High-stability dihydroartemisinin emulsion

Abstract

The invention relates to a high-stability dihydroartemisinin emulsion which is prepared by the following steps: preparing a mixed solution from dihydroartemisinin, sodium bicarbonate and polyethylene glycol 600, carrying out loading treatment in a carbon dioxide supercritical extraction instrument by taking glycerol and n-butyl alcohol as a composite solvent to form an intermediate product, and specifically, after running for 1-2 hours under the conditions that the CO2 flow is 10-15kg / h, the pressure is 15-20Mpa and the temperature is 35 DEG C, increasing the pressure to 25-30Mpa, keeping the temperature for 1-2 hours, and carrying out constant-temperature extraction to obtain the dihydroartemisinin emulsion. The temperature is raised to 45-50 DEG C and kept for 30-60 min, a product is collected and placed at the room temperature after the temperature is raised to 45-50 DEG C, an intermediate product is obtained, and the intermediate product is added into an emulsion matrix to form the nano-emulsion. The transfer rate of the dihydroartemisinin in the prepared intermediate product reaches 94.37%, the particle size of the loaded nano intermediate product is uniformly distributed at about 50nm, the prepared emulsion is uniform, the dihydroartemisinin has excellent stability in the system, the dihydroartemisinin is not easy to decompose in environments of long-term high temperature, high-humidity illumination and the like, the stability of the emulsion property is excellent, and the stability of the product is good. The problems of layering, sedimentation and the like are avoided, and the bioavailability is excellent.

Description

[0001] The present invention is a divisional application of patent application number 202411288104.7, and the invention name is “A dihydroartemisinin nanomedicine and its preparation method”. Technical Field

[0002] The invention relates to the technical field of drug preparation, and in particular to a high-stability dihydroartemisinin emulsion. Background Art

[0003] Dihydroartemisinin is the main active metabolite of artemisinin. It has a strong and rapid killing effect on the erythrocytic stage of Plasmodium and can quickly control clinical attacks and symptoms. With continuous research, it is found that dihydroartemisinin has anti-inflammatory, immunosuppressive, anti-liver fibrosis and anti-tumor effects in addition to its antimalarial effect.

[0004] Nanomedicine is a nanosuspension made by directly crushing the drug in the presence of surfactants and water and other additives. It is suitable for administration through oral and injection routes to improve absorption or targeting. By selecting additives, particles with different surface properties can be obtained. The advantages of nanomedicine are: first, it improves the oral absorbability of poorly soluble drugs. Nanoparticles can improve dissolution and solubility, increase adhesion, form metastable crystals or amorphous forms, and eliminate the supersaturation phenomenon caused by particle size differences; second, it has targeted and localized drug release. Nanoparticles have the characteristics of long circulation, invisibility and three-dimensional stability in the body, which are all conducive to drug targeting; third, it can be used as a special carrier of biomacromolecules. Improving the mucosal adhesion properties of nanoparticles obviously helps to improve effectiveness and prolong the duration of action. Therefore, preparing poorly soluble dihydroartemisinin into nanomedicine is conducive to improving its solubility, thereby improving its absorption and utilization rate. Summary of the invention

[0005] The present invention aims to provide a method for preparing the above-mentioned dihydroartemisinin nanomedicine. In the process of preparing the dihydroartemisinin nanomedicine, the dihydroartemisinin transfer loading efficiency is high.

[0006] The purpose of the present invention is to provide a dihydroartemisinin nano drug, specifically a dihydroartemisinin nanoemulsion preparation, which has excellent stability, is not easily degraded by external interference, and improves the bioavailability of the drug.

[0007] The purpose of the present invention is achieved through the following technical solutions: A method for preparing a dihydroartemisinin nano drug is characterized by comprising the steps of preparing an intermediate containing dihydroartemisinin, preparing an emulsion matrix, and mixing the intermediate and the emulsion matrix to prepare an emulsion, wherein the intermediate is prepared by mixing polyethylene glycol 600, dihydroartemisinin and a sodium bicarbonate solution to prepare a mixed solution, placing the mixed solution in a carbon dioxide supercritical extraction instrument, adding a composite solvent composed of glycerol and n-butanol, and introducing carbon dioxide for loading treatment to prepare the intermediate.

