Preparation of dihydroartemisinin in antitumor drugs

Abstract

The invention relates to the field of medicines, in particular to preparation of dihydroartemisinin in antitumor drugs, which comprises the steps of raw material preparation, solvent selection, drug solution preparation, emulsification and encapsulation, post-treatment and purification, quality detection and control and preparation storage. According to the preparation method disclosed by the invention, the stability of the dihydroartemisinin antitumor drug is remarkably improved, the shelf life of the drug is prolonged, the encapsulation efficiency and the drug loading capacity of the drug are improved by optimizing the process, the waste of the drug is reduced, the treatment effect is enhanced, and the preparation method is suitable for industrial production. The prepared pharmaceutical preparation has more uniform particle size distribution and good in-vivo distribution characteristics, the bioavailability of the medicine is improved, the safety and effectiveness of the medicine are ensured by a comprehensive quality detection and control system, the risk of clinical application is reduced, and the clinical application prospect is wide. Scientific and reasonable preparation storage conditions ensure that the quality of the medicine is stable in the storage period, and reliable guarantee is provided for clinical medication.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical technology, specifically to the preparation of dihydroartemisinin in anti-tumor drugs. Background Art

[0002] As a potential anti-tumor drug, the efficacy of dihydroartemisinin has been preliminarily confirmed in many studies. However, there are many deficiencies in the existing preparation methods of dihydroartemisinin drugs, such as poor drug stability, unsatisfactory distribution in vivo, low bioavailability, etc., which seriously limit its wide application in tumor treatment. Therefore, developing a preparation method of dihydroartemisinin anti-tumor drugs with high efficiency, stability and improved bioavailability has important clinical significance and application value. Summary of the Invention

[0003] In view of the problems in the prior art, the present invention provides the preparation of dihydroartemisinin in anti-tumor drugs.

[0004] The technical solution adopted by the present invention to solve its technical problems is: the preparation of dihydroartemisinin in anti-tumor drugs, including the steps of raw material preparation, solvent selection, drug solution preparation, emulsification and encapsulation, post-treatment and purification, quality inspection and control, and preparation storage; The raw materials are selected as high-purity dihydroartemisinin raw materials to ensure that its chemical purity is not less than 98%, and pharmaceutical excipients are prepared, including but not limited to polyethylene glycol, poloxamer, and phospholipids; The solvent selection uses a solvent that can dissolve dihydroartemisinin well and has high safety for the human body, such as ethanol, propylene glycol, or dimethyl sulfoxide; The drug solution preparation dissolves the dihydroartemisinin raw material in the selected solvent in a certain proportion and stirs evenly to form a drug solution with an appropriate concentration; For emulsification and packaging, if liposomes are used as carriers, lipid components such as phospholipids are dissolved in an organic solvent to form an organic phase, and then the drug solution is slowly added dropwise to the organic phase, and emulsification is carried out by methods such as ultrasonic or high-pressure homogenization to form a liposome suspension; if polymer nanoparticles are used as carriers, the polymer material and the dihydroartemisinin solution are mixed under appropriate conditions, and nanoparticle suspensions are prepared by methods such as emulsification-solvent evaporation or precipitation; The post-treatment and purification perform operations such as centrifugation and filtration on the emulsified or encapsulated suspension to remove unencapsulated drugs and impurities; the product is purified by methods such as dialysis, gel filtration, or column chromatography to obtain a high-purity dihydroartemisinin anti-tumor drug preparation; The quality inspection and control detect the appearance, particle size, encapsulation efficiency, drug loading, and other indicators of the prepared drug preparation; high-performance liquid chromatography and other methods are used to determine the content and purity of the drug to ensure that the drug quality meets relevant standards; The prepared dihydroartemisinin anti-tumor drug preparation is stored under low temperature, light protection and dry conditions to ensure the stability and activity of the drug.

[0005] In the selection of solvents, organic solvents are purified by molecular sieve drying and vacuum distillation, and the pH value and osmotic pressure of the aqueous solvent are precisely controlled.

