A highly stable dihydroartemisinin emulsion

Abstract

A highly stable dihydroartemisinin emulsion is prepared by mixing dihydroartemisinin, sodium bicarbonate and polyethylene glycol 600 to form a mixed solution. In a supercritical carbon dioxide extraction instrument, glycerol and n-butanol are used as a composite solvent for loading treatment to form an intermediate product. Specifically, the CO2 flow rate is 10-15 kg / h, the pressure is 15-20 Mpa, the temperature is 35 °C, and after running for 1-2 h, the pressure is increased to 25-30 Mpa, the temperature is raised to 45-50 °C and maintained for 30-60 min. After completion, the product is collected and allowed to cool to room temperature to obtain the intermediate product. The intermediate product is added to the emulsion matrix to form a nanoemulsion. The transfer rate of dihydroartemisinin in the intermediate product prepared by the present invention reaches 94.37%. The particle size of the loaded nano-intermediate product is evenly distributed around 50 nm. The prepared emulsion is uniform. Dihydroartemisinin has excellent stability in this system, is not easily decomposed under long-term high temperature, high humidity, light and other environments, has excellent emulsion property stability, does not have problems such as delamination and sedimentation, and has excellent bioavailability.

Description

[0001] This invention is a divisional application of the patent application with the application number 202411288104.7 and the invention title "A Dihydroartemisinin Nanodrug and Its Preparation Method". Technical Field

[0002] This invention relates to the technical field of drug preparation, and particularly to a highly stable dihydroartemisinin emulsion. Background Art

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

[0004] Nanosuspensions are directly prepared by pulverizing drugs in the presence of additives such as surfactants and water. They are suitable for administration through various routes including oral and injection to improve absorption or targeting. By selecting different additives, nanoparticles with different surface properties can be obtained. The advantages of nanodrugs are as follows: First, it can improve the oral absorption of poorly soluble drugs. Nanoparticles can increase the dissolution rate and solubility, enhance adhesion, form metastable crystalline or amorphous forms, and eliminate supersaturation caused by particle size differences. Second, it has the function of targeted and controlled drug release. Nanoparticles have the characteristics of long circulation, stealth and steric stability in vivo, which are beneficial for drug targeting. Third, it can be used as a special carrier for biological macromolecules. Improving the mucosal adhesion properties of nanoparticles can obviously help improve the effectiveness and prolong the action time. Therefore, preparing poorly soluble dihydroartemisinin into nanodrugs is beneficial to improving its solubility and thus its absorption and utilization rate. Summary of the Invention

[0005] The purpose of this invention is to provide a preparation method for the above dihydroartemisinin nanodrug, with high transfer and loading efficiency of dihydroartemisinin during the preparation process.

[0006] The purpose of this invention is to provide a dihydroartemisinin nanodrug, specifically a dihydroartemisinin nanoemulsion preparation, with excellent stability of dihydroartemisinin, not easily degraded by external interference, and improved bioavailability of the drug.

[0007] The purpose of this invention is achieved through the following technical solutions:

[0008] A preparation method of dihydroartemisinin nano-drug, characterized in that: it includes the preparation of an intermediate containing dihydroartemisinin, the preparation of an emulsion matrix, and the mixing of the intermediate and the emulsion matrix to prepare an emulsion. The preparation of the intermediate is to mix polyethylene glycol 600, dihydroartemisinin and sodium bicarbonate solution to form a mixed solution, place the mixed solution in a carbon dioxide supercritical extraction instrument, add a composite solvent composed of glycerol and n-butanol, and pass carbon dioxide for loading treatment to make the intermediate.

[0009] Further, 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 sodium bicarbonate solution is 100:15-18:5-8. The sodium bicarbonate solution is prepared by taking 95 mL of purified water, adding 5 g of sodium bicarbonate, and stirring and dissolving.