[0008] Furthermore, the mass percentage concentration of the sodium bicarbonate solution in the mixed solution is 5%, the mass ratio of polyethylene glycol 600, dihydroartemisinin and sodium bicarbonate solution is 100:15~18:5~8, and the sodium bicarbonate solution is prepared by taking 95mL of purified water, adding 5g of sodium bicarbonate, and stirring to dissolve.

[0009] Furthermore, during the load treatment process, the CO2 flow rate is 10~15kg / h, the pressure is 15~20Mpa, and the temperature is 35°C. After running for 1~2h, the pressure is increased to 25~30Mpa, the temperature is increased to 45~50°C and maintained for 30~60min. After the end, the product is collected and cooled to room temperature to obtain an intermediate product. The mass ratio of the mixed liquid and the composite solvent is 100:30~40, and the mass ratio of glycerol and n-butanol in the composite solvent is 3:0.8~1.

[0010] Furthermore, the preparation of the emulsion base is as follows: liquid paraffin, stearyl alcohol, white vaseline, palm oil, and hydrogenated vegetable oil are mixed to form an oil phase base, glycerol, sodium lauryl sulfate, propylene glycol, ethyl hydroxybenzoate, and purified water are mixed to form an aqueous phase base, and the oil phase base is added to the aqueous phase base and stirred to prepare the emulsion base. In parts by weight, the oil phase base contains 8 to 10 parts of paraffin, 3 to 7 parts of stearyl alcohol, 6 to 8 parts of white vaseline, 5 parts of palm oil, and 5 to 7 parts of hydrogenated vegetable oil; the aqueous phase base contains 15 to 18 parts of glycerol, 1 to 2 parts of sodium lauryl sulfate, 10 to 12 parts of propylene glycol, 0.5 to 1 part of ethyl hydroxybenzoate, and 70 to 80 parts of purified water.

[0011] Furthermore, the oil phase matrix is ​​added to the aqueous phase matrix by keeping the aqueous phase matrix at 75-80° C., adding the oil phase matrix at the same temperature to the aqueous phase matrix under stirring at 60-70 rpm, continuing stirring for 10-15 minutes after the addition, and then cooling in an ice bath to obtain an emulsion matrix.

[0012] Furthermore, the preparation of the emulsion is to keep the emulsion matrix at 35-40°C, add the intermediate product while stirring at a speed of 25-30 rpm, continue stirring for 20-30 minutes after the addition is completed, and cool to room temperature to obtain the emulsion, and the mass ratio of the emulsion matrix to the intermediate product is 100:15-20.

[0013] Most specifically, a method for preparing a dihydroartemisinin nanomedicine is characterized by comprising the following steps: Step 1: Preparation of intermediates (1) Polyethylene glycol 600 is heated to 35-40°C, and dihydroartemisinin is added under stirring at 60-70 rpm. After the addition is completed, stirring is continued for 10-20 minutes. Under the same stirring conditions, a sodium bicarbonate solution with a mass concentration of 5% is added, and stirring is continued for 30-40 minutes to form a mixed solution. The mass ratio of the polyethylene glycol 600, dihydroartemisinin and sodium bicarbonate solution is 100:15-18:5-8; (2) Add the mixed liquid into a supercritical carbon dioxide extractor, add a solvent composed of glycerol and n-butanol, set the CO2 flow rate to 10-15 kg / h, the pressure to 15-20 MPa, the temperature to 35-45 °C, the operating time to 1-2 h, then increase the pressure to 25-30 MPa, increase the temperature to 45-50 °C, and continue to maintain for 30-60 min. After the end, collect the product and cool it to room temperature to obtain the intermediate product; Step (ii) Preparation of emulsion matrix (1) According to weight, take 8-10 parts of liquid paraffin, 3-7 parts of octadecyl alcohol, 6-8 parts of white vaseline, 5 parts of palm oil, and 5-7 parts of hydrogenated vegetable oil, mix them, heat them to 75-80°C until they are melted, and obtain an oil phase matrix; separately take 15-18 parts of glycerin, 1-2 parts of sodium lauryl sulfate, 10-12 parts of propylene glycol, 0.5-1 part of ethylparaben, and 70-80 parts of purified water, heat them to 75-80°C, and stir them until they become a clear liquid, and obtain an aqueous phase matrix; (2) Keep the water phase matrix at 75-80°C, add the oil phase matrix at the same temperature at 60-70 rm, continue stirring for 10-15 min after the addition is complete, and quickly cool to 35-40°C in an ice bath to obtain an emulsion matrix; Step (iii) Preparation of emulsion The emulsion matrix kept at 35-40° C. is added to the intermediate under stirring at 25-30 rpm. After the addition is completed, stirring is continued for 20-30 minutes, and then naturally cooled to room temperature to obtain an emulsion. The mass ratio of the emulsion matrix to the intermediate is 100:15-20.

