WO2019184994A1 - 一种提高缬沙坦溶解性的环糊精-金属有机骨架组合物 - Google Patents

一种提高缬沙坦溶解性的环糊精-金属有机骨架组合物 Download PDF

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WO2019184994A1
WO2019184994A1 PCT/CN2019/080211 CN2019080211W WO2019184994A1 WO 2019184994 A1 WO2019184994 A1 WO 2019184994A1 CN 2019080211 W CN2019080211 W CN 2019080211W WO 2019184994 A1 WO2019184994 A1 WO 2019184994A1
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valsartan
cyclodextrin
composition
mof
metal organic
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PCT/CN2019/080211
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English (en)
French (fr)
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张继稳
陈益智
伍丽
何远志
王彩芬
张国庆
郭涛
蒋莉娟
李军
郑朝武
林扬晶
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海南皇隆制药股份有限公司
中国科学院上海药物研究所
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Publication of WO2019184994A1 publication Critical patent/WO2019184994A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/40—Cyclodextrins; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5107—Excipients; Inactive ingredients
    • A61K9/513—Organic macromolecular compounds; Dendrimers
    • A61K9/5161—Polysaccharides, e.g. alginate, chitosan, cellulose derivatives; Cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Definitions

  • the present invention relates to a cyclodextrin-metal organic framework composition for improving the solubility of valsartan.
  • 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 a major risk factor for Chinese stroke, coronary heart disease, heart failure and kidney disease. The incidence of heart and cerebrovascular diseases and the number of deaths in China are rising. The death toll accounts for 40% of China's total mortality. Hypertension has become a common problem that threatens health.
  • “Sartan” drugs angiotensin II receptor antagonist (ARB) antihypertensive drugs
  • ARB angiotensin II receptor antagonist
  • It has unique curative effect and protective effect on cardiovascular diseases, and has become one of the most common antihypertensive drugs in clinical practice, causing widespread clinical attention, and long-term application of dry cough, withdrawal rebound and orthostatic hypotension and other adverse reactions occur.
  • the low rate has been recommended by WHO multiple treatment guidelines as first-line antihypertensive drugs for patients with hypertension with cardiovascular disease and proteinuria.
  • sartan drugs are BCS class II drugs, which have poor solubility in water, resulting in low oral bioavailability of sartans.
  • solubility of sartans In order to improve the oral bioavailability of sartans, the solubility of sartans must be increased.
  • Valsartan is an angiotensin II receptor antagonist (ARB) antihypertensive drug. It has been used for more than 10 years because of its obvious antihypertensive effect and good tolerance, especially in clinical trials and evidence-based evidence. The unique curative effect and protective effect of cardiovascular disease has become one of the most common antihypertensive drugs in clinical practice, which has caused widespread clinical attention, and the incidence of adverse reactions such as dry cough, withdrawal rebound and orthostatic hypotension after long-term application is low. It has been recommended by WHO as a first-line antihypertensive drug for patients with hypertension with cardiovascular disease and proteinuria.
  • Valsartan is a BCS class 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 increased.
  • a valsartan cyclodextrin-metal organic framework composition comprising: (a) a cyclodextrin-metal organic framework material; and (b) supported on said framework material Valsartan.
  • valsartan is supported on the framework material in two ways: inclusion of a valsartan molecule by a bicyclodextrin molecule; and formation of a nanogroup in a large cavity in the middle of a cyclodextrin-metal organic framework by valsartan cluster.
  • the metal ion in the cyclodextrin-metal organic framework material is selected from the group consisting of Li + , Na + , K + , Rb + , Cs + , Mg 2+ , Cd 2+ , Sn 2+ , Ag + , Yb + , Ba 2+ , Sr 2+ , Ca 2+ , Pb 2+ , La 3+ .
  • the metal ion is Ca 2+ , Na + or K + , further preferably K + .
  • 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 Skeleton material, potassium acetate cyclodextrin-metal organic framework material, preferably potassium acetate ⁇ -cyclodextrin-metal organic framework material.
  • the cyclodextrin in the cyclodextrin-metal organic framework material is selected from the group consisting of ⁇ -cyclodextrin, ⁇ -cyclodextrin, ⁇ -cyclodextrin, hydroxypropyl- ⁇ . - cyclodextrin, sulfobutyl- ⁇ -cyclodextrin, methyl- ⁇ -cyclodextrin, carboxymethyl- ⁇ -cyclodextrin.
  • the cyclodextrin is selected from the group consisting of ⁇ -cyclodextrin, ⁇ -cyclodextrin, ⁇ -cyclodextrin, and further preferably ⁇ -cyclodextrin.
  • the cyclodextrin-metal organic framework material is an alkaline or neutral cyclodextrin-metal organic framework material.
  • the basic cyclodextrin-metal organic framework material is dispersed in an organic solvent containing organic acid to obtain a neutral cyclodextrin-metal organic framework material.
  • 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 mixture thereof.
  • the solvent is most preferably acetic acid.
  • the organic solvent is selected from the group consisting of methanol, ethanol, propanol, isopropanol, n-butanol or a mixed solvent thereof, preferably methanol, ethanol or a mixed solvent thereof, and most preferably ethanol.
  • the molar ratio of the cyclodextrin-metal organic skeleton to valsartan in the composition is from 1:0.2 to 1:2.
  • the molar ratio of the cyclodextrin-metal organic skeleton to valsartan in the composition is from 1:0.5 to 1:1.8.
  • the molar ratio of the cyclodextrin-metal organic skeleton to valsartan in the composition is preferably 1:1.5.
  • composition further has one or more of the following characteristics:
  • the cyclodextrin-metal organic framework material has an average particle diameter of 5 nm to 1000 ⁇ m;
  • composition has a drug loading of 5% to 50%.
  • the cyclodextrin-metal organic framework material has an average particle diameter of 100 to 1000 nm (nanoscale); or the cyclodextrin-metal organic framework material has an average particle diameter of 1-100. Micron (micron).
  • the composition has a drug loading of from 8% to 48%. In another preferred embodiment, the composition has a drug loading of from 10% to 45%.
  • the drug loading of the composition is further preferably from 15% to 40%. In another preferred embodiment, the drug loading of the composition is further preferably from 25% to 30%.
  • composition of the present application has a solubilizing effect on valsartan, and the solubility of valsartan in water is increased by 2 to 200 times, preferably 5 to 100 times, and more preferably 10 to 50 times.
  • the results show that the valsartan-cyclodextrin-metal organic framework composition can significantly improve the laksa compared with the Daiwen capsule and the representative tablet.
  • a process for the preparation of the composition of the first aspect which comprises mixing the cyclodextrin-metal organic framework material with the valsartan to obtain the composition. step.
  • the manner of mixing is a mixture of a valsartan solution and a cyclodextrin-metal organic framework material.
  • the mixing temperature is 0 to 70 ° C, preferably 30 to 50 ° C, and most preferably 30 to 40 ° C.
  • the mixing time is from 10 minutes to 3 days, preferably from 1 hour to 12 hours, and most preferably from 10 minutes to 2 hours.
  • the valsartan solution is prepared by dissolving valsartan in a solvent selected from the group consisting of methanol, ethanol, propanol, isopropanol, n-butanol, chloroform, dimethylformamide.
  • the mixed solvent thereof is preferably methanol, ethanol or a mixed solvent thereof, and most preferably ethanol.
  • the cyclodextrin-metal organic framework material has a cyclodextrin to valsartan molar ratio of 1:1 to 1:50.
  • the cyclodextrin-metal organic framework material has a cyclodextrin to valsartan molar ratio of 1:1 to 1:30 or 1:1 to 1:25.
  • the molar ratio of cyclodextrin to valsartan in the cyclodextrin-metal organic framework material is from 1:1 to 1:22 or from 1:15 to 1:25.
  • the molar ratio of cyclodextrin to valsartan is 1:1.5-1:25.
  • the preparation method further comprises a post-treatment step of collecting the solid and drying.
  • composition of the first aspect comprising the steps of:
  • the source of metal ions is selected from the group consisting of potassium hydroxide, potassium carbonate, and potassium chloride.
  • the concentration of the cyclodextrin in the first solution is from 0.01 to 200 mM.
  • the molar ratio of the cyclodextrin to the metal ion in the metal ion source is from 1:1 to 1:10.
  • the second solution is prepared by dissolving valsartan in an organic solution selected from the group consisting of methanol, ethanol, propanol, isopropanol, n-butanol, chloroform, dimethylformamide.
  • the mixed solvent thereof is preferably methanol, ethanol or a mixed solvent thereof, and most preferably ethanol.
  • step ii) the second solution is added to the first solution for mixing, and a mixture of morphological regulators may be added to obtain a mixture.
  • the morphological regulator is polyethylene glycol, povidone, polysorbate, sorbitan monolaurate, polyoxyethylene lauryl ether, emulsifier OP, lactulin A, Pluronic, sodium lauryl sulfate, sodium dodecylbenzene sulfonate, cetyltrimethylammonium bromide, or a combination thereof.
  • the morphological regulator is polyethylene glycol 20000, polyethylene glycol 2000, polyethylene glycol 4000, polyethylene glycol 6000, polyethylene glycol 8000, polyethylene glycol 10000, poly Ethylene glycol 20000, or a combination thereof.
  • the morphological regulator preferably 5-10 mg/mL of the supernatant, is added in a ratio of 1-20 mg/mL of the supernatant.
  • a pharmaceutical composition comprising:
  • composition of the first aspect The composition of the first aspect;
  • a pharmaceutically acceptable carrier is selected from:
  • “Pharmaceutically acceptable carrier” means: one or more compatible solid or liquid fillers or gel materials which are suitable for human use and which must be of sufficient purity and of sufficiently low toxicity. By “compatibility” it is meant herein that the components of the composition are capable of intermingling with the compounds of the invention and with each other without significantly reducing the efficacy of the compound.
  • pharmaceutically acceptable carriers are cellulose and its derivatives (such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid).
  • magnesium stearate magnesium stearate
  • calcium sulfate vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as Tween), wetting Agents (such as sodium lauryl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, and the like.
  • vegetable oils such as soybean oil, sesame oil, peanut oil, olive oil, etc.
  • polyols such as propylene glycol, glycerin, mannitol, sorbitol, etc.
  • emulsifiers such as Tween
  • wetting Agents such as sodium lauryl sulfate
  • colorants such as sodium lauryl sulfate
  • flavoring agents such as pepperminophen, sorbitol, etc
  • the carrier is selected from the group consisting of diluents, excipients, fillers, binders, wetting agents, disintegrating agents, absorption enhancers, surfactants, adsorption carriers, lubrication Agent, or a combination thereof.
  • the pharmaceutical composition is formulated as a solid dosage form or a liquid dosage form, preferably for oral administration.
  • the solid dosage form comprises capsules, tablets, pills, powders, and granules.
  • the liquid dosage form comprises a pharmaceutically acceptable emulsion, solution, suspension, syrup or elixir.
  • the pharmaceutical composition is a capsule, a tablet, an osmotic pump sheet, a gel skeleton sustained release sheet, and a granule.
  • the pharmaceutical composition further comprises a surfactant selected from the group consisting of polysorbate-80, polysorbate-60, polyethylene glycol glyceryl fatty acid ester, sorbitan fatty acid Ester and a mixture of two or more.
  • a surfactant selected from the group consisting of polysorbate-80, polysorbate-60, polyethylene glycol glyceryl fatty acid ester, sorbitan fatty acid Ester and a mixture of two or more.
  • DSC differential scanning calorimetry
  • Example 13 is a gas adsorption diagram of Example 13.
  • Fig. 3 is an infrared spectrum chart of Example 13.
  • Figure 5 is a dissolution profile of the valsartan-loaded CD-MOF composition capsule prepared in Example 14 in four different media.
  • Figure 6 is a dissolution profile of a commercially available Daiwen capsule in Example 14 in four different media.
  • Figure 7 is a graph showing the dissolution profile of the valsartan CD-MOF composition tablet and a commercially available tablet in water in Example 17.