[0010] Further, during the loading treatment process, the CO 2 flow rate is 10-15 kg / h, the pressure is 15-20 Mpa, the temperature is 35 °C, after running for 1-2 h, the pressure is raised to 25-30 Mpa, the temperature is raised to 45-50 °C and maintained for 30-60 min. After completion, the product is collected and left to room temperature to obtain the intermediate. The mass ratio of the mixed solution 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.

[0011] Further, the preparation of the emulsion matrix is to mix liquid paraffin, stearyl alcohol, white petrolatum, palm oil, and hydrogenated vegetable oil to form an oil phase matrix, and mix glycerol, sodium lauryl sulfate, propylene glycol, ethylparaben, and purified water to form an aqueous phase matrix. The oil phase matrix is added to the aqueous phase matrix and stirred to obtain the emulsion matrix. By weight, in the oil phase matrix, there are 8-10 parts of paraffin, 3-7 parts of stearyl alcohol, 6-8 parts of white petrolatum, 5 parts of palm oil, and 5-7 parts of hydrogenated vegetable oil. In the aqueous phase matrix, there are 15-18 parts of glycerol, 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.

[0012] Further, the addition of the oil phase matrix to the aqueous phase matrix is specifically to keep the aqueous phase matrix at 75-80 °C, under stirring at 60-70 rpm, add the oil phase matrix at the same temperature to the aqueous phase matrix. After the addition is completed, continue stirring for 10-15 min, and then cool in an ice bath to obtain the emulsion matrix.

[0013] Further, the preparation of the emulsion is to keep the emulsion matrix at 35-40 °C, and add the intermediate while stirring at a rate of 25-30 rpm. After the addition is completed, continue stirring for 20-30 min, and cool to room temperature to obtain the emulsion. The mass ratio of the emulsion matrix to the intermediate is 100:15-20.

[0014] Specifically, a method for a dihydroartemisinin nano-drug, characterized by comprising the following steps:

[0015] Step (I) Prepare an intermediate

[0016] (1) Take polyethylene glycol 600 and heat it to 35 - 40°C. Under stirring at 60 - 70 rpm, add dihydroartemisinin. After the addition, continue stirring for 10 - 20 min. Under the same stirring conditions, add a sodium bicarbonate solution with a mass concentration of 5%, and continue stirring for 30 - 40 min to form a mixed solution. The mass ratio of polyethylene glycol 600, dihydroartemisinin, and sodium bicarbonate solution is 100:15 - 18:5 - 8;

[0017] (2) Add the mixed solution into a supercritical carbon dioxide extraction instrument, add a cosolvent composed of glycerol and n-butanol, set the CO 2 flow rate to 10 - 15 kg / h, the pressure to 15 - 20 Mpa, the temperature to 35 - 45°C, and the running time to 1 - 2 h. Then raise the pressure to 25 - 30 Mpa and the temperature to 45 - 50°C, and continue to maintain for 30 - 60 min. After completion, collect the product and cool it to room temperature to obtain the intermediate;

[0018] Step (II) Prepare an emulsion matrix

[0019] (1) By weight, take 8 - 10 parts of liquid paraffin, 3 - 7 parts of stearyl alcohol, 6 - 8 parts of white petrolatum, 5 parts of palm oil, and 5 - 7 parts of hydrogenated vegetable oil, and mix them. Heat to 75 - 80°C until in a molten state to obtain an oil-phase matrix; separately take 15 - 18 parts of glycerol, 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 to 75 - 80°C, and stir into a clear liquid to obtain a water-phase matrix;

[0020] (2) Keep the water-phase matrix at 75 - 80°C, add the oil-phase matrix at the same temperature under stirring at 60 - 70 rpm. After the addition, continue stirring for 10 - 15 min, and quickly cool to 35 - 40°C using an ice bath to obtain the emulsion matrix;

[0021] Step (III) Prepare an emulsion

[0022] Add the above emulsion matrix maintained at 35 - 40°C to the intermediate under stirring at 25 - 30 rpm. After the addition, continue stirring for 20 - 30 min, and then naturally cool to room temperature to obtain the emulsion. The mass ratio of the emulsion matrix to the intermediate is 100:15 - 20.

