Dihydroartemisinic acid inclusion compound as well as preparation method and application thereof

Abstract

The invention relates to a dihydroartemisinic acid inclusion compound as well as a preparation method and application thereof. The dihydroarteannuic acid clathrate compound comprises dihydroarteannuic acid and a cyclodextrin compound wrapping the dihydroarteannuic acid. The cyclodextrin compound comprises cyclodextrin and / or a cyclodextrin derivative. According to the invention, the inclusion effect of the cyclodextrin compound on the dihydroarteannuic acid is utilized, so that dihydroarteannuic acid molecules are embedded in the tubular structure of the cyclodextrin compound, and the water solubility of the dihydroarteannuic acid is greatly improved.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical chemistry, and particularly relates to a dihydroartemisinic acid inclusion compound and a preparation method and application thereof. Background Art

[0002] Dihydroartemisinic acid is an important precursor and derivative of artemisinin compounds. Its chemical structure belongs to the sesquiterpene lactone class and is the product of hydrogenation reduction of artemisinic acid extracted from the Asteraceae plant Artemisia annua. Dihydroartemisinic acid, which contains a lactone ring and a ketone group in its chemical structure, has antimalarial effects. Studies have shown that it can interfere with the respiratory chain of Plasmodium, releasing reactive oxygen species within the parasite, thereby producing a bactericidal effect against the parasite. Furthermore, dihydroartemisinic acid also exhibits anti-inflammatory, anti-tumor, and antiviral effects, and has promising application prospects in related fields.

[0003] However, because the molecular structure of dihydroartemisinic acid is mainly composed of a hydrophobic sesquiterpene lactone skeleton, its solubility in aqueous environments is extremely low, which directly restricts its development and application in pharmaceutical preparations. On the one hand, insufficient water solubility will significantly reduce the oral bioavailability of the drug, making it impossible to form an effective blood drug concentration in the body and difficult to exert its efficacy; on the other hand, for injectable preparations, low water solubility may cause the drug to precipitate in the solvent, causing safety risks such as vascular embolism, and it is impossible to quickly take effect through intravenous administration. In addition, in local administration, poor water solubility will hinder the drug from passing through the biological membrane, reducing the drug concentration in the local tissue and affecting the therapeutic effect.

[0004] CN119191971A discloses artemisinic acid derivatives, including water-soluble organic salts formed by the reaction of artemisinic acid or dihydroartemisinic acid with a small alkaline organic compound, water-soluble complexes formed by the reaction of artemisinic acid or dihydroartemisinic acid with a small peptide, or water-soluble salts formed by the reaction of artemisinic acid or dihydroartemisinic acid with an alkaline metal compound. The artemisinic acid derivatives provided by this invention address the problem of artemisinic acid and dihydroartemisinic acid being poorly soluble in water.

[0005] However, in the prior art, there are few reports on encapsulating dihydroartemisinic acid to form a dihydroartemisinic acid inclusion complex, thereby improving the water solubility of dihydroartemisinic acid so as to better exert the efficacy of dihydroartemisinic acid. Summary of the Invention

[0006] To address the shortcomings of the prior art, the present invention provides a dihydroartemisinic acid inclusion compound, its preparation method, and its application. This dihydroartemisinic acid inclusion compound enhances the water solubility of dihydroartemisinic acid through the inclusion complexation of dihydroartemisinic acid with a cyclodextrin compound. The inclusion compound can be developed into a variety of solid and liquid dosage forms suitable for clinical use.

[0007] In order to achieve the purpose of the invention, the present invention adopts the following technical solutions:

[0008] In a first aspect, the present application provides a dihydroartemisinic acid inclusion compound, which comprises dihydroartemisinic acid and a cyclodextrin compound wrapping the dihydroartemisinic acid.

[0009] The cyclodextrin compound comprises cyclodextrin and / or cyclodextrin derivative.

[0010] The present application utilizes the inclusion effect of cyclodextrin compound on dihydroartemisinic acid to embed dihydroartemisinic acid molecules in the tubular structure of cyclodextrin compound, thereby significantly improving the water solubility of dihydroartemisinic acid.

[0011] Preferably, the cyclodextrin comprises β-cyclodextrin and / or γ-cyclodextrin.

[0012] Preferably, the cyclodextrin derivative comprises hydroxypropyl-β-cyclodextrin and / or sulfobutyl-β-cyclodextrin sodium.

[0013] Preferably, the average degree of substitution of the hydroxypropyl-β-cyclodextrin is 4.0-9.0, for example, it can be 4.0, 5.0, 6.0, 7.0, 8.0, 9.0, etc.