[0014] A highly stable dihydroartemisinin nanoemulsion, characterized in that: dihydroartemisinin, sodium bicarbonate and polyethylene glycol 600 are prepared into a mixed solution, and glycerol and n-butanol are used as a composite solvent in a carbon dioxide supercritical extraction instrument to carry out a load treatment to form an intermediate product, specifically, the CO2 flow rate is 10-15kg / h, the pressure is 15-20Mpa, the temperature is 35°C, after running for 1-2h, the pressure is increased to 25-30Mpa, the temperature is increased to 45-50°C and maintained for 30-60min, after the end, the product is collected and cooled to room temperature to obtain an intermediate product, and the intermediate product is added to an emulsion matrix to form a nanoemulsion.

[0015] In order to improve the biocompatibility and stability of nanoparticles, the present invention uses polyethylene glycol to load nanoparticles, but it is difficult to transfer dihydroartemisinin to polyethylene glycol, the loading efficiency is poor, and it is difficult for polyethylene glycol molecules to achieve uniform encapsulation of dihydroartemisinin. In addition, the particle size of the nano intermediate prepared by loading is large and the size uniformity is poor, which affects the absorption and utilization of the drug, and the emulsion matrix is ​​easily broken. If the particle size is too small, the problem of agglomeration is easy to occur. In addition, due to the presence of unstable groups (internal peroxide bonds) and the presence of diisomeric centers, dihydroartemisinin has poor self-stability. During long-term storage under high temperature, high humidity and strong light irradiation, dihydroartemisinin will decompose.

[0016] In the present invention, dihydroartemisinin, polyethylene glycol 600 and sodium bicarbonate are mixed into a solution, and loaded in a supercritical extractor. Glycerol and n-butanol are added during the loading process, which plays the role of an entrainer, and sodium bicarbonate plays a regulating role, further promoting the encapsulation of bicarbonate and dihydroartemisinin by polyethylene glycol 600, thereby improving the loading efficiency of dihydroartemisinin. On the other hand, due to the synergistic effect of glycerol, n-butanol and sodium bicarbonate, the prepared nano intermediate has a smaller particle size and a uniform size distribution, which inhibits the agglomeration of dihydroartemisinin. In addition, the addition of sodium bicarbonate regulates the pH of the final emulsion to be maintained at about 5.5 for a long time, improves the stability of dihydroartemisinin, and inhibits the degradation of dihydroartemisinin. On the other hand, the bicarbonate loaded in the system slowly decomposes and releases carbon dioxide in a long-term process. Under the cooperation of the emulsion matrix, dihydroartemisinin is effectively isolated from being affected by oxygen and light in the air, and the stability of dihydroartemisinin is further guaranteed.

[0017] In the process of using the emulsion matrix to wrap the nanostructured intermediate, demulsification is easy to occur, resulting in the inability of the emulsion matrix to form a complete wrapping of the intermediate, and the inability to form a nanoemulsion, so that the effective component dihydroartemisinin is easy to decompose, and the bioavailability of dihydroartemisinin is reduced. The intermediate prepared in the present invention has a small particle size and is simultaneously loaded with bicarbonate ions, which adjusts the emulsion pH, effectively inhibits the demulsification of the intermediate, thereby forming a uniform nanoemulsion, effectively inhibiting the decomposition of dihydroartemisinin caused by external environmental factors, and improving the bioavailability of dihydroartemisinin in the emulsion.

[0018] Furthermore, the nanoemulsion is prepared by keeping the emulsion matrix at 35-40° C., adding the intermediate product while stirring at a rate of 25-30 rpm, continuing to stir for 20-30 minutes after the addition is completed, and cooling to room temperature to obtain the emulsion, wherein the mass ratio of the emulsion matrix to the intermediate product is 100:15-20.

[0019] Furthermore, the mass ratio of the mixed solution to the composite solvent is 100:30-40, and the mass ratio of glycerol to n-butanol in the composite solvent is 3:0.8-1.

