CN110314241A - A kind of cyclodextrin-metal organic framework composition improving drug solubility - Google Patents
A kind of cyclodextrin-metal organic framework composition improving drug solubility Download PDFInfo
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- CN110314241A CN110314241A CN201810274282.2A CN201810274282A CN110314241A CN 110314241 A CN110314241 A CN 110314241A CN 201810274282 A CN201810274282 A CN 201810274282A CN 110314241 A CN110314241 A CN 110314241A
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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
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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
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- 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
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Abstract
The invention discloses a kind of cyclodextrin-metal organic framework compositions for improving drug solubility, include: (a) cyclodextrin-metal-organic framework materials;And it (b) is carried on the framework material or mixed drug, the drug is sartans.Composition of the invention, sartans are carried on cyclodextrin-metal-organic framework materials or mixed, sartans solubility in water and rate of dissolution can be significantly improved, solve the problems, such as that sartans dissolubility is poor, oral administration biaavailability is low, it is raw materials used cheap and easy to get with solvent to prepare composition, step is simple, is conducive to industrialized production.
Description
Technical field
The present invention relates to a kind of cyclodextrin-metal organic framework compositions for improving drug solubility.
Background technique
Hypertension is one of most common cardiovascular disease, and not only directly harm is healthy, also accelerates atherosclerosis
Process, blood pressure raising are the Major Risk Factors of Chinese population cerebral apoplexy, coronary heart disease, heart failure and kidney trouble.China's heart,
The generation of cranial vascular disease and death toll are constantly rising, and wherein death toll accounts for China's general mortality rate up to 40%, high blood
Pressure has become the common problem of harm health.
" Sha Tan " class drug, that is, Angiotensin Ⅱ receptor antagonist (ARB) class drug for hypertension came out more than 10 years,
Because its antihypertensive effect is obvious, tolerance is good, and especially clinical test and evidence-based evidence shows that it has the uniqueness to cardiovascular disease
Curative effect and protective effect, it has also become one of clinical most common drug for hypertension causes clinical common concern, and prolonged application
Afterwards dry cough, be discontinued knock-on and the adverse reaction rates such as postural hypotension it is low, by the more a treatment guidelines of WHO be recommended as with
The line depressor of the hypertensive patient of cardiovascular disease and albuminuria.Sartans are mostly II class drug of BCS, molten in water
Solution property is poor, causes sartans oral administration biaavailability low.In order to improve sartans oral administration biaavailability, it is necessary to mention
The dissolubility of high sartans.
Valsartan is Angiotensin Ⅱ receptor antagonist (ARB) class drug for hypertension, is come out more than 10 years, because of its drop
Pressure effect is obvious, and tolerance is good, especially clinical test and evidence-based evidence show its have to unique curative effect of cardiovascular disease and
Protective effect, it has also become one of clinical most common drug for hypertension has caused clinical common concern, and done after prolonged application
Cough, the adverse reaction rates such as knock-on and postural hypotension that are discontinued are low, are recommended as by the more a treatment guidelines of WHO with painstaking effort
The line depressor of the hypertensive patient of pipe disease and albuminuria.Valsartan is II class drug of BCS, and dissolubility is poor in water, leads
Cause Valsartan oral administration biaavailability low.In order to improve Valsartan oral administration biaavailability, it is necessary to improve the molten of valsartan pharmaceutical
Xie Xing.
Summary of the invention
The purpose of the present invention is to provide a kind of cyclodextrin-metal organic framework compositions for improving drug solubility.
In the first aspect of the present invention, a kind of drug cyclodextrin-metal organic framework composition is provided, includes: (a) ring
Dextrin-metal-organic framework materials;And (b) it is carried on the framework material or mixed drug, wherein the drug
For sartans.
In another preferred example, the sartans be olmesartan medoxomil, Olmesartan, Irbesartan, Telmisartan,
Valsartan, Losartan Potassium, Losartan, candesartan Cilexetil, Candesartan, eprosartan, Azilsartan or two or more combinations
Object.
In another preferred example, the molecular weight of the sartans is 350-650.
In another preferred example, the molecular weight of the sartans is 400-500.
In the present invention, drug is carried on the framework material: packet of the bicyclodextrin molecule to drug molecule in two ways
It closes;And drug forms nanocluster in cyclodextrin-metal organic framework cavity broad in the middle.
