A cyclodextrin-metal organic framework composition for improving drug solubility

Abstract

The invention discloses a cyclodextrin-metal organic framework composition for improving drug solubility, comprising: (a) cyclodextrin-metal organic framework material; and (b) a drug loaded on the framework material or mixed therewith, the drug being a sartan drug. The composition of the present invention, by loading sartan drugs on cyclodextrin-metal organic framework material or mixing therewith, can significantly improve the solubility and dissolution rate of sartan drugs in water, solve the problems of poor solubility and low oral bioavailability of sartan drugs, and the raw materials and solvents used for preparing the composition are cheap and easily available, and the steps are simple, which is conducive to industrial production.

Description

Technical Field

[0001] The invention relates to a cyclodextrin-metal organic framework composition capable of improving drug solubility. Background Art

[0002] Hypertension is one of the most common cardiovascular diseases. It not only directly harms health, but also accelerates the process of atherosclerosis. High blood pressure is the main risk factor for stroke, coronary heart disease, heart failure and kidney disease in the Chinese population. The incidence and death toll of cardiovascular and cerebrovascular diseases in my country are increasing, and the number of deaths accounts for 40% of the total mortality rate in my country. Hypertension has become a common problem that endangers health.

[0003] Sartan drugs, namely angiotensin II receptor antagonists (ARB) antihypertensive drugs, have been on the market for more than 10 years. Due to their significant antihypertensive effect and good tolerance, especially clinical trials and evidence-based evidence show that they have unique therapeutic effects and protective effects on cardiovascular diseases, they have become one of the most common antihypertensive drugs in clinical practice, attracting widespread clinical attention. In addition, the incidence of adverse reactions such as dry cough, drug withdrawal rebound and postural hypotension after long-term use is low. They have been recommended by multiple WHO treatment guidelines as first-line antihypertensive drugs for hypertensive patients with cardiovascular disease and proteinuria. Sartan drugs are mostly BCS II drugs with poor solubility in water, resulting in low oral bioavailability of sartan drugs. In order to improve the oral bioavailability of sartan drugs, the solubility of sartan drugs must be improved.

[0004] Valsartan is an angiotensin II receptor antagonist (ARB) antihypertensive drug. Over the past 10 years, it has become one of the most common antihypertensive drugs in clinical practice due to its significant antihypertensive effect and good tolerance. In particular, clinical trials and evidence-based evidence have shown that it has unique efficacy and protective effects on cardiovascular diseases. It has attracted widespread clinical attention, and the incidence of adverse reactions such as dry cough, drug withdrawal rebound and postural hypotension after long-term use is low. It has been recommended by multiple WHO treatment guidelines as a first-line antihypertensive drug for hypertensive patients with cardiovascular disease and proteinuria. Valsartan is a BCS II drug with poor solubility in water, resulting in low oral bioavailability of valsartan. In order to improve the oral bioavailability of valsartan, the solubility of valsartan must be improved. Summary of the invention

[0005] The object of the present invention is to provide a cyclodextrin-metal organic framework composition for improving drug solubility.

[0006] In a first aspect of the present invention, a drug cyclodextrin-metal organic framework composition is provided, comprising: (a) a cyclodextrin-metal organic framework material; and (b) a drug loaded on or mixed with the framework material, wherein the drug is a sartan drug.

[0007] In another preferred embodiment, the sartan drug is olmesartan medoxomil, olmesartan, irbesartan, telmisartan, valsartan, losartan potassium, losartan, candesartan cilexetil, candesartan, eprosartan, azilsartan or a combination of two or more thereof.

[0008] In another preferred embodiment, the molecular weight of the sartan drug is 350-650.

[0009] In another preferred embodiment, the molecular weight of the sartan drug is 400-500.

[0010] In the present invention, the drug is loaded on the framework material in two ways: the inclusion of the drug molecules by the bicyclodextrin molecules; and the drug forms nanoclusters in the large cavity in the middle of the cyclodextrin-metal organic framework.

[0011] In another preferred embodiment, the metal ions in the cyclodextrin-metal organic framework material are selected from the following group: Li + 、Na + , K + , Rb + , Cs + Mg 2+ 、Cd 2+ Sn 2+ 、Ag + , Yb + , Ba 2+ , Sr 2+ , Ca 2+ , Pb 2+ ,La 3+ .

[0012] In another preferred embodiment, the metal ion is Ca 2+ 、Na + or K + , further optimize K + .

[0013] In another preferred embodiment, anions that form salts or bases with metal ions include but are not limited to OH - 、NO 3 - , CO 3 2- , HCO 3 - , CH 3 COO - 、SCN - , C 6 H 5 COOH=C 6 H 5 COO - , Cl - Br - ,I- , O 2 - , S 2 - , HS - , HSO 4 - , ClO - , ClO 3 - 、MnO 4 - , preferably OH - .

[0014] In another preferred example, the cyclodextrin-metal organic framework material is potassium hydroxide cyclodextrin-metal organic framework material, potassium carbonate cyclodextrin-metal organic framework material, potassium chloride cyclodextrin-metal organic framework material, potassium acetate cyclodextrin-metal organic framework material, preferably potassium acetate γ-cyclodextrin-metal organic framework material.

[0015] In another preferred embodiment, the cyclodextrin in the cyclodextrin-metal organic framework material is selected from the following group: α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, hydroxypropyl-β-cyclodextrin, sulfobutyl-β-cyclodextrin, methyl-β-cyclodextrin, and carboxymethyl-β-cyclodextrin.

[0016] In another preferred embodiment, the cyclodextrin is selected from the group consisting of α-cyclodextrin, β-cyclodextrin, and γ-cyclodextrin, and more preferably γ-cyclodextrin.

[0017] In another preferred embodiment, the cyclodextrin-metal organic framework material is an alkaline or neutral cyclodextrin-metal organic framework material. The alkaline cyclodextrin-metal organic framework material is dispersed in an organic solvent containing an organic acid and incubated to obtain a neutral cyclodextrin-metal organic framework material. In another preferred embodiment, the organic acid is selected from the group consisting of formic acid, acetic acid, citric acid, fumaric acid, tartaric acid, metatartaric acid, malic acid, adipic acid or a mixed solvent thereof, preferably formic acid, acetic acid or a mixed solvent thereof, most preferably acetic acid. In another preferred embodiment, the organic solvent is selected from methanol, ethanol, propanol, isopropanol, n-butanol or a mixed solvent thereof, preferably methanol, ethanol or a mixed solvent thereof, most preferably ethanol.

[0018] In another preferred embodiment, the molar ratio of cyclodextrin-metal organic framework to drug in the composition is 1:0.2-1:2, preferably 1:0.5-1:1.8, and further preferably 1:1.5.

[0019] In another preferred embodiment, the composition further has one or more of the following characteristics:

[0020] (1) The average particle size of the cyclodextrin-metal organic framework material is 5 nanometers to 1000 micrometers;

[0021] (2) The drug loading of the composition is 0.1%-50%.

[0022] In another preferred embodiment, the average particle size of the cyclodextrin-metal organic framework material is 100-1000 nanometers (nanoscale) or 1-100 micrometers (microscale).

[0023] In another preferred embodiment, the drug loading of the composition is 10%-40%, and more preferably 20%-30%.

[0024] The composition of the present application has a solubilizing effect on sartan drugs, such as increasing the solubility of valsartan in water by 10-50 times, preferably 10-40 times, and further preferably 30-40 times, and for another example, increasing the solubility of azisartan in water by 10-200 times, and for another example, increasing the solubility of irbesartan in water by 10-1000 times.

[0025] The second aspect of the present invention provides a method for preparing the composition of the first aspect, the method comprising the step of mixing the cyclodextrin-metal organic framework material with a drug solution to obtain the composition.

[0026] In another preferred embodiment, the mixing temperature is 25-65°C, preferably 30-50°C, most preferably 30-40°C.

[0027] In another preferred embodiment, the mixing time is 10 minutes to 3 days, preferably 1 hour to 12 hours, and most preferably 30 minutes to 2 hours.

[0028] In another preferred embodiment, the drug is a sartan drug selected from the group consisting of: olmesartan medoxomil, olmesartan, irbesartan, telmisartan, valsartan, losartan potassium, losartan, candesartan cilexetil, candesartan, eprosartan, azilsartan or a combination of two or more thereof.

[0029] In another preferred embodiment, the drug solution is prepared by dissolving the drug in a solvent selected from the group consisting of methanol, ethanol, propanol, isopropanol, n-butanol, chloroform, dimethylformamide or a mixed solvent thereof, preferably methanol, ethanol or a mixed solvent thereof, most preferably ethanol.

[0030] In another preferred embodiment, the molar ratio of cyclodextrin to drug in the cyclodextrin-metal organic framework material is 1:1.5-1:25.

[0031] In another preferred embodiment, the molar ratio of cyclodextrin to drug is 1:1-1:50, preferably 1:1-1:30, 1:1-1:25, 1:1-1:22, 1:15-1:25.

[0032] In another preferred embodiment, the preparation method further comprises a post-processing step: collecting the solid and drying it.

[0033] The third aspect of the present invention provides a method for preparing the composition of the first aspect, the method comprising the steps of mixing the drug with the cyclodextrin-metal organic framework material and grinding them to obtain the composition.

[0034] In another preferred embodiment, the drug is a sartan drug selected from the group consisting of: olmesartan medoxomil, olmesartan, irbesartan, telmisartan, valsartan, losartan potassium, losartan, candesartan cilexetil, candesartan, eprosartan, azilsartan or a combination of two or more thereof.

[0035] In another preferred embodiment, the feed ratio of the cyclodextrin-metal organic framework material to the drug is 1:0.2-1:2, preferably 1:0.4-1:1.8.

