Ionic liquid based on mefloquine and artesunate and preparation of sustained-release suppository of ionic liquid

Abstract

The invention discloses an ionic liquid based on mefloquine and artesunate and a preparation method of a sustained-release suppository of the ionic liquid. The artesunate and the mefloquine are two medicines which are commonly used in a combined manner clinically. The method specifically comprises the following steps: replacing chloride ions in mefloquine hydrochloride into hydroxyl radicals by using anion exchange resin, and reacting with artesunate through an acid-base neutralization reaction to generate the ionic liquid; after the product is encapsulated by a metal organic framework ZIF-8, the bullet-shaped suppository is prepared from a series of common matrixes through a hot melting-dispersing-cooling method and a special mold. Through the way, not only is the active pharmaceutical ingredient different from that of a precursor obtained, but also the administration and release modes of the active pharmaceutical ingredient are expanded. The obtained finished product is ideal in appearance, good in character and uniform in size, and has expected slow release performance; in addition, the weight difference, the fusion time limit, the microbial limit and the like all meet the standards of Chinese pharmacopoeia. The related preparation process is simple, the method is mature, the formability is good, the composition is convenient to adjust, and large-scale preparation is easy to realize.

Description

Technical Field

[0001] The invention belongs to the field of medicines and preparations thereof, and in particular relates to an ionic liquid prepared based on clinical medicines and a sustained-release suppository thereof. Background Art

[0002] Artesunate (Art) is a water-soluble derivative made by structural modification of artemisinin, the active ingredient in the Asteraceae plant Artemisia annua, which is unique to my country. It has a strong killing effect on asexual parasites of Plasmodium, can quickly control malaria attacks, and has been widely used in clinical practice without toxic side effects. Recent reports have shown that Art also has antiviral activity against SARSCoV-2. In addition, Art can reduce inflammatory responses and clear signals that attract immune cells to tissues. When used to treat severe COVID-19 patients, it can block lung damage caused by immune responses. Mefloquine (MQ) is a blood schizont killer that can inhibit the formation of malarial parasite pigments, so it is also an antimalarial drug. Its hydrochloride is often used in combination with artesunate in clinical practice. Recent studies have also pointed out that MQ can interfere with viral load and reduce cellular responses, and can be used as a potential anti-new coronavirus drug (Khanna, N., Pawar, SV, Kumar, AA Review on repurposed drugs and vaccine trials for combating SARS CoV-2. Current Drug Research Reviews, 2021, 13 (3): 203-221), so the two can also be used in combination for the clinical treatment of patients infected with the new coronavirus. At present, artesunate has two dosage forms: oral and rectal. Among them, artesunate suppositories are the first choice for patients with severe malaria, especially children under 6 years old in remote malaria-endemic areas before referral; mefloquine is administered orally. In clinical practice, artesunate and mefloquine are generally used in combination by administering the two drugs separately. There is no report on the method of preparing artesunate and mefloquine as a whole by chemical synthesis and administering them rectally.

[0003] Ionic liquids refer to salts that are liquid at room temperature or near room temperature and are completely composed of anions and cations, also known as low-temperature molten salts. As ionic compounds, the main reason for their low melting point is that the asymmetry of certain substituents in the structure prevents the ions from being regularly stacked into crystals. They are generally composed of organic cations and inorganic or organic anions. Common cations include quaternary ammonium ions, quaternary phosphonium ions, imidazolium ions, and pyrrole ions; anions include halogen ions, tetrafluoroborate ions, hexafluorophosphate ions, etc. In recent years, ionic liquids formed by drug molecules have attracted much attention and have become one of the new directions in drug research and development (Shamshina, JL, Kelley, SP, Gurau, G. Chemistry: Develop ionic liquid drugs. Nature, 2015, 528: 188-189). For example, the active ions of the analgesic procaine are combined with the non-steroidal anti-inflammatory drug (NSAID) salicylic acid to generate a liquid salt-procaine salicylate. It can more effectively and cheaply exert the medicinal effects of the two precursor compounds, and also open up new treatment options. The industry has also begun to pay attention to the new target of ionic liquid drugs. An ionic liquid pain relief patch based on NSAID etodolac and painkiller lidocaine launched by Mindray Medical International Co., Ltd. (MEDRxUSA, Inc) can be used to treat back pain and has completed Phase III clinical trials (https: / / clinicaltrials.gov / ct2 / show / NCT01198834). At present, it is necessary to explore more such ionic liquid drugs.