In another preferred example, the metal ion in the cyclodextrin-metal-organic framework materials is selected from the group: Li+、Na+、K+、Rb+、Cs+、Mg2+、Cd2+、Sn2+、Ag+、Yb+、Ba2+、Sr2+、Ca2+、Pb2+、La3+。
In another preferred example, metal ion Ca2+、Na+Or K+, further preferred K+。
It in another preferred example, include but is not limited to OH at the anion of salt or alkali with metal ion-、NO3 -、CO3 2-、
HCO3 -、CH3COO-、SCN-、C6H5COOH=C6H5COO-、Cl-、Br-、I-、O2 -、S2 -、HS-、HSO4 -、ClO-、ClO3 -、MnO4 -,
It is preferred that OH-。
In another preferred example, the cyclodextrin-metal-organic framework materials are potassium hydroxide cyclodextrin-organic bone of metal
Frame material, potassium carbonate cyclodextrin-metal-organic framework materials, potassium chloride cyclodextrin-metal-organic framework materials, potassium acetate ring paste
Essence-metal-organic framework materials, preferably potassium acetate gamma-cyclodextrin-metal-organic framework materials.
In another preferred example, the cyclodextrin in the cyclodextrin-metal-organic framework materials is selected from the group: α-ring paste
Essence, beta-cyclodextrin, gamma-cyclodextrin, hydroxypropyl-β-cyclodextrin, Sulfobutyl ether β _ cyclodextrin, methyl-B-cyclodextrin, carboxymethyl-β-
Cyclodextrin.
In another preferred example, cyclodextrin is selected from the group: alpha-cyclodextrin, beta-cyclodextrin, gamma-cyclodextrin, further preferably
For gamma-cyclodextrin.
In another preferred example, the cyclodextrin-metal-organic framework materials are that alkalinity or neutral cyclodextrins-metal are organic
Framework material.Alkaline cyclodextrin-metal-organic framework materials, which are distributed to be incubated in the organic solvent containing organic acid, obtains neutrality
Cyclodextrin-metal-organic framework materials.In another preferred example, the organic acid is selected from the group: formic acid, acetic acid, citric acid, richness
Horse acid, tartaric acid, metatartaric acid, malic acid, adipic acid or its mixed solvent, preferably formic acid, acetic acid or its mixed solvent, it is optimal
Select acetic acid.In another preferred example, it is molten to be selected from methanol, ethyl alcohol, propyl alcohol, isopropanol, n-butanol or its mixing for the organic solvent
Agent, preferably methanol, ethyl alcohol or its mixed solvent, most preferred ethanol.
In another preferred example, the molar ratio of composition cyclodextrin-metal organic framework and drug is 1:
0.2-1:2, preferably 1:0.5-1:1.8, further preferably 1:1.5.
In another preferred example, the composition also has following one or more features:
(1) average grain diameter of the cyclodextrin-metal-organic framework materials is 5 nanometers -1000 microns;
(2) drugloading rate of the composition is 0.1%-50%.
In another preferred example, the average grain diameter of the cyclodextrin-metal-organic framework materials (is received for 100-1000 nanometers
Meter level) or 1-100 microns (micron order).
In another preferred example, the drugloading rate of the composition is 10%-40%, further preferably 20%-30%.
The application composition has solubilizing effect to sartans, such as improves the solubility of Valsartan in water
10-50 times, preferably 10-40 times, further preferably 30-40 times for another example improve the solubility of Azilsartan in water
10-200 times, the solubility of Irbesartan in water is improved 10-1000 times for another example.
The second aspect of the present invention, provides the preparation method of composition described in first aspect, and the preparation method includes
The step of obtaining the composition after the cyclodextrin-metal-organic framework materials are mixed with drug solution.
In another preferred example, the mixed temperature is 25~65 DEG C, preferably 30~50 DEG C, most preferably 30~40 DEG C.
In another preferred example, the mixed time be 10 minutes~3 days, preferably 1 hour~12 hours, most preferably
It is 30 minutes~2 hours.
In another preferred example, the drug is sartans, is selected from: olmesartan medoxomil, Olmesartan, E Beisha
Smooth, Telmisartan, Valsartan, Losartan Potassium, Losartan, candesartan Cilexetil, Candesartan, eprosartan, Azilsartan or two
Kind or more composition.
In another preferred example, drug is dissolved in solvent selected from the group below and prepares the drug solution: methanol, second
Alcohol, propyl alcohol, isopropanol, n-butanol, chloroform, dimethylformamide or its mixed solvent, preferably methanol, ethyl alcohol or its mixing are molten
Agent, most preferred ethanol.
In another preferred example, the cyclodextrin in the cyclodextrin-metal-organic framework materials and drug feed intake mole
Than for 1:1.5-1:25.
In another preferred example, the molar ratio of cyclodextrin and drug is 1:1-1:50, preferably 1:1-1:30,1:1-
1:25 or 1:1-1:22,1:15-1:25.