[0023] A highly stable dihydroartemisinin nanoemulsion, characterized in that: a mixed solution is prepared from dihydroartemisinin, sodium bicarbonate and polyethylene glycol 600, and in a carbon dioxide supercritical extraction instrument, glycerol and n-butanol are used as a composite solvent for loading treatment to form an intermediate product. Specifically, the CO 2 flow rate is 10 - 15 kg / h, the pressure is 15 - 20 Mpa, the temperature is 35 °C, after running for 1 - 2 h, the pressure is increased to 25 - 30 Mpa, the temperature is raised to 45 - 50 °C and maintained for 30 - 60 min. After completion, the product is collected and allowed to cool to room temperature to obtain the intermediate product. The intermediate product is added to the emulsion matrix to form a nanoemulsion.

[0024] In order to improve the biocompatibility and stability of nanoparticles, the present invention uses polyethylene glycol to load nanoparticles. However, it is difficult for dihydroartemisinin to be transferred and loaded into polyethylene glycol, and the loading efficiency is poor. It is difficult for polyethylene glycol molecules to uniformly wrap dihydroartemisinin, and the particle size of the nano-intermediate product prepared by loading is large and the size uniformity is poor, which affects the absorption and utilization of the drug, and it is easy to occur demulsification when wrapping the emulsion matrix. If the particle size is too small, the problem of agglomeration is likely to occur. In addition, due to the presence of unstable groups (endoperoxide bond) and the presence of an epimeric center in dihydroartemisinin, its own stability is poor, and dihydroartemisinin will decompose during long-term storage under high temperature, high humidity and strong light irradiation.

[0025] In the present invention, dihydroartemisinin, polyethylene glycol 600 and sodium bicarbonate are mixed into a solution, and loading is carried out in a supercritical extraction instrument. During the loading process, glycerol and n-butanol are added, which act as entrainers, and sodium bicarbonate plays a regulating role, further promoting the wrapping 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 product has a smaller particle size and a uniform size distribution, inhibiting the agglomeration of dihydroartemisinin. In addition, the addition of sodium bicarbonate adjusts the pH of the final emulsion to be maintained at about 5.5 for a long time, improving the stability of dihydroartemisinin and inhibiting the degradation of dihydroartemisinin. On the other hand, the bicarbonate loaded in the system slowly decomposes and releases carbon dioxide during the long process. With the cooperation of the emulsion matrix, it effectively isolates dihydroartemisinin from being affected by oxygen and light in the air, further ensuring the stability of dihydroartemisinin.

[0026] During the process of wrapping nanostructured intermediates with an emulsion matrix, demulsification easily occurs, resulting in the inability of the emulsion matrix to form a complete wrap around the intermediates, the failure to form nanoemulsions, the easy decomposition of the active ingredient dihydroartemisinin, and the reduction of the bioavailability of dihydroartemisinin. In the present invention, the prepared intermediates have a small particle size and simultaneously carry bicarbonate ions inside, which adjusts the pH of the emulsion, effectively inhibits the occurrence of demulsification of the intermediates, thus forming uniform nanoemulsions, effectively inhibits the decomposition of dihydroartemisinin caused by external environmental factors, and improves the bioavailability of dihydroartemisinin in the emulsion.

[0027] Further, the nanoemulsion is obtained by heating the emulsion matrix to 35 - 40 °C, adding the intermediate while stirring at a rate of 25 - 30 rpm, continuing to stir for 20 - 30 min after the addition is complete, and then cooling to room temperature. The mass ratio of the emulsion matrix to the intermediate is 100:15 - 20.

[0028] Further, 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.

[0029] Further, the mass percentage concentration of the sodium bicarbonate solution in the mixed solution is 5%, and the mass ratio of polyethylene glycol 600, dihydroartemisinin to the sodium bicarbonate solution is 100:15 - 18:5 - 8. The sodium bicarbonate solution is prepared by adding 5 g of sodium bicarbonate to 95 mL of purified water and stirring until dissolved.