[0006] The preparation of the drug solution adopts temperature-controlled magnetic stirring and ultrasonic-assisted dissolution.

[0007] During the preparation of the drug solution, the frequency of the ultrasonic probe is 28 kHz and the power is 1000 W.

[0008] During the emulsification process of liposome preparation, the probe diameter of the probe sonicator used is 6 mm.

[0009] In the centrifugation step of the post-treatment and purification, the centrifugal acceleration is 5 m / s².

[0010] In the detection of the drug release characteristics in the quality inspection and control, 1% albumin is also added to the release medium.

[0011] The preparation and application of dihydroartemisinin in anti-tumor drugs include the following steps: The first step: Prepare the required raw materials and equipment, including high-purity dihydroartemisinin, pharmaceutical excipients, purified organic solvents and aqueous solvents, as well as experimental equipment such as stirrers, ultrasonic instruments, centrifuges, rotary evaporators, dialysis bags, high-performance liquid chromatography instruments, etc.; The second step: Conduct raw material preparation, strictly conduct quality inspection and pretreatment on dihydroartemisinin and pharmaceutical excipients, precisely select appropriate organic solvents and aqueous solvents, prepare the drug solution according to the specified methods and conditions, and adopt corresponding emulsification and encapsulation processes according to the selected drug carrier (liposome or nanoparticle), and strictly control parameters such as dropping speed, stirring speed, ultrasonic time and power during the process; The third step: After completing emulsification and encapsulation, successively carry out post-treatment and purification steps such as centrifugation, filtration, dialysis and gel filtration to remove impurities and unencapsulated drugs, obtain a pure drug preparation, and comprehensively conduct quality inspection and control on the prepared drug preparation by using various detection techniques, such as appearance observation, particle size measurement, determination of encapsulation efficiency and drug loading, analysis of drug release characteristics, and stability investigation, etc.; For the drug preparations with qualified quality, carry out sub-packaging and storage according to the specified conditions, and regularly conduct random inspections on the quality of the preparations during storage to ensure their stability and effectiveness; The fourth step: In clinical application, select appropriate administration routes (such as intravenous injection, oral administration, etc.) and doses according to the patient's condition and the doctor's prescription. Before use, check the appearance, clarity, etc. of the preparation to ensure there is no abnormality.

[0012] Advantages of the present invention: For the preparation of dihydroartemisinin in anti-tumor drugs according to the present invention, the preparation method of the present invention significantly improves the stability of the dihydroartemisinin anti-tumor drug, extends the shelf life of the drug, optimizes the process, improves the encapsulation efficiency and drug loading capacity of the drug, reduces drug waste, enhances the therapeutic effect, and the prepared drug preparation has a more uniform particle size distribution and good in vivo distribution characteristics, improves the bioavailability of the drug, and the comprehensive quality inspection and control system ensures the safety and effectiveness of the drug, reduces the risk of clinical application, and the scientific and reasonable drug preparation storage conditions ensure the quality stability of the drug during storage, providing a reliable guarantee for clinical medication. Detailed implementation manners

[0013] In order to make the technical means, creative features, achieved purposes and functions of the present invention easy to understand, the present invention will be further described below in conjunction with specific implementation manners.