In another preferred example, the preparation method further includes post-processing step: collecting solid and is dried.
The third aspect of the present invention, provides the preparation method of composition described in first aspect, and the preparation method includes
The drug is mixed with the cyclodextrin-metal-organic framework materials and is ground the step of obtaining the composition.
In another preferred example, the drug is sartans, is selected from: olmesartan medoxomil, Olmesartan, E Beisha
Smooth, Telmisartan, Valsartan, Losartan Potassium, Losartan, candesartan Cilexetil, Candesartan, eprosartan, Azilsartan or two
Kind or more composition.
In another preferred example, the feed ratio of the cyclodextrin-metal-organic framework materials and drug is 1:0.2-1:2,
Preferably 1:0.4-1:1.8.
In another preferred example, the drug is powder or drug solution form.In another preferred example, by drug
It is dissolved in solvent selected from the group below and prepares the drug solution: methanol, ethyl alcohol, propyl alcohol, isopropanol, n-butanol, chloroform, diformazan
Base formamide or its mixed solvent, preferably methanol, ethyl alcohol or its mixed solvent, most preferred ethanol.
In another preferred example, the cyclodextrin-metal-organic framework materials are powder or drug solution form.?
In another preferences, cyclodextrin-metal-organic framework materials are dissolved in solvent selected from the group below and prepare the drug solution:
Methanol, ethyl alcohol, propyl alcohol, isopropanol, n-butanol, chloroform, dimethylformamide or its mixed solvent, preferably water, methanol, ethyl alcohol or
Its mixed solvent, most preferred ethanol, methanol.In another preferred example, the grinding is ground using ball mill.Another
In preference, the zirconium pearl that ball mill uses diameter to be preferably 8mm for 6-10mm is ground.In another preferred example, pearl and (medicine
Object+cyclodextrin-metal-organic framework materials) weight ratio 15:1-1:1, preferably 10:1-3:1.In another preferred example,
Milling time is 1min-2h, preferably 5-80min.
The fourth aspect of the present invention provides the preparation method of composition described in first aspect, comprising the following steps:
(i) cyclodextrin, metal ion source are dissolved in the water and are prepared into the first solution, the drug is mixed with organic solvent
The second solution is made in conjunction;
(ii) the second solution is added in the first solution and is mixed, obtain mixture;
(iii) solid collection and drying are carried out to get the composition to the mixture.
In another preferred example, the metal ion source is selected from the group: potassium hydroxide, potassium carbonate, potassium chloride.
In another preferred example, the concentration of cyclodextrin described in first solution is 0.01-200mM.
In another preferred example, the molar ratio of the cyclodextrin and metal ion in the metal ion source is 1:1-1:
10。
In another preferred example, the drug is sartans, is selected from: olmesartan medoxomil, Olmesartan, E Beisha
Smooth, Telmisartan, Valsartan, Losartan Potassium, Losartan, candesartan Cilexetil, Candesartan, eprosartan, Azilsartan or two
Kind or more composition
In another preferred example, drug is dissolved in organic solution selected from the group below and prepares second solution: methanol,
Ethyl alcohol, propyl alcohol, isopropanol, n-butanol, chloroform, dimethylformamide or its mixed solvent, preferably methanol, ethyl alcohol or its mixing are molten
Agent, most preferred ethanol.
In another preferred example, in step ii), the second solution is added in the first solution and is mixed, shape can be added
State regulator is mixed to get mixture.
In another preferred example, the morphology modifying agent is polyethylene glycol, povidone, polysorbate, anhydrous sorbitol list
Laurate, Brij30, polyoxyethylene nonylphenol ether, newborn lark A, pluronic, lauryl sodium sulfate, detergent alkylate
Sodium sulfonate, cetyl trimethylammonium bromide, or combinations thereof.
In another preferred example, the morphology modifying agent is PEG 20000, polyethylene glycol 2000, polyethylene glycol
4000, Macrogol 6000, PEG 8000, polyethylene glycol 10000, PEG 20000, or combinations thereof.
In another preferred example, the morphology modifying agent, preferably 5- is added in the ratio of 1-20mg/mL supernatant
10mg/mL supernatant.
The fifth aspect of the present invention provides a kind of pharmaceutical composition, includes:
Composition described in first aspect;With
Pharmaceutically acceptable carrier.