[0004] Metal Organic Frameworks (MOFs) are porous materials that use metal ions as connection points and organic ligands as support to form a 3D extension of space. There are many types of MOFs. Their large specific surface area and adjustable pore structure enable them to load many objects with extremely high efficiency. They are currently widely used in the fields of catalysis, energy storage, separation and drug delivery. In particular, the open metal sites or acid-base sites in MOFs molecules can enhance their interaction with drug molecules and achieve their controlled release, thereby improving drug efficacy and reducing the toxic side effects of drugs on normal human cells. Zeolitic Imidazolate Frameworks (ZIFs), a type of MOFs, are a new type of nanoporous material with a zeolite topological structure formed by connecting transition metal atoms (such as Zn salts) with imidazole or imidazole derivatives. Among them, ZIF-8 is the most commonly used ZIFs. Due to its high porosity, simple preparation, and ability to effectively encapsulate small molecules to biomacromolecules, it also has pH-responsive biodegradability. As an excellent drug carrier, it has attracted widespread attention. At the same time, it also has certain therapeutic effects (such as Ding, B., Chen, H., Tan J., et al. ZIF-8 nanoparticles evoke pyroptosis for high-efficiency cancer immunotherapy. Angewandte Chemie International Edition, 2023, 62(10): e202215307). In addition, the safety and biocompatibility of ZIF-8 in the medical field have been verified to a certain extent in existing literature (such as He, L., Huang, G., Liu, H., et al. Highly bioactive zeolitic imidazolate framework-8–capped nanotherapeutics for efficient reversal of reperfusion-induced injury in ischemic stroke. Science Advances, 2020, 6(12):eaay9751).

[0005] Suppositories are a traditional semisolid preparation that can act in local cavities or throughout the body. Semisynthetic or fully synthetic fatty acid glycerides and cocoa butter are commonly used fat-soluble matrices, while representatives of water-soluble matrices include glycerol-gelatin, polyethylene glycols, etc. In recent years, with the continuous development of formulation technology, researchers have developed a variety of new sustained-release suppositories. For example, microcapsules are prepared by modifying the surface of theophylline and hydroxyphenylbutazone with polycarboxyvinyl polymers. In vitro release experiments show that the release of these two drugs is first-order release kinetics, which shows better sustained-release effects than unmodified microcapsules. For gel suppositories, commonly used matrices are hydrophilic and bioadhesive materials, such as carbomer and cellulose derivatives. These aqueous gel matrices will absorb water and swell when exposed to water, becoming soft and elastic, and have adhesion to biological mucosa, and can adhere to the mucosal surface for a long time, thereby continuously releasing drugs, while slowly releasing and improving the bioavailability of drugs. In addition, skeleton controlled-release materials can be added to make sustained-release suppositories. This material acts as a physical barrier to the dissolution and release of drugs, and increases the drug concentration at the site of action. Commonly used skeleton controlled-release materials include polymer materials that are insoluble in water or have low water solubility, such as ethyl cellulose and polypropylene; biodegradable skeleton materials such as waxes, fatty acids and their esters; and hydrophilic gel skeleton materials including hydroxypropyl cellulose, chitosan, polyethylene glycol, sodium alginate, etc. Finally, sustained-release preparation technologies such as β-cyclodextrin inclusion compounds and micelles are also used in the development of new suppositories. Summary of the invention

[0006] The purpose of the present invention is to provide an ionic liquid based on mefloquine and artesunate and a method for preparing a sustained-release suppository thereof, wherein the ionic liquid synthesis raw material comes from two drugs, artesunate and mefloquine, which are used in combination in clinical practice. Specifically, an anion exchange resin is used to replace the chloride ions in mefloquine hydrochloride with hydroxide, and then the ionic liquid product is generated by acid-base neutralization reaction with artesunate. After encapsulating it with a metal organic framework ZIF-8, a series of commonly used matrices are used to prepare bullet-shaped suppositories through a hot melt-dispersion-cooling method and a special mold. The obtained finished product has an ideal appearance, good properties, uniform size, and expected sustained-release performance; in addition, the weight difference, melting time limit, and microbial limit all meet the standards of the Chinese Pharmacopoeia. The preparation process involved is simple, the method is mature, the formability is good, and the composition is convenient to adjust, and it is easy to achieve large-scale preparation. Through the above method, not only the active pharmaceutical ingredient different from the precursor is obtained, the administration route is expanded, but also a sustained-release suppository system with a scientific and reasonable composition is constructed, which has a good development and application prospect.

[0007] Technical solution: In order to achieve the above purpose, a preparation method of an ionic liquid based on mefloquine and artesunate and its sustained-release suppository was established:

[0008] The invention discloses an ionic liquid based on mefloquine and artesunate and a sustained-release suppository thereof, wherein the ionic liquid is prepared from two drugs, artesunate (Art) and mefloquine (MQ), which are used in combination in clinical practice.

[0009] The preparation of the ionic liquid based on mefloquine and artesunate and its sustained-release suppository according to claim 1 is characterized in that, in the preparation process of the ionic liquid, the chloride ions in mefloquine hydrochloride [MQ][Cl] are first replaced with hydroxide [MQ][OH] by an anion exchange resin, and then reacted with artesunate through an acid-base neutralization reaction to generate an ionic liquid product [MQ][Art].

[0010] The preparation of the ionic liquid based on mefloquine and artesunate and the sustained-release suppository thereof according to claim 1 is characterized in that the suppository is prepared after the ionic liquid is encapsulated with the metal organic framework ZIF-8.