  • Figure 8 is a molecular simulation diagram of CD-MOF-loaded valsartan in Example 22.
  • Figure 9 is an X-ray small angle scatter plot of CD-MOF-loaded valsartan in Example 22.
  • Figure 10 is a solid-state nuclear magnetic diagram of CD-MOF-loaded valsartan in Example 22.
  • Figure 11 is an in vitro release profile of the CD-MOF-loaded valsartan osmotic pump tablets of Examples 25-26.
  • Figure 12 is a graph showing the in vivo drug time of CD-MOF-loaded valsartan osmotic pump tablets and Daiwen capsules in Beagle dogs under fasting conditions in Example 27.
  • Figure 13 is a graph showing the in vivo drug time of CD-MOF-loaded valsartan osmotic pump tablets and daiwen capsules in the Beagle diet in Example 27.
  • Figure 14 is a graph showing the in vitro release profile of CD-MOF-loaded valsartan sustained-release tablets in four dissolution media in Example 28.
  • Figure 15 is a graph showing the in vitro release profile of the transcripts in Example 28 in four dissolution media.
  • Figure 16 is a graph showing the in vivo drug-time curve of CD-MOF-loaded valsartan sustained-release tablets and essay tablets in Beagle dogs under fasting conditions in Example 28.
  • Figure 17 is a graph showing the in vivo drug-time curve of CD-MOF-loaded valsartan sustained-release tablets and essay tablets in the Beagle diet in Example 28.
  • the inventors have extensively and intensively researched and developed a cyclodextrin-metal organic framework composition containing valsartan for the first time, and valsartan is supported on a cyclodextrin-metal organic framework material, which can significantly improve the laksa
  • the solubility and dissolution rate of Tan in water solve the problem of poor solubility of valsartan and low oral bioavailability.
  • the raw materials and solvents used in the preparation of the composition are cheap and easy to obtain, and the steps are simple, which is advantageous for industrial production.
  • Cyclodextrin is a general term for a series of cyclic oligosaccharides produced by amylose by glucosyltransferase, usually containing 6 to 12 D-glucopyranose units. Among them, which have been studied more and have practical significance, are molecules containing 6, 7, or 8 glucose units, which are called ⁇ , ⁇ -, and ⁇ -cyclodextrin, respectively. Cyclodextrins are ideal host molecules similar to those found to date, and have the properties of an enzyme model by themselves.
  • Metal-organic frameworks are crystalline materials in which an inorganic bridged metal is joined by an organic bridging ligand to form an infinitely extended network-like structure by means of coordinate bonds. Due to the ultra-high porosity and large specific surface area of MOFs, and its structure consisting of inorganic and organic different components, its structure is diverse and adjustable, which makes MOFs potential in many fields such as gas storage, catalysis, drug carriers and other fields. Value.
  • CD-MOF Cyclodextrin-Metal-Organic Frameworks
  • cyclodextrin-based metal-organic framework materials cyclodextrin-metal organic framework materials
  • Cyclodextrin-metal organic framework compound is used interchangeably to form a new crystal by using cyclodextrin in an aqueous solution to form an organic coordination with the first and second main metal ions.
  • the crystals are porous, have a large surface area, and store gases. This green, porous material is capable of adsorbing some structurally unstable drugs, and its huge cavity can protect the drug, which makes it possible for commercial development, especially due to the cyclodextrin-metal organic framework.
  • cyclodextrin as an organic ligand and metal ions as the center of inorganic metal, a new, safe and pharmaceutically acceptable cyclodextrin-metal organic skeleton, CD-MOF, can be formed.
  • basic cyclodextrin-metal organic framework material is a cyclodextrin-metal organic framework material prepared from an alkali metal and a cyclodextrin, which is alkaline and is dissolved in water to make 10 mg. When the aqueous solution is /mL, its pH is about 11-13.
  • neutral cyclodextrin-metal organic framework material As used herein, the terms “neutral cyclodextrin-metal organic framework material”, “acidified cyclodextrin-metal organic framework material” are used interchangeably to acidify a basic cyclodextrin-metal organic framework material.
  • the obtained near-neutral cyclodextrin-metal organic framework material was treated, and when it was dissolved in water to prepare an aqueous solution of 10 mg/mL, the pH was about 5-8.
  • a preferred method of acidification is as follows: a certain amount of cyclodextrin-metal organic framework is weighed in ethanol, a certain amount of glacial acetic acid is added, and after shaking for a certain period of time at 25 ° C, the obtained solid is washed with ethanol. , dry, that is, near neutral cyclodextrin-metal organic skeleton.
  • cyclodextrin-metal organic framework composition containing valsartan As used herein, the term “cyclodextrin-metal organic framework composition containing valsartan”, “cyclodextrin-metal organic framework composite containing valsartan”, “cyclodextrin-metal loaded with valsartan” “Organic skeleton”, “CD-MOF complex containing valsartan”, “CD-MOF containing valsartan”, “CD-MOF-loaded valsartan”, “valsartan CD-MOF composition”, “ CD-MOF-loaded valsartan is used interchangeably and the above terms all refer to samples obtained by loading valsartan on a cyclodextrin-metal organic framework material.
  • valsartan content (1) UV spectrophotometry: Refer to the Chinese Pharmacopoeia 2015 edition of the second part of the valsartan capsule dissolution method, the detection wavelength is 250nm.
  • High performance liquid chromatography (HPLC) method The content of valsartan capsule was determined by reference to the 2015 edition of Chinese Pharmacopoeia. The column was Platisil ODS C18 (250 x 4.6 mm, 5 ⁇ m); the mobile phase was acetonitrile-water-glacial acetic acid (500:500:1); the flow rate was 1.2 mL/min; the column temperature was 35 ° C; the detection wavelength was 230 nm.
  • 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 valsartan in the solution according to the above method for determination of valsartan content. . Recorded as the solubility of the sample to be tested in water at 25 ° C.
  • Solubilization factor The solubility of the sample to be compared is compared to the solubility of the valsartan material in water (25 ° C) (0.08 mg/mL).
  • Determination and calculation method of drug loading and drug loading molar ratio accurately weigh 5mg (m 1 ) sample to be tested, placed in a 100mL volumetric flask, dissolved in pure water, filtered, according to the "valsartan content determination conditions" The valsartan content was determined and the mass m 2 of valsartan was calculated.
  • Drug loading (%) m 2 /m 1 ⁇ 100; the molar ratio of carrier to valsartan is (m 2 /435.52): ((m 1 -m 2 ) / M carrier ), M carrier is carrier ring paste
  • M carrier is carrier ring paste
  • the molecular weight of the refined metal organic skeleton, 435.52 is the molecular weight of valsartan.
  • the drug-loaded amount 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 valsartan raw material was 25).
  • the solubility in water at °C was 0.08 mg/mL).
  • micron-sized potassium acetate CD-MOF on the basis of Example 1: adding 0.4 L of absolute ethanol dispersion to the lower layer precipitate, performing centrifugal washing, and then adding 0.4 anhydrous ethanol and 20 mL of glacial acetic acid to the precipitate, stirring Neutralize and centrifuge to remove the supernatant. Finally, 0.4 ethanol was added to the precipitate and washed twice by centrifugation (4000 rpm, 5 min). The washed precipitate was dried in a vacuum oven at 60 ° C for 4 h. That is, a micron-sized potassium acetate cyclodextrin-metal organic skeleton having a particle diameter of 1-10 micrometers.
  • the valsartan CD-MOF composition was prepared according to the drug loading method described in Example 1 (the molar ratio of cyclodextrin to valsartan in the cyclodextrin-metal organic framework material was 1:20), and the resulting combination was obtained.
  • the drug loading was 30.7% (w/w)
  • the molar ratio of CD-MOF to valsartan was 1:1.6, and the solubility of valsartan in water was increased by 33.7 times.
  • the drug loading in the resulting composition was 29.7%, and the molar ratio of CD-MOF to valsartan in the composition was 1:1.5, and the solubilization factor was 35.6.
  • Example 2 40 g of the micron-sized potassium acetate CD-MOF in Example 2 was weighed into a beaker, and 1 L of a 0.25 g/mL valsartan ethanol solution (cyclodextrin and valsartan in a cyclodextrin-metal organic framework material) was added. The molar ratio of the feed was 1:22), and the drug was loaded according to the method of Example 3.
  • valsartan ⁇ -CD composition was prepared in the same manner by simultaneously replacing CD-MOF with ⁇ -CD.
  • 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.
  • valsartan CD-MOF composition 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 multiple was 39.5, which was significantly higher than that of valsartan ⁇ .
  • - CD composition solubility factor is 4.6).
  • Dissolution assay A valsartan CD-MOF composition equivalent to one dose (80 mg) was weighed and run in parallel for 6 times for dissolution experiments. The rotation speed was 100 rpm, the temperature was 37.0 ⁇ 0.5 ° C, the medium was 900 mL of deionized water, 5 mL was sampled at different time points, and the absorbance was measured by ultraviolet light at 250 nm to calculate the dissolution amount. At the same time, the physical mixture of valsartan starting material, valsartan and CD-MOF was determined.
  • 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 the valsartan nanometer potassium hydroxide CD-MOF composition was obtained.
  • the nano-scale potassium acetate CD-MOF was prepared according to the method of Example 2, and the particle diameter was 100-500 nm.
  • 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 the valsartan nanometer potassium hydroxide CD-MOF composition was obtained.
  • 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 the valsartan potassium carbonate CD-MOF composition was obtained.
  • results The drug loading in the resulting composition was 24.6%, the molar ratio of CD-MOF to valsartan was 1:1.1, and the solubilization factor was 30.5.
  • ⁇ -CD and potassium chloride were dissolved in 5 mL of water to a concentration of 0.125 M and 0.5 M, respectively, and fully dissolved by sonication for 10 min. Then, 0.5 mL of methanol was added to the mixed solution of ⁇ -CD and potassium chloride, and the methanol was heated at 50 ° C in a closed vessel. After reacting for 6 hours, the mixture was washed twice with ethanol and methanol, and the obtained crystal was vacuum dried at 50 ° C. In the hour, the potassium chloride CD-MOF is obtained, and the particle size is 1-10 micrometers.
  • 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 the valsartan potassium chloride CD-MOF composition was obtained.
  • results The drug loading in the resulting composition was 22.3%, the molar ratio of CD-MOF to valsartan was 1:1.3, and the solubilization factor was 34.8.
  • the drug loading in the resulting composition was 12.4%, and the molar ratio of CD-MOF to valsartan in the composition was 1:0.5, and the solubilization factor was 35.2.
  • the drug loading in the resulting composition was 22.82%, and the molar ratio of CD-MOF to valsartan in the composition was 1:1.0, and the solubilization factor was 34.9.
  • valsartan/ ⁇ -cyclodextrin inclusion complex was prepared: 1297 mg of ⁇ -cyclodextrin (1 mmol) was weighed and dissolved in 30 mL of water, and 435 mg of valsartan (1 mmol) was dissolved in 15 mL of ethanol to dissolve the laksa. The solution was added dropwise to the aqueous solution of ⁇ -cyclodextrin under stirring, and the temperature was maintained at 40 ° C, and stirring was continued at 500 rpm for 3 hours to remove the ethanol. The remaining liquid is freeze-dried to obtain the valsartan/ ⁇ -cyclodextrin inclusion complex.
  • the content (w/w) of valsartan in the obtained cyclodextrin inclusion complex was 15.5%, the molar ratio of ⁇ -cyclodextrin to valsartan was 1:0.64, and the solubility of the inclusion complex in water was 0.38 mg/ In mL, the solubility of valsartan in water was increased by 4.75 times.
  • Valsartan shows a broad melting endotherm at 108 ° C, while the cyclodextrin inclusion complex and the valsartan CD-MOF composition of Example 4 completely disappear, the absorption peak in the physical mixture Reappearing, indicating that valsartan is encapsulated by cyclodextrin, the valsartan in the composition is loaded by CD-MOF.