[0014] Preferably, the average degree of substitution of the sulfobutyl-β-cyclodextrin sodium is 6.2-6.9, for example, it can be 6.2, 6.4, 6.6, 6.8, 6.9, etc.

[0015] Preferably, the cyclodextrin compound comprises hydroxypropyl-β-cyclodextrin and sulfobutyl-β-cyclodextrin sodium.

[0016] Hydroxypropyl-β-cyclodextrin is a β-cyclodextrin whose hydroxyl groups are replaced by hydroxypropyl groups, and sulfobutyl-β-cyclodextrin sodium is a β-cyclodextrin whose 2,3,6-hydroxyl groups are replaced by sulfobutyl sodium groups. The present application creatively found that hydroxypropyl-β-cyclodextrin and sulfobutyl-β-cyclodextrin sodium together as an inclusion agent for dihydroartemisinic acid can significantly improve the solubility of dihydroartemisinic acid, and hydroxypropyl-β-cyclodextrin and sulfobutyl-β-cyclodextrin sodium have a significant synergistic effect in improving the solubility of dihydroartemisinic acid.

[0017] Preferably, the molar ratio of hydroxypropyl-β-cyclodextrin to sulfobutyl-β-cyclodextrin sodium is 1:(6-10), for example, it can be 1:6, 1:6.5, 1:7, 1:7.5, 1:8, 1:8.5, 1:9, 1:9.5, 1:10, etc.

[0018] Based on the inclusion effect of hydroxypropyl-β-cyclodextrin and sulfobutyl-β-cyclodextrin sodium on dihydroartemisinic acid, when they are compounded in the above molar ratio, the inclusion effect on dihydroartemisinic acid can be further improved, and the solubility of dihydroartemisinic acid can be improved.

[0019] Preferably, the molar ratio of dihydroartemisinic acid to cyclodextrin compounds is 1:(6-12), for example, it can be 1:6, 1:6.5, 1:7, 1:7.5, 1:8, 1:8.5, 1:9, 1:9.5, 1:10, 1:10.5, 1:11, 1:11.5, 1:12, etc.

[0020] In the present invention, the molar ratio of dihydroartemisinic acid to cyclodextrin compounds is controlled at 1:(6-12), which can further enhance the inclusion effect of cyclodextrin compounds on dihydroartemisinic acid and improve the solubility of dihydroartemisinic acid.

[0021] The structural diagram of the dihydroartemisinic acid inclusion compound of the present invention is shown in FIG. Figure 1 As shown, hydroxypropyl and sodium sulfobutyl groups independently replace the hydroxyl groups at C2, C3, and C6 of cyclodextrin, forming hydroxypropyl-β-cyclodextrin and sodium sulfobutyl-β-cyclodextrin, respectively. The barrel-shaped cyclodextrin derivatives (hydroxypropyl-β-cyclodextrin and sodium sulfobutyl-β-cyclodextrin) encapsulate dihydroartemisinic acid, with the molar ratio of dihydroartemisinic acid to cyclodextrin being 1:(6-12).

[0022] In a second aspect, the present invention provides a method for preparing the dihydroartemisinic acid inclusion compound according to the first aspect, the preparation method comprising:

[0023] The dihydroartemisinic acid and the cyclodextrin compound are mixed and stirred in a solvent, and then the solvent is removed by drying to obtain a dihydroartemisinic acid inclusion compound.

[0024] Preferably, the solvent includes any one of water, ethanol or acetone, or a combination of at least two of them.

[0025] Preferably, the ratio of the total mass of the cyclodextrin compound and dihydroartemisinic acid to the volume of the solvent is 1:(10-90) g / mL, for example, it can be 1:10 g / mL, 1:20 g / mL, 1:30 g / mL, 1:40 g / mL, 1:50 g / mL, 1:60 g / mL, 1:70 g / mL, 1:80 g / mL, 1:90 g / mL, etc.

[0026] Preferably, the mixing and stirring process further includes adding a pH adjuster to adjust the pH value of the solution to 6.5-8, for example, 6.5, 6.7, 6.9, 7.1, 7.3, 7.5, 7.7, 8, etc.

[0027] In the present invention, during the mixing and stirring of dihydroartemisinic acid and cyclodextrin compounds, the pH value of the solution is adjusted to 6.5-8, which can further improve the solubility of the prepared dihydroartemisinic acid inclusion complex.