[0011] The preparation of the ionic liquid based on mefloquine and artesunate and its sustained-release suppository according to claim 1 is characterized in that the process of encapsulating the ionic liquid with the metal organic framework ZIF-8 is: dissolving ZnNO3·6H2O in methanol, and dissolving [MQ][Art], 2-methylimidazole and triethylamine in methanol with mass ratios of 0.1:1 to 0.6:1, 1:1 to 5:1 and 1:1 to 10:1 respectively; then mixing equal volumes of the above two methanol solutions, stirring at 10 to 50°C for 1 to 3 hours, and then centrifuging, filtering, washing, desolvating and drying to obtain the metal organic framework [MQ][Art]@ZIF-8 encapsulated with the ionic liquid.

[0012] The preparation of the ionic liquid based on mefloquine and artesunate and its sustained-release suppository according to claim 1 is characterized in that the metal organic framework [MQ][Art]@ZIF-8 encapsulating the ionic liquid is prepared into a matrix of the sustained-release suppository including semi-synthetic fatty acid ester-36, cocoa butter, PEG1000, PEG2000, PEG4000, PEG1000-PEG4000 (1:1), glycerol-gelatin (2:7), polyoxyethylene-40 or poloxamer.

[0013] The preparation of the ionic liquid based on mefloquine and artesunate and the sustained-release suppository thereof according to claim 1 is characterized in that the semi-synthetic fatty acid ester-36 type suppository and the cocoa butter type suppository based on the fat-soluble matrix are prepared respectively in the following manner: (1) In the preparation of ionic liquid semi-synthetic fatty acid ester-36 type suppositories, the mass ratio of [MQ][Art]@ZIF-8 to semi-synthetic fatty acid ester-36 is 0.1:1 to 0.75:1; the matrix semi-synthetic fatty acid ester-36 is first stirred at 50 to 80°C until it is completely melted, and then the metal organic framework [MQ][Art]@ZIF-8 encapsulating the ionic liquid is added and fully mixed, and after the mixture is evenly dispersed, the mixture is poured into a pre-cleaned and lubricated suppository mold while hot, and the suppository is demolded after cooling, sterilized by ultraviolet light for 60 minutes, and then packaged and stored at 4°C; (2) In the preparation of ionic liquid cocoa butter suppositories, the mass ratio of [MQ][Art]@ZIF-8 to cocoa butter is 0.1:1 to 0.75:1. First, the cocoa butter is heated and stirred in a water bath at 30 to 50°C, and then the metal organic framework [MQ][Art]@ZIF-8 encapsulating the ionic liquid is added and mixed thoroughly. When the cocoa butter is melted to 2 / 3, the heating is stopped, and the remaining matrix is ​​completely melted with the residual heat. The mixture is then poured into a pre-cleaned and lubricated suppository mold while it is hot. After cooling, the suppository is demolded and taken out, sterilized by ultraviolet light for 60 minutes, and then packaged and stored at 4°C.

[0014] The preparation of the ionic liquid based on mefloquine and artesunate and its sustained-release suppository according to claim 1 is characterized in that in the preparation of the ionic liquid polyoxyethylene-40 suppository, the mass ratio of [MQ][Art]@ZIF-8 and polyoxyethylene-40 is 0.1:1 to 0.75:1; the matrix is ​​first stirred at 60 to 80°C until it is completely melted, and then the metal organic framework [MQ][Art]@ZIF-8 encapsulating the ionic liquid is added and fully mixed, and after it is evenly dispersed, it is poured into a pre-cleaned and lubricated suppository mold while hot, and the suppository is demolded after cooling, sterilized by ultraviolet light for 60 minutes, and then packaged and stored at 4°C.

[0015] The preparation of the ionic liquid based on mefloquine and artesunate and its sustained-release suppository according to claim 1 is characterized in that the mass ratio of [MQ][Art]@ZIF-8 and poloxamer in the preparation of the ionic liquid poloxamer suppository is 0.1:1 to 0.75:1; the matrix is ​​first stirred at 75 to 95°C until it is completely melted, and then the metal organic framework [MQ][Art]@ZIF-8 encapsulating the ionic liquid is added and fully mixed, and after it is evenly dispersed, it is poured into a pre-cleaned and lubricated suppository mold while hot, and the suppository is demolded after cooling, sterilized by ultraviolet light for 60 minutes, and then packaged and stored at 4°C.

[0016] The preparation of the ionic liquid based on mefloquine and artesunate and its sustained-release suppository according to claim 1 is characterized in that in the preparation of ionic liquid PEG1000, PEG2000, PEG4000 or PEG1000-PEG4000 (1:1) type suppositories, the mass ratio of [MQ][Art]@ZIF-8 and the four PEG matrices is 0.1:1 to 0.75:1; the above-mentioned matrices are first stirred at 50-70°C, 55-85°C, 65-90°C or 60-90°C until completely melted, and then the metal organic framework [MQ][Art]@ZIF-8 encapsulating the ionic liquid is added and stirred, and after it is evenly dispersed, it is poured into a pre-cleaned and lubricated suppository mold while hot, and the suppository is demolded after cooling, and sterilized by ultraviolet light for 60 minutes and then packaged and stored at 4°C.