  • FIG. 2 Gas adsorption results show that the specific surface area of potassium acetate CD-MOF is 996 m 2 /g, and the Langmuir specific surface area of the valsartan CD-MOF composition (Example 11) with a drug loading molar ratio of 1:0.5 is reduced. The Langmuir specific surface area of 307 m 2 /g, while the valsartan CD-MOF composition (Example 4) with a drug loading molar ratio of 1:1.5 was almost zero, indicating that valsartan was loaded by CD-MOF.
  • Figure 3 Infrared spectroscopy showing that the valsartan neutral micron-sized CD-MOF composition differs from the valsartan bulk drug and the neutral micron-sized CD-MOF and a physical mixture of the two. Comparing the spectra of CD-MOF, VAL/CD-MOF and CD-MOF with VAL, the three samples have a wide absorption band at 2926 cm -1 and can be assigned to the stretching vibration of -CH- in CD-MOF. ( ⁇ CH ).
  • FIG. 4 Powder X-ray diffraction results show that valsartan has two broad diffraction peaks at 13-15 ° and 20-22 ° ; CD-MOF has a typical crystal structure. The corresponding CD-MOF diffraction peaks in the valsartan CD-MOF composition remained after drug loading, indicating that the valsartan CD-MOF composition after drug loading remained crystalline.
  • Preparation process Weigh 10 g of valsartan micron-sized potassium acetate CD-MOF composition prepared in Example 4, uniformly wet with 10 mL of polysorbate-80 ethanol solution at a concentration of 0.05 mg/mL, and blow with high-purity nitrogen gas. After 30 min, the granules were sieved through a 30 mesh sieve, dried, granulated, and filled into capsules. The dissolution and dissolution rates were compared with commercially available Daiwen capsules in four different pH media.
  • Dissolution measurement using the basket method, rotating 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 each 1000 mL, At 3, 5, 10, 15, 30, 60, 90, 120 min, take 5 mL each time and measure the absorbance at 250 nm with UV.
  • valsartan CD-MOF composition Twelve healthy male Sprague-Dawley rats were purchased from Shanghai Experimental Animal Research Center and weighed about 200 ⁇ 20g. They were randomly divided into two groups, 6 rats in each group.
  • the valsartan CD-MOF composition was administered by intragastric administration. 6 Preparation), Yuanyan Daiwen Capsule 15mg/kg, 0.3mL of blood was taken from the eyelids at 0, 0.08, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 8, 12 and 24h, respectively.
  • the bioavailability of the valsartan-neutral micron-sized CD-MOF composition was compared with that of the original research capsule.
  • the concentration of valsartan in rat plasma samples was determined by high performance liquid chromatography-tandem mass spectrometry (LC-MS/MS).
  • the pharmacokinetic parameters of 12 healthy male Sprague-Dawley rats were calculated by DAS2.0 software. The results are shown in Table 2. Compared with the progeny group, the average relative bioavailability of the valsartan/CD-MOF group was 149.3%, indicating After CD-MOF was loaded with valsartan, the bioavailability of valsartan in rats was significantly improved.
  • Valsartan CD-MOF composition Daiwen Capsule AUC 0-24h ( ⁇ g/mL ⁇ h) 77.71 ⁇ 13.12 * 52.05 ⁇ 23.02 T max (h) 0.72 ⁇ 0.25 ** 2.22 ⁇ 1.08 C max ( ⁇ g/mL) 16.88 ⁇ 4.85 ** 7.90 ⁇ 3.70
  • the first three groups of oral valsartan/CD-MOF composition capsules (A drug, prepared according to Example 4, added Tween-80 ethanol solution granulation), Daiwen capsule (B drug), valsartan / ⁇ -CD inclusion compound capsule (C medicine);
  • the three groups were given C, A, and B, respectively, and the cleaning period was 2 weeks between each two weeks.
  • the Beagle dogs were fasted for 12 hours, free to drink water, and the diet was forbidden within 4 hours after taking the medicine. The uniform meal was eaten during the test.
  • the capsule When the drug is administered, the capsule is directly inserted into the pharyngeal part, and the beagle dog is automatically swallowed and injected with about 50 mL of clean water, and is sent at 0, 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, and 8. At 10, 12, 24, 36, and 48 hours, 2 mL of blood was taken from the medial subcutaneous vein of the forelimb.
  • the concentration of valsartan in Beagle plasma samples was determined by LC-MS/MS analysis.
  • Valsartan/CD-MOF Dai Valsartan / ⁇ -CD AUC 0-48h ( ⁇ g/mL ⁇ h) 10.52 ⁇ 6.10 6.58 ⁇ 2.45 7.14 ⁇ 3.69 T max (h) 1.08 ⁇ 0.56 1.75 ⁇ 0.99 1.08 ⁇ 0.52 C max ( ⁇ g/mL) 4.38 ⁇ 2.09 * 2.00 ⁇ 0.77 3.08 ⁇ 1.73
  • CD-MOF can increase the bioavailability of valsartan in beagle dogs compared with the other two groups after valsartan.
  • the valsartan-micron potassium acetate CD-MOF composition tablet was dissolved in 91% for 30 minutes, and the commercially available valsartan tablet was eluted in an amount of 58% for 30 minutes.
  • the micron-sized potassium acetate CD-MOF was selected from Example 2, and the valsartan was loaded at 20, 60 and 70 ° C, respectively.
  • the heating speed of the water bath was 400 rpm
  • the drug loading time was 2 h
  • the drug-suspension suspension was centrifuged to take a precipitate
  • the mixture was vacuum dried at 40 ° C to prepare a composition.
  • results The drug loadings at 22, 60 and 70 °C were 22.9%, 28.8%, 29.3%, respectively.
  • the molar ratio of CD-MOF to valsartan in the composition was 1:1.0, 1:1.4, 1:1.4. .
  • Methanol, ethanol: methanol 1:1 mixed solvent and ethyl acetate were selected as drug-loading solvents.
  • the micron-sized potassium acetate CD-MOF is selected from the second embodiment, the drug loading condition is 40 ° C, the valsartan ethanol solution concentration is 250 mg/mL, the water bath heating stirring speed is 400 rpm, the drug loading time is 2 h, and the drug-loaded suspension is centrifuged. The precipitate was taken and dried under vacuum at 40 ° C to prepare a composition.
  • the valsartan ethanol solution concentration 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 heating speed of the water bath was 400 rpm, the drug loading time was 2 h, the drug-suspension suspension was centrifuged to take a precipitate, and the mixture was vacuum dried at 40 ° C to prepare a composition.
  • RESULTS The molar ratio of micron-sized potassium acetate CD-MOF to valsartan was 1:10, 1:15 and 1:20, respectively, 23.7%, 26.6%, 28.7%, CD-MOF in the composition.
  • the molar ratio of valsartan was 1:1.1, 1:1.2, and 1:1.4, respectively.
  • the valsartan ethanol solution concentration was set to 100 mg/mL and 150 mg/mL, and the micron-sized potassium hydroxide CD-MOF was selected from Example 1.
  • the heating speed of the water bath was 400 r/min, the drug loading time was 2 h, the drug-suspension suspension was centrifuged to obtain a precipitate, and the mixture was vacuum dried at 40 ° C to prepare a composition.
  • the molar ratio of micron-sized potassium hydroxide CD-MOF to valsartan was 1:24% and 15.15, respectively.
  • the molar ratio of CD-MOF to valsartan in the composition was 22.4% and 25.9%, respectively. They are 1:1.0 and 1:1.2 respectively.
  • valsartan The distribution of valsartan in ⁇ CD-MOF is mainly in two states: one is the inclusion of valsartan by cyclodextrin molecule; and the other is valsartan to form nanoclusters in the large cavity of ⁇ CD-MOF.
  • the first valsartan molecule is more prone to contraction in the hydrophobic cavity produced by the bicyclodextrin structure in ⁇ CD-MOF (butt free energy -8.5kcal/mol), thereby vacating the hydrophilic cavity to accept more The valsartan molecule.
  • the carboxyl group in valsartan electrostatically interacts with the hydroxide in the gap of the ⁇ CD-MOF crystal and the hydroxyl group in the cyclodextrin to generate a hydrogen bond.
  • the docking valsartan molecules continue to dock into the large cavity of ⁇ CD-MOF with different system energies.
  • Figure 9 is a graph of X-ray small angle scattering (SAXS) results, showing that CD-MOF is a typical body-centered cubic crystal with long-range order and good periodicity.
  • SAXS X-ray small angle scattering
  • Figure 10 is a solid-state nuclear magnetic result showing that the overall signal line width is significantly increased after drug-loading of CD-MOF (valsartan/CD-MOF1:1.5 of Example 4 and valsartan/CD-MOF1:0.5 of Example 11), Especially for the high drug-loading VAL/CD-MOF (1:1.5), the split signal of valsartan benzene ring (C 12-23 ) disappeared, and the line width of glycosidic bond (C 4 ) on CD-MOF increased significantly. This indicates a strong interaction between the drug and the CD-MOF vector.
  • the valsartan molecule is in a restricted environment and is likely to enter the pair of gamma-CD molecules.
  • the CD-MOF hydroxyl group (C 6 ) was shifted to a high field after drug loading, and VAL/CD-MOF1: 0.5 and 1:1.5 were shifted by 1.9 ppm and 1.7 ppm at 57.5 ppm, respectively; correspondingly, VAL/CD-MOF1:
  • the carboxyl group (C 10 ) at 170-180 ppm of valsartan at 0.5 and 1:1.5 changed from a split peak to a broad peak, indicating that the carboxyl group of valsartan and the hydroxyl group of CD-MOF may form hydrogen during drug loading.
  • the keys interact.
  • VAL/CD-MOF1:0.5 has significant changes in line type and intensity here, while VAL/CD-MOF1:1.5 signals and laksa
  • the linearity of tantalum is similar, indicating that the valsartan molecular moiety aggregates in the large cavity in the middle of the CD-MOF to form nanoclusters.
  • 3,000 mL of pure water was weighed into a beaker, 97.3 g of ⁇ -CD was added to stir, and 33.6 g of sodium hydroxide was added thereto, and ultrasonication was performed to completely dissolve ⁇ -CD and sodium hydroxide to prepare a mother liquid.
  • the mother liquor was poured into a reaction vessel at a rotational speed of 300 rpm and a temperature of 50 °C. Further, 1800 mL of methanol was added to the reaction vessel, and after dissolution and clarification, 38.4 g of PEG 20000 was added. After standing overnight at room temperature, the mixture was centrifuged, and the supernatant was removed.
  • the precipitate was washed twice with 100 mL of ethanol and twice with 100 mL of methanol.
  • the precipitate was dried in a vacuum oven at 40 ° C for 12 h to obtain a micron-sized sodium hydroxide cyclodextrin metal organic skeleton.
  • 3,000 mL of pure water was weighed into a beaker, 97.3 g of ⁇ -CD was added thereto, and then 16.8 g of calcium hydroxide was added thereto, and ultrasonication was carried out to completely dissolve ⁇ -CD and calcium hydroxide to prepare a mother liquid.
  • the mother liquor was poured into a reaction vessel at a rotational speed of 300 rpm and a temperature of 50 °C. Further, 1800 mL of ethanol was added to the reaction vessel, and after dissolution and clarification, 38.4 g of PEG 4000 was added.
  • the valsartan cyclodextrin metal-organic framework composition was prepared in accordance with the procedure of Example 4.
  • Preparation process all the raw materials in the prescription are passed through 100 mesh sieve, VAL/CD-MOF is weighed according to the prescription amount, and copolyvidone S630 is added for uniform mixing, and then the prescribed amount of magnesium stearate is added, and after being uniformly mixed,
  • the tablet core was prepared by a powder direct pressing method.
  • the cellulose acetate-polyethylene glycol 4000 was dissolved in acetone as a coating liquid.
  • the core is placed in a coating pan, and hot air is blown. When the core temperature is about 50 ° C, the coating is carried out, the flow rate of the coating liquid is 5 mL/min, and the temperature in the coating pan is about 50 ° C, and the coating pan is coated.