[0014] The preparation of dihydroartemisinin in anti-tumor drugs according to the present invention includes steps of raw material preparation, solvent selection, drug solution preparation, emulsification and encapsulation, post-treatment and purification, quality inspection and control, and drug preparation storage; The raw materials selected are high-purity dihydroartemisinin raw materials, ensuring that their chemical purity is not less than 98%. High-purity dihydroartemisinin raw materials are purchased from well-known and reliable suppliers. In a laboratory with a cleanliness level of 10,000, an electronic analytical balance with an accuracy of up to 0.0001 g is used to accurately weigh a predetermined mass of dihydroartemisinin. After weighing, it is placed in a dry, sterile and ultraviolet disinfected brown glass bottle, sealed and stored for later use; Prepare pharmaceutical excipients, including but not limited to polyethylene glycol, poloxamer, phospholipids; high molecular polymers (such as PLA, PLGA, chitosan, etc.): Carefully select polymers with specific molecular weights and molecular weight distributions, and strictly perform pretreatment according to the product instructions. For example, for PLGA, it is dried in a vacuum drying oven at 40 °C for 24 hours to remove moisture and residual solvents, and then it is pulverized into fine powder with an average particle size of about 5 μm using an air flow pulverizer; Surfactants (such as Tween 80, Span 80, etc.) and solubilizers (such as PVP, HPMC, etc.): Only select pharmaceutical-grade products certified by Good Manufacturing Practice (GMP). Before use, strict quality inspections of these excipients are carried out, including indicators such as purity, impurity content, pH value, etc.; Conduct a comprehensive quality inspection on all raw materials. Use advanced analytical techniques such as high-performance liquid chromatography (HPLC) combined with mass spectrometry (MS) to detect the purity of dihydroartemisinin and ensure it meets national drug standards. For excipients, use methods such as infrared spectroscopy (IR) and nuclear magnetic resonance (NMR) for structural identification and determine their relevant physical and chemical properties, such as solubility, melting point, boiling point, etc.

[0015] The selected solvent should be one that can dissolve dihydroartemisinin well and has high safety for the human body, such as ethanol, propylene glycol, or dimethyl sulfoxide. Organic solvents: In a well-ventilated fume hood, slowly pour organic solvents such as dichloromethane, chloroform, or ethyl acetate that have been dried with molecular sieves into a dry and clean glass container that has been pickled with acid, washed with alkali, and rinsed with deionized water and then dried. Before use, further purify the organic solvents by vacuum distillation to remove possible trace impurities and moisture, ensuring that the purity of the organic solvents reaches the chromatographic pure level. Aqueous solvents: Prepare phosphate buffer solution (PBS, pH 7.4) or physiological saline using ultrapure water with a resistivity greater than 18.2 MΩ·cm. During the preparation process, use a high-precision pH meter and osmometer to monitor the pH value and osmotic pressure of the solution in real time to ensure that they are maintained within the ranges of 7.4 ± 0.1 and 280 - 320 mOsm / kg respectively.

[0016] The preparation of the drug solution: Dissolve the dihydroartemisinin raw material in the selected solvent in a certain proportion and stir evenly to form a drug solution with an appropriate concentration. On a class 100 clean bench, carefully add the weighed dihydroartemisinin to a round-bottom flask containing an appropriate amount of organic solvent. The round-bottom flask has been sterilized by high temperature and high pressure in advance and cooled to room temperature in a sterile environment. Fix the flask on a magnetic stirrer with temperature and rotation speed control functions, start stirring, set the initial rotation speed to 300 rpm, and gradually increase it to 500 rpm. At the same time, use a temperature-controlled oil bath to moderately heat the system (temperature controlled at 35 - 45 °C) until dihydroartemisinin is completely dissolved. If there are still a small number of undissolved particles, an ultrasonic cleaner with a power of 800 W can be used to assist in dissolution. Each ultrasonic treatment time does not exceed 5 minutes, with an interval of 1 minute, and repeat 3 - 5 times.