[0020] Furthermore, the mass percentage concentration of the sodium bicarbonate solution in the mixed solution is 5%, the mass ratio of polyethylene glycol 600, dihydroartemisinin and sodium bicarbonate solution is 100:15~18:5~8, and the sodium bicarbonate solution is prepared by taking 95mL of purified water, adding 5g of sodium bicarbonate, and stirring to dissolve.

[0021] Furthermore, the emulsion matrix is ​​specifically prepared by keeping the water phase matrix at 75-80° C., adding the oil phase matrix at the same temperature to the water phase matrix under stirring at 60-70 rpm, continuing stirring for 10-15 minutes after the addition, and then cooling in an ice bath to obtain the emulsion matrix.

[0022] Furthermore, the oil phase matrix is ​​prepared by mixing liquid paraffin, stearyl alcohol, white vaseline, palm oil, and hydrogenated vegetable oil, and the water phase matrix is ​​prepared by mixing glycerin, sodium lauryl sulfate, propylene glycol, ethylparaben, and purified water.

[0023] Furthermore, in parts by weight, the oil phase matrix comprises 8 to 10 parts of paraffin, 3 to 7 parts of octadecyl alcohol, 6 to 8 parts of white vaseline, 5 parts of palm oil, and 5 to 7 parts of hydrogenated vegetable oil; the aqueous phase matrix comprises 15 to 18 parts of glycerol, 1 to 2 parts of sodium lauryl sulfate, 10 to 12 parts of propylene glycol, 0.5 to 1 part of ethylparaben, and 70 to 80 parts of purified water.

[0024] The present invention has the following technical effects: In the present invention, when dihydroartemisinin is loaded, sodium bicarbonate is added, a carbon dioxide supercritical extraction instrument is used, glycerol and n-butanol are used as a composite solvent, the transfer rate of dihydroartemisinin in polyethylene glycol reaches 94.37%, the loaded nano intermediate product has a small particle size, and the size is evenly distributed at about 50 nm, which effectively solves the technical problem of easy demulsification. The prepared emulsion preparation has uniform texture, dihydroartemisinin has excellent stability in the system, is not easy to decompose under long-term high temperature, high humidity and light conditions, has excellent emulsion stability, does not have the problems of stratification and sedimentation, and has excellent bioavailability. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] Figure 1 : Scanning electron microscope image of the intermediate prepared by the present invention. DETAILED DESCRIPTION

[0026] The present invention is described in detail below through examples. It is necessary to point out that the following examples are only used to further illustrate the present invention and cannot be understood as limiting the scope of protection of the present invention. Those skilled in the art can make some non-essential improvements and adjustments to the present invention based on the above-mentioned contents of the present invention.

[0027] Example 1 A highly stable dihydroartemisinin emulsion is prepared according to the following steps: Step 1: Preparation of intermediates (1) Polyethylene glycol 600 was heated to 28°C, and dihydroartemisinin was added under stirring at 65 rpm. After the addition was completed, stirring was continued for 15 minutes. Under the same stirring conditions, a sodium bicarbonate solution with a mass concentration of 5% was added, and stirring was continued for 35 minutes to form a mixed solution. The mass ratio of the polyethylene glycol 600, dihydroartemisinin and sodium bicarbonate solution was 100:16:6; (2) Add the mixed liquid into a supercritical carbon dioxide extractor, add a solvent consisting of glycerol and n-butanol, set the CO2 flow rate to 12 kg / h, the pressure to 18 MPa, the temperature to 40°C, and the operating time to 1.5 h. Then increase the pressure to 28 MPa and the temperature to 48°C and maintain for 40 min. After the end, collect the product and cool it to room temperature to obtain the intermediate. Step (ii) Preparation of emulsion matrix (1) According to weight, 9 parts of liquid paraffin, 5 parts of octadecyl alcohol, 7 parts of white vaseline, 5 parts of palm oil, and 6 parts of hydrogenated vegetable oil are mixed and heated to 80°C until they are molten to obtain an oil phase matrix; 15-18 parts of glycerin, 1.5 parts of sodium lauryl sulfate, 11 parts of propylene glycol, 0.8 parts of ethylparaben, and 75 parts of purified water are heated to 80°C and stirred to form a clear liquid to obtain an aqueous phase matrix; (2) The water phase matrix was kept at 80°C, and the oil phase matrix at the same temperature was added at 65 rm. After the addition was completed, stirring was continued for 12 min, and then the mixture was rapidly cooled to 38°C in an ice bath to obtain an emulsion matrix; Step (iii) Preparation of emulsion The emulsion matrix kept at 38° C. was added to the intermediate under stirring at 28 rpm. After the addition was completed, stirring was continued for 25 minutes, and then naturally cooled to room temperature to obtain an emulsion. The mass ratio of the emulsion matrix to the intermediate was 100:18.