  • the rotation speed is 30r/min, and the inclination angle is 45°.
  • the hot air is continuously blown for 0.5 h.
  • the 40mg specification was coated with cellulose acetate-polyethylene glycol 4000 (5:1) to increase the weight by 4%
  • the 40mg specification was coated with cellulose acetate-polyethylene glycol 4000 (4:1) to increase the weight by 2%.
  • a 0.8 mm hole was made in the center of one side surface of the tablet with a laser punch (speed 800 mm/s, power 100%).
  • the valsartan cyclodextrin metal-organic framework composition was prepared in accordance with the procedure of Example 4.
  • Preparation process all the raw materials in the prescription are passed through a 100 mesh sieve, VAL/CD-MOF is weighed according to the prescription amount, and copolyvidone S630 and KCl are added for uniform mixing, and then a prescribed amount of magnesium stearate is added, to be mixed. After evenly, a powder of 80 mg was prepared by a direct pressure method.
  • the tablet core was designed to have a tablet weight of 600 mg and was pressed with a 12 mm punch.
  • Cellulose acetate was selected as the coating material
  • PEG 4000 was used as the porogen
  • cellulose acetate and polyethylene glycol 4000 were dissolved in acetone at a mass ratio of 4:1 to obtain a coating liquid.
  • the core is placed in a coating pan, and hot air is blown.
  • the core temperature is about 50 ° C
  • the coating is carried out, the flow rate of the coating liquid is 5 mL/min, and the temperature in the coating pan is about 50 ° C, and the coating pan is coated.
  • the rotation speed is 30r/min
  • the inclination angle is 45°
  • after the core weight gain is 2% (the actual weight gain is 2.0%)
  • the hot air is continuously blown for 0.5 h.
  • a laser punch speed 800mm/s, power 100%
  • Fasting group The rats were fasted for 12 hours before the experiment, and each of the valsartan/CD-MOF osmotic pump tablets was given. The rats were fasted within 4 hours, and 500g/standard dog food was eaten during the test. 2 mL of blood was taken from the forelimb vein before and after administration and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 24 h after administration, and placed in a heparinized vacuum tube. After centrifugation (4,000 rpm, 5 min), the plasma was separated and stored in a -80 ° C freezer. After one week of drug withdrawal, a crossover experiment was performed as described above.
  • Diet group fasting for 12 hours before the experiment, 500g/standard dog food was given 30min before administration, and each tablet of valsartan/CD-MOF sustained release tablets was given before and after administration, 0.25, 0.5 after administration. 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, 24h, respectively, 2 mL of blood was taken from the forelimb vein, placed in a heparinized vacuum tube, centrifuged (4,000 rpm, 5 min), and the plasma was separated. Store in a -80 ° C refrigerator. After one week of drug withdrawal, a crossover experiment was performed as described above.
  • the drug-time curve of valsartan osmotic pump tablets and Daiwen capsules was compared (Fig. 13, Table 5). From the pharmacokinetic parameters, the peak time of valsartan/CD-MOF osmotic pump tablets was known. T max and in vivo residence time MRT 0-t were longer than those of Daiwen capsule, which was consistent with the results under fasting conditions, indicating that valsartan/CD-MOF osmotic pump tablets had a sustained release effect.
  • the valsartan cyclodextrin metal-organic framework composition was prepared in accordance with the procedure of Example 4.
  • Preparation process the original auxiliary material was passed through a 60 mesh sieve, and the powder was directly mixed; and the sheet was pressed into a sheet with a diameter of 9 mm, and the thickness was 3 mm.
  • Group A was the valsartan fasting experimental group. Among them, 1-3 was firstly administered with self-made preparation (valsartan/CD-MOF sustained-release tablets, specification 80mg), and 4-6 was given first. Drug reference preparation; after a week of washing, cross-over experiments were performed.
  • Group B No. 7-12 was the valsartan diet experimental group (No. 7 to No. 12), among which, No. 7-9 was first administered with self-made preparation (valsartan/CD-MOF sustained-release tablet, specification 80 mg), 10 The reference preparation was administered first on the -12th; after one week of the washout period, a crossover experiment was performed.
  • Both the fasting group and the diet group were fasted for 12 hours before the experiment, free to drink water, and the standard dog food of Beagle dogs was given 4 hours after the fasting group.
  • the diet group was given a standard dog of 300g each beagle half an hour before the administration. Food, free diet, record different beagle food intake at each time point.

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Abstract

一种提高缬沙坦溶解性的环糊精-金属有机骨架组合物，包含：(a)环糊精-金属有机骨架材料；以及(b)负载于所述骨架材料的缬沙坦。本发明的组合物，将缬沙坦负载于环糊精-金属有机骨架材料，能显著提高缬沙坦在水中的溶解度和溶解速率，解决缬沙坦药物溶解性差、口服生物利用度低的问题，制备组合物所用原料和溶剂廉价易得，步骤简单，利于工业化生产。

Description

一种提高缬沙坦溶解性的环糊精-金属有机骨架组合物 技术领域
本发明涉及一种提高缬沙坦溶解性的环糊精-金属有机骨架组合物。
背景技术