[0036] In another preferred embodiment, the drug is in the form of powder or drug solution. In another preferred embodiment, the drug solution is prepared by dissolving the drug in a solvent selected from the group consisting of methanol, ethanol, propanol, isopropanol, n-butanol, chloroform, dimethylformamide or a mixed solvent thereof, preferably methanol, ethanol or a mixed solvent thereof, and most preferably ethanol.

[0037] In another preferred embodiment, the cyclodextrin-metal organic framework material is in the form of a powder or a drug solution. In another preferred embodiment, the drug solution is prepared by dissolving the cyclodextrin-metal organic framework material in a solvent selected from the group consisting of methanol, ethanol, propanol, isopropanol, n-butanol, chloroform, dimethylformamide or a mixed solvent thereof, preferably water, methanol, ethanol or a mixed solvent thereof, most preferably ethanol and methanol. In another preferred embodiment, the grinding is performed using a ball mill. In another preferred embodiment, the ball mill uses zirconium beads with a diameter of 6-10 mm, preferably 8 mm, for grinding. In another preferred embodiment, the weight ratio of beads to (drug + cyclodextrin-metal organic framework material) is 15:1-1:1, preferably 10:1-3:1. In another preferred embodiment, the grinding time is 1 min-2 h, preferably 5-80 min.

[0038] The fourth aspect of the present invention provides a method for preparing the composition of the first aspect, comprising the following steps:

[0039] (i) dissolving cyclodextrin and a metal ion source in water to prepare a first solution, and mixing the drug with an organic solvent to prepare a second solution;

[0040] (ii) adding the second solution to the first solution and mixing them to obtain a mixture;

[0041] (iii) collecting and drying the mixture as solid to obtain the composition.

[0042] In another preferred embodiment, the metal ion source is selected from the following group: potassium hydroxide, potassium carbonate, and potassium chloride.

[0043] In another preferred embodiment, the concentration of the cyclodextrin in the first solution is 0.01-200 mM.

[0044] In another preferred embodiment, the molar ratio of the cyclodextrin to the metal ions in the metal ion source is 1:1-1:10.

[0045] In another preferred embodiment, the drug is a sartan drug selected from: Olmesartan Medoxomil, Olmesartan, Irbesartan, Telmisartan, Valsartan, Losartan Potassium, Losartan, Candesartan Cilexetil, Candesartan, Eprosartan, Azilsartan or a combination of two or more thereof

[0046] In another preferred embodiment, the second solution is prepared by dissolving the drug in an organic solution selected from the group consisting of methanol, ethanol, propanol, isopropanol, n-butanol, chloroform, dimethylformamide or a mixed solvent thereof, preferably methanol, ethanol or a mixed solvent thereof, most preferably ethanol.

[0047] In another preferred embodiment, in step ii), the second solution is added to the first solution for mixing, and a morphology regulator may be added for mixing to obtain a mixture.

[0048] In another preferred embodiment, the morphology regulator is polyethylene glycol, povidone, polysorbate, sorbitan monolaurate, polyoxyethylene lauryl ether, emulsifier OP, lactobacillus A, pluronic acid, sodium dodecyl sulfate, sodium dodecylbenzene sulfonate, hexadecyltrimethylammonium bromide, or a combination thereof.

[0049] In another preferred embodiment, the morphology regulator is polyethylene glycol 20000, polyethylene glycol 2000, polyethylene glycol 4000, polyethylene glycol 6000, polyethylene glycol 8000, polyethylene glycol 10000, polyethylene glycol 20000, or a combination thereof.

[0050] In another preferred embodiment, the morphology regulator is added at a ratio of 1-20 mg / mL supernatant, preferably 5-10 mg / mL supernatant.

[0051] A fifth aspect of the present invention provides a pharmaceutical composition comprising:

[0052] The composition of the first aspect; and

[0053] A pharmaceutically acceptable carrier.

[0054] "Pharmaceutically acceptable carrier" refers to: one or more compatible solid or liquid fillers or gel substances, which are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" here means that the components in the composition can be mixed with the compounds of the present invention and with each other without significantly reducing the efficacy of the compounds. Some examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as ), wetting agents (such as sodium lauryl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0055] In another preferred embodiment, the carrier is selected from the following group: diluent, excipient, filler, binder, wetting agent, disintegrant, absorption promoter, surfactant, adsorption carrier, lubricant, or a combination thereof.

[0056] In another preferred embodiment, the pharmaceutical composition is formulated as a solid dosage form or a liquid dosage form, preferably suitable for oral administration. In another preferred embodiment, the solid dosage form includes capsules, tablets, pills, powders and granules. In another preferred embodiment, the liquid dosage form includes a pharmaceutically acceptable emulsion, solution, suspension, syrup or tincture.

[0057] In another preferred embodiment, the pharmaceutical composition is in the form of capsules, tablets or granules.

[0058] In another preferred embodiment, the pharmaceutical composition further comprises a surfactant selected from the group consisting of polysorbate-80, polysorbate-60, polyethylene glycol glycerol fatty acid esters, sorbitan fatty acid esters and a mixture of two or more thereof.

[0059] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described below (such as embodiments) can be combined with each other to form a new or preferred technical solution. Due to space limitations, they will not be described one by one here. BRIEF DESCRIPTION OF THE DRAWINGS

[0060] Figure 1 This is the differential scanning calorimetry (DSC) diagram of Example 13.

[0061] Figure 2 This is the gas adsorption diagram of Example 13.

[0062] Figure 3 This is the infrared spectrum of Example 13.

[0063] Figure 4 This is the powder X-ray diffraction (PXRD) pattern of Example 13.

[0064] Figure 5 These are the dissolution curves of the valsartan-loaded CD-MOF composition capsules prepared in Example 14 in four different media.

[0065] Figure 6 The dissolution curves of the commercially available Daiwen capsules in Example 14 in four different media are shown.

[0066] Figure 7 The dissolution curves of the valsartan CD-MOF composition tablets in Example 17 and a domestic commercially available tablet in water are shown.

[0067] Figure 8 This is the dissolution rate diagram of Example 18.

[0068] Fig. 9 Characterization diagrams of the azilsartan CD-MOF composition in Example 20, (a) X-ray diffraction, (b) infrared, (c) gas adsorption, and (d) differential scanning calorimetry.

[0069] Fig.10 This is the X-ray small angle scattering diagram of the azilsartan CD-MOF composition in Example 20.

[0070] Fig.11 This is a molecular simulation diagram of CD-MOF loaded with azilsartan in Example 27, where a is the inclusion of cyclodextrin molecular pairs, and b is the formation of nanoclusters of azilsartan in the cavity.

[0071] Fig.12 This is the molecular simulation diagram of valsartan loaded on CD-MOF in Example 28.

[0072] Fig.13 This is the X-ray small-angle scattering diagram of valsartan, etc. loaded on CD-MOF in Example 28.

[0073] Fig.14 This is the solid-state NMR image of CD-MOF loaded with valsartan, etc. in Example 28. DETAILED DESCRIPTION

[0074] After extensive and in-depth research, the inventors have developed for the first time a cyclodextrin-metal organic framework complex loaded with sartan drugs. Loading sartan drugs on cyclodextrin-metal organic framework materials or mixing them with them can significantly improve the solubility and dissolution rate of sartan drugs in water, solving the problems of poor solubility and low oral absolute bioavailability of sartan drugs. The raw materials and solvents used to prepare the composition are cheap and easily available, the steps are simple, and it is conducive to industrial production.

[0075] Cyclodextrin

[0076] Cyclodextrin is a general term for a series of cyclic oligosaccharides generated by amylose under the action of glucosyltransferase, usually containing 6 to 12 D-pyranose units. Among them, the molecules containing 6, 7, and 8 glucose units are studied more and have important practical significance, which are called α, β- and γ-cyclodextrin respectively. Cyclodextrin is the ideal host molecule similar to enzyme discovered so far, and it has the characteristics of enzyme model itself.

[0077] Metal-organic framework materials

[0078] Metal-organic frameworks (MOFs) are crystalline materials that form an infinitely extended network structure by connecting inorganic metal centers with organic bridging ligands through coordination bonds. Due to the ultra-high porosity and huge specific surface area of ​​MOFs, as well as their structure composed of different inorganic and organic components, their structure is diverse and adjustable, which makes MOFs have potential application value in many fields such as gas storage, catalysis, and drug carriers.

[0079] Cyclodextrin-metal organic framework materials

[0080] As used herein, the terms "cyclodextrin-based metal organic framework materials", "cyclodextrin-metal organic framework materials", and "cyclodextrin-metal organic framework compounds" are used interchangeably, and are based on the ability of cyclodextrin to form a new crystal with the first and second main group metal ions in an organic coordination manner in aqueous solution. This crystal has the characteristics of being porous, having a large surface area, and being able to store gas. This green, porous material can adsorb some structurally unstable drugs, and its huge cavity can protect the drugs, which makes its commercial development possible, especially because the cyclodextrin-metal organic framework is an edible derivative suitable for human consumption. Using cyclodextrin as an organic ligand and metal ions as inorganic metal centers, a new, safer, and pharmaceutically usable cyclodextrin-metal organic framework, i.e., CD-MOF, can be formed.

[0081] As used herein, the term "basic cyclodextrin-metal organic framework material" is a cyclodextrin-metal organic framework material prepared with alkali metal and cyclodextrin as raw materials, which is alkaline and has a pH of about 11-13 when dissolved in water to prepare a 10 mg / mL aqueous solution.