[0017] The preparation of the ionic liquid based on mefloquine and artesunate and its sustained-release suppository according to claim 1 is characterized in that in the preparation of the ionic liquid glycerol-gelatin (2:7) matrix suppository, the mass ratio of [MQ][Art]@ZIF-8 and glycerol-gelatin is 0.1:1~0.75:1; first, the gelatin is added to deionized water with a mass of 1 / 7 of its mass for pre-swelling, and then placed in a 65-95°C water bath for heating to dissolve the gelatin to form a homogeneous saturated solution, and glycerol and the metal organic framework [MQ][Art]@ZIF-8 encapsulating the ionic liquid are added while stirring, so that the latter is evenly dispersed in the matrix, and then the water is evaporated and the mixture is poured into a pre-cleaned and lubricated suppository mold while hot, and the suppository is demolded after cooling, sterilized by ultraviolet light for 60 minutes, and then packaged and stored at 4°C. BRIEF DESCRIPTION OF THE DRAWINGS

[0018] In order to more completely illustrate the technical solution of the specific embodiment of the present invention, the following briefly describes the drawings required in the embodiment. The drawings described are only part of the embodiment of the present invention. For those skilled in the art, it should be possible to obtain other drawings of the embodiment based on these drawings. Among them:

[0019] Figure 1 The infrared spectra (FT-IR) of MQ, Art and [MQ][Art] are shown;

[0020] Figure 2 The H NMR spectra of (a) MQ, (b) Art and (c) [MQ][Art] are shown in Figure 2. 1 H NMR) spectra;

[0021] Figure 3 Mass spectra (MS) of (a) MQ and (b) [MQ]Art in positive ion mode;

[0022] Figure 4Infrared spectra (FT-IR) of ZIF-8, [MQ][Art] and [MQ][Art]@ZIF-8;

[0023] Figure 5 (a) Appearance of nine blank plugs (1-9 are: semi-synthetic fatty acid glyceride, cocoa butter, S-40, poloxamer, PEG1000, PEG2000, PEG4000, PEG1000-PEG4000, glycerol-gelatin) and (b) Hardness comparison results of eight of the blank plugs;

[0024] Figure 6 This is the dissolution curve of [MQ][Art] in poloxamer suppositories. DETAILED DESCRIPTION

[0025] The following is a detailed description of the present invention. Although specific embodiments of the present invention are shown, it should be understood that the present invention can be implemented in various forms and should not be limited by the embodiments set forth herein. On the contrary, these embodiments are provided to enable a more thorough understanding of the present invention and to fully convey the scope of the present invention to those skilled in the art.

[0026] This specification and claims do not use differences in terms as a way to distinguish components, but use differences in the functions of the components as the criteria for distinction. The "include" or "comprising" mentioned in this application is an open-ended term and should be interpreted as "including but not limited to". The embodiments described in the subsequent description are preferred embodiments of the present invention and are based on the general principles of the specification and are not intended to limit the scope of the present invention.

[0027] Example 1

[0028] 70 mL of pre-treated 717 type styrene strong basic anion exchange resin (particle size 0.42-0.58 mm, volume density: 0.66-0.75 g / mL) was loaded into a glass chromatography column (column height: 30 cm, column diameter: 30 mm), and 0.11 mol of mefloquine hydrochloride [MQ] [Cl] was dissolved in 50 mL of methanol and added to the resin bed of the chromatography column. The column outflow rate was controlled to 3 seconds / drop, and the Cl in it was detected with AgNO3 - ; When the outflowing Cl - After the test is negative, the alkaline effluent with pH>7 is collected, and [MQ][OH] is obtained after desolvation. Subsequently, 0.1 mol of artesunate is weighed, dispersed in 30 mL of methanol, and an equimolar amount of [MQ][OH] is added and stirred at room temperature for 8 hours. After the reaction is completed, the methanol is removed by vacuum distillation, and then washed with deionized water and ethanol in turn and dried in vacuum. The product is the ionic liquid [MQ][Art].

[0029] The ionic liquid product [MQ][Art] and its synthetic raw materials were identified by infrared spectroscopy (KBr pellet), nuclear magnetic resonance hydrogen spectrum (400MHz, solvent is deuterated methanol) and electrospray ionization mass spectrometry. The results are shown in the attached Figure 1 ~Attached Figure 3 The relevant spectral data indicate that after the two raw materials are used to synthesize the ionic liquid product, the characteristic signal peaks of the infrared spectrum and nuclear magnetic resonance hydrogen spectrum corresponding to the respective structural fragments can be retained, and no obvious by-products other than the neutralization reaction appear; for the mass spectrum, the attached Figure 3 The quasi-molecular ion peak m / z of mefloquine hydrochloride [MQ][Cl] in a measured in positive ion mode is 379, and its mass number corresponds to [MQ] + part; and Figure 3 In b, the ionic liquid product [MQ][Art] was completely ionized in the positive ion mode, and the relative molecular mass of its cationic part was still 379, which also proved that there was no abnormal change in the molecular structure of the raw material.

[0030] Example 2

[0031] 1.50 g ZnNO3·6H2O was dissolved in 50 mL methanol, and 0.2 g [MQ][Art], 1.8 g 2-methylimidazole and 3.5 g triethylamine were dissolved in 50 mL methanol. The two methanol solutions were mixed and stirred for reaction at room temperature for 1 h. The product was centrifuged at 5000 rpm for 10 min, filtered, washed and dried to obtain the organic metal framework [MQ][Art]@ZIF-8 encapsulating the ionic liquid.