高血压是最常见的心血管疾病之一，不仅直接危害健康，还加速动脉粥样硬化的过程，血压升高是中国人群脑卒中、冠心病、心力衰竭和肾脏疾病的主要危险因素。我国心、脑血管疾病的发生和死亡人数在不断上升，其中死亡人数占我国总死亡率已达40％，高血压已经成为危害健康的普遍问题。
“沙坦”类药物即血管紧张素Ⅱ受体拮抗剂(ARB)类抗高血压药物，问世10年多来,因其降压作用明显，耐受性好，尤其临床试验和循证证据表明其具有对心血管疾病的独特疗效和保护作用，已成为临床最普遍的抗高血压药物之一，引起临床普遍关注，且长期应用后干咳、停药反跳及体位性低血压等不良反应发生率低，已被WHO多个治疗指南推荐为伴有心血管疾病和蛋白尿的高血压患者的一线降压药。沙坦类药物多为BCSⅡ类药物，在水中溶解性差，导致沙坦类药物口服生物利用度低。为了提高沙坦类药物口服生物利用度，必须提高沙坦类药物的溶解性。
缬沙坦是血管紧张素Ⅱ受体拮抗剂(ARB)类抗高血压药物，问世10年多来,因其降压作用明显，耐受性好，尤其临床试验和循证证据表明其具有对心血管疾病的独特疗效和保护作用，已成为临床最普遍的抗高血压药物之一，已引起临床普遍关注，且长期应用后干咳、停药反跳及体位性低血压等不良反应发生率低，已被WHO多个治疗指南推荐为伴有心血管疾病和蛋白尿的高血压患者的一线降压药。缬沙坦为BCSⅡ类药物，在水中溶解性差，导致缬沙坦口服生物利用度低。为了提高缬沙坦口服生物利用度，必须提高缬沙坦药物的溶解性。
发明内容
本发明的目的在于提供一种提高缬沙坦溶解性的环糊精-金属有机骨架组合物。
在本发明的第一方面，提供了一种缬沙坦环糊精-金属有机骨架组合物，包含：(a)环糊精-金属有机骨架材料；以及(b)负载于所述骨架材料的缬沙坦。
本发明中，缬沙坦以两种方式负载于所述骨架材料：双环糊精分子对缬沙坦分子的包合；以及缬沙坦在环糊精-金属有机骨架中间大空腔中形成纳米团簇。
在另一优选例中，所述环糊精-金属有机骨架材料中的金属离子选自下组：Li +、Na +、K +、Rb +、Cs +、Mg 2+、Cd 2+、Sn 2+、Ag +、Yb +、Ba 2+、Sr 2+、Ca 2+、Pb 2+、La 3+。
在另一优选例中，金属离子为Ca 2+、Na +或K +，进一步优选K +。
在另一优选例中，与金属离子成盐或碱的阴离子包括但不限于OH -、NO 3 -、CO 3 2-、HCO 3 -、CH 3COO -、SCN -、C 6H 5COOH＝C 6H 5COO -、Cl -、Br -、I -、O 2 -、S 2 -、HS -、HSO 4 -、 ClO -、ClO 3 -、MnO 4 -，优选OH -。
在另一优选例中，所述环糊精-金属有机骨架材料为氢氧化钾环糊精-金属有机骨架材料、碳酸钾环糊精-金属有机骨架材料、氯化钾环糊精-金属有机骨架材料、乙酸钾环糊精-金属有机骨架材料，优选乙酸钾γ-环糊精-金属有机骨架材料。
在另一优选例中，所述环糊精-金属有机骨架材料中的环糊精选自下组：α-环糊精、β-环糊精、γ-环糊精、羟丙基-β-环糊精、磺丁基-β-环糊精、甲基-β-环糊精、羧甲基-β-环糊精。
在另一优选例中，环糊精选自下组：α-环糊精、β-环糊精、γ-环糊精，进一步优选为γ-环糊精。
在另一优选例中，所述环糊精-金属有机骨架材料为碱性或中性环糊精-金属有机骨架材料。碱性环糊精-金属有机骨架材料分散到含有机酸的有机溶剂中孵育即得到中性环糊精-金属有机骨架材料。在另一优选例中，所述有机酸选自下组：甲酸、乙酸、柠檬酸、富马酸、酒石酸、偏酒石酸、苹果酸、己二酸或其混合溶剂，优选甲酸、乙酸或其混合溶剂，最优选乙酸。在另一优选例中，所述有机溶剂选自甲醇、乙醇、丙醇、异丙醇、正丁醇或其混合溶剂，优选甲醇、乙醇或其混合溶剂，最优选乙醇。
在另一优选例中，所述的组合物中环糊精-金属有机骨架与缬沙坦的摩尔比例为1:0.2-1:2。
在另一优选例中，所述的组合物中环糊精-金属有机骨架与缬沙坦的摩尔比例为1:0.5-1:1.8。
在另一优选例中，所述的组合物中环糊精-金属有机骨架与缬沙坦的摩尔比例优选为1:1.5。
在另一优选例中，所述组合物还具有以下一个或多个特征：
(1)所述环糊精-金属有机骨架材料的平均粒径为5纳米-1000微米；
(2)所述组合物的载药量为5％-50％。
在另一优选例中，所述环糊精-金属有机骨架材料的平均粒径为100-1000纳米(纳米级)；或者所述环糊精-金属有机骨架材料的平均粒径为1-100微米(微米级)。
在另一优选例中，所述组合物的载药量为8％-48％。在另一优选例中，所述组合物的载药量为10％-45％。
在另一优选例中，所述组合物的载药量进一步优选为15％-40％。在另一优选例中，所述组合物的载药量进一步优选为25％-30％。
本申请组合物对缬沙坦具有增溶效果，将缬沙坦在水中的溶解度提高了2-200倍，优选为5-100倍，进一步优选为10-50倍。
根据药动学数据(AUC 0-t、C max等)统计分析，结果显示缬沙坦-环糊精-金属有机骨架组合物与代文胶囊、代文片剂相比较，可显著提高缬沙坦在大鼠、比格犬体内的生物利用度。
本发明的第二方面，提供第一方面所述的组合物的制备方法，所述制备方法包括将所述环糊精-金属有机骨架材料与所述缬沙坦混合后得到所述组合物的步骤。
在另一优选例中，所述混合的方式为缬沙坦溶液与环糊精-金属有机骨架材料的混合。
在另一优选例中，所述混合的温度为0～70℃，优选30～50℃，最优选30～40℃。
在另一优选例中，所述混合的时间为10分钟～3天，优选为1小时～12小时，最优选为10分钟～2小时。
在另一优选例中，将缬沙坦溶解于选自下组的溶剂中制备所述缬沙坦溶液：甲醇、乙醇、丙醇、异丙醇、正丁醇、氯仿、二甲基甲酰胺或其混合溶剂，优选甲醇、乙醇或其混合溶剂，最优选乙醇。
在另一优选例中，所述环糊精-金属有机骨架材料中的环糊精与缬沙坦的投料摩尔比为1:1-1:50。
在另一优选例中，所述环糊精-金属有机骨架材料中的环糊精与缬沙坦的投料摩尔比为1:1-1:30或1:1-1:25。
在另一优选例中，所述环糊精-金属有机骨架材料中的环糊精与缬沙坦的投料摩尔比为1:1-1:22或1:15-1:25。
在另一优选例中，环糊精与缬沙坦的投料摩尔比为1:1.5-1:25。
在另一优选例中，所述制备方法还包括后处理步骤：收集固体并进行干燥。
本发明的第三方面，提供第一方面所述的组合物的制备方法，包括以下步骤：
(i)将环糊精、金属离子源溶解于水中制备成第一溶液，将所述缬沙坦与有机溶剂混合制成第二溶液；
(ii)将第二溶液加入第一溶液中进行混合，得到混合物；
(iii)对所述混合物进行固体收集和干燥，即得所述的组合物。
在另一优选例中，所述金属离子源选自下组：氢氧化钾、碳酸钾、氯化钾。
在另一优选例中，所述第一溶液中所述环糊精的浓度为0.01-200mM。
在另一优选例中，所述环糊精与所述金属离子源中金属离子的摩尔比为1:1-1:10。
在另一优选例中，将缬沙坦溶解于选自下组的有机溶液中制备所述第二溶液：甲醇、乙醇、丙醇、异丙醇、正丁醇、氯仿、二甲基甲酰胺或其混合溶剂，优选甲醇、乙醇或其混合溶剂，最优选乙醇。
在另一优选例中，在步骤ii)中，将第二溶液加入第一溶液中进行混合，可加入形态调节剂混合得到混合物。
在另一优选例中，所述形态调节剂为聚乙二醇、聚维酮、聚山梨醇、失水山梨醇单月桂酸酯、聚氧乙烯月桂醇醚、乳化剂OP、乳百灵A、普流罗尼、十二烷基硫酸钠、十二烷基苯磺酸钠、十六烷基三甲基溴化铵、或其组合。
在另一优选例中，所述形态调节剂为聚乙二醇20000、聚乙二醇2000、聚乙二醇 4000、聚乙二醇6000、聚乙二醇8000、聚乙二醇10000、聚乙二醇20000、或其组合。
在另一优选例中，按1-20mg/mL上清液的比例加入所述形态调节剂，较佳为5-10mg/mL上清液。
本发明的第四方面，提供一种药物组合物，包含：
第一方面所述的组合物；和
药学上可接受的载体。
“药学上可接受的载体”指的是：一种或多种相容性固体或液体填料或凝胶物质，它们适合于人使用，而且必须有足够的纯度和足够低的毒性。“相容性”在此指的是组合物中各组份能和本发明的化合物以及它们之间相互掺和，而不明显降低化合物的药效。药学上可以接受的载体部分例子有纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂(如吐温)、润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。
在另一优选例中，所述的载体选自下组：稀释剂、赋形剂、填充剂、粘合剂、润湿剂、崩解剂、吸收促进剂、表面活性剂、吸附载体、润滑剂、或其组合。
在另一优选例中，所述的药物组合物配制为固体剂型或液体剂型，较佳适用于口服给药。在另一优选例中，固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在另一优选例中，液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。
在另一优选例中，所述药物组合物为胶囊剂、片剂、渗透泵片、凝胶骨架缓释片、颗粒剂。
在另一优选例中，所述药物组合物还包含表面活性剂，选自下组：聚山梨坦-80、聚山梨坦-60、聚乙二醇甘油脂肪酸酯、脱水山梨糖醇脂肪酸酯及两种以上的混合物。
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。
附图说明
图1为实施例13的差示扫描量热(DSC)图。
图2为实施例13的气体吸附图。
图3为实施例13的红外光谱图。
图4为实施例13的粉末X-射线衍射(PXRD)图。
图5为实施例14制备的载缬沙坦CD-MOF组合物胶囊在四种不同介质中的溶出曲线。
图6为实施例14中市售代文胶囊在四种不同介质中的溶出曲线。
图7为实施例17中缬沙坦CD-MOF组合物片剂与国产某市售片剂在水中的溶出曲线。
图8为实施例22中CD-MOF载缬沙坦的分子模拟图。
图9为实施例22中CD-MOF载缬沙坦的X-射线小角散射图。
图10为实施例22中CD-MOF载缬沙坦的固态核磁图。
图11为实施例25-26中CD-MOF载缬沙坦渗透泵片的体外释放曲线。
图12为实施例27中CD-MOF载缬沙坦渗透泵片与代文胶囊在比格犬禁食条件下的体内药时曲线。
图13为实施例27中CD-MOF载缬沙坦渗透泵片与代文胶囊在比格犬饮食条件下的体内药时曲线。
图14为实施例28中CD-MOF载缬沙坦缓释片在四种溶出介质中的体外释放曲线。
图15为实施例28中代文片在四种溶出介质中的体外释放曲线。
图16为实施例28中CD-MOF载缬沙坦缓释片与代文片在比格犬禁食条件下的体内药时曲线。
图17为实施例28中CD-MOF载缬沙坦缓释片与代文片在比格犬饮食条件下的体内药时曲线。
具体实施方式
本发明人经过广泛而深入地研究，首次研发出一种载缬沙坦的环糊精-金属有机骨架组合物，将缬沙坦负载于环糊精-金属有机骨架材料，能显著提高缬沙坦在水中的溶解度和溶解速率，解决缬沙坦药物溶解性差、口服绝对生物利用度低的问题，制备组合物所用原料和溶剂廉价易得，步骤简单，利于工业化生产。
环糊精
环糊精是由直链淀粉经葡萄糖基转移酶作用下生成的一系列环状低聚糖的总称，通常含有6～12个D-吡喃葡萄糖单元。其中研究得较多并且具有重要实际意义的是含有6、7、8个葡萄糖单元的分子，分别称为α、β-和γ-环糊精。环糊精是迄今所发现的类似于酶的理想宿主分子，并且其本身就有酶模型的特性。
金属有机骨架材料
金属有机骨架材料(Metal-organic frameworks，MOFs)是由有机桥连配体通过配位键的方式将无机金属中心连接起来形成无限延伸的网络状结构的晶体材料。由于MOFs超高的孔隙率和巨大的比表面积，以及其由无机和有机不同成分组成的结构使得其结构多样并可调节，促使MOFs在许多方面如气体储存、催化、药物载体等领域具有潜在的应用价值。
环糊精-金属有机骨架材料