[0082] As used herein, the terms "neutral cyclodextrin-metal organic framework material" and "acidified cyclodextrin-metal organic framework material" are used interchangeably, and are nearly neutral cyclodextrin-metal organic framework materials obtained by acidifying alkaline cyclodextrin-metal organic framework materials, and when the cyclodextrin-metal organic framework material is dissolved in water to prepare a 10 mg / mL aqueous solution, the pH value is about 5-8. A preferred method for acidification treatment is as follows: weigh a certain amount of cyclodextrin-metal organic framework and place it in ethanol, add a certain amount of glacial acetic acid, shake and incubate at 25°C for a certain period of time, and then wash the obtained solid with ethanol to obtain a nearly neutral cyclodextrin-metal organic framework.

[0083] Cyclodextrin-metal organic framework complexes of drugs

[0084] As used herein, the terms "drug-loaded cyclodextrin-metal organic framework composition", "drug-loaded cyclodextrin-metal organic framework complex", "drug-loaded cyclodextrin-metal organic framework", "drug-loaded CD-MOF complex", "drug-loaded CD-MOF", "CD-MOF-loaded drug", "drug CD-MOF composition", and "CD-MOF-loaded drug" can be used interchangeably, and the above terms all represent samples obtained by loading sartan drugs on cyclodextrin-metal organic framework materials or mixing sartan drugs with cyclodextrin-metal organic framework materials.

[0085] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention. The experimental methods in the following examples without specifying specific conditions are usually based on conventional conditions or the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are calculated by weight.

[0086] General Methods

[0087] Method for determining the content of sartan drugs: using ultraviolet spectrophotometry, for example, the ultraviolet detection wavelength of valsartan is 250nm, the ultraviolet detection wavelength of azilsartan is 250nm, the ultraviolet detection wavelength of telmisartan is 290nm, and the ultraviolet detection wavelength of irbesartan is 245nm.

[0088] Solubility determination method: Weigh an excess of the sample to be tested, place it in water, shake it on a shaker (25°C, 200 rpm) for three days, centrifuge and filter, and determine the concentration of the drug in the solution according to the above "Content Determination Method". Record it as the solubility of the sample to be tested in 25°C water.

[0089] Solubilization factor: the ratio of the solubility of the sample to be compared to the solubility of the drug in water (25°C).

[0090] Determination and calculation method of drug loading and drug loading molar ratio: accurately weigh 5 mg (m 1) The sample to be tested is placed in a 100mL volumetric flask, dissolved in pure water, filtered, and the drug content is determined according to the "content determination conditions" to calculate the drug mass m 2 .

[0091] Drug loading (%) = m 2 / m 1 ×100;

[0092] The molar ratio of carrier to drug is: 2 / M 药物 ):((m 1 -m 2 ) / M 载体 ), M 载体 is the molecular weight of the carrier, M 药物 is the molecular weight of the drug.

[0093] Example 1: Valsartan Micronized Potassium Hydroxide CD-MOF Composition - Incubation

[0094] Measure 3000mL of pure water in a beaker, add 97.3g of γ-CD and stir, then add 33.6g of KOH, and ultrasonicate to completely dissolve γ-CD and KOH to obtain a mother liquor. Pour the mother liquor into a reactor, set the speed to 300rpm, and the temperature to 50°C. Add 1800mL of methanol to the reactor, and add 38.4g of PEG20000 after dissolving and clarifying. Centrifuge at room temperature overnight, remove the supernatant, and wash the precipitate twice with 100mL of ethanol and then with 100mL of methanol. Dry the precipitate in a vacuum drying oven at 40°C for 12h to obtain a micron-sized potassium hydroxide-cyclodextrin-metal organic framework with a particle size of 1-10 microns.

[0095] Weigh 200 mg of micron-sized potassium hydroxide CD-MOF into a 15 mL centrifuge tube, add 10 mL of valsartan ethanol solution (the molar ratio of cyclodextrin to valsartan in the cyclodextrin-metal organic framework material is 1:22), incubate on a shaker (37°C, 150 rpm) for 20 h, centrifuge, and vacuum dry the lower precipitate at 60°C for 4 h to obtain a micron-sized potassium hydroxide CD-MOF composition loaded with valsartan.

[0096] The drug loading in the obtained composition was 29.4% (w / w), the molar ratio of CD-MOF to valsartan was 1:1.4, and the solubility of valsartan in water was increased by 34.5 times (the solubility of valsartan raw material in water at 25° C. was 0.08 mg / mL).

[0097] Example 2: Valsartan Micronized Potassium Acetate CD-MOF Composition - Incubation

[0098] On the basis of Example 1, micron-sized potassium acetate CD-MOF was further prepared: 0.4L of anhydrous ethanol was added to the lower precipitate for dispersion, centrifugal washing was performed, and then 0.4L of anhydrous ethanol and 20mL of glacial acetic acid were added to the precipitate, stirred for neutralization, and the supernatant was removed by centrifugation. Finally, 0.4L of ethanol was added to the precipitate, and centrifuged (4000rpm, 5min) for washing twice. The washed precipitate was placed in a vacuum drying oven at 60°C and dried for 4h. A micron-sized potassium acetate cyclodextrin-metal organic framework was obtained, with a particle size of 1-10 microns.

[0099] According to the drug loading method described in Example 1 (the molar ratio of cyclodextrin to valsartan in the cyclodextrin-metal organic framework material is 1:20), a valsartan CD-MOF composition was prepared, and the drug loading in the resulting composition was 30.7% (w / w), and the molar ratio of CD-MOF to valsartan was 1:1.6, which increased the solubility of valsartan in water by 33.7 times.

[0100] Example 3: Valsartan Micronized Potassium Hydroxide CD-MOF Composition - Stirring

[0101] Weigh 200 mg of the micron-sized potassium hydroxide CD-MOF prepared in Example 1 into a 20 mL vial, add 10 mL of valsartan ethanol solution (the molar ratio of cyclodextrin to valsartan in the cyclodextrin-metal organic framework material is 1:20), heat at 40°C with magnetic stirring for 1 h, centrifuge, and vacuum dry the lower precipitate to obtain a valsartan-loaded micron-sized potassium hydroxide CD-MOF composition. The drug loading in the obtained composition is 29.7%, the molar ratio of CD-MOF to valsartan in the composition is 1:1.5, and the solubilization multiple is 35.6.

[0102] Example 4: Valsartan Micronized Potassium Acetate CD-MOF Composition - Stirring

[0103] 40 g of the micron-sized potassium acetate CD-MOF in Example 2 was weighed into a beaker, and 1 L of 0.25 g / mL valsartan ethanol solution was added (the molar ratio of γ-CD to valsartan was 1:22), and the drug was loaded according to the method of Example 3. As a control, γ-CD was used instead of CD-MOF, and a valsartan γ-CD composition was prepared by the same method.

[0104] Preparation of valsartan CD-MOF physical mixture: Valsartan and micron-sized potassium acetate CD-MOF were weighed according to the drug loading ratio, placed in a beaker, and stirred and mixed with a glass rod to obtain a physical mixture.

[0105] Results: The drug loading of the obtained valsartan CD-MOF composition was 31.1%, the molar ratio of CD-MOF to valsartan in the composition was 1:1.5, and the solubilization factor was 39.5, which was significantly higher than that of the valsartan γ-CD composition (the solubilization factor was 4.6).

[0106] Dissolution assay: Weigh a dose (80 mg) of valsartan CD-MOF composition, and conduct a dissolution experiment 6 times in parallel. The speed is 100 rpm, the temperature is 37.0 ± 0.5 ° C, the medium is 900 mL of deionized water, and 5 mL is sampled at different time points. The absorbance is measured by ultraviolet at 250 nm to calculate the dissolution amount. At the same time, the valsartan raw material and the physical mixture of valsartan and CD-MOF are compared and determined.

[0107] Results: Table 1, valsartan micronized potassium acetate CD-MOF composition and physical mixture are significantly higher than valsartan raw material, and the composition is significantly higher than the physical mixture.

[0108] Table 1 Dissolution of valsartan CD-MOF compositions, physical mixtures and raw materials

[0109]

[0110] Example 5: Valsartan Nano-Potassium Hydroxide CD-MOF Composition

[0111] Take 2000mL pure water in a 5000mL beaker, weigh 64.9g γ-CD in the beaker, stir, then add 22.4g KOH to the beaker, ultrasonicate to completely dissolve γ-CD and KOH to obtain mother liquor. Pour the mother liquor into the reactor, at a speed of 300rpm and a temperature of 50°C, add 1200mL methanol to the reactor, and then add PEG20000 (8mg / mL). Let stand overnight in a cold water bath. Centrifuge to remove the supernatant, wash the precipitate twice with 150mL ethanol, and dry it in a vacuum drying oven at 40°C for 12h. The particle size is 100-500 nanometers.

[0112] The drug loading was performed according to the method of Example 3 (the molar ratio of cyclodextrin to valsartan in the cyclodextrin-metal organic framework material was 1:20) to obtain a valsartan nano-scale potassium hydroxide CD-MOF composition. Results: The drug loading in the obtained composition was 31.7%, the molar ratio of CD-MOF to valsartan was 1:1.5, and the solubilization multiple was 36.2.

[0113] Example 6: Valsartan Nano-scale Potassium Acetate CD-MOF Composition

[0114] Based on Example 5, the method of Example 2 was improved to prepare nano-scale potassium acetate CD-MOF, with a particle size of 100-500 nanometers. The drug was loaded according to the method of Example 3 (the molar ratio of cyclodextrin to valsartan in the cyclodextrin-metal organic framework material was 1:20), and a valsartan nano-scale potassium hydroxide CD-MOF composition was obtained. Results: The drug loading in the obtained composition was 32.8%, the molar ratio of CD-MOF to valsartan was 1:1.7, and the solubilization multiple was 36.3.