[0032] Example 3

[0033] 2.0 g ZnNO3·6H2O was dissolved in 60 mL methanol, and 0.5 g [MQ][Art], 2.8 g 2-methylimidazole and 6.3 g triethylamine were dissolved in 60 mL methanol. The two methanol solutions were mixed and stirred at room temperature for 2 h. The product was centrifuged at 5000 rpm for 10 min, filtered, washed and dried to obtain the organic metal framework [MQ][Art]@ZIF-8 encapsulating the ionic liquid.

[0034] Example 4

[0035] 3.5 g ZnNO3·6H2O was dissolved in 75 mL methanol, and 1 g [MQ][Art], 5.0 g 2-methylimidazole and 10 g triethylamine were dissolved in 75 mL methanol. The two methanol solutions were mixed and stirred at room temperature for 3 h. The product was centrifuged at 5000 rpm for 10 min, filtered, washed and dried to obtain the organic metal framework [MQ][Art]@ZIF-8 encapsulating the ionic liquid.

[0036] The organic metal framework [MQ][Art]@ZIF-8 encapsulated with ionic liquid in Example 4 was measured by infrared spectroscopy. The results are shown in the attached figure. Figure 4 As shown; the relevant spectral data show that the infrared spectrum of [MQ][Art]@ZIF-8 integrates the characteristic signals of [MQ][Art] and ZIF-8, indicating that [MQ][Art]@ZIF-8 was successfully prepared.

[0037] Example 5

[0038] Weigh 2g of semi-synthetic fatty acid ester-36 matrix and place it in a 60℃ water bath and heat and stir until it is completely melted, then add 0.1g of [MQ][Art]@ZIF-8 fine powder and stir thoroughly to make it evenly dispersed; then pour the drug-containing matrix into a pre-cleaned and lubricated suppository mold while it is still hot, demould and take out the suppository after cooling; after sterilization under ultraviolet light for 60 minutes, divide it into packages and store it in a refrigerator at 4℃.

[0039] The appearance of the blank suppository without adding [MQ][Art]@ZIF-8 in Example 5 is as shown in the attached figure. Figure 5 As shown in (a), suppository No. ① has a length of 12 mm and a cross-sectional diameter of 5 mm, and is a white bullet shape. The hardness of the suppository was tested using a YPD-3000 hardness tester, and the average value of three parallel measurements was 30 N. Figure 5 (b) as shown.

[0040] Example 6

[0041] Weigh 2 g of cocoa butter matrix and place it in a 50°C water bath and heat and stir. When the cocoa butter is melted to 2 / 3, stop heating and use the residual heat to completely melt the remaining matrix. Pour it into a suppository mold that has been lubricated with glycerin beforehand while it is still hot. Then add 0.1 g of [MQ][Art]@ZIF-8 fine powder and stir it thoroughly to make it evenly dispersed. Then pour the drug-containing matrix into the pre-cleaned and lubricated suppository mold while it is still hot. After cooling, demould and take out the suppository. After sterilization under ultraviolet light for 60 minutes, divide it into portions and store it in a refrigerator at 4°C.

[0042] The appearance of the blank suppository without adding [MQ][Art]@ZIF-8 in Example 6 is as shown in the attached figure. Figure 5 As shown in (a), suppository No. ② has a length of 12 mm and a cross-sectional diameter of 5 mm, and is a yellow bullet shape. The hardness of the suppository was tested using a YPD-3000 hardness tester, and the average value of three parallel measurements was 20 N. Figure 5 (b) as shown.

[0043] Example 7

[0044] Weigh 2g of S-40 matrix and heat and stir it in an 80℃ water bath to melt it, then add 0.1g of [MQ][Art]@ZIF-8 fine powder and stir it thoroughly to make it evenly dispersed; then pour the drug-containing matrix into the pre-cleaned and lubricated suppository mold while it is still hot, demould it after cooling and take out the suppository; after sterilization under ultraviolet light for 60 minutes, divide it into packages and store it in a refrigerator at 4℃.

[0045] The appearance of the blank suppository without adding [MQ][Art]@ZIF-8 in Example 7 is as shown in the attached figure. Figure 5 As shown in (a), the suppository No. ③ has a length of 12 mm and a cross-sectional diameter of 5 mm, and is a white bullet shape. The hardness of the suppository was tested using a YPD-3000 hardness tester, and the average value of three parallel measurements was 45 N. Figure 5 (b) as shown.

[0046] Example 8

[0047] Weigh 2 g of poloxamer matrix and heat and stir it in an 85°C water bath until it is completely melted, then add 0.1 g of [MQ][Art]@ZIF-8 fine powder and stir thoroughly to evenly disperse it; then pour the drug-containing matrix into a pre-cleaned and lubricated suppository mold while it is still hot, demould and take out the suppository after cooling; sterilize it under ultraviolet light for 60 minutes, then divide it into packages and store it in a refrigerator at 4°C.