[0028] The scanning electron microscope image of the intermediate product prepared in Example 1 is as follows Figure 1 As shown, it can be seen that the particle size distribution uniformity of the dihydroartemisinin intermediate prepared by the present invention is excellent, the particle size is basically distributed at about 50nm, the dispersion is good, and no agglomeration occurs.

[0029] Comparative Example 1 Compared with Example 1, low-concentration NaOH solution was used instead of sodium bicarbonate solution in Comparative Example 1 to ensure that the final emulsion pH was about 5.5. The remaining steps were the same as in Example 1.

[0030] The intermediate product prepared in this scheme has a wide particle size distribution, ranging from 100 to 170 nm, with a main distribution of 130 to 160 nm.

[0031] Comparative Example 2 Compared with Example 1, in Comparative Example 2, in the loading treatment step, an equal amount of propylene glycol is used to replace the n-butanol in the composite solvent to form a new composite solvent with glycerol, and the remaining steps are the same as those in Example 1.

[0032] The intermediate product prepared in this scheme has a wide particle size distribution, ranging from 140 to 210 nm, with 140 to 170 nm being the main distribution.

[0033] Blank control: In the process of preparing the intermediate, no sodium bicarbonate solution was added when preparing the mixed solution, and during loading, only glycerol was used as the solvent. The remaining steps were completely consistent with Example 1.

[0034] The particle size distribution and loading efficiency of the intermediates prepared in the blank control, Example 1, Comparative Example 1 and Comparative Example 2, wherein the loading efficiency of dihydroartemisinin is calculated by the transfer rate of dihydroartemisinin to polyethylene glycol during the preparation process, and the test method is as follows: The intermediate prepared in Example 1 was washed with ethanol, the supernatant was collected, and the content of dihydroartemisinin in the intermediate was determined by UC-vis absorption spectroscopy. Specifically, the supernatant was incubated in a 0.2% NaOH solution at 50°C for 30 minutes to convert dihydroartemisinin into an ultraviolet absorption compound, and the characteristic absorption spectrum at 290m was detected. The calculation formula is as follows: Transfer rate = (load content of dihydroartemisinin in polyethylene glycol ÷ total amount of added dihydroartemisinin) * 100%. The results are shown in Table 1.

[0035] Table 1:

[0036] It can be seen that the particle size of the intermediate prepared in the blank control group is relatively large, and the transfer loading of dihydroartemisinin in polyethylene glycol 600 is relatively low, and the intermediate affects the bioavailability of dihydroartemisinin. The particle size distribution of the dihydroartemisinin intermediate prepared in Example 1 is uniform, the average particle size is 49.27nm, and the transfer rate of dihydroartemisinin to polyethylene glycol is as high as 94.37%, while the particle sizes of the intermediates prepared in Comparative Examples 1 and 2 are relatively large, 147.34nm and 180.57nm, respectively, and the transfer rates of dihydroartemisinin also decrease to varying degrees, 62.73% and 79.68%, respectively.

[0037] Emulsion properties stability test: At room temperature, 10 g of each of the emulsions prepared in Example 1, Comparative Example 1 and Comparative Example 2 were taken and placed in 5 mL centrifuge tubes, respectively, and centrifuged at 2000, 4000, 6000, 8000 and 10000 rpm for 30 min. The samples were taken out to observe whether they were stratified or agglomerated. The test results are shown in Table 2.

[0038] Table 2:

[0039] It can be seen that the blank control group has a large particle size and the pH of the prepared emulsion is low. At a low pH, it is easier to break the emulsion and stratify, and the nanoemulsion cannot be formed. In the emulsion prepared in Example 1, under the action of high-speed centrifugation, the emulsion has excellent stability and does not have stratification, agglomeration, etc. In Comparative Examples 1 and 2, due to the large particle size of the intermediate product in the preparation, demulsification also occurred during the high-speed centrifugation process, resulting in obvious oil-water stratification in the emulsion.