[0017] The emulsification and packaging: If liposomes are used as carriers, dissolve lipid components such as phospholipids in organic solvents to form an organic phase, and then slowly drip the drug solution into the organic phase and emulsify it by methods such as ultrasonic or high-pressure homogenization to form a liposome suspension; if polymer nanoparticles are used as carriers, mix the polymer material and the dihydroartemisinin solution under appropriate conditions and prepare a nanoparticle suspension by methods such as emulsification-solvent evaporation or precipitation. Liposome preparation: Weigh precisely the phospholipids (such as soybean phospholipids or lecithin) and cholesterol, and place them in another dry round-bottom flask that has undergone the same sterilization treatment, in a molar ratio of 3:1 - 5:1. Add an appropriate amount of organic solvent to completely dissolve them, forming a homogeneous and transparent organic phase. Under magnetic stirring (at a rotational speed of 800 rpm), use a micropipette with a precision of 0.1 μL to slowly and evenly drip the drug solution into the organic phase at a constant speed of 1 - 2 mL per minute. During the dripping process, closely observe the state of the solution to ensure there are no obvious precipitation or stratification phenomena. After the dripping is completed, transfer the mixture to an ice-water bath and perform ultrasonic treatment using a probe sonicator (with a power of 600 W and a working frequency of 20 kHz), ultrasonicate for 5 seconds each time, with a 5-second interval, for a total of 8 - 10 minutes to form the primary emulsion. Quickly transfer the primary emulsion to a rotary evaporator. At a water bath temperature of 40 °C and a vacuum degree of 0.1 MPa, slowly rotate and evaporate the organic solvent at a rotational speed of 50 rpm until a uniform, light blue lipid film forms on the flask wall. Add the preheated aqueous solvent at 55 °C to the flask. The volume of the aqueous solvent is 3 - 5 times that of the organic phase. Use a vortex oscillator to oscillate at a rotational speed of 2500 rpm for 5 minutes to fully hydrate and detach the lipid film. Then, use an ultrasonic cleaner to further process it for 10 - 15 minutes under the conditions of a power of 400 W and a working frequency of 25 kHz to obtain a liposome suspension. Nanoparticle preparation: Accurately weigh a certain amount of polymer (such as PLGA), dissolve it in an organic solvent to form an organic phase, and control the polymer concentration at 10 - 20 mg / mL. Dissolve dihydroartemisinin in an aqueous phase containing a surfactant (such as Tween 80, with a concentration of 0.5 - 1.0%) and a solubilizer (such as PVP, with a concentration of 1.0 - 2.0%), stir evenly to form an aqueous phase, and the concentration of dihydroartemisinin in the aqueous phase is 2 - 5 mg / mL. Under strong stirring of a high-speed shear emulsifier (with a rotational speed set at 10000 - 12000 rpm), slowly drip the organic phase into the aqueous phase through a constant flow pump at a speed of 0.5 - 1 mL per minute to form an emulsion, and continue stirring for 20 - 30 minutes to ensure a uniform and stable emulsion is formed. Transfer the emulsion to a rotary evaporator. At a water bath temperature of 35 °C and a vacuum degree of 0.08 MPa, slowly evaporate the organic solvent at a rotational speed of 40 rpm until polymer precipitation forms a nanoparticle suspension. During the evaporation process, continuously stir to prevent nanoparticle aggregation.

[0018] The post-treatment and purification involve operations such as centrifugation and filtration on the emulsified or encapsulated suspension to remove unencapsulated drugs and impurities; methods such as dialysis, gel filtration, or column chromatography are used to purify the product to obtain a high-purity dihydroartemisinin anti-tumor drug preparation; Centrifugation: Transfer the emulsified or encapsulated suspension to a centrifuge tube pre-cooled at 4°C, ensure the quality and balanced symmetry of the centrifuge tube, and then carefully place it in a high-speed refrigerated centrifuge. Set the centrifuge speed to 12,000 rpm, the centrifugation time to 30 minutes, and the temperature to 4°C. After centrifugation, carefully aspirate the supernatant using a pipette, and redisperse the precipitate in a small amount of aqueous solvent for subsequent detection and analysis; Filtration: Filter the supernatant through a sterile microporous membrane with a pore size of 0.22 μm to remove possible fine particles and impurities. The filtration process is carried out in a sterile operating bench, and the supernatant is slowly pushed through the membrane using a disposable sterile syringe; Dialysis: Load the filtered solution into a dialysis bag with a molecular weight cut-off of 10,000 - 14,000 Da, ensure the two ends of the dialysis bag are tightly sealed without leakage, immerse the dialysis bag in a large amount of aqueous solvent for dialysis. The volume of the external dialysis solution is at least 50 times the volume of the sample solution, and the external dialysis solution is changed every 4 hours. The total dialysis time is 24 hours, and the external dialysis solution is continuously stirred during this period to improve the dialysis efficiency; Gel filtration: Select a suitable gel column such as Sephadex G-50 or G-100, first balance the column with a PBS equilibration solution at pH 7.4 at a flow rate of 1 ml per minute for at least 2 column volumes until the baseline shown by the UV detector is stable. Gently load the dialyzed solution onto the top of the gel column, avoiding the generation of bubbles and impact on the column bed, and then elute with the same PBS eluent, controlling the elution speed at 0.8 ml per minute. Monitor the absorbance of the eluate at a wavelength of 280 nm using a UV detector, and collect the eluate containing dihydroartemisinin nanoparticles or liposomes.