[0048] The appearance of the blank suppository without [MQ][Art]@ZIF-8 in Example 8 is as shown in the attached figure. Figure 5 As shown in (a), the suppository No. ④ has a length of 12 mm, a cross-sectional diameter of 5 mm, and a white bullet-shaped appearance. The hardness of the suppository was tested using a YPD-3000 hardness tester, and the average value of three parallel measurements was 33 N. Figure 5 (b) as shown.

[0049] Example 9

[0050] Weigh 2 g of PEG1000 matrix and heat and stir it in a 65°C water bath until it is completely melted, then add 0.1 g of [MQ][Art]@ZIF-8 fine powder and stir it thoroughly to make it evenly dispersed; then pour the drug-containing matrix into the pre-cleaned and lubricated suppository mold while it is still hot, demould and take out the suppository after cooling; sterilize it under ultraviolet light for 60 minutes, then divide it into packages and store it in a refrigerator at 4°C.

[0051] The appearance of the blank suppository without adding [MQ][Art]@ZIF-8 in Example 9 is as shown in the attached figure. Figure 5 As shown in (a), suppository No. ⑤ has a length of 12 mm, a cross-sectional diameter of 5 mm, and a white waxy bullet-shaped appearance. The hardness of the suppository was tested using a YPD-3000 hardness tester, and the average value of three parallel measurements was 14 N. Figure 5 (b) as shown.

[0052] Example 10

[0053] Weigh 2 g of PEG2000 matrix and heat and stir it in a 70°C water bath until it is completely melted, then add 0.1 g of [MQ][Art]@ZIF-8 fine powder and stir it thoroughly to make it evenly dispersed; then pour the drug-containing matrix into the pre-cleaned and lubricated suppository mold while it is still hot, demould and take out the suppository after cooling; sterilize it under ultraviolet light for 60 minutes, then divide it into packages and store it in a refrigerator at 4°C.

[0054] The appearance of the blank suppository without adding [MQ][Art]@ZIF-8 in Example 10 is as shown in the attached figure. Figure 5 As shown in (a), suppository No. ⑥ has a length of 12 mm, a cross-sectional diameter of 5 mm, and a white bullet-shaped appearance. The hardness of the suppository was tested using a YPD-3000 hardness tester, and the average value of three parallel measurements was 54 N. Figure 5 (b) as shown.

[0055] Embodiment 11

[0056] Weigh 2 g of PEG4000 matrix and heat and stir it in an 80°C water bath until it is completely melted, then add 0.1 g of [MQ][Art]@ZIF-8 fine powder and stir it thoroughly to make it evenly dispersed; then pour the drug-containing matrix into the pre-cleaned and lubricated suppository mold while it is still hot, demould it after cooling and take out the suppository; after sterilization under ultraviolet light for 60 minutes, divide it into packages and store it in a refrigerator at 4°C.

[0057] The appearance of the blank suppository without adding [MQ][Art]@ZIF-8 in Example 11 is as shown in the attached figure. Figure 5 As shown in suppository No. 7 in (a), the suppository is 12 mm long, 5 mm in cross-sectional diameter, and has a white bullet-shaped appearance. The hardness of the suppository was tested using a YPD-3000 hardness tester, and the average value of three parallel measurements was 45 N. Figure 5 (b) as shown.

[0058] Example 12

[0059] Weigh 1g of PEG1000-PEG4000 (1:1) matrix, heat and stir in an 80℃ water bath until completely melted, then add 0.1g of [MQ][Art]@ZIF-8 fine powder and stir thoroughly to make it evenly dispersed; then pour the drug-containing matrix into the pre-cleaned and lubricated suppository mold while it is still hot, demould and take out the suppository after cooling; sterilize it under ultraviolet light for 60 minutes, then divide it into packages and store it in a refrigerator at 4℃.

[0060] The appearance of the blank suppository without adding [MQ][Art]@ZIF-8 in Example 12 is as shown in the attached figure. Figure 5 As shown in (a), suppository No. ⑧ has a length of 12 mm, a cross-sectional diameter of 5 mm, and a white bullet-shaped appearance. The hardness of the suppository was tested using a YPD-3000 hardness tester, and the average value of three parallel measurements was 33 N. Figure 5 (b) as shown.

[0061] Embodiment 13

[0062] Weigh 0.4 g of gelatin and add 0.2 mL of deionized water for pre-swelling, then heat it in a water bath at 80°C to dissolve the gelatin to form a saturated solution, and add 1.4 g of glycerol while stirring; grind the metal organic framework [MQ][Art]@ZIF-8 encapsulating the ionic liquid into a very fine powder in an agate mortar, weigh 0.1 g of the fine powder and evenly disperse it in the glycerol-gelatin matrix, then evaporate the excess water, and pour the drug-containing base into a pre-cleaned and lubricated suppository mold while it is hot, demould and take out the suppository after cooling; sterilize it under ultraviolet light for 60 minutes, then divide it into portions and store it in a refrigerator at 4°C.

[0063] The appearance of the blank suppository without adding [MQ][Art]@ZIF-8 in Example 13 is as shown in the attached figure. Figure 5 As shown in suppository No. 9 in (a), the suppository is 12 mm in length, 5 mm in cross-sectional diameter, and has a yellow gel bullet-shaped appearance. Due to its soft texture and low hardness, no hardness test was performed.