如本文所用，术语“环糊精-金属有机骨架材料(Cyclodextrin-Metal-Organic Frameworks，CD-MOF)”、“基于环糊精的金属有机骨架材料”、“环糊精-金属有机骨架材料”、“环糊精-金属有机骨架化合物”可互换使用，是利用环糊精在水溶液中能与第一、二主族金属离子以一种有机配位的方式形成一种新的晶体，这种晶体具有多孔、表面积大、储存气体等特点。这种绿色、多孔材料能够吸附一些结构不稳定的药物，其巨大的空腔能够对药物起到保护作用，这使得其用于商业发展成为可能，尤其是由于环糊精-金属有机骨架为可食用衍生物，适于人类食用。将环糊精作为有机配体，金属离子作为无机金属中心，可形成新的、安全性较高、可药用的环糊精-金属有机骨架，即CD-MOF。
如本文所用，术语“碱性环糊精-金属有机骨架材料”是以碱金属和环糊精为原料制备的环糊精-金属有机骨架材料，呈碱性，将其溶解于水中制成10mg/mL的水溶液时，其pH约为11-13。
如本文所用，术语“中性环糊精-金属有机骨架材料”、“经酸化的环糊精-金属有机骨架材料”可互换使用，是将碱性环糊精-金属有机骨架材料进行酸化处理得到的近中性的环糊精-金属有机骨架材料，将其溶解于水中制成10mg/mL的水溶液时，其pH约为5-8。一种优选的酸化处理的方法如下：称取一定量的环糊精-金属有机骨架置于乙醇中，加入一定量的冰醋酸，25℃下，振摇孵育一定时间后，所得固体用乙醇洗涤，干燥，即得近中性的环糊精-金属有机骨架。
载缬沙坦的环糊精-金属有机骨架复合物
如本文所用，术语“载缬沙坦的环糊精-金属有机骨架组合物”、“载缬沙坦的环糊精-金属有机骨架复合物”、“载缬沙坦的环糊精-金属有机骨架”、“载缬沙坦的CD-MOF复合物”、“载缬沙坦的CD-MOF”、“CD-MOF载缬沙坦”、“缬沙坦CD-MOF组合物”、“CD-MOF载缬沙坦”可互换使用，上述术语均代表将缬沙坦负载于环糊精-金属有机骨架材料所得的样品。
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件(如Sambrook等人，分子克隆：实验室手册(New York:Cold Spring Harbor Laboratory Press,1989)中所述的条件)或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数是重量百分比和重量份数。
除非另行定义，文中所使用的所有专业与科学用语与本领域熟练人员所熟悉的意义相同。此外，任何与所记载内容相似或均等的方法及材料皆可应用于本发明方法中。文中所述的较佳实施方法与材料仅作示范之用。
通用方法
缬沙坦含量测定条件：(1)紫外分光光度法：参照《中国药典》2015年版二部 缬沙坦胶囊溶出度测定法，检测波长为250nm。(2)高效液相色谱(HPLC)法：参照《中国药典》2015年版建立缬沙坦胶囊的含量测定法。色谱柱为Platisil ODS C18(250×4.6mm，5μm)；流动相为乙腈-水-冰醋酸(500:500:1)；流速1.2mL/min；柱温35℃；检测波长230nm。
溶解度测定方法：称取过量的待测样品，置于水中，摇床振摇(25℃、200rpm)三天，离心过滤，按照上述“缬沙坦含量测定方法”测定溶液中缬沙坦的浓度。记为待测样品在25℃水中的溶解度。
增溶倍数：待比较样品的溶解度与缬沙坦原料在水中(25℃)的溶解度(0.08mg/mL)的相比。
载药量与载药摩尔比的测定与计算方法：精密称定5mg(m 1)待测样品，置于100mL容量瓶中，用纯水溶解，过滤后，按照“缬沙坦含量测定条件”对缬沙坦含量进行测定，计算缬沙坦的质量m 2。载药量(％)＝m 2/m 1×100；载体与缬沙坦的摩尔比为(m 2/435.52):((m 1-m 2)/M 载体)，M 载体为载体环糊精金属有机骨架的分子量，435.52为缬沙坦的分子量。
实施例1 缬沙坦微米级氢氧化钾CD-MOF组合物-孵育
量取3000mL纯水于烧杯中，加入97.3gγ-CD搅拌，再加入33.6g KOH，超声，使γ-CD和KOH完全溶解，制得母液。将母液倒入反应釜中，设置转速为300rpm，温度50℃。再向反应釜中加入1800mL甲醇，溶解澄清后加入38.4g PEG20000。室温静置过夜后离心，去上清，沉淀分别使用100mL乙醇洗涤两遍，再用100mL甲醇洗涤两遍。沉淀于40℃真空干燥箱中干燥12h，即得微米级氢氧化钾-环糊精-金属有机骨架，粒径为1-10微米。
称取200mg微米级氢氧化钾CD-MOF于15mL离心管中，加入10mL缬沙坦乙醇溶液(环糊精-金属有机骨架材料中的环糊精与缬沙坦的摩尔比例为1:22)，摇床振摇孵育(37℃，150rpm)20h，离心，下层沉淀物60℃真空干燥4h，即得载缬沙坦的微米级氢氧化钾CD-MOF组合物。
所得组合物中载药量为29.4％(w/w)，CD-MOF与缬沙坦的摩尔比为1:1.4，将缬沙坦在水中的溶解度提高了34.5倍(缬沙坦原料在25℃的水中溶解度为0.08mg/mL)。
实施例2 缬沙坦微米级乙酸钾CD-MOF组合物-孵育
在实施例1中的基础上进一步制备微米级乙酸钾CD-MOF：向下层沉淀物中加入0.4L无水乙醇分散，进行离心洗涤，再向沉淀中加入0.4无水乙醇和20mL冰醋酸，搅拌中和，离心去除上清。最后向沉淀中加入0.4乙醇，离心(4000rpm，5min)洗涤两遍。将洗涤后的沉淀置于60℃真空干燥箱中干燥4h。即得微米级乙酸钾环糊精-金属有机骨架，粒径为1-10微米。
按照实施例1中所述的载药方法(环糊精-金属有机骨架材料中的环糊精与缬沙坦的摩尔比例为1:20)，制备缬沙坦CD-MOF组合物，所得组合物中载药量为30.7％(w/w)，CD-MOF与缬沙坦的摩尔比为1:1.6，将缬沙坦在水中的溶解度提高33.7倍。
实施例3 缬沙坦微米级氢氧化钾CD-MOF组合物-搅拌
称取200mg实施例1中制备的微米级氢氧化钾CD-MOF于20mL西林瓶中，加入10mL缬沙坦乙醇溶液(环糊精-金属有机骨架材料中的环糊精与缬沙坦的摩尔比例为1:20)，40℃加热磁力搅拌1h，离心，下层沉淀物真空干燥，即得载缬沙坦微米级氢氧化钾CD-MOF组合物。
所得组合物中载药量为29.7％，组合物中CD-MOF与缬沙坦的摩尔比为1:1.5，增溶倍数为35.6。
实施例4 缬沙坦微米级乙酸钾CD-MOF组合物-搅拌
称取40g实施例2中的微米级乙酸钾CD-MOF于烧杯中，加入1L浓度为0.25g/mL缬沙坦乙醇溶液(环糊精-金属有机骨架材料中的环糊精与缬沙坦的投料摩尔比为1:22)，按照实施例3方法进行载药。作为对照，同时以γ-CD代替CD-MOF，用相同的方法制备缬沙坦γ-CD组合物。
缬沙坦CD-MOF物理混合物的制备：按照载药比例分别称取缬沙坦与微米级乙酸钾CD-MOF，置于烧杯中，用玻璃棒进行搅拌混合，得物理混合物。
结果：所得缬沙坦CD-MOF组合物中载药量为31.1％，组合物中CD-MOF与缬沙坦的摩尔比为1:1.5，增溶倍数为39.5，显著高于缬沙坦γ-CD组合物(增溶倍数为4.6)。
溶出测定：称取相当于一个剂量(80mg)的缬沙坦CD-MOF组合物，平行6次，进行溶出实验。转速100rpm，温度为37.0±0.5℃，介质为900mL去离子水，不同时间点取样5mL，在250nm处用紫外测吸光度，计算溶出量。同时对比测定缬沙坦原料、缬沙坦与CD-MOF的物理混合物。
结果如表1所示。
表1 缬沙坦CD-MOF组合物、物理混合物及原料的溶出
Figure PCTCN2019080211-appb-000001
表1结果表明，缬沙坦微米级乙酸钾CD-MOF组合物和物理混合物均显著高于缬沙坦原料，而组合物又显著高于物理混合物。
实施例5 缬沙坦纳米级氢氧化钾CD-MOF组合物
取2000mL纯水于5000mL大烧杯中，称取64.9gγ-CD于大烧杯中，搅拌，再向烧杯中加入22.4g KOH，超声，使γ-CD和KOH完全溶解，制得母液。将母液倒入反应釜中，转速300rpm，温度50℃时，向反应釜中加入1200mL甲醇，再加入PEG20000(8mg/mL)。冷水浴中静置过夜。离心去上清，沉淀分别使用150mL乙醇洗涤两遍，于40℃真空干燥箱中干燥12h。粒径为100-500纳米。
按照实施例3方法进行载药(环糊精-金属有机骨架材料中的环糊精与缬沙坦的摩尔比例为1:20)，得缬沙坦纳米级氢氧化钾CD-MOF组合物。结果：所得组合物中载药量为31.7％，CD-MOF与缬沙坦的摩尔比为1:1.5，增溶倍数为36.2。
实施例6 缬沙坦纳米级乙酸钾CD-MOF组合物
在实施例5的基础上按照实施例2的方法进行改进制备纳米级乙酸钾CD-MOF，粒径为100-500纳米。
按照实施例3方法进行载药(环糊精-金属有机骨架材料中的环糊精与缬沙坦的摩尔比例为1:20)，得缬沙坦纳米级氢氧化钾CD-MOF组合物。
结果：所得组合物中载药量为32.8％，CD-MOF与缬沙坦的摩尔比为1:1.7，增溶倍数为36.3。
实施例7 缬沙坦碳酸钾CD-MOF组合物
取2500mL纯水于烧杯中，加入81.1gγ-CD和34.5g碳酸钾，制得母液。将母液倒入反应釜中，加入2500mL甲醇，反应澄清后加入40.0g PEG20000使完全溶解后，将反应液室温静置过夜后离心去上清，沉淀分别使用100mL乙醇洗涤两遍，再用100mL甲醇洗涤两遍。于40℃真空干燥箱中干燥12h，即得碳酸钾微米级CD-MOF，粒径为300-700微米。
按照实施例3的方法进行载药(环糊精-金属有机骨架材料中的环糊精与缬沙坦的摩尔比例为1:20)，得缬沙坦碳酸钾CD-MOF组合物。
结果：所得组合物中载药量为24.6％，CD-MOF与缬沙坦的摩尔比为1:1.1，增溶倍数为30.5。
实施例8 缬沙坦氯化钾CD-MOF的制备
将γ-CD、氯化钾溶于5mL水中，使其浓度分别为0.125M、0.5M，超声10min使其充分溶解。然后预加0.5mL甲醇至γ-CD与氯化钾混合溶液内，在密闭容器中50℃条件下加热甲醇，反应6h后，用乙醇和甲醇各洗涤2次，将所得晶体50℃真空干燥12小时，即得氯化钾CD-MOF，粒径为1-10微米。
按照实施例3的方法进行载药(环糊精-金属有机骨架材料中的环糊精与缬沙坦的摩尔比例为1:20)，得缬沙坦氯化钾CD-MOF组合物。
结果：所得组合物中载药量为22.3％，CD-MOF与缬沙坦的摩尔比为1:1.3，增溶倍数为34.8。
实施例9 共结晶法
将163.0mgγ-CD与56.0mg KOH溶解于5mL水中，超声溶解。再加入5mL缬沙坦甲醇溶液(γ-CD与缬沙坦的投料摩尔比为1:22)，再按8mg/mL上清液的比例加入PEG20000作为形态调节剂，静置半小时后，离心，弃去上清液，下层固体用异丙醇洗涤，将所得晶体50℃条件下真空干燥过夜，即得缬沙坦环糊精-金属有机骨架共结晶组合物。
结果：所得组合物中载药量为33.9％，CD-MOF与缬沙坦的摩尔比为1:1.8，增溶倍数为38.9。
实施例10 缬沙坦乙酸钾β-CD-MOF组合物
称取β-环糊精200g、氢氧化钾78.9g加2L纯水至烧杯中溶解后，加入至5L反应釜中，室温25℃条件下，转速为100rpm，加入2L甲醇，搅拌16h，将混悬的反应液离心，沉淀即为氢氧化钾β-CD-MOF。将40mL冰醋酸加入至氢氧化钾β-CD-MOF的乙醇混悬体系中，搅拌5min使之分散均匀，用滤纸进行抽滤，滤饼继续用无水乙醇洗涤2次，滤饼干燥后即为乙酸钾β-CD-MOF。
称取200mg乙酸钾β-CD-MOF于20mL西林瓶中，加入10mL缬沙坦乙醇溶液(环糊精-金属有机骨架材料中的环糊精与缬沙坦的摩尔比例为1:22)，37℃加热搅拌1h，离心，下层沉淀物真空干燥，即得缬沙坦乙酸钾β-CD-MOF组合物。
结果：所得组合物中载药量为14.7％，CD-MOF与缬沙坦的摩尔比为1:0.5，增溶倍数为15.2。
实施例11 缬沙坦微米级乙酸钾CD-MOF组合物
称取20g实施例1中制备的微米级乙酸钾CD-MOF于1L烧杯中，加入300mL浓度为0.1g/mL缬沙坦乙醇溶液(环糊精-金属有机骨架材料中的环糊精与缬沙坦的摩尔比例为1:5)，40℃加热磁力搅拌1h，离心，下层沉淀物真空干燥，即得载缬沙坦微米级氢氧化钾CD-MOF组合物。
所得组合物中载药量为12.4％，组合物中CD-MOF与缬沙坦的摩尔比为1:0.5，增溶倍数为35.2。
实施例12 缬沙坦微米级乙酸钾CD-MOF组合物
称取20g实施例1中制备的微米级乙酸钾CD-MOF于1L烧杯中，加入500mL浓度为0.18g/mL缬沙坦乙醇溶液(环糊精-金属有机骨架材料中的环糊精与缬沙坦的摩尔比例为1:16)，40℃加热磁力搅拌1h，离心，下层沉淀物真空干燥，即得载缬沙坦微米级氢氧化钾CD-MOF组合物。