[0019] The quality inspection and control involve detecting indicators such as the appearance, particle size, encapsulation efficiency, and drug loading of the prepared drug preparation; methods such as high-performance liquid chromatography are used to determine the content and purity of the drug to ensure that the drug quality meets relevant standards; Appearance: Under a drug detection lamp that meets national standards, carefully observe the color, transparency, and uniformity of the preparation from different angles. The preparation should show uniform opalescence or light blue, without obvious turbidity, precipitation, and stratification. Use a high-definition digital camera to take pictures of the appearance of the preparation and compare and analyze them with the standard sample; Particle size and particle size distribution: Use a dynamic light scattering particle size analyzer (such as Malvern Zetasizer Nano ZS), place an appropriate amount (about 1 mL) of the preparation sample in a quartz cuvette, ensure that the sample is free of bubbles and impurities, set the measurement parameters according to the instrument operating instructions, such as temperature (25°C), scattering angle (90°), etc., repeat the measurement three times for each sample, and each measurement time is 60 seconds. Calculate the average particle size, polydispersity index (PDI) and particle size distribution curve through the software provided by the instrument, and record the measurement results; Encapsulation efficiency and drug loading: The drug content was determined by high performance liquid chromatography (HPLC). First, a series of standard solutions with a concentration gradient (0.1-100 μg / mL) were prepared using a dihydroartemisinin standard with a purity greater than 99%. The standard curve was plotted and the correlation coefficient (R²) should be greater than 0.999. For sample treatment, for liposome preparations, the demulsification method was used, that is, adding an appropriate amount of isopropanol to destroy the liposome structure and release the drug; for nanoparticle preparations, an organic solvent extraction method was used, such as adding dichloromethane to ultrasonically extract the drug. The treated samples were filtered through a 0.22 μm microporous membrane and then analyzed by HPLC; the drug content was calculated based on the standard curve, and then the encapsulation efficiency (EE%) and drug loading (DL%) were calculated according to the following formula: Encapsulation efficiency (EE%) = amount of drug encapsulated in the preparation / total amount of drug input × 100% Drug loading (DL%) = amount of drug encapsulated in the preparation / total amount of carrier material and drug in the preparation × 100% Drug release characteristics: About 1 mL of the preparation sample is placed in a pre-treated dialysis bag (molecular weight cutoff of 8000-14000 Da), and the two ends are tightly sealed with clips. The dialysis bag is placed in a stoppered conical flask containing 20 mL of release medium (such as PBS, pH 7.4, containing 0.1% Tween80), and incubated in a constant temperature oscillator at 37°C and 100 rpm. At predetermined time points (such as 0.5, 1, 2, 4, 6, 8, 12, 24, 36, 48 hours), 1 mL of release medium is taken out and immediately supplemented with an equal amount of fresh preheated release medium. After the taken out release medium is filtered through a 0.22 μm microporous filter membrane, the drug concentration is determined by HPLC, the cumulative drug release amount is calculated, and the release curve is plotted. According to the characteristics of the release curve, a suitable mathematical model (such as zero-order, first-order, Higuchi model, etc.) is used to fit the release data and evaluate the drug release mechanism; Stability: The preparation samples were placed under the following conditions for stability testing; High temperature test: Place in a constant temperature drying oven at 60°C for 10 days, and take samples for testing on the 5th and 10th days; High humidity test: Place it in a thermostatic and humidistatic chamber at 25°C and relative humidity of 90% ± 5% for 10 days, and take samples for testing on the 5th and 10th days; Light exposure test: Place it under a light intensity of 4500 ± 500 lux for 10 days, and take samples for testing on the 5th and 10th days; Accelerated test: Place it under the conditions of 40°C ± 2°C and relative humidity of 75% ± 5% for 6 months, and take samples for testing at the end of the 1st, 2nd, 3rd, and 6th months respectively; Long-term test: Place it under the conditions of 25°C ± 2°C and relative humidity of 60% ± 10% for 12 months, and take samples for testing at the end of the 3rd, 6th, 9th, and 12th months respectively; The detection indexes include appearance, particle size, drug content, encapsulation efficiency, etc. Compare with the initial value to evaluate the stability changes of the preparation under different conditions.