[0030] Further, the emulsion matrix is obtained by heating the aqueous matrix to 75 - 80 °C, adding the oil-phase matrix at the same temperature while stirring at 60 - 70 rpm, continuing to stir for 10 - 15 min after the addition is complete, and then cooling in an ice bath.

[0031] Further, the oil-phase matrix is made by mixing liquid paraffin, stearyl alcohol, white petrolatum, palm oil, and hydrogenated vegetable oil, and the aqueous matrix is made by mixing glycerol, sodium lauryl sulfate, propylene glycol, ethylparaben, and purified water.

[0032] Further, by weight, in the oil-phase matrix, there are 8 - 10 parts of paraffin, 3 - 7 parts of stearyl alcohol, 6 - 8 parts of white petrolatum, 5 parts of palm oil, 5 - 7 parts of hydrogenated vegetable oil; in the aqueous matrix, there are 15 - 18 parts of glycerol, 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.

[0033] The present invention has the following technical effects:

[0034] In the present invention, when loading dihydroartemisinin, sodium bicarbonate is added, and a carbon dioxide supercritical extraction instrument is used. With glycerol and n-butanol as the composite solvent, the transfer rate of dihydroartemisinin in polyethylene glycol reaches 94.37%. The obtained nano intermediate product has a small particle size, and the size is uniformly distributed around 50 nm, effectively solving the technical problem of easy demulsification. The prepared emulsion preparation has a uniform texture. Dihydroartemisinin has excellent stability in this system, is not easily decomposed under environments such as long-term high temperature, high humidity, and light, has excellent stability in the emulsion properties, does not have problems such as delamination and sedimentation, and has excellent bioavailability. Description of the Drawings

[0035] Figure 1 : Scanning electron micrograph of the intermediate prepared by the present invention. Detailed Embodiments

[0036] The present invention will be specifically described below through examples. It is necessary to point out here that the following examples are only used to further illustrate the present invention and cannot be understood as limiting the protection scope of the present invention. Those skilled in the art can make some non-essential improvements and adjustments to the present invention according to the above content of the present invention.

[0037] Example 1

[0038] A highly stable dihydroartemisinin emulsion is prepared according to the following steps:

[0039] Step (I) Preparation of the intermediate

[0040] (1) Take polyethylene glycol 600 and heat it to 28 °C. Under stirring at 65 rpm, add dihydroartemisinin. After the addition is complete, continue stirring for 15 min. Under the same stirring conditions, add a sodium bicarbonate solution with a mass concentration of 5%, and continue stirring for 35 min to form a mixed solution. The mass ratio of polyethylene glycol 600, dihydroartemisinin, and the sodium bicarbonate solution is 100:16:6;

[0041] (2) Add the mixed solution into a carbon dioxide supercritical extraction instrument, add the composite solvent composed of glycerol and n-butanol, set the CO 2 flow rate to 12 kg / h, the pressure to 18 Mpa, the temperature to 40 °C, and the running time to 1.5 h. Then raise the pressure to 28 Mpa and the temperature to 48 °C, and continue to maintain for 40 min. After completion, collect the product and cool it to room temperature to obtain the intermediate;

[0042] Step (II) Preparation of the emulsion matrix

[0043] (1) By weight, take 9 parts of liquid paraffin, 5 parts of stearyl alcohol, 7 parts of white petrolatum, 5 parts of palm oil, and 6 parts of hydrogenated vegetable oil, mix them, and heat to 80 °C until in a molten state to obtain an oil-phase matrix; separately take 15 - 18 parts of glycerol, 1.5 parts of sodium lauryl sulfate, 11 parts of propylene glycol, 0.8 parts of ethylparaben, and 75 parts of purified water, heat to 80 °C, and stir into a clear liquid to obtain an aqueous-phase matrix;

[0044] (2) Keep the aqueous-phase matrix at 80 °C, add the oil-phase matrix at the same temperature under 65 rpm, continue to stir for 12 min after adding, and quickly cool to 38 °C using an ice bath to obtain an emulsion matrix;

[0045] Step (III) Preparation of emulsion

[0046] Add the above-mentioned emulsion matrix kept at 38 °C to the intermediate product under stirring at 28 rpm. After adding, continue to stir for 25 min, and then naturally cool to room temperature to obtain the emulsion. The mass ratio of the emulsion matrix to the intermediate product is 100:18.