[0115] Example 7: Valsartan Potassium Carbonate CD-MOF Composition

[0116] Take 2500mL of pure water in a beaker, add 81.1g of γ-CD and 34.5g of potassium carbonate to obtain a mother liquor. Pour the mother liquor into a reactor, add 2500mL of methanol, add 40.0g of PEG20000 to completely dissolve after the reaction is clarified, let the reaction solution stand overnight at room temperature and centrifuge to remove the supernatant, wash the precipitate twice with 100mL of ethanol, and then wash it twice with 100mL of methanol. Dry it in a vacuum drying oven at 40°C for 12h to obtain potassium carbonate micron-sized CD-MOF with a particle size of 300-700 microns. According to the method of Example 3, the drug loading (the molar ratio of cyclodextrin to valsartan in the cyclodextrin-metal organic framework material is 1:20) is carried out to obtain a valsartan potassium carbonate CD-MOF composition. Result: The drug loading in the obtained composition is 24.6%, the molar ratio of CD-MOF to valsartan is 1:1.1, and the solubilization multiple is 30.5.

[0117] Example 8: Preparation of valsartan potassium chloride CD-MOF

[0118] Dissolve γ-CD and potassium chloride in 5 mL of water to a concentration of 0.125 M and 0.5 M, respectively, and ultrasonicate for 10 min to fully dissolve them. Then pre-add 0.5 mL of methanol to the mixed solution of γ-CD and potassium chloride, heat methanol at 50 ° C in a closed container, react for 6 hours, wash twice with ethanol and methanol respectively, and vacuum dry the resulting crystals at 50 ° C for 12 hours to obtain potassium chloride CD-MOF with a particle size of 1-10 microns. Carry out drug loading according to the method of Example 3 (the molar ratio of cyclodextrin to valsartan in the cyclodextrin-metal organic framework material is 1:20) to obtain a valsartan potassium chloride CD-MOF composition. Result: The drug loading in the obtained composition is 22.3%, the molar ratio of CD-MOF to valsartan is 1:1.3, and the solubilization multiple is 34.8.

[0119] Example 9: Co-crystallization

[0120] 163.0 mg γ-CD and 56.0 mg KOH were dissolved in 5 mL water and dissolved by ultrasonic. Then 5 mL valsartan methanol solution was added (the molar ratio of γ-CD to valsartan was 1:22), and PEG20000 was added as a morphology regulator at a ratio of 8 mg / mL supernatant. After standing for half an hour, centrifugation was performed, the supernatant was discarded, the lower solid was washed with isopropanol, and the obtained crystals were vacuum dried overnight at 50 ° C to obtain a valsartan cyclodextrin-metal organic framework co-crystallization composition. Results: The drug loading in the obtained composition was 33.9%, the molar ratio of CD-MOF to valsartan was 1:1.8, and the solubilization multiple was 38.9.

[0121] Example 10: Valsartan Potassium Acetate β-CD-MOF Composition

[0122] Weigh 200g of β-cyclodextrin and 78.9g of potassium hydroxide and add 2L of pure water to a beaker to dissolve, then add to a 5L reactor, add 2L of methanol at room temperature of 25°C, at a speed of 100rpm, stir for 16h, centrifuge the suspended reaction solution, and the precipitate is potassium hydroxide β-CD-MOF. Add 40mL of glacial acetic acid to the ethanol suspension of potassium hydroxide β-CD-MOF, stir for 5min to disperse it evenly, filter with filter paper, and continue to wash the filter cake with anhydrous ethanol twice. After the filter cake is dried, it is potassium acetate β-CD-MOF.

[0123] Weigh 200 mg of potassium acetate β-CD-MOF in a 20 mL vial, add 10 mL of valsartan ethanol solution (the molar ratio of cyclodextrin to valsartan in the cyclodextrin-metal organic framework material is 1:22), heat and stir at 37 ° C for 1 hour, centrifuge, and vacuum dry the lower precipitate to obtain a valsartan potassium acetate β-CD-MOF composition. Results: The drug loading in the obtained composition is 14.7%, the molar ratio of CD-MOF to valsartan is 1:0.5, and the solubilization multiple is 15.2.

[0124] Example 11: Valsartan micron-sized potassium acetate CD-MOF composition

[0125] Weigh 20g of the micron-sized potassium acetate CD-MOF prepared in Example 1 into a 1L beaker, add 300mL of 0.1g / mL valsartan ethanol solution (the molar ratio of cyclodextrin to valsartan in the cyclodextrin-metal organic framework material is 1:5), heat at 40°C with magnetic stirring for 1h, centrifuge, and vacuum dry the lower precipitate to obtain a valsartan-loaded micron-sized potassium hydroxide CD-MOF composition. The drug loading in the obtained composition is 12.4%, the molar ratio of CD-MOF to valsartan in the composition is 1:0.5, and the solubilization multiple is 35.2.

[0126] Example 12: Valsartan micron-sized potassium acetate CD-MOF composition

[0127] Weigh 20g of the micron-sized potassium acetate CD-MOF prepared in Example 1 into a 1L beaker, add 500mL of 0.18g / mL valsartan ethanol solution (the molar ratio of cyclodextrin to valsartan in the cyclodextrin-metal organic framework material is 1:16), heat at 40°C with magnetic stirring for 1h, centrifuge, and vacuum dry the lower precipitate to obtain a valsartan-loaded micron-sized potassium hydroxide CD-MOF composition. The drug loading in the obtained composition is 22.82%, the molar ratio of CD-MOF to valsartan in the composition is 1:1.0, and the solubilization multiple is 34.9.

[0128] Example 13: Characterization of Valsartan / CD-MOF Compositions

[0129] As a comparison, valsartan / γ-cyclodextrin inclusion complex was prepared: 1297 mg γ-cyclodextrin (1 mmol) was weighed and dissolved in 30 mL water, 435 mg valsartan (1 mmol) was weighed and dissolved in 15 mL ethanol, and the valsartan solution was added dropwise to the γ-cyclodextrin aqueous solution under stirring, and the temperature was maintained at 40 ° C, and stirring was continued at 500 rpm for 3 hours, and the ethanol was removed. The remaining liquid was freeze-dried to obtain the valsartan / γ-cyclodextrin inclusion complex. The content (w / w) of valsartan in the obtained cyclodextrin inclusion complex was 15.5%, the molar ratio of γ-cyclodextrin to valsartan was 1:0.64, and the solubility of the inclusion complex in water was 0.38 mg / mL, which increased the solubility of valsartan in water by 4.75 times.

[0130] Figure 1 : A broad melting endothermic peak is observed for valsartan at 108°C, while this peak completely disappears in the cyclodextrin inclusion complex and the valsartan CD-MOF composition in Example 4, and this absorption peak reappears in the physical mixture, indicating that valsartan is included in the cyclodextrin and valsartan in the composition is loaded by CD-MOF.

[0131] Figure 2 :The gas adsorption results show that the specific surface area of ​​potassium acetate CD-MOF is 996m 2 / g, the Langmuir specific surface area of ​​the valsartan CD-MOF composition (Example 11) with a drug loading molar ratio of 1:0.5 is as high as 307 m 2 / g, while the Langmuir specific surface area of ​​the valsartan CD-MOF composition with a drug loading molar ratio of 1:1.5 (Example 4) is almost zero, indicating that valsartan is loaded by CD-MOF.

[0132] Figure 3: The infrared spectra of the valsartan-loaded neutral micron-sized CD-MOF composite are different from the valsartan API and neutral micron-sized CD-MOF and the physical mixture of the two. Comparing the spectra of CD-MOF, VAL / CD-MOF and the physical mixture of CD-MOF and VAL, the three samples have a peak at 2926 cm -1 All of them have relatively broad absorption bands, which can be attributed to the stretching vibration of -CH- in CD-MOF (ν CH ). Due to the presence of its own amide bond and carbonyl group, VAL has a peak at 1731 cm -1 and 1600cm -1 There is strong absorption at 1445cm (characteristic absorption of carbon-oxygen double bond) and -1 ν (C＝C) Aromatic ring vibration, CD-MOF does not have the above characteristic absorption; VAL / CD-MOF has 1731cm -1 (amide carboxyl) and 1445cm -1 ν (C＝C) The vibrations were significantly weakened or disappeared in intensity, while the physical mixture still existed. The characteristic peaks of VAL were masked, indicating that valsartan was loaded by CD-MOF.

[0133] Figure 4 :The powder X-ray diffraction results show that valsartan has a o With 20-22 o There are two broad diffraction peaks; CD-MOF has a typical crystal structure. The corresponding CD-MOF diffraction peaks in the valsartan CD-MOF composite after drug loading still exist, indicating that the valsartan CD-MOF composite after drug loading is still a crystal structure.

[0134] Example 14: Preparation of valsartan micron-sized potassium acetate CD-MOF composition capsules

[0135] Preparation process: Weigh 10 g of the valsartan-loaded micron-sized potassium acetate CD-MOF composition prepared in Example 4, add 10 mL of 0.05 mg / mL polysorbate-80 ethanol solution to evenly wet it, blow with high-purity nitrogen for 30 minutes, granulate through a 30-mesh sieve, dry, granulate, and fill capsules. The dissolution and dissolution rate were compared with those of the commercially available Diovan capsules in four different pH media.

[0136] Dissolution determination: using the basket method, rotation speed 100 rpm, temperature 37 ° C, four different media: pH 6.8 phosphate buffer, pH 4.5 acetate buffer, pH 1.2 hydrochloric acid solution and deionized water 1000 mL each, take points at 3, 5, 10, 15, 30, 60, 90, 120 min, take 5 mL each time, measure the absorbance at 250 nm using UV.

[0137] The results showed that the CD-MOF composite capsules loaded with valsartan micron potassium acetate ( Figure 5 ) in various media showed lower dissolution differences than commercially available capsules ( Figure 6 ), significantly improving the dissolution rate of commercially available capsules at pH 1.2 and in water, and helping to improve the bioavailability of valsartan.