[0020] Storage of the preparation: Store the prepared dihydroartemisinin anti-tumor drug preparation under low temperature, light-proof and dry conditions to ensure the stability and activity of the drug; The preparation that has passed the comprehensive quality inspection is sub-packed into pre-sterilized vials or ampoules using aseptic filling technology. The filling volume per bottle is accurately controlled according to the clinical use requirements, with an error not exceeding ±5%. The filling process is carried out under a Class 100 laminar flow hood to ensure the sterility of the operating environment. Use nitrogen to purge the bottle mouth to remove the oxygen in the bottle, and then use a sealing machine for sealing. The integrity and tightness of the seal are strictly tested, such as vacuum leak detection and pressure testing; Place the sub-packed preparation in a medical refrigerator with a temperature set at 2-8°C for light-proof storage. The refrigerator is equipped with a temperature and humidity monitoring system, which can record the parameters of the storage environment in real time. Regularly conduct quality random inspections on the stored preparation, including appearance inspection, pH value determination, drug content analysis, particle size detection, etc., to ensure the stability and effectiveness of the preparation during storage.

[0021] In the selection of the solvent, the organic solvent is purified by molecular sieve drying and vacuum distillation, and the pH value and osmotic pressure of the aqueous solvent are accurately controlled.

[0022] The preparation of the drug solution adopts temperature-controlled magnetic stirring and ultrasonic-assisted dissolution.

[0023] During the preparation process of the drug solution, the frequency of the ultrasonic probe is 28 kHz and the power is 1000 W.

[0024] During the emulsification process of the liposome preparation, the probe diameter of the probe sonicator used is 6 mm.

[0025] In the centrifugation step of the post-treatment and purification, the centrifugation acceleration is 5 m / s².

[0026] In the detection of the drug release characteristics of the quality inspection and control, 1% albumin was also added to the release medium.

[0027] Example 1: Preparation of liposome formulation. In this example, liposomes were used as drug carriers to prepare dihydroartemisinin anti-tumor drugs: Weigh 100 mg of dihydroartemisinin and dissolve it in 5 mL of ethanol. Dissolve 200 mg of soybean phospholipid and 50 mg of cholesterol in 10 mL of chloroform to form an organic phase. Under stirring conditions, slowly drip the drug solution into the organic phase, and then perform ultrasonic treatment for 10 minutes to form a liposome suspension. Remove the organic solvent from the suspension on a rotary evaporator to obtain a liposome film. Add an appropriate amount of phosphate buffer solution and hydrate for 30 minutes, and further disperse by probe ultrasound to obtain a liposome suspension. Finally, purify by centrifugation and dialysis to obtain a dihydroartemisinin liposome formulation. After testing, the average particle size of this formulation is about 120 nm, the encapsulation efficiency is 85%, and the drug loading is 15%.

[0028] Example 2: Preparation of polymer nanoparticle formulation. In this example, polymer nanoparticles were used as drug carriers to prepare dihydroartemisinin anti-tumor drugs Dissolve 200 mg of poly(lactic-co-glycolic acid) (PLGA) in 5 mL of dichloromethane as the organic phase, and dissolve 100 mg of dihydroartemisinin in 2 mL of ethanol as the aqueous phase. Under high-speed stirring, drip the aqueous phase into the organic phase to form a primary emulsion. Then pour the primary emulsion into 20 mL of an aqueous solution of polyvinyl alcohol (PVA) and continue stirring for 3 hours to volatilize the organic solvent and form a nanoparticle suspension. Remove large particles and impurities by centrifugation and filtration, and then purify by dialysis to obtain a dihydroartemisinin polymer nanoparticle formulation. After testing, the average particle size of this formulation is about 180 nm, the encapsulation efficiency is 78%, and the drug loading is 12%.