所得组合物中载药量为22.82％，组合物中CD-MOF与缬沙坦的摩尔比为1:1.0，增溶倍数为34.9。
实施例13 缬沙坦/CD-MOF组合物的表征
作为对比，制备缬沙坦/γ-环糊精包合物：称取1297mgγ-环糊精(1mmol)溶解于30mL水中，称取435mg缬沙坦(1mmol)溶解于15mL乙醇中，将缬沙坦溶液滴加到搅拌状态下的γ-环糊精水溶液中，维持温度在40℃，500rpm下继续搅拌3h，除去乙醇。余下液体冷冻干燥，即得缬沙坦/γ-环糊精包合物。所得环糊精包合物中缬沙坦的含量(w/w)为15.5％，γ-环糊精与缬沙坦的摩尔比为1:0.64，包合物在水中的溶解度为0.38mg/mL，将缬沙坦在水中的溶解度提高了4.75倍。
图1：缬沙坦在108℃可见一个宽的融化吸热峰，而环糊精包合物和实施例4中的缬沙坦CD-MOF组合物该峰完全消失，物理混合物中该吸收峰重新出现，表明缬沙坦被环糊精包合，组合物中缬沙坦被CD-MOF负载。
图2：气体吸附结果显示，乙酸钾CD-MOF的比表面积为996m 2/g，载药摩尔比为1:0.5的缬沙坦CD-MOF组合物(实施例11)的Langmuir比表面积降至307m 2/g，而载药摩尔比为1:1.5的缬沙坦CD-MOF组合物(实施例4)的Langmuir比表面积几乎为零，表明缬沙坦被CD-MOF负载。
图3：红外光谱图显示载缬沙坦中性微米级CD-MOF组合物有别于缬沙坦原料药和中性微米级CD-MOF以及其两者的物理混合物。对比CD-MOF、VAL/CD-MOF和CD-MOF与VAL的物理混合物的图谱，三个样品在2926cm -1均有较宽的吸收带，可以归属为CD-MOF中-CH-的伸缩振动(ν CH)。VAL由于自身酰胺键和羰基的存在，在1731cm -1以及1600cm -1处有强吸收(碳氧双键特征吸收)以及1445cm -1处ν (C＝C)芳环振动，CD-MOF均不具有以上特征吸收；VAL/CD-MOF在1731cm -1(酰胺羧基)以及1445cm -1ν (C＝C)振动在强度上明显减弱或消失，而物理混合物依然存在。VAL的特征峰被掩盖表明缬沙坦被CD-MOF负载。
图4：粉末X-射线衍射结果表明缬沙坦在13-15 °与20-22 °有两个宽衍射峰；CD-MOF具有典型的晶体结构。载药后缬沙坦CD-MOF组合物中相应的CD-MOF衍射峰仍然存在，表明载药后的缬沙坦CD-MOF组合物仍为晶体结构。
实施例14 缬沙坦微米级乙酸钾CD-MOF组合物胶囊剂的制备
制备工艺：称取实施例4制备的载缬沙坦微米级乙酸钾CD-MOF组合物10g，加入10mL浓度为0.05mg/mL的聚山梨坦-80乙醇溶液均匀润湿，用高纯氮气吹30min，过30目筛制粒，干燥，整粒，填充胶囊。并与市售代文胶囊在四种不同pH介质中进行溶出度与溶出速率比较。
溶出度测定：采用转篮法，转速100rpm，温度37℃，四种不同介质：pH6.8磷酸盐缓冲液、pH4.5醋酸盐缓冲液、pH1.2盐酸溶液和去离子水各1000mL，在3，5，10，15，30，60，90，120min取点，每次取5mL，在250nm处用紫外测吸光度。
结果表明，载缬沙坦微米乙酸钾CD-MOF组合物胶囊(图5)在各介质中的溶出差异低于市售胶囊(图6)，显著提高了市售胶囊在pH1.2和水中的溶出速率，有助于改善缬沙坦的生物利用度。
实施例15 大鼠体内生物利用度
12只健康雄性SD大鼠购自上海实验动物研究中心，体重约为200±20g，随机分为2组，每组6只，分别灌胃给药给予缬沙坦CD-MOF组合物(实施例6制备)、原研代文胶囊15mg/kg，于0、0.08、0.25、0.5、0.75、1、1.5、2、3、4、8、12与24h分别眼眶取血0.3mL。将载缬沙坦中性微米级CD-MOF组合物与原研代文胶囊进行生物利用度对比并评价。
采用高效液相色谱串联质谱(LC-MS/MS)分析方法测定大鼠血浆样品中缬沙坦浓度。采用DAS2.0软件计算12只健康雄性SD大鼠的药动学参数，结果见表2，与代文组相比，缬沙坦/CD-MOF组的平均相对生物利用度为149.3％，表明CD-MOF载缬沙坦后，显著提高了缬沙坦在大鼠体内的生物利用度。同时采用SPSS17.0软件对药动学参数(药时曲线下面积AUC 0-24h、达峰浓度C max、达峰时间T max)进行t检验统计分析，结果显示，两组的AUC 0-24h、C max及T max均具有显著性差异，进一步说明了缬沙坦被CD-MOF载药后生物利用度得到显著提高。
表2.大鼠体内药动学参数
药动学参数 缬沙坦CD-MOF组合物 代文胶囊
AUC 0-24h(μg/mL·h) 77.71±13.12 * 52.05±23.02
T max(h) 0.72±0.25 ** 2.22±1.08
C max(μg/mL) 16.88±4.85 ** 7.90±3.70
注：与代文组比较 *p＜0.05； **p＜0.01。
实施例16 比格犬体内生物利用度
12只健康成年比格犬购自上海交大农学院教学实验实习场，体重约为8～12kg，分成3组，每组4只(雌雄各半)，采用三周期三交叉实验设计：
第一周期三组分别口服缬沙坦/CD-MOF组合物胶囊(A药，按照实施例4制备，加入吐温-80乙醇溶液制粒)、代文胶囊(B药)、缬沙坦/γ-CD包合物胶囊(C药)；
第二周期三组分别口服B药、C药、A药；
第三周期三组分别口服C药、A药、B药，每两周期间的清洗期为2周。
实验前比格犬禁食12h，自由饮水，服药后4h内禁止饮食，受试期间进食统一餐。
给药时将胶囊直接塞入会咽部，使比格犬自动吞咽并注入约50mL清水送下，于0、0.25、0.5、1、1.5、2、2.5、3、3.5、4、6、8、10、12、24、36、48h分别前肢内侧皮下静脉取血2mL。
采用LC-MS/MS分析方法测定比格犬血浆样品中缬沙坦浓度。
比格犬药动学结果显示于表3。
表3 比格犬体内药动学参数
药动学参数 缬沙坦/CD-MOF 代文 缬沙坦/γ-CD
AUC 0-48h(μg/mL·h) 10.52±6.10 6.58±2.45 7.14±3.69
T max(h) 1.08±0.56 1.75±0.99 1.08±0.52
C max(μg/mL) 4.38±2.09 * 2.00±0.77 3.08±1.73
注：与代文组比较 *p＜0.05。
表3结果表明：缬沙坦/CD-MOF组合物胶囊与缬沙坦γ-CD包合物胶囊相比，平均AUC 0-48h提高了47.3％、平均C max提高了42.2％；缬沙坦/CD-MOF组合物胶囊与代文胶囊相比，平均AUC 0-48h提高了59.8％、平均C max提高了119.1％。
以上结果表明，CD-MOF载缬沙坦后，与其他两组相比，可提高缬沙坦在比格犬体内的生物利用度。
实施例17：缬沙坦/CD-MOF组合物片剂
处方：
Figure PCTCN2019080211-appb-000002
制备工艺：称取上述处方中的载缬沙坦中性微米级CD-MOF组合物与各辅料至混合机中均匀混合，选用12mm冲头进行粉末直压法压片。
溶出测定：采用桨法，在转速100rpm，温度为37.0±0.5℃，介质为900mL去离子水，在0.5，3，5，10，15，30，60min取点，每次取5mL，用0.45μm滤膜过滤，稀释适当倍数，在250nm处用紫外测吸光度(n＝6)。
结果如图7所示，缬沙坦微米级乙酸钾CD-MOF组合物片剂30min溶出91％，而市售某缬沙坦片剂30min的溶出量为58％。
实施例18 载缬沙坦不同温度考察
微米级乙酸钾CD-MOF选自实施例2，分别在20、60和70℃条件下对缬沙坦进行载药。水浴加热搅拌转速为400rpm，载药时间为2h，载药混悬液离心取沉淀，40℃真空干燥，制备组合物。
结果：20、60和70℃条件下的载药量分别为22.9％、28.8％、29.3％，组合物中CD-MOF与缬沙坦的摩尔比为1:1.0、1:1.4、1:1.4。
实施例19 载缬沙坦不同溶剂考察
选择甲醇、乙醇：甲醇1:1混合溶剂、乙酸乙酯作为载药溶剂。微米级乙酸钾CD-MOF选自实施例2，载药条件为40℃，缬沙坦乙醇溶液浓度为250mg/mL，水浴加热搅拌转速为400rpm，载药时间为2h，载药混悬液离心取沉淀，40℃真空干燥，制备组合物。
结果：甲醇、甲醇：乙醇1:1混合溶剂、以及乙酸乙酯中的载药量分别为26.4％、24.5％、22.37％，组合物中CD-MOF与缬沙坦的摩尔比分别为1:1.2、1:1.1、1:1.0。
实施例20 不同投料摩尔比-微米级乙酸钾CD-MOF
设置缬沙坦乙醇溶液浓度为100mg/mL，150mg/mL和200mg/mL，微米级乙酸钾CD-MOF选自实施例2。水浴加热搅拌转速为400rpm，载药时间为2h，载药混悬液离心取沉淀，40℃真空干燥，制备组合物。
结果：微米级乙酸钾CD-MOF与缬沙坦投料摩尔比为1:10、1:15和1:20的载药量分别为23.7％、26.6％、28.7％，组合物中CD-MOF与缬沙坦的摩尔比分别为1:1.1、1:1.2、1:1.4。
实施例21 不同投料摩尔比-微米级氢氧化钾CD-MOF
设置缬沙坦乙醇溶液浓度为100mg/mL和150mg/mL，微米级氢氧化钾CD-MOF选自实施例1。水浴加热搅拌转速为400r/min，载药时间为2h，载药混悬液离心取沉淀，40℃真空干燥，制备组合物。
结果：微米级氢氧化钾CD-MOF与缬沙坦投料摩尔比为1:10和1:15的载药量分别为22.4％、25.9％，组合物中CD-MOF与缬沙坦的摩尔比分别为1:1.0、1:1.2。
实施例22 CD-MOF载缬沙坦的分子模拟及表征
缬沙坦在γCD-MOF中的分布形式主要为两种状态：一部分为环糊精分子对缬沙坦的包合；一部分为缬沙坦在γCD-MOF的大空腔中形成纳米团簇。
具体为：第一个缬沙坦分子更倾向于蜷缩在γCD-MOF中双环糊精结构产生的疏水空腔中(对接自由能-8.5kcal/mol)，从而空出亲水空腔接纳更多的缬沙坦分子。缬沙坦中的羧基与γCD-MOF晶体缝隙中的氢氧根以及环糊精中的羟基发生静电相互作用，产生氢键。利用缬沙坦分子中亲水部位和疏水部位的特性，继续对接的缬沙坦分子以不同的体系能量对接到γCD-MOF的大空腔中。
图8所示，6个缬沙坦分子被6个环糊精分子对包合，5个缬沙坦分子负载于大空腔中，组合物中γCD-MOF与缬沙坦的理论载药摩尔比为1:1.3。
图9为X-射线小角散射(SAXS)结果图，表明：CD-MOF为典型的体心立方晶体，长程有序，具有较好的周期性。载药后(实施例4的缬沙坦/CD-MOF1:1.5和实施例11的缬沙坦/CD-MOF1:0.5)，缬沙坦/CD-MOF的布拉格长周期(2.2nm)均与CD-MOF保 持一致，但由于药物分子进入CD-MOF的骨架导致半高宽均增加。当缬沙坦/CD-MOF为1:0.5时，CD-MOF在各个峰的位置没有发明显位移，当缬沙坦/CD-MOF为1:1.5时，(200)晶面上1.6nm空腔位置由于被药物分子占据信号显著减弱。
图10为固态核磁结果，表明CD-MOF载药后(实施例4的缬沙坦/CD-MOF1:1.5和实施例11的缬沙坦/CD-MOF1:0.5)整体信号线宽显著增加，尤其对于高载药量的VAL/CD-MOF(1:1.5)，缬沙坦苯环(C 12-23)的裂分信号消失，CD-MOF上糖苷键(C 4)线宽明显增加，说明药物与CD-MOF载体之间存在较强相互作用。缬沙坦分子处于一个受限环境中并很可能进入双γ-CD分子对中。载药后CD-MOF羟基(C 6)向高场偏移，VAL/CD-MOF1:0.5和1:1.5在57.5ppm处分别偏移1.9ppm和1.7ppm；相应地，VAL/CD-MOF1:0.5和1:1.5中缬沙坦在170-180ppm处的羧基(C 10)由裂分峰变为一个宽峰，表明载药过程中缬沙坦的羧基和CD-MOF的羟基可能通过形成氢键发生相互作用。载药后对于缬沙坦的烷基链(8-36ppm)，VAL/CD-MOF1:0.5在此处的线型和强度均发生显著变化，而VAL/CD-MOF1:1.5中信号与缬沙坦的线型相似，表明缬沙坦分子部分聚集在CD-MOF中间的大空腔内形成纳米团簇。