[0040] Example 2 A highly stable dihydroartemisinin emulsion is prepared according to the following steps: Step 1: Preparation of intermediates (1) Polyethylene glycol 600 was heated to 35°C, and dihydroartemisinin was added under stirring at 60 rpm. After the addition was completed, stirring was continued for 20 minutes. Under the same stirring conditions, a sodium bicarbonate solution with a mass concentration of 5% was added, and stirring was continued for 30 minutes to form a mixed solution. The mass ratio of the polyethylene glycol 600, dihydroartemisinin and sodium bicarbonate solution was 100:15:5; (2) Add the mixed liquid into a carbon dioxide supercritical extractor, add a solvent consisting of glycerol and n-butanol, set the CO2 flow rate to 10 kg / h, the pressure to 15 MPa, the temperature to 35 °C, the operating time to 2 h, then increase the pressure to 30 MPa, increase the temperature to 45 °C, and continue to maintain for 60 min. After the end, collect the product and cool it to room temperature to obtain the intermediate product; Step (ii) Preparation of emulsion matrix (1) According to weight, take 8 parts of liquid paraffin, 3 parts of octadecyl alcohol, 6 parts of white vaseline, 5 parts of palm oil, and 5 parts of hydrogenated vegetable oil, mix them, and heat them to 75°C until they are molten to obtain an oil phase matrix; separately take 15 parts of glycerin, 1 part of sodium lauryl sulfate, 10 parts of propylene glycol, 0.5 parts of ethylparaben, and 70 parts of purified water, heat them to 75°C, and stir them until they become a clear liquid to obtain an aqueous phase matrix; (2) Keep the water phase matrix at 75°C, add the oil phase matrix at the same temperature at 70 rm, continue stirring for 15 min after the addition is complete, and quickly cool to 35°C in an ice bath to obtain an emulsion matrix; Step (iii) Preparation of emulsion The emulsion matrix kept at 35° C. was added to the intermediate under stirring at 25 rpm. After the addition was completed, stirring was continued for 30 minutes, and then naturally cooled to room temperature to obtain an emulsion. The mass ratio of the emulsion matrix to the intermediate was 100:15.

[0041] In the intermediate prepared in this example, the transfer rate of dihydroartemisinin was 93.92%, and the average particle size of the intermediate was 51.18 nm.

[0042] Example 3 A highly stable dihydroartemisinin emulsion is prepared according to the following steps: Step 1: Preparation of intermediates (1) Polyethylene glycol 600 was heated to 40°C, and dihydroartemisinin was added under stirring at 70 rpm. After the addition was completed, stirring was continued for 10 minutes. Under the same stirring conditions, a sodium bicarbonate solution with a mass concentration of 5% was added, and stirring was continued for 40 minutes to form a mixed solution. The mass ratio of the polyethylene glycol 600, dihydroartemisinin and sodium bicarbonate solution was 100:18:8; (2) Add the mixed liquid into a supercritical carbon dioxide extractor, add a solvent consisting of glycerol and n-butanol, set the CO2 flow rate to 15 kg / h, the pressure to 20 MPa, the temperature to 45 °C, the operating time to 1 h, then increase the pressure to 25 MPa, increase the temperature to 50 °C, and continue to maintain for 30 min. After the end, collect the product and cool it to room temperature to obtain the intermediate product; Step (ii) Preparation of emulsion matrix (1) According to weight, take 10 parts of liquid paraffin, 7 parts of octadecyl alcohol, 8 parts of white vaseline, 5 parts of palm oil, and 7 parts of hydrogenated vegetable oil, mix them, and heat them to 80°C until they are molten to obtain an oil phase matrix; separately take 18 parts of glycerin, 2 parts of sodium lauryl sulfate, 12 parts of propylene glycol, 1 part of ethylparaben, and 80 parts of purified water, heat them to 80°C, and stir them until they become a clear liquid to obtain an aqueous phase matrix; (2) Keep the water phase matrix at 80°C, add the oil phase matrix at the same temperature at 60 rm, continue stirring for 10 min after the addition is complete, and quickly cool to 40°C in an ice bath to obtain an emulsion matrix; Step (iii) Preparation of emulsion The emulsion matrix kept at 40° C. was added to the intermediate under stirring at 25 rpm. After the addition was completed, stirring was continued for 20 minutes, and then naturally cooled to room temperature to obtain an emulsion. The mass ratio of the emulsion matrix to the intermediate was 100:20.