[0029] Specific use: Prepare the required raw materials and equipment, including high-purity dihydroartemisinin, pharmaceutical excipients, purified organic solvents and aqueous solvents, as well as experimental equipment such as stirrers, ultrasonic instruments, centrifuges, rotary evaporators, dialysis bags, high-performance liquid chromatography instruments, etc.; Conduct raw material preparation, conduct strict quality inspections and pretreatment on dihydroartemisinin and pharmaceutical excipients, accurately select appropriate organic solvents and aqueous solvents, and prepare the drug solution according to the specified methods and conditions. According to the selected drug carriers (liposomes or nanoparticles), adopt the corresponding emulsification and encapsulation processes for operation, and strictly control parameters such as the dropping speed, stirring speed, ultrasonic time, and power during the process; After emulsification and encapsulation are completed, successively carry out post-treatment and purification steps such as centrifugation, filtration, dialysis, and gel filtration to remove impurities and unencapsulated drugs, and obtain a pure drug preparation. Use various detection techniques, such as appearance observation, particle size measurement, encapsulation efficiency and drug loading determination, drug release characteristic analysis, and stability investigation, etc., to conduct comprehensive quality inspection and control on the prepared drug preparation; For the preparations with qualified quality, carry out sub-packaging and storage according to the specified conditions. During storage, regularly sample and inspect the quality of the preparations to ensure their stability and effectiveness; During clinical application, according to the patient's condition and the doctor's prescription, select the appropriate administration route (such as intravenous injection, oral administration, etc.) and dosage. Before use, check the appearance, clarity, etc. of the preparation to ensure there is no abnormality.

[0030] Application: A pharmaceutical laboratory plans to prepare a batch of dihydroartemisinin anti-tumor drugs for pre-clinical research. The experimental personnel first prepared high-purity dihydroartemisinin raw materials and various pharmaceutical excipients according to the requirements in the patent and conducted quality inspections on them. Then, they selected appropriate solvents and successfully prepared the drug solution. Next, according to the predetermined plan, they adopted the liposome encapsulation technology. After a series of treatment and purification steps, they obtained a liposome suspension. After strict quality inspection and determination that the preparation met the requirements, it was sub-packaged and stored in a low-temperature and light-proof environment. In the subsequent animal experiments, according to the body weight of the experimental animals and the tumor model, the appropriate administration dosage was calculated, and the drug was administered by intravenous injection to observe the anti-tumor effect of the drug and the reaction of the animals.

[0031] The above shows and describes the basic principles, main features, and advantages of the present invention. Those skilled in the art should understand that the present invention is not limited by the above embodiments. The above embodiments and the descriptions in the specification only illustrate the principles of the present invention. Without departing from the spirit and scope of the present invention, the present invention will have various changes and improvements, and these changes and improvements all fall within the scope claimed by the present invention. The scope claimed by the present invention is defined by the appended claims and their equivalents.