实施例23
量取3000mL纯水于烧杯中，加入97.3gγ-CD搅拌，再加入33.6g氢氧化钠，超声，使γ-CD和氢氧化钠完全溶解，制得母液。将母液倒入反应釜中，设置转速为300rpm，温度50℃。再向反应釜中加入1800mL甲醇，溶解澄清后加入38.4g PEG20000。室温静置过夜后离心，去上清，沉淀分别使用100mL乙醇洗涤两遍，再用100mL甲醇洗涤两遍。沉淀于40℃真空干燥箱中干燥12h，即得微米级氢氧化钠环糊精金属有机骨架。称取200mg微米级氢氧化钠CD-MOF于15mL离心管中，加入10mL缬沙坦乙醇溶液(环糊精-金属有机骨架材料中的环糊精与缬沙坦的摩尔比例为1:22)，摇床振摇孵育(37℃，150rpm)20h，离心，下层沉淀物60℃真空干燥4h，即得缬沙坦微米级氢氧化钠环糊精金属有机骨架组合物。
实施例24
量取3000mL纯水于烧杯中，加入97.3gγ-CD搅拌，再加入16.8g氢氧化钙，超声，使γ-CD和氢氧化钙完全溶解，制得母液。将母液倒入反应釜中，设置转速为300rpm，温度50℃。再向反应釜中加入1800mL乙醇，溶解澄清后加入38.4g PEG4000。室温静置过夜后离心，去上清，沉淀分别使用100mL乙醇洗涤两遍，再用100mL乙醇洗涤两遍。沉淀于40℃真空干燥箱中干燥12h，即得微米级氢氧化钙环糊精金属有机骨架。称取200mg微米级氢氧化钠环糊精金属有机骨架于15mL离心管中，加入10mL缬沙坦乙醇溶液(环糊精-金属有机骨架材料中的环糊精与缬沙坦的摩尔比例为1:22)，摇床振摇孵育(37℃，150rpm)20h，离心，下层沉淀物60℃真空干燥4h，即得缬沙坦微米级氢氧化钙环糊精金属有机骨架组合物。
实施例25-26
按照实施例4的方法制备缬沙坦环糊精金属有机骨架组合物。
渗透泵片片芯处方信息：
Figure PCTCN2019080211-appb-000003
制备工艺：将处方中各原辅料均过100目筛，按照处方量称取VAL/CD-MOF，加入共聚维酮S630进行混合均匀后，再加入处方量的硬脂酸镁，待混合均匀后进行粉末直压法制备片芯。以醋酸纤维素-聚乙二醇4000溶于丙酮中为包衣液。将片芯置于包衣锅中，吹入热空气，待片芯温度为50℃左右时，进行包衣，包衣液流速5mL/min，包衣锅内温度约为50℃，包衣锅转速30r/min，倾斜角45°，待片芯增重达要求后，继续吹入热空气0.5h。其中，40mg规格以醋酸纤维素-聚乙二醇4000(5:1)包衣增重4％，40mg规格以醋酸纤维素-聚乙二醇4000(4:1)包衣增重2％。用激光打孔机(速度800mm/s，功率100％)在片剂的一侧表面中心打一个0.8mm的小孔。
释放度测定：以900mL去离子水为溶出介质，超声脱气处理，温度为37.0±0.5℃，转速为50rpm，在0.5、1、2、4、6h分别取点，每次取5mL，同时补充同温同体积的介质5mL，用0.22μm微孔虑膜过滤，稀释适当倍数在250nm处紫外测定吸光度值(n＝6)，计算平均累积释放量。
结果：12h内40mg规格渗透泵片平均累积释放99.28％，零级拟合相关系数R＝0.9899；80mg规格平均累积释放90.30％，零级拟合相关系数R＝0.9949(图11)。
实施例27
按照实施例4的方法制备缬沙坦环糊精金属有机骨架组合物。
处方信息：
Figure PCTCN2019080211-appb-000004
制备工艺：将处方中各原辅料均过100目筛，按照处方量称取VAL/CD-MOF，加入共聚维酮S630、KCl进行混合均匀后，再加入处方量的硬脂酸镁，待混合均匀后进行粉末直压法制备80mg规格片芯。设计片重为600mg的片芯处方，采用12mm冲头压片。选用醋酸纤维素为包衣材料，PEG 4000为致孔剂，醋酸纤维素与聚乙二醇4000以质量比4：1溶于丙酮中，即得包衣液。将片芯置于包衣锅中，吹入热空气，待片芯温度为50℃左右时，进行包衣，包衣液流速5mL/min，包衣锅内温度约为50℃，包衣锅转速30r/min，倾斜角45°，待片芯增重2％后(实际增重2.0％)，继续吹入热空气0.5h。用激光打孔机(速度800mm/s，功率100％)在片剂的一侧表面中心或在片剂侧面对称中心打一个至多个直径为0.8mm的小孔，得缬沙坦CD-MOF渗透泵片。
释放度测定：以900mL去离子水为溶出介质，超声脱气处理，温度为37.0±0.5℃，转速为50rpm，在0.5、1、2、4、6h分别取点，每次取5mL，同时补充同温同体积的介质5mL，用0.22μm微孔滤膜过滤，稀释适当倍数在250nm处紫外测定吸光度值(n＝6)，计算平均累积释放量。
结果：单面打一个孔6h释药69.6％，零级释放拟合，相关系数R＝0.9971；双面以及侧面打孔(四孔)后4h释药80.1％，6h释药91.8％，零级释放拟合，相关系数R＝0.9819。
动物实验总体设计：采用单剂量、双周期(禁食与饮食)、自身对照、交叉实验设计方法进行实验，取12只成年健康比格犬，雌雄各半，体重11～18kg，分为2组，分别为禁食组、饮食组，每组6只。
禁食组：实验前12h禁食不禁水，分别给予缬沙坦/CD-MOF渗透泵片各一片，服药4h内禁食，受试期间进食500g/只标准狗粮。于给药前及给药后0.25、0.5、1、1.5、2、2.5、3、3.5、4、6、8、10、12、24h分别于前肢静脉取血2mL，置肝素化的真空管中，离心(4,000rpm，5min)，分离血浆，置-80℃冰箱中保存。停药清洗一周后，进行交叉实验，方法同上。
饮食组：实验前12h禁食不禁水，给药前30min给予500g/只标准狗粮，分别给予缬沙坦/CD-MOF缓释片各一片，于给药前及给药后0.25、0.5、1、1.5、2、2.5、3、3.5、4、6、8、10、12、24h分别于前肢静脉取血2mL，置肝素化的真空管中，离心(4,000rpm，5min)，分离血浆，置-80℃冰箱中保存。停药清洗一周后，进行交叉实验，方法同上。
将缬沙坦渗透泵片与代文胶囊禁食条件下的药-时曲线进行比较(图12，表4)，从药动学参数可知，缬沙坦/CD-MOF渗透泵片组达峰时间T max、体内驻留时间MRT 0-t较代文胶囊长，说明缬沙坦/CD-MOF渗透泵片具有缓释作用(针对比格犬的6h缓释)
将缬沙坦渗透泵片与代文胶囊饮食条件下的药-时曲线进行比较(图13，表5)，从药动学参数可知，缬沙坦/CD-MOF渗透泵片组达峰时间T max、体内驻留时间MRT 0-t较代文胶囊长，与禁食条件下结果一致，表明缬沙坦/CD-MOF渗透泵片具有缓释作 用。
表4 禁食条件缬沙坦/CD-MOF渗透泵片与代文的药动学参数比较
Figure PCTCN2019080211-appb-000005
表5 饮食条件缬沙坦/CD-MOF渗透泵片与代文的药动学参数比较
Figure PCTCN2019080211-appb-000006
实施例28
按照实施例4的方法制备缬沙坦环糊精金属有机骨架组合物。
处方信息：
Figure PCTCN2019080211-appb-000007
制备工艺：将原辅料过60目筛，粉末直接混合；用直径9mm的浅凹型冲头压成片，厚度3mm。
溶出条件：介质体积900mL，温度37.0±0.5℃，转速50rpm，用紫外分光光度法测定在波长250nm处测定，计算累积释放量(n＝6)。
结果(图14、图15)：pH1.2中2h释放8.5％、4h释放22.4％；pH6.8中2h释放33.0％、4h释放58.8％。市售代文片剂(80mg)pH1.2中2h释放19％、pH6.8中15min释放97％，pH4.5中释放差异较大。四种pH介质中，缬沙坦/CD-MOF的释放差异显著降低，具有明显缓释作用。
动物实验：采用双交叉实验设计，取12只成年健康比格犬，体重9-13kg，随机分为A、B两组，每组6只比格犬，雌雄各半。A组(1-6号)为缬沙坦禁食实验组，其中，1-3号先给药自制制剂(缬沙坦/CD-MOF缓释片，规格80mg)，4-6号先给药参比制剂；一周清洗期后，进行交叉实验。B组(7-12号)为缬沙坦饮食实验组 (7～12号)，其中，7-9号先给药自制制剂(缬沙坦/CD-MOF缓释片，规格80mg)，10-12号先给药参比制剂；一周清洗期后，进行交叉实验。
禁食组和饮食组比格犬均在实验前禁食12h，自由饮水，禁食组给药后4h给予比格犬标准狗粮；饮食组给药前半小时给予每只比格犬300g标准狗粮，自由饮食，记录不同比格犬各时间点进食量。给药前取空白血，将缬沙坦/CD-MOF缓释片和代文片塞入比格犬会咽部，分次注入约30mL清水送服，使比格犬自动吞咽，并于给药后0.25，0.5，1，1.5，2，2.5，3，4，6，8，10，12，24h于前肢内侧皮下静脉取血2mL。分别放置于肝素化的离心管中，在4000rpm条件下离心10min，分离上层血浆，-20℃冰箱保存，待测。
结果(表6、图16)：与代文片组相比，0.5h到4h缬沙坦/CD-MOF缓释片有一定缓释效果。缬沙坦/CD-MOF缓释片禁食与代文片禁食相比，两组AUC (0-24h)和C max没有显著差异；峰时间T max延长2倍；平均驻留时间MRT (0～t)延长1.23倍；吸收速率K a明显小于代文组。
结果(表7、图17)：在比格犬饮食条件下，与代文片组相比缬沙坦/CD-MOF缓释片的达峰时间仍然延后，具有缓释效果。缬沙坦凝胶骨架片饮食与代文饮食相比，相对生物利用度为244.5％；C max提高1.38倍；达峰时间T max延长到4.88倍；平均驻留时间MRT (0-t)延长2.11倍。
表6 禁食条件缬沙坦/CD-MOF缓释片与代文的药动学参数比较
Figure PCTCN2019080211-appb-000008
表7 饮食条件缬沙坦/CD-MOF缓释片与代文的药动学参数比较
Figure PCTCN2019080211-appb-000009
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。

Claims (10)

  1. 一种缬沙坦环糊精-金属有机骨架组合物，其特征在于，所述组合物包含：(a)环糊精-金属有机骨架材料；以及(b)负载于所述骨架材料的缬沙坦。
  2. 如权利要求1所述的组合物，其特征在于，所述环糊精-金属有机骨架材料中的金属离子选自下组：Li +、Na +、K +、Rb +、Cs +、Mg 2+、Cd 2+、Sn 2+、Ag +、Yb +、Ba 2+、Sr 2+、Ca 2+、Pb 2+、La 3+。
  3. 如权利要求1所述的组合物，其特征在于，所述环糊精-金属有机骨架材料中的环糊精选自下组：α-环糊精、β-环糊精、γ-环糊精、羟丙基-β-环糊精、磺丁基-β-环糊精、甲基-β-环糊精、羧甲基-β-环糊精。
  4. 如权利要求1所述的组合物，其特征在于，所述的组合物中环糊精-金属有机骨架与缬沙坦的摩尔比例为1:0.2-1:2。
  5. 如权利要求1所述的组合物，其特征在于，所述组合物的载药量为5％-50％。
  6. 一种如权利要求1所述的组合物的制备方法，其特征在于，所述制备方法包括将所述环糊精-金属有机骨架材料与所述缬沙坦混合后得到所述组合物的步骤。
  7. 如权利要求6所述的制备方法，其特征在于，所述混合具有以下一个或多个特征：
    1)所述混合的温度为0～70℃；
    2)所述混合的时间为10分钟～3天；
    3)所述混合的方式为缬沙坦溶液与环糊精-金属有机骨架材料混合。
  8. 一种如权利要求1所述的组合物的制备方法，其特征在于，所述制备方法包括以下步骤：
    (i)将环糊精、金属离子源溶解于水中制备成第一溶液，将所述缬沙坦与有机溶剂混合制成第二溶液；
    (ii)将第二溶液加入第一溶液中进行混合得到混合物；
    (iii)对所述混合物进行固体收集和干燥，即得所述的组合物。
  9. 一种药物组合物，其特征在于，所述药物组合物包含：
    如权利要求1所述的组合物；和
    药学上可接受的载体。
  10. 如权利要求9所述的药物组合物，其特征在于，所述药物组合物为胶囊剂、片剂、渗透泵片、凝胶骨架缓释片、颗粒剂。
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