152] While 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 these embodiments without departing from the principles and spirit of the invention, and that the scope of the invention is defined by the appended claims and their equivalents.

Claims

1. A preparation process for 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%. The preparation of the hydroxypropyl-sulfobutyl ether-β-cyclodextrin is as follows: First, a hydroxypropylation reaction is carried out under alkaline conditions of pH 10-11, 1,2-propylene oxide is added, and the reaction is carried out for 6 hours. Then, a sulfobutyl ether reaction is carried out, 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; Sp2: Preparation of microsphere precursor: 50 mg of trehalose, 10 mg of polyglutamic acid, and 0.01% polyvinyl alcohol 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 form a microsphere precursor with a particle size of 200-300 nm, a polymer dispersion index of less than 0.3, and a surface potential of -25 ± 3 mV. 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: The preliminary microspheres in Sp3 were freeze-dried in an environment of -50±1°C for 4 hours, with a vacuum degree of 0.1-0.2 mbar, and dried for 12 hours to obtain dry microspheres with a residual moisture content of ≤1.0%; Sp5: Reconstitution of injection: 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 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: 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. Ascorbic acid with a mass concentration of 0.1% was added as an antioxidant during the stirring process.

3. 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.

4. 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 range from 150 to 400 nm.

5. The preparation process of a high-stability piracetam injection according to claim 1, characterized in that: During the freeze-drying process of the Sp4, a programmed temperature rising strategy was adopted. After pre-freezing, the temperature was 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 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%.

6. The preparation process of a high-stability piracetam injection according to claim 1, characterized in that: During the reconstitution process 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.

7. The preparation process of the high-stability piracetam injection according to any one of claims 1 to 6, 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 test the purity of piracetam to be ≥99.5%, total impurities ≤0.5%, single impurities ≤0.1%, Karl Fischer method was used to determine the moisture content to be ≤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 to be 4500-5500Da; Sp2: Preparation process monitoring: Online monitoring of the inclusion complex preparation temperature at 40±1°C, pH 7.2±0.1, dynamic light scattering detection of microsphere precursor particle size of 200-300nm, polymer dispersion index less than 0.3, and Karl Fischer method determination of microsphere moisture content ≤1.0% after freeze-drying; Sp3: Final product testing: including physical and chemical testing, microsphere characteristics testing, biological testing and stability verification; Physical and chemical testing: 95-105% piracetam content by HPLC, ≤1.0% total impurities by LC-MS; pH 7.0-7.5 by pH meter, 270-310 mosm / kg osmotic pressure by freezing point depression method; Microsphere property testing: Dynamic light scattering determined the microsphere particle size to be 150-400 nm, and the polymer dispersion index to be less than 0.2; Zeta potential was used to determine the surface potential to be -20 to -30 mV; and in vitro dissolution testing was performed to verify that the release rate was ≥80% within 30 minutes. Biological testing: membrane filtration method to test sterility, rabbit method to test the absence of pyrogen 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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