[0047] The SEM image of the intermediate product prepared in Example 1 is as Figure 1 shown. It can be seen that the particle size distribution of the artemisinin diphosphate intermediate product prepared by the present invention is excellent in uniformity, the particle size is basically distributed around 50 nm, the dispersion is good, and there is no agglomeration phenomenon.

[0048] Comparative Example 1

[0049] Compared with Example 1, in Comparative Example 1, a low-concentration NaOH solution is used instead of sodium bicarbonate solution for preparation to ensure that the final pH of the emulsion is about 5.5. The remaining steps are the same as those in Example 1.

[0050] The particle size distribution of the intermediate product prepared by this scheme is relatively wide, distributed between 100 - 170 nm, mainly distributed in the range of 130 - 160 nm.

[0051] Comparative Example 2

[0052] Compared with Example 1, in Comparative Example 2, during the loading treatment step, an equal amount of propylene glycol is used instead of n-butanol in the composite solvent to form a new composite solvent with glycerol. The remaining steps are the same as those in Example 1.

[0053] The particle size distribution of the intermediate product prepared by this scheme is wide, distributed between 140 - 210 nm, mainly distributed in the range of 140 - 170 nm.

[0054] Blank control:

[0055] During the preparation of the intermediate product, when preparing the mixed solution, sodium bicarbonate solution is not added. During loading, only a single glycerol is used as the solvent, and the remaining steps are exactly the same as those in Example 1.

[0056] The particle size distribution and loading efficiency of the intermediates prepared from the blank control, Example 1, Comparative Example 1, and Comparative Example 2. The loading efficiency of dihydroartemisinin was calculated as the transfer rate of dihydroartemisinin transferred and loaded into polyethylene glycol during the preparation process. The test method is as follows:

[0057] Take the intermediate prepared in Example 1, wash it with ethanol, collect the supernatant, and determine the content of dihydroartemisinin in the intermediate by UC-vis absorption spectroscopy technology. Specifically, incubate the supernatant with a 0.2% NaOH solution at 50 °C for 30 min to convert dihydroartemisinin into an ultraviolet-absorbing compound, and detect the characteristic absorption spectrum at 290 nm. The calculation formula is as follows:

[0058] Transfer rate = (loading content of dihydroartemisinin in polyethylene glycol ÷ total amount of dihydroartemisinin added) * 100%. The results are shown in Table 1.

[0059] Table 1:

[0060]

[0061] It can be seen that the intermediate prepared in the blank control group has a larger particle size, and the transfer and loading amount of dihydroartemisinin in polyethylene glycol 600 is relatively low, which affects the bioavailability of dihydroartemisinin. The particle size distribution of the dihydroartemisinin intermediate prepared in Example 1 is uniform, with an average particle size of 49.27 nm, and the transfer rate of dihydroartemisinin transferred and loaded into polyethylene glycol is as high as 94.37%. However, the particle sizes of the intermediates prepared in Comparative Example 1 and Comparative Example 2 are relatively large, 147.34 nm and 180.57 nm respectively, and the transfer rates of dihydroartemisinin also show varying degrees of decline, 62.73% and 79.68% respectively.

[0062] Emulsion property stability test:

[0063] At room temperature, take 10 g of each emulsion prepared in Example 1, Comparative Example 1, and Comparative Example 2, respectively, and put them into 5 mL centrifuge tubes. Place them in a centrifuge and centrifuge at 2000, 4000, 6000, 8000, 10000 rpm for 30 min. Take them out and observe whether the samples are stratified or agglomerated. The test results are shown in Table 2.