" pharmaceutically acceptable carrier " refers to: one or more biocompatible solids or liquid filler or gelatinous mass,
They are suitable for people's use and it is necessary to have enough purity and sufficiently low toxicity." compatibility " referred to herein as composition
Middle each component energy and the compound of the present invention and they between mutually admix, and significantly reduce the drug effect of compound.Pharmacy
Upper acceptable carrier part example has cellulose and its derivates (such as sodium carboxymethylcellulose, ethyl cellulose sodium, fiber
Plain acetic acid esters etc.), gelatin, talcum, solid lubricant (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oil (such as soya-bean oil, sesame
Oil, peanut oil, olive oil etc.), polyalcohol (such as propylene glycol, glycerol, mannitol, sorbierite), emulsifier (such as), profit
Humectant (such as lauryl sodium sulfate), colorant, flavoring agent, stabilizer, antioxidant, preservative, apirogen water.
In another preferred example, the carrier is selected from the group: diluent, excipient, filler, adhesive, wetting agent,
Disintegrating agent, sorbefacient, surfactant, absorption carrier, lubricant, or combinations thereof.
In another preferred example, the pharmaceutical composition is formulated as solid dosage forms or liquid dosage form, is preferably suitable for mouth
Clothes administration.In another preferred example, solid dosage forms includes capsule, tablet, pill, powder and granule.In another preference
In, liquid dosage form includes pharmaceutically acceptable lotion, solution, suspension, syrup or tincture.
In another preferred example, described pharmaceutical composition is capsule, tablet, granule.
In another preferred example, described pharmaceutical composition also includes surfactant, is selected from the group: poly- sorb is smooth -80, poly-
Sorb is smooth -60, polyethylene glycol glycerol aliphatic ester, sorbitan fatty acid esters and two or more mixtures.
It should be understood that above-mentioned each technical characteristic of the invention and having in below (eg embodiment) within the scope of the present invention
It can be combined with each other between each technical characteristic of body description, to form a new or preferred technical solution.As space is limited, exist
This no longer tires out one by one states.
Detailed description of the invention
Fig. 1 is differential scanning calorimetry (DSC) figure of embodiment 13.
Fig. 2 is the gas absorption figure of embodiment 13.
Fig. 3 is the infrared spectrogram of embodiment 13.
Fig. 4 is powder x-ray diffraction (PXRD) figure of embodiment 13.
Fig. 5 is that dissolution of the load Valsartan CD-MOF composition capsule of the preparation of embodiment 14 in four kinds of different mediums is bent
Line.
Fig. 6 is dissolution curve of the commercially available Valsartan capsule in four kinds of different mediums in embodiment 14.
Fig. 7 is that the dissolution of Valsartan CD-MOF composition tablet and certain domestic marketed tablet in water is bent in embodiment 17
Line.
Fig. 8 is 18 rate of dissolution figure of embodiment.
Fig. 9 is Azilsartan CD-MOF composition phenogram in embodiment 20, and (a) X-ray diffraction, (b) be infrared, (c) gas
Body absorption, (d) differential scan calorimetric.
Figure 10 is the X-ray small-angle scattering figure of Azilsartan CD-MOF composition in embodiment 20.
Figure 11 is the molecular simulation figure that CD-MOF carries Azilsartan in embodiment 27, and a is the inclusion of cyclodextrin molecular pair, b
Nanocluster is formed in the cavities for Azilsartan.
Figure 12 is the molecular simulation figure that CD-MOF carries Valsartan in embodiment 28.
Figure 13 is the X-ray small-angle scattering figure that CD-MOF carries Valsartan etc. in embodiment 28.
Figure 14 is the solid-state nmr figure that CD-MOF carries Valsartan etc. in embodiment 28.
Specific embodiment
The present inventor develops a kind of cyclodextrin-metal for carrying sartans by depth studying extensively for the first time
Sartans are carried on cyclodextrin-metal-organic framework materials or mixed, can significantly improved by organic backbone compound
Sartans solubility in water and rate of dissolution, solve that sartans dissolubility is poor, takes orally absolute bioavailability
Low problem, prepares that composition is raw materials used and solvent is cheap and easy to get, and step is simple, is conducive to industrialized production.
Cyclodextrin
Cyclodextrin is the general name for acting on a series of lower cyclic oligosaccharides generated through glucosyltransferase by amylose,
Usually contain 6~12 D- glucopyranose units.Wherein study more and with important practical usage be containing 6,
7, the molecule of 8 glucose units, is referred to as α, β-and gamma-cyclodextrin.Cyclodextrin is found so far similar to enzyme
Ideal host molecule, and itself just has the characteristic of catalator.
Metal-organic framework materials
Metal-organic framework materials (Metal-organic frameworks, MOFs) are by organic bridging ligand by matching
Inorganic metal center is connected the crystalline material to form the network-like structure infinitely extended by the mode of position key.Since MOFs is super
High porosity and huge specific surface area and its its various structures made by the structure that inorganic and organic heterogeneity forms
And be adjusted, promoting MOFs, such as gas storage, catalysis, pharmaceutical carrier field have potential application in many aspects.