[0064] Embodiment 14

[0065] Based on the dissolution and release determination method of General Chapter 0931 of the Chinese Pharmacopoeia (2020 Edition), the poloxamer-type suppository prepared in Example 8 was placed in a small cup, and then the small cup was placed in a constant temperature shaker at 150 rpm to investigate its release behavior in a dissolution medium of 0.01 M PBS (pH = 7.4, 37 ° C ± 0.1 ° C); every 5 min, 10 min, 20 min, 30 min, 45 min, 60 min, 90 min, 120 min, 180 min, 240 min, 360 min, 420 min, 480 min, 540 min, 600 min, the solution in the small cup was sampled and supplemented with PBS with the same volume as the sampling. The ultraviolet absorbance (x) of the [MQ] [Art] dissolution solution at 310 nm was determined by ultraviolet spectroscopy, and according to the quantitative working curve y = 3.20x-0.043 (R 2 =0.998) to calculate its concentration (y, mM) and obtain the cumulative release rate at different time points.

[0066] The dissolution curve obtained in Example 14 is shown in the attached figure. Figure 6 As shown in the figure, it can be found that the prepared suppository has a more obvious sustained-release characteristic; when the dissolution time is 10h (600min), the cumulative release rate is 90.22%, which meets the requirements of the Chinese Pharmacopoeia (2020 edition) for sustained-release suppositories: "The time of the entire drug release process should not be less than the interval between drug administrations, and the cumulative release percentage is required to reach more than 90%."

[0067] Embodiment 15

[0068] Three poloxamer suppositories prepared in Example 8 were placed in an RB-1 melting time instrument, and the melting time was measured to be 30.7 min at 37±0.5°C; this result meets the requirement of the "Melting Time Test Method" of the "Chinese Pharmacopoeia" (2020 edition) that "under the condition of 37±0.5°C, all three suppositories of water-soluble matrix should be completely dissolved within 60 minutes".

[0069] Example 16

[0070] Take 10 poloxamer-type medicated suppositories prepared in Example 8, first weigh the total mass of the 10 suppositories on a precision electronic balance, then calculate the average mass of a single suppository, and then weigh the mass of each of the 10 suppositories to calculate the weight difference of this batch of suppository samples. The results show that the weight difference of the 10 suppositories is ≤8.39%; this result is in line with the requirement of the "Chinese Pharmacopoeia" (2020 edition) on the weight difference of suppositories that "for average particle weight less than 1 g, no more than 1 particle shall exceed the weight difference limit of 10%, and shall not exceed the limit by twice".

[0071] Embodiment 17

[0072] According to the methods in the microbial count method (General Rule 1105) and the control bacteria inspection method (General Rule 1106) of the 2020 edition of the "Chinese Pharmacopoeia" and the microbial limit standards for non-sterile drugs (General Rule 1107), the microorganisms in 10 poloxamer-type suppositories prepared in Example 8 were tested; the results showed that the number of bacteria was ≤1000 per 1g, the number of molds and yeasts was ≤100 per 1g, and Staphylococcus aureus, Pseudomonas aeruginosa and Escherichia coli were not detected; this result is in line with the provisions on microbial limits in the "Chinese Pharmacopoeia" (2020 edition).

Claims

1. Preparation of ionic liquid based on mefloquine and artesunate and sustained-release suppository thereof, characterized in that: The ionic liquid is prepared from two drugs, artesunate (Art) and mefloquine (MQ), which are used in combination in clinical practice.

2. The preparation of the ionic liquid based on mefloquine and artesunate and the sustained-release suppository thereof according to claim 1, characterized in that: In the preparation process of the ionic liquid, an anion exchange resin is first used to replace the chloride ions in mefloquine hydrochloride [MQ][Cl] with hydroxide [MQ][OH], and then the ionic liquid product [MQ][Art] is generated through an acid-base neutralization reaction with artesunate.

3. The preparation of the ionic liquid based on mefloquine and artesunate and the sustained-release suppository thereof according to claim 1, characterized in that: The ionic liquid is encapsulated with a metal organic framework ZIF-8 to prepare a suppository.

4. The preparation of the ionic liquid based on mefloquine and artesunate and the sustained-release suppository thereof according to claim 1, characterized in that: The process of encapsulating the ionic liquid with the metal organic framework ZIF-8 is as follows: dissolving ZnNO3·6H2O in methanol, and dissolving [MQ][Art], 2-methylimidazole and triethylamine in methanol at mass ratios of 0.1:1-0.6:1, 1:1-5:1 and 1:1-10:1 respectively; then mixing equal volumes of the two methanol solutions, stirring at 10-50°C for 1-3h, and then centrifuging, filtering, washing, removing the solvent and drying to obtain the metal organic framework [MQ][Art]@ZIF-8 encapsulating the ionic liquid.

5. The preparation of the ionic liquid based on mefloquine and artesunate and the sustained-release suppository thereof according to claim 1, characterized in that: The matrix of the metal organic framework [MQ][Art]@ZIF-8 encapsulating ionic liquids to prepare sustained-release suppositories includes semi-synthetic fatty acid ester-36, cocoa butter, PEG1000, PEG2000, PEG4000, PEG1000-PEG4000 (1:1), glycerol-gelatin (2:7), polyoxyethylene-40 or poloxamer.