[0028] Preferably, the pH adjuster comprises hydrochloric acid.

[0029] Preferably, the temperature of the mixing and stirring is 20-70℃, and the time of the mixing and stirring is 5-20h.

[0030] Preferably, the rotating speed of the mixing and stirring is 500-6000rpm.

[0031] Specific point values in 20-70℃ can be selected as 20℃, 30℃, 40℃, 50℃, 60℃, 70℃, etc., specific point values in 5-20h can be selected as 5h, 10h, 15h, 20h, etc., and specific point values in 500-6000rpm can be selected as 500rpm, 1000rpm, 2000rpm, 3000rpm, 4000rpm, 5000rpm, 6000rpm, etc.

[0032] Preferably, the drying method comprises spray drying, freeze vacuum drying or vacuum rotary thin film concentration drying.

[0033] In a third aspect, the present application provides a pharmaceutical preparation comprising the dihydroartemisinic acid inclusion compound of the first aspect.

[0034] Preferably, the pharmaceutical preparation further comprises a pharmaceutically acceptable excipient.

[0035] Preferably, the pharmaceutically acceptable excipient comprises any one or a combination of at least two of diluent, excipient, filler, binder, wetting agent or disintegrant.

[0036] Preferably, the dosage form of the pharmaceutical preparation comprises tablet, capsule, patch, oral liquid, gel, cream, soluble microneedle or injection.

[0037] The numerical range of the present application includes not only the point values listed above, but also any point values between the above numerical ranges that are not listed, and the present application does not exhaustively list the specific point values included in the range for the sake of brevity and simplicity.

[0038] Compared with the prior art, the present application has the following beneficial effects:

[0039] The present application significantly improves the water solubility of dihydroartemisinic acid by the inclusion of dihydroartemisinic acid by cyclodextrin compounds, embedding dihydroartemisinic acid molecules in the tubular structure of cyclodextrin compounds.

[0040] Furthermore, hydroxypropyl-β-cyclodextrin and sodium sulfobutyl-β-cyclodextrin are used together as inclusion agents to include dihydroartemisinic acid, which can significantly improve the solubility of dihydroartemisinic acid. Hydroxypropyl-β-cyclodextrin and sodium sulfobutyl-β-cyclodextrin have a significant synergistic effect in improving the solubility of dihydroartemisinic acid. In addition, based on the inclusion effect of hydroxypropyl-β-cyclodextrin and sodium sulfobutyl-β-cyclodextrin on dihydroartemisinic acid, when the molar ratio of hydroxypropyl-β-cyclodextrin to sodium sulfobutyl-β-cyclodextrin is controlled at 1:(6-10), the inclusion effect of dihydroartemisinic acid can be further enhanced, thereby improving the solubility of dihydroartemisinic acid.

[0041] Furthermore, controlling the molar ratio of dihydroartemisinic acid to cyclodextrin compounds at 1:(6-12) can further enhance the inclusion effect of cyclodextrin compounds on dihydroartemisinic acid and improve the solubility of dihydroartemisinic acid.

[0042] Furthermore, during the preparation of the dihydroartemisinic acid inclusion complex, the pH value of the solution is adjusted to 6.5-8, which can further improve the solubility of the prepared dihydroartemisinic acid inclusion complex. BRIEF DESCRIPTION OF THE DRAWINGS

[0043] Figure 1 It is a schematic structural diagram of the dihydroartemisinic acid inclusion compound involved in the present invention. DETAILED DESCRIPTION

[0044] In order to further illustrate the technical means and effects adopted by the present invention, the technical solutions of the present invention are further described below in conjunction with the preferred embodiments of the present invention, but the present invention is not limited to the scope of the embodiments.

[0045] The sources of the reagents in the following specific embodiments are shown in Table 1:

[0046] Table 1

[0047] name Manufacturer Item No. Hydroxypropyl-β-cyclodextrin Xi'an Deli Biochemical Co., Ltd. 20240409 Sodium sulfobutyl-β-cyclodextrin Xi'an Deli Biochemical Co., Ltd. 20240426 β-cyclodextrin Xi'an Deli Biochemical Co., Ltd. 20240348

[0048] Example 1

[0049] This embodiment provides a dihydroartemisinic acid inclusion compound, the preparation raw materials including: dihydroartemisinic acid and a cyclodextrin compound in a molar ratio of 1:9 (the cyclodextrin compound is hydroxypropyl-β-cyclodextrin and sulfobutyl-β-cyclodextrin sodium in a molar ratio of 1:8).