Cyclodextrin-metal-organic framework materials
As used herein, term " metal-organic framework materials based on cyclodextrin ", " cyclodextrin-metal organic framework material
Material ", " cyclodextrin-metal organic framework compound " are used interchangeably, and being in aqueous solution can be with the first and second master using cyclodextrin
Race's metal ion forms a kind of new crystal in a manner of a kind of organic coordination, and this crystal is with porous, surface area is big, storage
The features such as gas.This green, porous material can adsorb some structural unstable drugs, and huge cavity can be to medicine
Object plays a protective role, this makes it possible that it is used for business development, be particularly due to cyclodextrin-metal organic framework be can
Edible derivative, it is edible suitable for the mankind.Using cyclodextrin as organic ligand, metal ion can be formed as inorganic metal center
It is new, safety is higher, pharmaceutical cyclodextrin-metal organic framework, i.e. CD-MOF.
As used herein, term " alkaline cyclodextrin-metal-organic framework materials " is using alkali metal and cyclodextrin as raw material
Cyclodextrin-metal-organic framework materials of preparation, in alkalinity, when being dissolved in that the aqueous solution of 10mg/mL is made in water, pH
About 11-13.
As used herein, term " neutral cyclodextrins-metal-organic framework materials ", " acidified cyclodextrin-metal is organic
Framework material " is used interchangeably, and is that alkaline cyclodextrin-metal-organic framework materials are carried out the weakly acidic pH that acidification obtains
Cyclodextrin-metal-organic framework materials, when being dissolved in that the aqueous solution of 10mg/mL is made in water, pH is about 5-8.It is a kind of
The method of preferred acidification is as follows: weighing a certain amount of cyclodextrin-metal organic framework and is placed in ethyl alcohol, is added a certain amount of
Glacial acetic acid, at 25 DEG C, shaking is incubated for after a certain period of time, obtained solid ethanol washing to get weakly acidic pH cyclodextrin-metal
Organic backbone.
The cyclodextrin of drug-metal organic framework compound
As used herein, term " cyclodextrin-metal organic framework composition for carrying drug ", " cyclodextrin-gold of load drug
Category organic backbone compound ", " the CD-MOF compound for carrying drug ", " carries medicine at " cyclodextrin-metal organic framework for carrying drug "
The CD-MOF " of object, " CD-MOF carries drug ", " drug CD-MOF composition ", " CD-MOF carries drug " are used interchangeably, above-mentioned art
Language, which is represented, is carried on cyclodextrin-metal-organic framework materials for sartans or by sartans and cyclodextrin-metal
Organic framework material mixes resulting sample.
Present invention will be further explained below with reference to specific examples.It should be understood that these embodiments are merely to illustrate the present invention
Rather than it limits the scope of the invention.In the following examples, the experimental methods for specific conditions are not specified, usually according to conventional strip
Part, or according to the normal condition proposed by manufacturer.Unless otherwise stated, otherwise percentage and number are calculated by weight.
Universal method
Sartans content assaying method: ultraviolet spectrophotometry is used, e.g., the ultraviolet detection wavelength of Valsartan is
250nm, the ultraviolet detection wavelength of Azilsartan are 250nm, and the ultraviolet detection wavelength of Telmisartan is 290nm, Irbesartan
Ultraviolet detection wavelength is 245nm.
Solubility test method: weighing excessive sample to be tested, be placed in water, and shaking table shakes (25 DEG C, 200rpm) three days,
Centrifugal filtration, according to the concentration of above-mentioned " content assaying method " measurement drug in solution.Sample to be tested is denoted as in 25 DEG C of water
Solubility.
Solubilized multiple: the ratio of the solubility of sample to be compared and the drug solubility of (25 DEG C) in water.
Drugloading rate and the measurement and calculation method for carrying medicine molar ratio: accurately weighed 5mg (m1) sample to be tested, it is placed in 100mL
It in volumetric flask, is dissolved with pure water, after filtering, medicament contg is measured according to " assay condition ", calculates the matter of drug
Measure m2。
Drugloading rate (%)=m2/m1×100;
The molar ratio of carrier and drug are as follows: (m2/MDrug):((m1-m2)/MCarrier), MCarrierFor the molecular weight of carrier, MDrugFor medicine
The molecular weight of object.