[0064] Table 2:

[0065]

[0066] It can be seen that the particle size of the blank control group is large, and the pH of the prepared emulsion is low. At a lower pH, it is easier to cause demulsification and stratification, and it is impossible to form a nanoemulsion. In the emulsion prepared in Example 1, under the action of high-speed centrifugation, the emulsion has excellent stability, and no stratification, agglomeration and other phenomena occur. In Comparative Example 1 and Comparative Example 2, due to the large particle size of the prepared intermediate product, demulsification also occurred during high-speed centrifugation, resulting in obvious oil-water stratification in the emulsion.

[0067] Example 2

[0068] A highly stable dihydroartemisinin emulsion is prepared according to the following steps:

[0069] Step (I) Preparation of intermediate

[0070] (1) Take polyethylene glycol 600 and heat it to 35 °C. Under stirring at 60 rpm, add dihydroartemisinin. After the addition is complete, continue stirring for 20 min. Under the same stirring conditions, add a sodium bicarbonate solution with a mass concentration of 5%, and continue stirring for 30 min to form a mixed solution. The mass ratio of polyethylene glycol 600, dihydroartemisinin and sodium bicarbonate solution is 100:15:5;

[0071] (2) Add the mixed solution into a carbon dioxide supercritical extraction instrument, add a cosolvent composed of glycerol and n-butanol, set the CO 2 flow rate to 10 kg / h, the pressure to 15 Mpa, the temperature to 35 °C, and the running time to 2 h. Then raise the pressure to 30 Mpa and the temperature to 45 °C, and continue to maintain for 60 min. After completion, collect the product and cool it to room temperature to obtain the intermediate;

[0072] Step (II) Preparation of emulsion matrix

[0073] (1) By weight, take 8 parts of liquid paraffin, 3 parts of stearyl alcohol, 6 parts of white petrolatum, 5 parts of palm oil, and 5 parts of hydrogenated vegetable oil, and heat them to 75 °C until they are in a molten state to obtain an oil-phase matrix; separately take 15 parts of glycerol, 1 part of sodium lauryl sulfate, 10 parts of propylene glycol, 0.5 part of ethylparaben, and 70 parts of purified water, heat them to 75 °C, and stir to form a clear liquid to obtain a water-phase matrix;

[0074] (2) Keep the water-phase matrix at 75 °C, add the oil-phase matrix at the same temperature under 70 rm, continue stirring for 15 min after the addition is complete, and quickly cool it to 35 °C using an ice bath to obtain the emulsion matrix;

[0075] Step (III) Preparation of emulsion

[0076] Add the above emulsion matrix maintained at 35°C to the intermediate product under stirring at 25 rpm. After the addition is complete, continue stirring for 30 min, and then naturally cool to room temperature to obtain the emulsion. The mass ratio of the emulsion matrix to the intermediate product is 100:15.

[0077] In the intermediate product prepared in this example, the transfer rate of dihydroartemisinin is 93.92%, and the average particle size of the intermediate product is 51.18 nm.

[0078] Example 3

[0079] A highly stable dihydroartemisinin emulsion is prepared according to the following steps:

[0080] Step (I) Prepare the intermediate product

[0081] (1) Take polyethylene glycol 600 and heat it to 40°C. Under stirring at 70 rpm, add dihydroartemisinin. After the addition is complete, continue stirring for 10 min. Under the same stirring conditions, add a sodium bicarbonate solution with a mass concentration of 5%, and continue stirring for 40 min to form a mixed solution. The mass ratio of polyethylene glycol 600, dihydroartemisinin, and sodium bicarbonate solution is 100:18:8;

[0082] (2) Add the mixed solution to a carbon dioxide supercritical extraction instrument, add a cosolvent composed of glycerol and n-butanol, set the CO 2 flow rate to 15 kg / h, the pressure to 20 Mpa, the temperature to 45°C, and the running time to 1 h. Then raise the pressure to 25 Mpa and the temperature to 50°C, and continue to maintain for 30 min. After completion, collect the product and cool it to room temperature to obtain the intermediate product;