6. The preparation of the ionic liquid based on mefloquine and artesunate and the sustained-release suppository thereof according to claim 1, characterized in that: The semi-synthetic fatty acid ester-36 type suppositories and cocoa butter type suppositories based on fat-soluble matrix were prepared as follows: (1) In the preparation of ionic liquid semi-synthetic fatty acid ester-36 type suppositories, the mass ratio of [MQ][Art]@ZIF-8 to semi-synthetic fatty acid ester-36 is 0.1:1 to 0.75:1; the matrix semi-synthetic fatty acid ester-36 is first stirred at 50 to 80°C until it is completely melted, and then the metal organic framework [MQ][Art]@ZIF-8 encapsulating the ionic liquid is added and fully mixed, and after the mixture is evenly dispersed, the mixture is poured into a pre-cleaned and lubricated suppository mold while hot, and the suppository is demolded after cooling, sterilized by ultraviolet light for 60 minutes, and then packaged and stored at 4°C; (2) In the preparation of ionic liquid cocoa butter suppositories, the mass ratio of [MQ][Art]@ZIF-8 to cocoa butter is 0.1:1 to 0.75:

1. First, the cocoa butter is heated and stirred in a water bath at 30 to 50°C, and then the metal organic framework [MQ][Art]@ZIF-8 encapsulating the ionic liquid is added and mixed thoroughly. When the cocoa butter is melted to 2 / 3, the heating is stopped, and the remaining matrix is ​​completely melted with the residual heat. The mixture is then poured into a pre-cleaned and lubricated suppository mold while it is hot. After cooling, the suppository is demolded and taken out, sterilized by ultraviolet light for 60 minutes, and then packaged and stored at 4°C.

7. The preparation of the ionic liquid based on mefloquine and artesunate and the sustained-release suppository thereof according to claim 1, characterized in that: In the preparation of ionic liquid polyoxyethylene-40 type suppositories, the mass ratio of [MQ][Art]@ZIF-8 and polyoxyethylene-40 is 0.1:1 to 0.75:1; the matrix is ​​first stirred at 60 to 80°C until it is completely melted, and then the metal organic framework [MQ][Art]@ZIF-8 encapsulating the ionic liquid is added and mixed thoroughly. After it is evenly dispersed, it is poured into a pre-cleaned and lubricated suppository mold while hot, and the suppository is demolded and taken out after cooling. It is sterilized by ultraviolet light for 60 minutes, then packaged and stored at 4°C.

8. The preparation of the ionic liquid based on mefloquine and artesunate and the sustained-release suppository thereof according to claim 1, characterized in that: In the preparation of ionic liquid poloxamer suppositories, the mass ratio of [MQ][Art]@ZIF-8 to poloxamer is 0.1:1 to 0.75:1; the matrix is ​​first stirred at 75 to 95°C until it is completely melted, and then the metal organic framework [MQ][Art]@ZIF-8 encapsulating the ionic liquid is added and mixed thoroughly. After it is evenly dispersed, it is poured into a pre-cleaned and lubricated suppository mold while hot, and the suppository is demolded and taken out after cooling. It is sterilized by ultraviolet light for 60 minutes, then packaged and stored at 4°C.

9. The preparation of the ionic liquid based on mefloquine and artesunate and the sustained-release suppository thereof according to claim 1, characterized in that: In the preparation of ionic liquid PEG1000, PEG2000, PEG4000 or PEG1000-PEG4000 (1:1) type suppositories, the mass ratio of [MQ][Art]@ZIF-8 and four PEG matrices is 0.1:1 to 0.75:1; the above matrices are first stirred at 50-70°C, 55-85°C, 65-90°C or 60-90°C until completely melted, and then the metal organic framework [MQ][Art]@ZIF-8 encapsulating the ionic liquid is added and stirred. After it is evenly dispersed, it is poured into a pre-cleaned and lubricated suppository mold while hot, and the suppository is demolded and taken out after cooling. It is sterilized by ultraviolet light for 60 minutes, and then packaged and stored at 4°C.

10. The preparation method of the ionic liquid based on mefloquine and artesunate and the sustained-release suppository thereof according to claim 1, characterized in that: In the preparation of ionic liquid glycerol-gelatin (2:7) matrix suppositories, the mass ratio of [MQ][Art]@ZIF-8 and glycerol-gelatin is 0.1:1~0.75:1; gelatin is first added to deionized water with a mass of 1 / 7 of its mass for pre-swelling, and then placed in a water bath at 65~95℃ for heating to dissolve the gelatin to form a homogeneous saturated solution, glycerol and metal organic framework [MQ][Art]@ZIF-8 encapsulating the ionic liquid are added while stirring to make the latter evenly dispersed in the matrix, and then the water is evaporated and the mixture is poured into a pre-cleaned and lubricated suppository mold while hot, and the suppository is demolded and taken out after cooling, sterilized by ultraviolet light for 60 minutes, and then packaged and stored at 4℃.

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