Embodiment 1: Valsartan micron order potassium hydroxide CD-MOF composition-incubation
3000mL pure water is measured in beaker, 97.3g γ-CD stirring is added, adds 33.6g KOH, ultrasound makes γ-
CD and KOH are completely dissolved, and mother liquor is made.Mother liquor is poured into reaction kettle, setting revolving speed is 300rpm, temperature 50 C.Again to anti-
Addition 1800mL methanol in kettle is answered, 38.4gPEG20000 is added after dissolution clarification.It is centrifuged after being stored at room temperature overnight, removes supernatant, sunk
It forms sediment and uses twice of 100mL ethanol washing respectively, then washed twice with 100mL methanol.It is deposited in 40 DEG C of vacuum ovens dry
For 12h to get micron order potassium hydroxide-cyclodextrin-metal organic framework, partial size is 1-10 microns.
200mg micron order potassium hydroxide CD-MOF is weighed in 15mL centrifuge tube, 10mL Valsartan ethanol solution (ring is added
The molar ratio of cyclodextrin and Valsartan in dextrin-metal-organic framework materials is 1:22), shaking table shaking incubation (37 DEG C,
150rpm) 20h, centrifugation, 60 DEG C of lower sediment thing vacuum drying 4h are to get the micron order potassium hydroxide CD-MOF group for carrying Valsartan
Close object.
Drugloading rate is 29.4% (w/w) in resulting composition, and the molar ratio of CD-MOF and Valsartan is 1:1.4, by figured silk fabrics sand
Smooth solubility in water improves 34.5 times (Valsartan raw material solubility in 25 DEG C of water is 0.08mg/mL).
Embodiment 2: Valsartan micron order potassium acetate CD-MOF composition-incubation
Micron order potassium acetate CD-MOF is further prepared on the basis of in embodiment 1: being added into lower sediment thing
The dispersion of 0.4L dehydrated alcohol, carries out centrifuge washing, then 0.4L dehydrated alcohol and 20mL glacial acetic acid are added into precipitating, in stirring
With centrifugation removal supernatant.0.4L ethyl alcohol is finally added into precipitating, centrifugation (4000rpm, 5min) is washed twice.After washing
Precipitating be placed in 60 DEG C of vacuum ovens dry 4h.Up to micron order potassium acetate cyclodextrin-metal organic framework, partial size 1-
10 microns.
According to medicine-carrying method described in embodiment 1 (cyclodextrin and Valsartan in cyclodextrin-metal-organic framework materials
Molar ratio be 1:20), prepare Valsartan CD-MOF composition, in resulting composition drugloading rate be 30.7% (w/w), CD-
The molar ratio of MOF and Valsartan is 1:1.6, and the solubility of Valsartan in water is improved 33.7 times.
Embodiment 3: Valsartan micron order potassium hydroxide CD-MOF composition-stirring
The micron order potassium hydroxide CD-MOF prepared in 200mg embodiment 1 is weighed in 20mL cillin bottle, 10mL figured silk fabrics is added
Husky smooth ethanol solution (molar ratio of cyclodextrin and Valsartan in cyclodextrin-metal-organic framework materials is 1:20), 40 DEG C
Magnetic agitation 1h, centrifugation are heated, lower sediment thing vacuum drying is combined to get Valsartan micron order potassium hydroxide CD-MOF is carried
Object.Drugloading rate is 29.7% in resulting composition, and the molar ratio of CD-MOF and Valsartan is 1:1.5, solubilized multiple in composition
It is 35.6.
Embodiment 4: Valsartan micron order potassium acetate CD-MOF composition-stirring
The micron order potassium acetate CD-MOF in 40g embodiment 2 is weighed in beaker, it is that 0.25g/mL figured silk fabrics is husky that 1L concentration, which is added,
Smooth ethanol solution (molar ratio of γ-CD and Valsartan is 1:22), carries out load medicine according to 3 method of embodiment.As control,
CD-MOF is replaced with γ-CD simultaneously, prepares Valsartan γ-CD composition with identical method.
The preparation of Valsartan CD-MOF physical mixture: Valsartan and micron order potassium acetate are weighed respectively according to medicine ratio is carried
CD-MOF is placed in a beaker, and is stirred mixing with glass bar, is obtained physical mixture.
As a result: drugloading rate is 31.1% in gained Valsartan CD-MOF composition, CD-MOF and Valsartan in composition
Molar ratio is 1:1.5, and solubilized multiple is 39.5, is significantly higher than Valsartan γ-CD composition (solubilized multiple is 4.6).
Dissolution measurement: the Valsartan CD-MOF composition for being equivalent to a dosage (80mg) is weighed, parallel 6 times, is carried out molten
It tests out.Revolving speed 100rpm, temperature are 37.0 ± 0.5 DEG C, and medium is 900mL deionized water, and different time points sample 5mL,
With ultraviolet survey absorbance at 250nm, the amount of dissolution is calculated.The physics of comparative determination Valsartan raw material, Valsartan and CD-MOF simultaneously
Mixture.