[0138] Example 15: Bioavailability in rats

[0139] 12 healthy male SD rats were purchased from Shanghai Experimental Animal Research Center, weighing about 200±20g, and randomly divided into 2 groups, 6 rats in each group, and given valsartan CD-MOF composition (prepared in Example 6) and original Daiwen capsule 15mg / kg by gavage, and 0.3mL of blood was collected from the eye socket at 0, 0.08, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 8, 12 and 24h. The bioavailability of the neutral micron-sized CD-MOF composition loaded with valsartan was compared and evaluated with that of the original Daiwen capsule.

[0140] The valsartan concentration in rat plasma samples was determined by high performance liquid chromatography tandem mass spectrometry (LC-MS / MS) analysis. The pharmacokinetic parameters of 12 healthy male SD rats were calculated using DAS2.0 software. The results are shown in Table 2. Compared with the Diovan group, the average relative bioavailability of the valsartan / CD-MOF group was 149.3%, indicating that the bioavailability of valsartan in rats was significantly improved after CD-MOF was loaded with valsartan. At the same time, SPSS17.0 software was used to analyze the pharmacokinetic parameters (area under the drug-time curve AUC 0-24h , peak concentration C max , peak time T max ) were used for t-test statistical analysis, and the results showed that the AUC of the two groups 0-24h , C max and T max There are significant differences, which further illustrates that the bioavailability of valsartan is significantly improved after being loaded into CD-MOF.

[0141] Table 2. Pharmacokinetic parameters in rats

[0142] Pharmacokinetic parameters Valsartan CD-MOF composition Daiwen Capsules AUC0-24h (μg / mL·h) 77.71±13.12* 52.05±23.02 Tmax(h) 0.72±0.25** 2.22±1.08 Cmax(μg / mL) 16.88±4.85** 7.90±3.70

[0143] Note: Compared with the Daiwen group *p<0.05; **p<0.01.

[0144] Example 16: Bioavailability in Beagle Dogs

[0145] 12 healthy adult beagles were purchased from the teaching experiment practice field of the Agricultural College of Shanghai Jiaotong University, weighing about 8-12kg, and were divided into 3 groups, each with 4 (half male and half female). A three-cycle three-crossover experimental design was adopted. In the first cycle, the three groups were respectively orally administered with valsartan / CD-MOF composition capsules (drug A, prepared according to Example 4, granulated with Tween-80 ethanol solution), Daiwen capsules (drug B), and valsartan / γ-CD inclusion compound capsules (drug C); in the second cycle, the three groups were respectively orally administered with drug B, drug C, and drug A; in the third cycle, the three groups were respectively orally administered with drug C, drug A, and drug B, and the washout period between every two weeks was 2 weeks. The beagles were fasted for 12 hours before the experiment, and were free to drink water. They were prohibited from eating within 4 hours after taking the medicine, and they ate a unified meal during the test. When administering the drug, the capsule was directly inserted into the pharynx, and the beagle dogs were allowed to swallow it automatically and injected with about 50 mL of clean water. 2 mL of blood was collected from the subcutaneous vein of the inner side of the forelimb at 0, 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 24, 36, and 48 hours. The concentration of valsartan in the plasma samples of beagle dogs was determined by LC-MS / MS analysis.

[0146] The pharmacokinetic results of beagle dogs showed (Table 3) that the average AUC of valsartan / CD-MOF composite capsules was higher than that of valsartan γ-CD inclusion compound capsules. 0-48h Improved by 47.3%, average C max The average AUC of valsartan / CD-MOF composite capsules was increased by 42.2% compared with that of Daiwen capsules. 0-48h Improved by 59.8%, average C max The above results show that CD-MOF loaded with valsartan can improve the bioavailability of valsartan in beagle dogs compared with the other two groups.

[0147] Table 3 Pharmacokinetic parameters in beagle dogs

[0148] Pharmacokinetic parameters Valsartan / CD-MOF Daiwen Valsartan / γ-CD AUC0-48h (μg / mL·h) 10.52±6.10 6.58±2.45 7.14±3.69 Tmax(h) 1.08±0.56 1.75±0.99 1.08±0.52 Cmax(μg / mL) 4.38±2.09* 2.00±0.77 3.08±1.73

[0149] Note: Compared with the Daiwen group * p<0.05.

[0150] Example 17: Valsartan / CD-MOF Composition Tablets

[0151] Preparation process: Weigh the valsartan-loaded neutral micron-sized CD-MOF composition and various auxiliary materials in the following formula and mix them evenly in a mixer, and use a 12 mm punch to perform powder direct compression tableting.

[0152] prescription:

[0153]

[0154] Dissolution assay: using the paddle method, at a rotation speed of 100 rpm, a temperature of 37.0 ± 0.5 °C, the medium is 900 mL of deionized water, sampling points are taken at 0.5, 3, 5, 10, 15, 30, and 60 min, 5 mL is taken each time, filtered with a 0.45 μm filter membrane, diluted appropriately, and the absorbance is measured at 250 nm using UV (n = 6).

[0155] The results are as follows Figure 7 As shown, the dissolution rate of the valsartan micron-sized potassium acetate CD-MOF composite tablet was 91% in 30 minutes, while the dissolution rate of a commercially available valsartan tablet was 58% in 30 minutes.

[0156] Example 18: Valsartan Micronized Potassium Acetate CD-MOF Composition - Grinding Method

[0157] Weigh 7.0g of the micron-sized potassium acetate CD-MOF prepared in Example 1 and 3.0g of valsartan (the molar ratio of cyclodextrin to valsartan in the cyclodextrin-metal organic framework material is 1: 1.5), and grind them for 5, 10 and 60min respectively in a ball mill (the weight ratio of zirconium beads to powder is 3: 1) to obtain a valsartan micron-sized potassium acetate CD-MOF composition. Its solubilization multiples are 32.2, 32.5, and 38.9 times, respectively, which is significantly higher than the valsartan γ-CD composition (solubilization multiple is 4.5 times) prepared by the grinding method (the molar ratio of cyclodextrin to valsartan is 1: 1.5, the weight ratio of zirconium beads to powder is 3: 1, and the grinding is 60min).

[0158] The dissolution rate of the composition obtained by grinding for 5 min was tested. The results were as follows: Figure 8 As shown, 87.1% was dissolved in 10 min.

[0159] The same method was used to grind the simple drug valsartan (the weight ratio of zirconium beads to powder was 3:1) for 60 minutes, and the solubilization factor was 1.4 times. Figure 8 As shown, 4.8% was dissolved in 10 min.

[0160] Weigh 7.0 g of micron-sized potassium acetate CD-MOF and 3.0 g of valsartan (the molar ratio of cyclodextrin to valsartan in the cyclodextrin-metal organic framework material is 1:1.5), and simply mix them to obtain a valsartan micron-sized potassium acetate CD-MOF composition. The solubilization multiple is 23.3 times. The dissolution rate is as follows Figure 8 As shown, 19.6% was dissolved in 10 min, and the release rate was slower than that of the milled composition.

[0161] 7.0 g of valsartan and gamma cyclodextrin were simply physically mixed (the molar ratio of cyclodextrin to valsartan was 1:1.5) to prepare a valsartan and gamma cyclodextrin composition, which increased the solubility of valsartan by 4.5 times. Figure 8 As shown, 24.8% was dissolved in 10 min.

[0162] Example 19: Telmisartan CD-MOF composition

[0163] Weigh 1.944 g of γ-CD (1.5 mmol), 0.672 g of KOH (12 mmol) (n γ-CD :n KOH =1:8) and 1543.85mg (3mmol) of telmisartan were placed in a 100mL conical flask, 40mL of pure water was added to dissolve it, heated in a 50℃ water bath and stirred (300rpm) for 1h, 24mL of anhydrous methanol was added, stirring continued for 5min, and allowed to stand at room temperature for 2h. Centrifuged (4000rpm, 5min), the precipitate was washed with methanol 3 times, and then dried in a 70℃ forced air drying oven. The drug loading was measured to be 9.8%, and the experimentally measured saturated solubility of telmisartan in water (25℃) was 0.117mg / mL, while the saturated solubility of CD-MOF loaded with telmisartan in water was 11.425mg / mL, which was 98 times higher than the solubility of telmisartan in water.

[0164] Example 20: Azilsartan Potassium Acetate Nano-CD-MOF Composition

[0165] Weigh 520 mg of azilsartan into a 50 mL stoppered conical flask, add 40 mL of anhydrous ethanol, heat and stir in a 60 ° C water bath to completely dissolve the drug, and obtain an azilsartan anhydrous ethanol solution (13 mg / mL). Weigh 1.2 g of potassium acetate nano CD-MOF into a 50 mL stoppered conical flask, heat and stir in a water bath at 60 ° C, 400 rpm for 4 hours. Centrifuge (4000 rpm, 5 min), discard the supernatant, and take the precipitate and dry it in an oven.

[0166] Azilsartan / γ-CD inclusion complex: weigh 8.45 g γ-CD (dissolved in 10 mL pure water) and 1.5 g azilsartan (dissolved in 10 mL anhydrous ethanol), with a molar ratio of CD: azilsartan = 2:1. Use a planetary ball mill and add half the volume of 8 mm diameter zirconium beads for grinding. After grinding for 1 hour, the suspension is rotary evaporated and then oven-dried.

[0167] Results: The drug loading of azilsartan / CD-MOF was 22.77%, and the drug loading molar ratio (AZL:CD) was 1:1. The drug content of the obtained cyclodextrin / azilsartan inclusion complex was 13.14%, and the drug loading molar ratio (AZL:CD) = 0.49:1. The azilsartan cyclodextrin inclusion complex increased the solubility of azilsartan in water by 9.4 times, and the azilsartan / CD-MOF increased the solubility of azilsartan in water by 339.7 times. The solubilization ability of CD-MOF was significantly higher than that of cyclodextrin inclusion (36.1 times).