Claims

1. Preparation of dihydroartemisinin for anti-tumor drugs, characterized in that, Steps including raw material preparation, solvent selection, drug solution preparation, emulsification and encapsulation, post-treatment and purification, quality inspection and control, and preparation storage; For the raw materials, high-purity dihydroartemisinin raw materials are selected to ensure that their chemical purity is not less than 98%. Medicinal excipients are prepared, including but not limited to polyethylene glycol, poloxamer, and phospholipids; For the solvent selection, a solvent that can dissolve dihydroartemisinin well and has high safety for the human body is selected, such as ethanol, propylene glycol, or dimethyl sulfoxide; For the drug solution preparation, the dihydroartemisinin raw materials are dissolved in the selected solvent in a certain proportion and stirred evenly to form a drug solution with an appropriate concentration; For the emulsification and packaging, if liposomes are used as the carrier, lipid components such as phospholipids are dissolved in an organic solvent to form an organic phase, and then the drug solution is slowly dropped into the organic phase, and emulsification is carried out by methods such as ultrasonic or high-pressure homogenization to form a liposome suspension; if polymer nanoparticles are used as the carrier, the polymer material and the dihydroartemisinin solution are mixed under appropriate conditions, and nanoparticle suspensions are prepared by methods such as emulsification-solvent evaporation or precipitation; For the post-treatment and purification, operations such as centrifugation and filtration are carried out on the emulsified or encapsulated suspension to remove unencapsulated drugs and impurities; the product is purified by methods such as dialysis, gel filtration, or column chromatography to obtain a high-purity dihydroartemisinin anti-tumor drug preparation; For the quality inspection and control, indicators such as appearance, particle size, encapsulation efficiency, and drug loading of the prepared drug preparation are detected; high-performance liquid chromatography and other methods are used to determine the content and purity of the drug to ensure that the drug quality meets relevant standards; For the preparation storage, the prepared dihydroartemisinin anti-tumor drug preparation is stored under low-temperature, light-proof, and dry conditions to ensure the stability and activity of the drug.

2. The preparation of dihydroartemisinin in the anti-tumor drug according to claim 1, characterized in that: In the solvent selection, the organic solvent is purified by molecular sieve drying and vacuum distillation, and the pH value and osmotic pressure of the aqueous solvent are precisely controlled.

3. The preparation of dihydroartemisinin in the anti-tumor drug according to claim 1, characterized in that: For the drug solution preparation, temperature-controlled magnetic stirring and ultrasonic-assisted dissolution are used.

4. The preparation of dihydroartemisinin in the anti-tumor drug according to claim 1, characterized in that: During the drug solution preparation process, the frequency of the ultrasonic probe is 28 kHz and the power is 1000 W.

5. The preparation of dihydroartemisinin in the anti-tumor drug according to claim 1, wherein: During the emulsification process of liposome preparation, the probe diameter of the probe sonicator used is 6 mm.

6. The preparation of dihydroartemisinin in the anti-tumor drug according to claim 1, characterized in that: In the centrifugation step of the post-treatment and purification, the centrifugation acceleration is 5 m / s².

7. The preparation of dihydroartemisinin in the anti-tumor drug according to claim 1, characterized in that: In the drug release property detection of the quality inspection and control, 1% albumin is also added to the release medium.

8. Preparation and application of dihydroartemisinin in anti-tumor drugs, characterized in that: Including the following steps: The first step: Prepare the required raw materials and equipment, including high-purity dihydroartemisinin, medicinal excipients, purified organic solvents and aqueous solvents, and experimental equipment such as stirrers, ultrasonic instruments, centrifuges, rotary evaporators, dialysis bags, and high-performance liquid chromatographs; The second step: Carry out raw material preparation, conduct strict quality inspections and pre-treatments on dihydroartemisinin and medicinal excipients, precisely select appropriate organic solvents and aqueous solvents, and prepare the drug solution according to the specified methods and conditions. According to the selected drug carrier (liposome or nanoparticle), corresponding emulsification and encapsulation processes are carried out, and parameters such as dropping speed, stirring speed, ultrasonic time, and power are strictly controlled during the process; Step 3: After the emulsification and encapsulation are completed, post-treatment and purification steps such as centrifugation, filtration, dialysis, and gel filtration are carried out in sequence to remove impurities and unencapsulated drugs, obtaining a pure drug preparation. Various detection techniques, such as appearance observation, particle size measurement, determination of encapsulation efficiency and drug loading, analysis of drug release characteristics, and stability investigation, etc., are used to conduct comprehensive quality inspection and control on the prepared drug preparation; for the preparations with qualified quality, they are sub-packed and stored under specified conditions. During the storage period, the quality of the preparations is randomly inspected regularly to ensure their stability and effectiveness; Step 4: During clinical application, according to the patient's condition and the doctor's prescription, select an appropriate administration route (such as intravenous injection, oral administration, etc.) and dose. Before use, it is necessary to check the appearance, clarity, etc. of the preparation to ensure there is no abnormality.