As a result: table 1, Valsartan micron order potassium acetate CD-MOF composition and physical mixture are all remarkably higher than Valsartan original
Material, and composition is significantly higher than physical mixture.
The dissolution of table 1 Valsartan CD-MOF composition, physical mixture and raw material
Embodiment 5: Valsartan nanoscale potassium hydroxide CD-MOF composition
It takes 2000mL pure water in 5000mL large beaker, weighs 64.9g γ-CD in large beaker, stir, then into beaker
22.4g KOH is added, ultrasound is completely dissolved γ-CD and KOH, and mother liquor is made.Mother liquor is poured into reaction kettle, revolving speed
300rpm when temperature 50 C, 1200mL methanol is added into reaction kettle, adds PEG20000 (8mg/mL).It is quiet in cold bath
It sets overnight.Supernatant is removed in centrifugation, and precipitating uses twice of 150mL ethanol washing respectively, the dry 12h in 40 DEG C of vacuum ovens.Grain
Diameter is 100-500 nanometers.
Carrying out load medicine according to 3 method of embodiment, (cyclodextrin and Valsartan in cyclodextrin-metal-organic framework materials rub
Your ratio is 1:20), obtain Valsartan nanoscale potassium hydroxide CD-MOF composition.As a result: drugloading rate is in resulting composition
The molar ratio of 31.7%, CD-MOF and Valsartan is 1:1.5, and solubilized multiple is 36.2.
Embodiment 6: Valsartan nanoscale potassium acetate CD-MOF composition
It is improved on the basis of embodiment 5 according to the method for embodiment 2 and prepares nanoscale potassium acetate CD-MOF, partial size
It is 100-500 nanometers.Carrying out load medicine according to 3 method of embodiment, (cyclodextrin and figured silk fabrics in cyclodextrin-metal-organic framework materials are husky
Smooth molar ratio is 1:20), obtain Valsartan nanoscale potassium hydroxide CD-MOF composition.As a result: medicine is carried in resulting composition
Amount is 32.8%, CD-MOF and the molar ratio of Valsartan is 1:1.7, and solubilized multiple is 36.3.
Embodiment 7: Valsartan potassium carbonate CD-MOF composition
It takes 2500mL pure water in beaker, 81.1g γ-CD and 34.5g potassium carbonate is added, mother liquor is made.Mother liquor is poured into
In reaction kettle, 2500mL methanol is added, 40.0g PEG20000, which is added, after reaction clarification makes after being completely dissolved, by reaction solution room temperature
Supernatant is removed in centrifugation after standing overnight, and precipitating uses twice of 100mL ethanol washing respectively, then is washed twice with 100mL methanol.In 40
For dry 12h to get potassium carbonate micron order CD-MOF, partial size is 300-700 microns in DEG C vacuum oven.According to embodiment 3
Method carries out load medicine (molar ratio of cyclodextrin and Valsartan in cyclodextrin-metal-organic framework materials is 1:20), obtains figured silk fabrics
Husky smooth potassium carbonate CD-MOF composition.As a result: drugloading rate is the molar ratio of 24.6%, CD-MOF and Valsartan in resulting composition
For 1:1.1, solubilized multiple is 30.5.
Embodiment 8: the preparation of Valsartan potassium chloride CD-MOF
γ-CD, potassium chloride are dissolved in 5mL water, making its concentration is respectively 0.125M, 0.5M, and ultrasonic 10min makes it sufficiently
Dissolution.Then in pre-add 0.5mL methanol to γ-CD and potassium chloride mixed solution, first is heated under the conditions of 50 DEG C in closed container
Alcohol is respectively washed 2 times after reacting 6h with ethyl alcohol and methanol, is dried in vacuo 12 hours for 50 DEG C of gained crystal to get potassium chloride CD-
MOF, partial size are 1-10 microns.Load medicine (the ring paste in cyclodextrin-metal-organic framework materials is carried out according to the method for embodiment 3
The molar ratio of essence and Valsartan is 1:20), obtain Valsartan potassium chloride CD-MOF composition.As a result: medicine is carried in resulting composition
Amount is 22.3%, CD-MOF and the molar ratio of Valsartan is 1:1.3, and solubilized multiple is 34.8.