[0168] Preparation of azilsartan CD-MOF physical mixture (PM): Azilsartan and potassium acetate nano-CD-MOF were weighed according to the drug loading ratio, placed in a beaker, and stirred with a glass rod to obtain a physical mixture.

[0169] Characterization of Azilsartan / CD-MOF Compositions:

[0170] XRD results ( Fig. 9 Figure a) shows that both azilsartan and CD-MOF have obvious characteristic diffraction peaks. After drug loading, the XRD results show no azilsartan diffraction peak, indicating that the drug exists in the form of amorphous in CD-MOF. Similarly, after γ-CD contains azilsartan, the form of azilsartan is also amorphous.

[0171] FT-IR results ( Fig. 9 b) shows that azilsartan is at 1775 cm -1 and 1693cm -1 There are amide bond vibrations at 1770 cm-1 and 1770 cm-2, which are amide carboxyl and amide carbonyl, respectively. After CD-MOF loading, the amide carboxyl of azilsartan / CD-MOF shifts to 1770 cm-1. -1 The amide carbonyl group shifts to 1646 cm -1 , indicating that the strong interaction between CD-MOF and azilsartan is the intermolecular hydrogen bonding between the carboxyl or carbonyl group of azilsartan and the hydroxyl group on CD-MOF. However, the physical mixture (PM, Example) did not shift. After γ-CD inclusion of azilsartan, the 1693 cm -1 The carbonyl group of the amide shifts to 1640 cm -1 , which shows that the interaction sites between γ-CD and azilsartan are mainly the amide carbonyl and the hydroxyl group on γ-CD.

[0172] Gas adsorption ( Fig. 9 c) shows that the Langmuir specific surface area of ​​CD-MOF is 996 m 2 / g, and has a certain pore size distribution, while after drug loading, the specific surface area of ​​azilsartan / CD-MOF decreases due to drug loading.

[0173] DSC results ( Fig. 9 Figure d) shows that azilsartan has a melting endothermic peak at 205°C, and after drug loading, its melting endothermic peak disappears while the physical mixture still exists, indicating that the existence state of azilsartan in CD-MOF has changed, and the same change has also occurred in azilsartan in the inclusion complex.

[0174] SAXS results ( Fig.10 ) showed that when CD-MOF was loaded with azilsartan, due to the loading of azilsartan in CD-MOF, especially the occupation of the large cavity position of CD-MOF, the scattering signal at 1.6nm was significantly weakened, and each scattering peak shifted to the high field. It was inferred that azilsartan was loaded by CD-MOF and occupied the large cavity of CD-MOF, forming nanoclusters in situ.

[0175] Example 21: Bioavailability of Azilsartan in Rats

[0176] 8.45g of γ-cyclodextrin was dissolved in 10mL of pure water, and 1.5g of azilsartan was dissolved in 10mL of anhydrous ethanol solution, with a feed molar ratio of CD:AZL2:1. The two solvents were mixed and added to a planetary ball mill, and half the volume of 8mm diameter pickaxe beads was added and ground for 1h. The suspension was rotary evaporated and oven dried to obtain an inclusion compound. The obtained cyclodextrin / azilsartan inclusion compound had a drug content of 13.14% and a molar ratio (AZL:CD) = 0.49:1. Compared with the azilsartan raw material, it was solubilized 9.4 times.

[0177] 18 healthy male SD rats were randomly divided into 3 groups, namely, the Azilsartan API group, the Azilsartan / CD-MOF group, and the Azilsartan / γ-CD inclusion group, with 6 rats in each group. Rats were fasted for 12 hours before the experiment, weighed, and given 5 mL / kg (Azilsartan dosage was 1 mg / kg) by gavage to the Azilsartan API group, the Azilsartan / CD-MOF group prepared in Example 20, and the Azilsartan / γ-CD inclusion group prepared in Example 20, respectively. About 0.3 mL of blood was collected from the eye sockets at 5 min, 15 min, 30 min, 1 h, 1.5 h, 2 h, 4 h, 8 h, 12 h, and 24 h before and after administration. The blood samples were placed in heparinized EP tubes, centrifuged (4000 rpm, 5 min), and plasma was separated and stored in a -80 ° C refrigerator. Rats were allowed to drink water freely during the experiment. Results: The absorption of Azilsartan / CD-MOF was significantly higher and faster than that of Azilsartan / γ-CD inclusion complex and API. The AUC of Azilsartan / CD-MOF was 9.7 times higher than that of API and 1.4 times higher than that of Azilsartan / γ-CD inclusion complex.

[0178] Table 4 Pharmacokinetic parameters of azilsartan in rats

[0179] Pharmacokinetic parameters Azilsartan / CD-MOF Azilsartan / γ-CD inclusion complex Azilsartan API <![CDATA[AUC (0-12h) (mg / L*h)]]> 30.65±14.24 21.80±7.70 3.16±0.42 <![CDATA[T max (h)]]> 1.50±1.30 0.90±0.42 6.67±2.07 <![CDATA[C max (mg / L)]]> 2.63±1.02 2.06±0.41 0.19±0.01

[0180] Example 22: Valsartan loading at different temperatures

[0181] The micron-sized potassium acetate CD-MOF was selected from Example 2, and the preparation method of Reference Example 3 was used to load valsartan at 20, 60 and 70°C. The water bath heating stirring speed was 400r / min, the drug loading time was 2h, the drug loading suspension was centrifuged to obtain a precipitate, and vacuum dried at 40°C to prepare a composition. Results: The drug loading amounts at 20, 60 and 70°C were 22.9%, 28.8% and 29.3%, respectively, and the molar ratio of CD-MOF to valsartan in the composition was 1:1.0, 1:1.4 and 1:1.4.

[0182] Example 23: Investigation of different solvents for loading valsartan

[0183] With reference to the preparation method of Example 3, methanol, ethanol: methanol 1: 1 mixed solvent, and ethyl acetate were selected as drug-loading solvents. Micron-sized potassium acetate CD-MOF was selected from Example 2, the drug-loading conditions were 40°C, the concentration of valsartan ethanol solution was 250 mg / mL, the water bath heating stirring speed was 400 r / min, the drug-loading time was 2h, the drug-loaded suspension was centrifuged to obtain a precipitate, and vacuum dried at 40°C to prepare a composition. Results: The drug loading in methanol, methanol: ethanol 1: 1 mixed solvent, and ethyl acetate were 26.4%, 24.5%, and 22.37%, respectively, and the molar ratios of CD-MOF and valsartan in the composition were 1: 1.2, 1: 1.1, and 1: 1.0, respectively.

[0184] Example 24: Different feed molar ratios - micron-sized potassium acetate CD-MOF

[0185] Referring to the preparation method of Example 3, the concentration of valsartan ethanol solution was set to 100 mg / mL, 150 mg / mL and 200 mg / mL, and the micron-sized potassium acetate CD-MOF was selected from Example 2. The water bath heating stirring speed was 400 r / min, the drug loading time was 2 h, the drug loading suspension was centrifuged to obtain a precipitate, and vacuum dried at 40 ° C to prepare a composition. Results: The drug loading amounts of the micron-sized potassium acetate CD-MOF and valsartan feed molar ratios of 1:10, 1:15 and 1:20 were 23.7%, 26.6% and 28.7%, respectively, and the molar ratios of CD-MOF and valsartan in the composition were 1:1.1, 1:1.2 and 1:1.4, respectively.

[0186] Example 25: Different feed molar ratios - micron-sized potassium hydroxide CD-MOF

[0187] Referring to the preparation method of Example 3, the concentration of valsartan ethanol solution was set to 100 mg / mL and 150 mg / mL, and the micron-sized potassium hydroxide CD-MOF was selected from Example 1. The water bath heating stirring speed was 400 r / min, the drug loading time was 2 h, the drug loading suspension was centrifuged to obtain a precipitate, and vacuum dried at 40°C to prepare a composition. Results: The drug loading amounts of the micron-sized potassium hydroxide CD-MOF and valsartan feed molar ratios of 1:10 and 1:15 were 22.4% and 25.9%, respectively, and the molar ratios of CD-MOF and valsartan in the composition were 1:1.0 and 1:1.2, respectively.

[0188] Example 26: Irbesartan

[0189] Weigh 1g of irbesartan raw material in a 100mL conical flask, add 50mL of anhydrous ethanol (concentration of 20mg / mL), place in a 50℃ constant temperature water bath with magnetic stirring and heating, after the drug is completely dissolved, add 1.16g of micron-grade potassium acetate CD-MOF in Example 2 (the molar ratio of drug to CD-MOF is 3:1), and heat and stir (300rpm) for 4h. Centrifuge to remove the supernatant, and place the precipitate in a vacuum drying oven to dry (50℃, 5h). Weigh 5mg of drug-loaded CD-MOF in a 10mL volumetric flask, dissolve it in pure water and make up to the scale. After centrifugation (4000rpm, 5min), take the supernatant and use ultraviolet spectrophotometry to measure the drug content. The results show that the drug loading is 11.19%, the molar ratio of CD-MOF to irbesartan in the composition is 1:0.4, and the solubilization multiple is 339 times.