[0043] In the intermediate prepared in this example, the transfer rate of dihydroartemisinin was 93.87%, and the average particle size of the intermediate was 50.42 nm.

[0044] Initially, the apparent properties of Examples 1-3 and the comparative examples were basically the same. According to the relevant provisions of the 2010 edition of the Chinese Pharmacopoeia on stability research, the test environment conditions of the stability test were as follows: high temperature (60°C), high humidity (relative humidity of 92.5%), and light treatment (4500Lux). After being placed in the above single environment for 24 months, the properties of the emulsion and the content of dihydroartemisinin were tested, and the test results are shown in Table 3.

[0045] Table 3:

[0046] As can be seen from the above table, the emulsions prepared in each embodiment of the present invention have excellent stability. After being placed under high temperature and high humidity conditions for 24 months, the properties are stable, no emulsion stratification occurs, and the content of dihydroartemisinin in the emulsion is stable and no decomposition occurs; in Comparative Example 1, due to the fact that no sodium bicarbonate was added when the intermediate was loaded and prepared, the emulsion was placed under a high temperature environment, and stratification occurred, and solid matter precipitation and agglomeration problems obviously occurred in the emulsion, and the content of dihydroartemisinin also decreased significantly under high humidity and illumination environments. In Comparative Example 2, glycerol + propylene glycol was used as a composite solvent when preparing the intermediate. Under high humidity and illumination environments, the emulsion did not stratify, but when placed at high temperature, the emulsion also had a small amount of solid matter precipitation, agglomeration and sedimentation problems, and the content of dihydroartemisinin effective components decreased significantly.

Claims

1. A highly stable dihydroartemisinin emulsion, characterized in that: The method is to prepare a mixed liquid of dihydroartemisinin, sodium bicarbonate and polyethylene glycol 600, and carry out load treatment in a carbon dioxide supercritical extractor with glycerol and n-butanol as a composite solvent to form an intermediate. Specifically, the CO2 flow rate is 10-15kg / h, the pressure is 15-20Mpa, and the temperature is 35°C. After running for 1-2h, the pressure is increased to 25-30Mpa, the temperature is increased to 45-50°C and maintained for 30-60min. After the end, the product is collected and cooled to room temperature to obtain an intermediate, and the intermediate is added to an emulsion matrix to form a nanoemulsion.

2. A highly stable dihydroartemisinin emulsion according to claim 1, characterized in that: The mass ratio of the mixed solution to the composite solvent is 100:30-40, and the mass ratio of glycerol to n-butanol in the composite solvent is 3:0.8-1.

3. A highly stable dihydroartemisinin emulsion according to claim 1 or 2, characterized in that: The mass percentage concentration of the sodium bicarbonate solution in the mixed solution is 5%, and the mass ratio of polyethylene glycol 600, dihydroartemisinin and the sodium bicarbonate solution is 100:15-18:5-8.

4. A highly stable dihydroartemisinin emulsion according to any one of claims 1 to 3, characterized in that: The emulsion matrix is ​​specifically prepared by keeping the water phase matrix at 75-80° C., adding the oil phase matrix at the same temperature to the water phase matrix under stirring at 60-70 rpm, continuing stirring for 10-15 minutes after the addition, and then cooling in an ice bath to obtain the emulsion matrix.

5. A highly stable dihydroartemisinin emulsion according to claim 4, characterized in that: The oil phase matrix is ​​prepared by mixing liquid paraffin, octadecyl alcohol, white vaseline, palm oil and hydrogenated vegetable oil, and the water phase matrix is ​​prepared by mixing glycerin, sodium lauryl sulfate, propylene glycol, ethyl hydroxybenzoate and purified water.

6. A highly stable dihydroartemisinin emulsion according to claim 5, characterized in that: In terms of weight parts, the oil phase matrix includes 8 to 10 parts of paraffin, 3 to 7 parts of octadecyl alcohol, 6 to 8 parts of white vaseline, 5 parts of palm oil, and 5 to 7 parts of hydrogenated vegetable oil; the aqueous phase matrix includes 15 to 18 parts of glycerol, 1 to 2 parts of sodium lauryl sulfate, 10 to 12 parts of propylene glycol, 0.5 to 1 part of ethylparaben, and 70 to 80 parts of purified water.

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