[0083] Step (II) Prepare the emulsion matrix

[0084] (1) By weight, take 10 parts of liquid paraffin, 7 parts of stearyl alcohol, 8 parts of white petrolatum, 5 parts of palm oil, and 7 parts of hydrogenated vegetable oil, and mix them and heat to 80°C until in a molten state to obtain an oil-phase matrix; separately take 18 parts of glycerol, 2 parts of sodium lauryl sulfate, 12 parts of propylene glycol, 1 part of ethylparaben, and 80 parts of purified water, heat to 80°C, and stir into a clear liquid to obtain an aqueous-phase matrix;

[0085] (2) Keep the aqueous-phase matrix at 80°C, add the oil-phase matrix at the same temperature under stirring at 60 rpm. After the addition is complete, continue stirring for 10 min, and quickly cool to 40°C using an ice bath to obtain the emulsion matrix;

[0086] Step (III) Prepare the emulsion

[0087] Add the above emulsion matrix maintained at 40°C to the intermediate product under stirring at 25 rpm. After the addition is complete, continue stirring for 20 min, and then naturally cool to room temperature to obtain the emulsion. The mass ratio of the emulsion matrix to the intermediate product is 100:20.

[0088] In the intermediate product prepared in this example, the transfer rate of dihydroartemisinin was 93.87%, and the average particle size of the intermediate product was 50.42 nm.

[0089] Initially, the apparent properties of Examples 1-3 and each comparative example were basically the same. According to the relevant regulations of the stability study in the Chinese Pharmacopoeia 2010 Edition, the test environmental conditions for the stability test were as follows: high temperature (60°C), high humidity (relative humidity of 92.5%), and light treatment (4500 Lux). Place in the above single environment for 24 months, and then detect the emulsion properties and the content of dihydroartemisinin. The test results are shown in Table 3.

[0090] Table 3:

[0091]

[0092] As can be seen from the above table, the emulsions prepared in each example of the present invention have excellent stability. After being placed at high temperature and high humidity for 24 months, the properties are stable, and no emulsion layering occurs. Moreover, the content of dihydroartemisinin in the emulsion is stable and no decomposition occurs. In Comparative Example 1, since sodium bicarbonate was not added during the preparation of the intermediate product for loading, during the placement process at high temperature, the emulsion showed a layering phenomenon, and obvious problems of solid precipitation and agglomeration occurred in the emulsion. The content of dihydroartemisinin also decreased significantly under high humidity and light environments. In Comparative Example 2, glycerol + propylene glycol was used as the composite solvent during the preparation of the intermediate product. Under high humidity and light environments, the emulsion did not show layering, but during high temperature placement, a small amount of solid precipitation, agglomeration and sedimentation problems also occurred in the emulsion, and the content of the effective component of dihydroartemisinin decreased significantly.

Claims

1. A highly stable dihydroartemisinin emulsion, characterized in that: The invention discloses a method for preparing a mixed liquid of dihydroartemisinin, sodium bicarbonate and polyethylene glycol 600, and carrying out a load treatment in a carbon dioxide supercritical extractor with glycerol and n-butanol as a composite solvent to form an intermediate product. Specifically, the CO2 flow rate is 10-15 kg / h, the pressure is 15-20 MPa, and the temperature is 35°C. After running for 1-2 hours, the pressure is increased to 25-30 MPa, and the temperature is increased to 45-50°C and maintained for 30-60 minutes. After the end, the product is collected and cooled to room temperature to obtain an intermediate product. The intermediate product is added into an emulsion matrix to form a nanoemulsion. The oil phase matrix in the emulsion matrix is ​​a mixture of liquid paraffin, octadecyl alcohol, white vaseline, palm oil and hydrogenated vegetable oil, and the water phase matrix in the emulsion matrix is ​​a mixture of glycerol, sodium lauryl sulfate, propylene glycol, ethylparaben and purified water.

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 claim 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: 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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