[0190] Example 27: Molecular simulation of γCD-MOF loaded with Azilsartan

[0191] The distribution of azilsartan in γCD-MOF is mainly in two states: one is the inclusion of azilsartan by cyclodextrin molecules ( Fig.11 a); one part is that azilsartan forms nanoclusters in the large cavity of γCD-MOF ( Fig.11 (b)

[0192] Specifically, the azilsartan molecules first tend to curl up in the hydrophobic cavity generated by the cyclodextrin structure in γCD-MOF (the docking free energy is -10.1 kcal / mol). The hydrophobic part of azilsartan just falls into the hydrophobic cavity of cyclodextrin, while the hydrophilic part exists in the gap of the cyclodextrin pair. Taking advantage of the characteristics of the hydrophobic part in the azilsartan molecule, the docked azilsartan molecules are docked into the large cavity of γCD-MOF with different system energies. Six azilsartan molecules are included by six cyclodextrin molecular pairs, and three azilsartan molecules are loaded in the large cavity. The theoretical drug loading molar ratio of γCD-MOF to valsartan in the composite is 1:1.

[0193] Example 28: Molecular simulation and characterization of γCD-MOF-loaded valsartan

[0194] The distribution of valsartan in γCD-MOF is mainly in two states: one is the inclusion of valsartan by cyclodextrin molecules; the other is the formation of nanoclusters of valsartan in the large cavity of γCD-MOF. Specifically: the first valsartan molecule prefers to curl up in the hydrophobic cavity generated by the dicyclodextrin structure in γCD-MOF (docking free energy -8.5kcal / mol), thereby freeing up the hydrophilic cavity to accommodate more valsartan molecules. The carboxyl group in valsartan interacts electrostatically with the hydroxide in the γCD-MOF crystal gap and the hydroxyl group in cyclodextrin to produce hydrogen bonds. Utilizing the characteristics of the hydrophilic and hydrophobic parts of the valsartan molecule, the valsartan molecules that continue to dock are docked into the large cavity of γCD-MOF with different system energies. Fig.12 As shown, six valsartan molecules are included by six cyclodextrin molecular pairs, and five valsartan molecules are loaded in the large cavity. The theoretical drug loading molar ratio of γCD-MOF to valsartan in the composition is 1:1.3.

[0195] Fig.13 :X-ray small angle scattering (SAXS) results show that CD-MOF is a typical body-centered cubic crystal with long-range order and good periodicity. After drug loading (Valsartan / CD-MOF 1:1.5 of Example 4 and Valsartan / CD-MOF 1:0.5 of Example 11), the Bragg long period (2.2nm) of Valsartan / CD-MOF is consistent with that of CD-MOF, but the half-height width increases due to the entry of drug molecules into the skeleton of CD-MOF. When Valsartan / CD-MOF is 1:0.5, CD-MOF does not have obvious displacement at the position of each peak. When Valsartan / CD-MOF is 1:1.5, the 1.6nm cavity position on the (200) crystal plane is significantly weakened due to the occupation of drug molecules.

[0196] Fig.14 : The solid-state NMR results show that after CD-MOF drug loading (VAL / CD-MOF 1:1.5 in Example 4 and valsartan / CD-MOF 1:0.5 in Example 11), the overall signal line width increases significantly, especially for VAL / CD-MOF with high drug loading (1:1.5), the valsartan benzene ring (C 12-23 ) disappeared, and the glycosidic bond (C 4 ) line width increased significantly, indicating that there is a strong interaction between the drug and the CD-MOF carrier. The valsartan molecule is in a confined environment and is likely to enter the double γ-CD molecular pair. 6) shifted to the high field, and the VAL / CD-MOF1:0.5 and 1:1.5 shifted by 1.9 ppm and 1.7 ppm at 57.5 ppm, respectively; accordingly, the carboxyl group (C 10 ) changes from a split peak to a broad peak, indicating that the carboxyl group of valsartan and the hydroxyl group of CD-MOF may interact by forming hydrogen bonds during the drug loading process. After drug loading, the line shape and intensity of the alkyl chain of valsartan (8-36ppm) in VAL / CD-MOF1:0.5 changed significantly, while the signal in VAL / CD-MOF1:1.5 was similar to the line shape of valsartan, indicating that the valsartan molecules partially aggregated in the large cavity in the middle of CD-MOF to form nanoclusters.

[0197] Example 29: Irbesartan

[0198] Measure 3000mL of pure water in a beaker, add 97.3g of γ-CD and stir, then add 33.6g of KOH, and ultrasonicate to completely dissolve γ-CD and KOH to obtain a mother liquor. Pour the mother liquor into a reactor, set the speed to 300rpm, and the temperature to 50°C. Then add 1800mL of methanol to the reactor, and add 38.4g of PEG20000 after dissolution and clarification. Centrifuge at room temperature overnight, remove the supernatant, add 0.4L of anhydrous ethanol to the lower precipitate for dispersion, centrifuge and wash, then add 0.4L of anhydrous ethanol and 20mL of glacial acetic acid to the precipitate, stir and neutralize, and centrifuge to remove the supernatant. Finally, add 0.4L of ethanol to the precipitate, centrifuge (4000rpm, 5min) and wash twice. The washed precipitate is placed in a 60°C vacuum drying oven and dried for 4h. The micron-sized potassium acetate cyclodextrin-metal organic framework is obtained, with a particle size of 1-10 microns.

[0199] Weigh 4.29g of irbesartan raw material and 14.93g of micron-sized potassium acetate CD-MOF (the molar ratio of cyclodextrin to irbesartan in the cyclodextrin-metal organic framework material is 1:1), mix thoroughly, grind at a molar ratio of 1:1, and use a ball mill (the weight ratio of zirconium beads to powder is 3:1) for 5, 15, and 20 minutes, respectively. Weigh 20mg (excess) of the ground sample in a 10mL centrifuge tube, add 5mL of pure water, vortex (1000rpm) for 1min immediately, filter with a 0.22μm filter membrane, and measure the saturated solubility by ultraviolet spectrophotometry. The results showed that the saturated solubility of irbesartan raw material in pure water was 8.4 μg / mL. After co-grinding irbesartan with CD-MOF for 5, 15, and 20 minutes, the saturated solubility was 145.2, 153.4, and 193.8 μg / mL, respectively, which was a solubilization increase of 17.3, 18.3, and 23.1 times, respectively.

[0200] Example 30 Azilsartan

[0201] Weigh 7.0 g of the micron-sized potassium acetate CD-MOF prepared in Example 29 and 3.0 g of azilsartan (the molar ratio of cyclodextrin to azilsartan in the cyclodextrin-metal organic framework material is 1:1), and grind for 5 min using a ball mill (the weight ratio of zirconium beads to powder is 3:1) to obtain an azilsartan micron-sized potassium acetate CD-MOF composition. The solubilization multiple is 25.4 times.

[0202] Example 31: Mixture of valsartan and cyclodextrin

[0203] Weigh 7.0 g of gamma-cyclodextrin and 3.0 g of valsartan (the molar ratio of gamma-cyclodextrin to valsartan is 1:1.5), use a ball mill (the weight ratio of zirconium beads to powder is 3:1) to grind for 60 min and 5 min, respectively, to obtain a valsartan and gamma-cyclodextrin composition, and the solubilization multiples are 5.7 times and 4.8 times, respectively.

[0204] Embodiment 32

[0205] Weigh 7.0 g of the micron-sized potassium acetate CD-MOF prepared in Example 29 and 3.0 g of valsartan (the molar ratios of cyclodextrin and valsartan in the cyclodextrin-metal organic framework material are 1:1.5 and 1:0.5, respectively), and grind them for 60 minutes using a ball mill (the weight ratios of zirconium beads to powder are 10:1 and 3:1, respectively) to obtain a valsartan micron-sized potassium acetate CD-MOF composition with solubilization multiples of 35.1 times and 23.0 times, respectively.

[0206] Embodiment 33

[0207] Weigh 648 mg of γ-CD and 224 mg of KOH, add 20 mL of pure water, stir until completely dissolved; pour into a 50 mL plastic centrifuge tube, add 12 mL of anhydrous methanol; place in a constant temperature water tank and heat at 50 ° C for 20 min. Add 8 mg / mL PEG20000 and shake well; after standing for 1 hour, centrifuge at 3500 rpm for 5 minutes and pour off the supernatant. Wash the precipitate with 12 mL of anhydrous ethanol 3 times and vacuum dry to prepare potassium hydroxide CD-MOF.

[0208] Weigh 7.0 g of micron-sized potassium hydroxide CD-MOF and 3.0 g of valsartan (the molar ratio of cyclodextrin to valsartan in the cyclodextrin-metal organic framework material is 1:1), grind for 5 min using a ball mill (the weight ratio of zirconium beads to powder is 3:1) to obtain a valsartan micron-sized potassium acetate CD-MOF composition. Its solubilization multiple is 53.9 times.

[0209] Embodiment 34

[0210] Take 2000mL pure water in a 5000mL beaker, weigh 64.9g γ-CD in the beaker, stir, then add 22.4g KOH to the beaker, ultrasonicate to completely dissolve γ-CD and KOH to obtain mother liquor. Pour the mother liquor into the reactor, at a speed of 300rpm and a temperature of 50°C, add 1200mL methanol to the reactor, and then add PEG20000 (8mg / mL). Let stand overnight in a cold water bath. Centrifuge to remove the supernatant, wash the precipitate twice with 150mL ethanol, and dry it in a vacuum drying oven at 40°C for 12h. The particle size is 100-500 nanometers.

[0211] 7.0 g of the prepared nanoscale potassium acetate CD-MOF and 3.0 g of valsartan (the molar ratio of cyclodextrin to valsartan in the cyclodextrin-metal organic framework material is 1:1.5) were weighed and ground for 5 min using a ball mill (the weight ratio of zirconium beads to powder is 3:1) to obtain a valsartan nanoscale potassium acetate CD-MOF composition. The solubilization multiple is 27.3 times.