[0050] The preparation method thereof comprises:

[0051] The cyclodextrin compounds were mixed and dissolved in a 50% (v / v) aqueous ethanol solution, and then dihydroartemisinic acid was added to the solution (the total mass of the cyclodextrin compounds and dihydroartemisinic acid was controlled to have a volume ratio of 1:50 g / mL). Hydrochloric acid was added to adjust the pH of the solution to 7.5, and the mixture was stirred at 50°C and 3000 rpm for 10 hours until the dihydroartemisinic acid was completely dissolved, thereby obtaining a mixed solution. The mixed solution was then freeze-dried (pre-freezing time 4 hours, temperature -45°C, vacuum degree 1000 mbar; sublimation drying time 10 hours, temperature -16-5°C, vacuum degree 0.2 mbar; desorption drying time 4 hours, temperature 16-40°C, vacuum degree 0.2-1013 mbar) to obtain a dihydroartemisinic acid inclusion complex.

[0052] Example 2

[0053] This embodiment provides a dihydroartemisinic acid inclusion compound, the preparation raw materials including: dihydroartemisinic acid and a cyclodextrin compound in a molar ratio of 1:6 (the cyclodextrin compound is hydroxypropyl-β-cyclodextrin and sulfobutyl-β-cyclodextrin sodium in a molar ratio of 1:6).

[0054] The preparation method comprises:

[0055] The cyclodextrin compounds were mixed and dissolved in water, and then dihydroartemisinic acid was added to the solution (the total mass of the cyclodextrin compounds and dihydroartemisinic acid was controlled to have a volume ratio of 1:10 g / mL). Hydrochloric acid was added to adjust the pH of the solution to 6.5. The mixture was stirred at 20°C and 1000 rpm for 20 hours until the dihydroartemisinic acid was completely dissolved, thereby obtaining a mixed solution. Next, the mixed solution was spray-dried (feed inlet temperature of 70°C, discharge outlet temperature of 30°C, air inlet temperature of 180°C, air outlet temperature of 150°C, air inlet velocity of 3 m / s, and air outlet velocity of 8 m / s) to obtain a dihydroartemisinic acid inclusion complex.

[0056] Example 3

[0057] This embodiment provides a dihydroartemisinic acid inclusion compound, the preparation raw materials including: dihydroartemisinic acid and a cyclodextrin compound at a molar ratio of 1:12 (the cyclodextrin compound is hydroxypropyl-β-cyclodextrin and sulfobutyl-β-cyclodextrin sodium at a molar ratio of 1:10).

[0058] The preparation method comprises:

[0059] The cyclodextrin compound was dissolved in a 40% (v / v) aqueous acetone solution, and then dihydroartemisinic acid was added to the solution (the ratio of the total mass of the cyclodextrin compound and dihydroartemisinic acid to the volume of the solvent was controlled to be 1:90 g / mL), hydrochloric acid was added to adjust the pH of the solution to 8, and the solution was mixed and stirred at 70°C at a rotation speed of 6000 rpm for 5 h, so that dihydroartemisinic acid was completely dissolved to obtain a mixed solution. Next, the mixed solution was spray-dried (the inlet temperature was 70°C, the outlet temperature was 30°C, the inlet air temperature was 180°C, the outlet air temperature was 150°C, the inlet air speed was 3 m / s, and the outlet air speed was 8 m / s) to obtain a dihydroartemisinic acid inclusion compound.

[0060] Example 4

[0061] This example provides a dihydroartemisinic acid inclusion compound, which is different from Example 1 only in that the preparation raw material is adjusted to be dihydroartemisinic acid and a cyclodextrin compound (the cyclodextrin compound is only hydroxypropyl-β-cyclodextrin) at a molar ratio of 1:9; and the preparation method remains consistent with Example 1.

[0062] Example 5

[0063] This example provides a dihydroartemisinic acid inclusion compound, which is different from Example 1 only in that the preparation raw material is adjusted to be dihydroartemisinic acid and a cyclodextrin compound (the cyclodextrin compound is only sulfobutyl-β-cyclodextrin sodium) at a molar ratio of 1:9; and the preparation method remains consistent with Example 1.

[0064] Example 6

[0065] This example provides a dihydroartemisinic acid inclusion compound, which is different from Example 1 only in that the preparation raw material is adjusted to be dihydroartemisinic acid and a cyclodextrin compound (the cyclodextrin compound is hydroxypropyl-β-cyclodextrin and sulfobutyl-β-cyclodextrin sodium at a molar ratio of 1:5) at a molar ratio of 1:9; and the preparation method remains consistent with Example 1.