[0212] Embodiment 35

[0213] Measure 3000mL of pure water in a beaker, add 97.3g of γ-CD and stir, then add 33.6g of sodium hydroxide, and ultrasonicate to completely dissolve γ-CD and sodium hydroxide to obtain a mother liquor. Pour the mother liquor into the reactor, set the speed to 300rpm, and the temperature to 50°C. Add 1800mL of methanol to the reactor, and add 38.4g of PEG20000 after dissolution and clarification. Centrifuge at room temperature overnight, remove the supernatant, and wash the precipitate twice with 100mL of ethanol and then with 100mL of methanol. Dry the precipitate in a vacuum drying oven at 40°C for 12h to obtain a micron-sized sodium hydroxide cyclodextrin metal organic framework. Weigh 7.0 g of micron-sized sodium hydroxide cyclodextrin metal organic framework and 3.0 g of valsartan (the molar ratio of cyclodextrin to valsartan in the cyclodextrin-metal organic framework material is 1:1), and grind them for 5 minutes using a ball mill (the weight ratio of zirconium beads to powder is 3:1) to obtain a valsartan micron-sized sodium hydroxide cyclodextrin metal organic framework composition.

[0214] Embodiment 36

[0215] Measure 3000mL of pure water in a beaker, add 97.3g of γ-CD and stir, then add 16.8g of calcium hydroxide, and ultrasonicate to completely dissolve γ-CD and calcium hydroxide to obtain a mother liquor. Pour the mother liquor into the reactor, set the speed to 300rpm, and the temperature to 50°C. Add 1800mL of ethanol to the reactor, and add 38.4g of PEG4000 after dissolving and clarifying. Centrifuge at room temperature overnight, remove the supernatant, and wash the precipitate twice with 100mL of ethanol and then wash it twice with 100mL of ethanol. Dry the precipitate in a vacuum drying oven at 40°C for 12h to obtain a micron-sized calcium hydroxide cyclodextrin metal organic framework. Weigh 7.0 g of micron-sized calcium hydroxide cyclodextrin metal-organic framework and 3.0 g of valsartan (the molar ratio of cyclodextrin to valsartan in the cyclodextrin-metal-organic framework material is 1:1), and grind them for 5 minutes using a ball mill (the weight ratio of zirconium beads to powder is 3:1) to obtain a valsartan micron-sized calcium hydroxide cyclodextrin metal-organic framework composition.

[0216] All documents mentioned in the present invention are cited as references in this application, just as each document is cited as reference individually. In addition, it should be understood that after reading the above teachings of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the claims attached to this application.

Claims

1. A pharmaceutical cyclodextrin-metal organic framework composition, characterized in that: The composition comprises: (a) a cyclodextrin-metal organic framework material; and (b) a drug loaded on or mixed with the framework material, wherein the drug is a sartan drug; the drug is loaded on the framework material in two ways: inclusion of the drug molecules by dicyclodextrin molecules; and the drug forms nanoclusters in the large cavity in the middle of the cyclodextrin-metal organic framework; the molar ratio of the cyclodextrin-metal organic framework to the drug in the composition is 1:0.2-1:2, Wherein, the sartan drug is irbesartan, telmisartan, azilsartan or a combination of two or more thereof; The metal ion in the cyclodextrin-metal organic framework material is K + .

2. The composition according to claim 1, characterized in that The cyclodextrin in the cyclodextrin-metal organic framework material is selected from the following group: α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, hydroxypropyl-β-cyclodextrin, sulfobutyl-β-cyclodextrin, methyl-β-cyclodextrin, and carboxymethyl-β-cyclodextrin.

3. The composition according to claim 1, characterized in that The molar ratio of the cyclodextrin-metal organic framework to the drug in the composition is 1:0.5-1:1.

8.

4. The composition according to claim 1, characterized in that The drug loading of the composition is 5%-50%.

5. The composition according to claim 1, characterized in that The molar ratio of cyclodextrin-metal organic framework to drug in the composition is 1:1.

5.

6. The composition according to claim 1, characterized in that The anion that forms a salt or base with the metal ion is selected from: OH - 、NO3 - 、CO3 2- 、HCO3 - 、CH3COO - 、SCN - 、C6H5COOH=C6H5COO - , Cl - Br - ,I - , HS - 、HSO4 - , ClO - 、ClO3 - 、MnO4 - .

7. The composition according to claim 1, characterized in that The cyclodextrin-metal organic framework material is a potassium hydroxide cyclodextrin-metal organic framework material, a potassium carbonate cyclodextrin-metal organic framework material, a potassium chloride cyclodextrin-metal organic framework material or a potassium acetate cyclodextrin-metal organic framework material.

8. The composition according to claim 1, characterized in that The composition also has one or more of the following characteristics: (1) The average particle size of the cyclodextrin-metal organic framework material is 5 nanometers to 1000 micrometers; (2) The drug loading of the composition is 0.1%-50%.

9. The composition according to claim 1, characterized in that The average particle size of the cyclodextrin-metal organic framework material is 100-1000 nanometers or 1-100 micrometers.

10. A method for preparing the composition according to claim 1, characterized in that: The preparation method comprises the step of mixing the cyclodextrin-metal organic framework material with a drug solution to obtain the composition, wherein the drug is a sartan drug selected from: irbesartan, telmisartan, azilsartan or a combination of two or more thereof.

11. The preparation method according to claim 10, characterized in that: The mixing temperature is 25-65°C.

12. The preparation method according to claim 10, characterized in that: The mixing time is 10 minutes to 3 days.

13. The preparation method according to claim 10, characterized in that: The drug solution is prepared by dissolving the drug in a solvent selected from the group consisting of methanol, ethanol, propanol, isopropanol, n-butanol, chloroform, dimethylformamide or a mixed solvent thereof.

14. The preparation method according to claim 10, characterized in that: The molar ratio of cyclodextrin to drug in the cyclodextrin-metal organic framework material is 1:1.5-1:

25.

15. A method for preparing the composition according to claim 1, characterized in that: The preparation method comprises the steps of mixing the drug with the cyclodextrin-metal organic framework material and grinding them to obtain the composition, wherein the drug is a sartan drug selected from: irbesartan, telmisartan, azilsartan or a combination of two or more thereof.

16. The preparation method according to claim 15, characterized in that: The feed ratio of the cyclodextrin-metal organic framework material to the drug is 1:0.4-1.

8.

17. The preparation method according to claim 15, characterized in that: The drug is in the form of powder or drug solution.

18. The preparation method according to claim 17, characterized in that: The drug solution is prepared by dissolving the drug in a solvent selected from the group consisting of methanol, ethanol, propanol, isopropanol, n-butanol, chloroform, dimethylformamide or a mixed solvent thereof.

19. The preparation method according to claim 15, characterized in that: The cyclodextrin-metal organic framework material is in the form of powder or drug solution.

20. The preparation method according to claim 19, characterized in that: The drug solution is prepared by dissolving the cyclodextrin-metal organic framework material in a solvent selected from the group consisting of methanol, ethanol, propanol, isopropanol, n-butanol, chloroform, dimethylformamide or a mixed solvent thereof.

21. The preparation method according to claim 15, characterized in that: The grinding is performed using a ball mill, which uses zirconium beads with a diameter of 6-10 mm for grinding, and the weight ratio of the beads to the total weight of the drug and the cyclodextrin-metal organic framework material is 15:1-1:1; the grinding time is 1 min-2 h.

22. A method for preparing the composition according to claim 1, characterized in that: The preparation method comprises the following steps: (i) dissolving cyclodextrin and a metal ion source in water to prepare a first solution, and mixing the drug with an organic solvent to prepare a second solution; (ii) adding the second solution to the first solution and mixing them to obtain a mixture; (iii) collecting and drying the mixture to obtain the composition, The drug is a sartan drug selected from: irbesartan, telmisartan, azilsartan or a combination of two or more thereof.

23. The preparation method according to claim 22, characterized in that: The metal ion source is selected from the group consisting of potassium hydroxide, potassium carbonate, and potassium chloride.

24. The preparation method according to claim 22, characterized in that: The concentration of the cyclodextrin in the first solution is 0.01-200 mM.

25. The preparation method according to claim 22, characterized in that: The molar ratio of the cyclodextrin to the metal ions in the metal ion source is 1:1-1:

10.

26. The preparation method according to claim 22, characterized in that: The second solution is prepared by dissolving the drug in an organic solvent selected from the group consisting of methanol, ethanol, propanol, isopropanol, n-butanol, chloroform, dimethylformamide or a mixed solvent thereof.

27. The preparation method according to claim 22, characterized in that: In step (ii), the second solution is added to the first solution and mixed, and a morphology regulator may be added and mixed to obtain a mixture.

28. The preparation method according to claim 27, characterized in that: The morphology regulator is polyethylene glycol, povidone, polysorbate, sorbitan monolaurate, polyoxyethylene lauryl ether, emulsifier OP, lactobacillus A, pulurone, sodium dodecyl sulfate, sodium dodecylbenzene sulfonate, hexadecyltrimethylammonium bromide or a combination thereof.

29. The preparation method according to claim 27, characterized in that: The morphology regulator is polyethylene glycol 20000, polyethylene glycol 2000, polyethylene glycol 4000, polyethylene glycol 6000, polyethylene glycol 8000, polyethylene glycol 10000 or a combination thereof.

30. A pharmaceutical composition, characterized in that The pharmaceutical composition comprises: The composition of claim 1; and A pharmaceutically acceptable carrier.

31. The pharmaceutical composition according to claim 30, characterized in that The pharmaceutical composition is in the form of capsules, tablets or granules.

32. The pharmaceutical composition according to claim 30, characterized in that The pharmaceutical composition further comprises a surfactant selected from the group consisting of polysorbate-80, polysorbate-60, polyethylene glycol glycerol fatty acid esters, sorbitan fatty acid esters and a mixture of two or more thereof.

Images