[0066] Example 7

[0067] This example provides a dihydroartemisinic acid inclusion compound, which is different from Example 1 only in that the preparation raw material is adjusted to be dihydroartemisinic acid and a cyclodextrin compound (the cyclodextrin compound is hydroxypropyl-β-cyclodextrin and sulfobutyl-β-cyclodextrin sodium at a molar ratio of 1:11) at a molar ratio of 1:9; and the preparation method remains consistent with Example 1.

[0068] Example 8

[0069] This embodiment provides a dihydroartemisinic acid inclusion compound, which differs from Example 1 only in that the preparation raw materials are adjusted to: dihydroartemisinic acid and a cyclodextrin compound (the cyclodextrin compound is β-cyclodextrin) in a molar ratio of 1:9; the preparation method is consistent with Example 1.

[0070] Example 9

[0071] This embodiment provides a dihydroartemisinic acid inclusion compound, which differs from Example 1 only in that the preparation raw materials are adjusted to: dihydroartemisinic acid and a cyclodextrin compound in a molar ratio of 1:5 (the cyclodextrin compound is hydroxypropyl-β-cyclodextrin and sulfobutyl-β-cyclodextrin sodium in a molar ratio of 1:8); the preparation method is consistent with Example 1.

[0072] Example 10

[0073] This embodiment provides a dihydroartemisinic acid inclusion compound, which differs from Example 1 only in that the preparation raw materials are adjusted to: dihydroartemisinic acid and a cyclodextrin compound with a molar ratio of 1:13 (the cyclodextrin compound is hydroxypropyl-β-cyclodextrin and sulfobutyl-β-cyclodextrin sodium with a molar ratio of 1:8); the preparation method is consistent with Example 1.

[0074] Example 11

[0075] This Example 1 provides a dihydroartemisinic acid inclusion compound, which differs from Example 1 only in that hydrochloric acid is not added in the preparation method to adjust the pH value, and the rest of the preparation method and preparation raw materials are consistent with Example 1.

[0076] Comparative Example 1

[0077] This comparative example provides a non-inclusion dihydroartemisinic acid, which differs from Example 1 in that the cyclodextrin compound is removed from the preparation raw materials. Accordingly, the preparation method is adjusted as follows:

[0078] Dihydroartemisinic acid was added to a 50% (v / v) aqueous ethanol solution (the mass ratio of dihydroartemisinic acid to the volume of the solvent was controlled to be 1:50 g / mL), and hydrochloric acid was added to adjust the pH of the solution to 7.5. The mixture was stirred at 50° C. and 3000 rpm for 10 hours until the dihydroartemisinic acid was completely dissolved, thereby obtaining a mixed solution. Next, the mixed solution was freeze-dried, and the freeze-drying step was consistent with that in Example 1, to finally obtain dihydroartemisinic acid without inclusion.

[0079] Test Example 1

[0080] This test example tests the solubility of dihydroartemisinic acid in different solvents.

[0081] Referring to the method for solubility test in the Preface of Chinese Pharmacopoeia 2020 Edition Part I, the dihydroartemisinic acid inclusion compound prepared in each example and the dihydroartemisinic acid prepared in Comparative Example 1 without inclusion were dissolved in water, 50% (v / v) ethanol aqueous solution, 50% (v / v) methanol aqueous solution respectively, and the solubility of each sample in different solvents is shown in Table 2.

[0082] Table 2

[0083]

[0084] From the data in Table 2, it can be seen that by wrapping dihydroartemisinic acid with cyclodextrin or cyclodextrin derivatives to form an inclusion compound, the solubility of dihydroartemisinic acid in different solvents can be greatly improved.

[0085] From the comparison of the data of Example 1 and Examples 4-5, 8, it can be seen that hydroxypropyl-β-cyclodextrin and sulfobutyl-β-cyclodextrin sodium are used as inclusion agents to include dihydroartemisinic acid, and they have a significant synergistic effect in improving the solubility of dihydroartemisinic acid, which can significantly improve the solubility of dihydroartemisinic acid inclusion compound, and the effect of improving the solubility of dihydroartemisinic acid is significantly better than that of β-cyclodextrin inclusion compound obtained by including dihydroartemisinic acid.

[0086] From the comparison of the data of Example 1 and Examples 6-7, it can be seen that by controlling the molar ratio of hydroxypropyl-β-cyclodextrin and sulfobutyl-β-cyclodextrin sodium to be 1:(6-10), the inclusion effect of dihydroartemisinic acid can be further improved, and the solubility of dihydroartemisinic acid can be improved.

[0087] From the comparison of the data of Example 1 and Examples 9-10, it can be seen that by controlling the molar ratio of dihydroartemisinic acid and cyclodextrin compounds to be 1:(6-12), the inclusion effect of cyclodextrin compounds on dihydroartemisinic acid can be further improved, and the solubility of dihydroartemisinic acid can be improved.

[0088] From the comparison of the data of Example 1 and Example 11, it can be seen that by adjusting the pH value of the solution to 6.5-8 during the preparation of dihydroartemisinic acid inclusion compound, the solubility of the prepared dihydroartemisinic acid inclusion compound can be further improved.

[0089] The applicant declares that the technical solutions of the present application are illustrated by the above examples, but the present application is not limited to the above examples, that is, it does not mean that the present application must rely on the above examples to be implemented. It should be understood by those skilled in the art that any improvement of the present application, equivalent replacement of each raw material of the product of the present application, addition of auxiliary ingredients, selection of specific mode, etc. fall within the protection scope and disclosure scope of the present application.

[0090] The preferred embodiments of the present application are described in detail above, but the present application is not limited to the specific details of the above-described embodiments, and various simple modifications can be made to the technical solutions of the present application within the technical concept of the present application, and these simple modifications all belong to the protection scope of the present application.

[0091] In addition, it should be noted that each specific technical feature described in the above specific embodiments can be combined in any appropriate manner without contradiction, and in order to avoid unnecessary repetition, various possible combinations are not described again by the present application.

Claims

1. A dihydroartemisinic acid inclusion compound, characterized in that: The dihydroartemisinic acid inclusion compound comprises dihydroartemisinic acid and a cyclodextrin compound encapsulating the dihydroartemisinic acid; The cyclodextrin compounds include cyclodextrin and / or cyclodextrin derivatives.

2. The dihydroartemisinic acid inclusion compound according to claim 1, characterized in that The cyclodextrin includes β-cyclodextrin and / or γ-cyclodextrin; Preferably, the cyclodextrin derivative comprises hydroxypropyl-β-cyclodextrin and / or sulfobutyl-β-cyclodextrin sodium; Preferably, the cyclodextrin compounds include hydroxypropyl-β-cyclodextrin and sulfobutyl-β-cyclodextrin sodium.

3. The dihydroartemisinic acid inclusion compound according to claim 2, characterized in that The molar ratio of the hydroxypropyl-β-cyclodextrin to sulfobutyl-β-cyclodextrin sodium is 1:(6-10).

4. The inclusion compound according to any one of claims 1 to 3, characterized in that The molar ratio of the dihydroartemisinic acid to the cyclodextrin compound is 1:(6-12).

5. A method for preparing the dihydroartemisinic acid inclusion compound according to any one of claims 1 to 4, characterized in that: The preparation method comprises: The dihydroartemisinic acid and the cyclodextrin compound are mixed and stirred in a solvent, and then the solvent is removed by drying to obtain a dihydroartemisinic acid inclusion compound.

6. The preparation method according to claim 5, characterized in that The solvent includes any one of water, ethanol or acetone or a combination of at least two; Preferably, the ratio of the total mass of the cyclodextrin compound and dihydroartemisinic acid to the volume of the solvent is 1:(10-90) g / mL.

7. The preparation method according to claim 5 or 6, characterized in that: The mixing and stirring process also includes adding a pH adjuster to adjust the pH value of the solution to 6.5-8; Preferably, the pH adjuster comprises hydrochloric acid.

8. The preparation method according to any one of claims 5 to 7, characterized in that The mixing temperature is 20-70°C, and the mixing time is 5-20h; Preferably, the mixing and stirring speed is 500-6000 rpm; Preferably, the drying method includes spray drying, freeze vacuum drying or vacuum rotary film concentration drying.

9. A pharmaceutical preparation, characterized in that The pharmaceutical preparation comprises the dihydroartemisinic acid inclusion compound according to any one of claims 1 to 4.

10. The pharmaceutical preparation according to claim 9, characterized in that The pharmaceutical preparation further includes pharmaceutically acceptable excipients; Preferably, the pharmaceutically acceptable excipients include any one or a combination of at least two of a diluent, an excipient, a filler, a binder, a wetting agent or a disintegrant; Preferably, the dosage form of the pharmaceutical preparation includes tablets, capsules, patches, oral liquids, gels, creams, soluble microneedles or injections.

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