Embodiment 9: cocrystallization method
163.0mg γ-CD and 56.0mg KOH are dissolved in 5mL water, ultrasonic dissolution.Add 5mL Valsartan methanol
Solution (molar ratio of γ-CD and Valsartan is 1:22), then PEG20000 conduct is added in the ratio of 8mg/mL supernatant
Morphology modifying agent, after standing half an hour, centrifugation discards supernatant liquid, lower layer's solid is washed with isopropanol, by 50 DEG C of items of gained crystal
It is dried in vacuum overnight under part to get Valsartan cyclodextrin-metal organic framework cocrystallization composition.As a result: in resulting composition
Drugloading rate is 33.9%, CD-MOF and the molar ratio of Valsartan is 1:1.8, and solubilized multiple is 38.9.
Embodiment 10: Valsartan potassium acetate β-CD-MOF composition
It weighs beta-cyclodextrin 200g, after potassium hydroxide 78.9g adds 2L pure water to dissolve into beaker, is added to 5L reaction kettle
In, under the conditions of 25 DEG C of room temperature, 2L methanol is added in revolving speed 100rpm, stirs 16h, and the reaction solution of suspension is centrifuged, and precipitating is
Potassium hydroxide β-CD-MOF.40mL glacial acetic acid is added into the ethyl alcohol suspending system of potassium hydroxide β-CD-MOF, 5min is stirred
It is allowed to be uniformly dispersed, be filtered with filter paper, filter cake continues to be washed 2 times with dehydrated alcohol, is potassium acetate β-after filtration cakes torrefaction
CD-MOF。
200mg potassium acetate β-CD-MOF is weighed in 20mL cillin bottle, 10mL Valsartan ethanol solution (cyclodextrin-is added
The molar ratio of cyclodextrin and Valsartan in metal-organic framework materials is 1:22), 37 DEG C of heating stirring 1h, centrifugation, lower layer
Sediment is dried in vacuo to get Valsartan potassium acetate β-CD-MOF composition.As a result: drugloading rate is in resulting composition
The molar ratio of 14.7%, CD-MOF and Valsartan is 1:0.5, and solubilized multiple is 15.2.
Embodiment 11: Valsartan micron order potassium acetate CD-MOF composition
The micron order potassium acetate CD-MOF prepared in 20g embodiment 1 is weighed in 1L beaker, 300mL concentration, which is added, is
0.1g/mL Valsartan ethanol solution (molar ratio of cyclodextrin and Valsartan in cyclodextrin-metal-organic framework materials is 1:
5), 40 DEG C of heating magnetic agitation 1h, centrifugation, lower sediment thing vacuum drying is to get load Valsartan micron order potassium hydroxide CD-
MOF composition.Drugloading rate is 12.4% in resulting composition, and the molar ratio of CD-MOF and Valsartan is 1:0.5 in composition, is increased
Molten multiple is 35.2.
Embodiment 12: Valsartan micron order potassium acetate CD-MOF composition
The micron order potassium acetate CD-MOF prepared in 20g embodiment 1 is weighed in 1L beaker, 500mL concentration, which is added, is
(molar ratio of cyclodextrin and Valsartan in cyclodextrin-metal-organic framework materials is 0.18g/mL Valsartan ethanol solution
1:16), 40 DEG C of heating magnetic agitation 1h, centrifugation, lower sediment thing vacuum drying is to get load Valsartan micron order potassium hydroxide
CD-MOF composition.Drugloading rate is 22.82% in resulting composition, and the molar ratio of CD-MOF and Valsartan is 1 in composition:
1.0, solubilized multiple is 34.9.
Embodiment 13: Valsartan/CD-MOF composition characterization
As a comparison, it prepares Valsartan/gamma-cyclodextrin inclusion compound: weighing 1297mg gamma-cyclodextrin (1mmol) and be dissolved in
In 30mL water, weighs 435mg Valsartan (1mmol) and be dissolved in 15mL ethyl alcohol, Valsartan solution is added drop-wise under stirring
Gamma-cyclodextrin aqueous solution in, maintain temperature continue under 40 DEG C, 500rpm stir 3h, remove ethyl alcohol.Remaining liquid freezing is dry
It is dry to get Valsartan/gamma-cyclodextrin inclusion compound.The content (w/w) of Valsartan is 15.5%, γ-in gained cyclodextrin inclusion compound
The molar ratio of cyclodextrin and Valsartan is 1:0.64, and the solubility of inclusion compound in water is 0.38mg/mL, in water by Valsartan
Solubility improve 4.75 times.
Fig. 1: Valsartan is in 108 DEG C of visible one wide thawing endothermic peaks, and the figured silk fabrics in cyclodextrin inclusion compound and embodiment 4
Husky smooth CD-MOF composition peak completely disappears, and the absorption peak reappears in physical mixture, shows Valsartan by cyclodextrin
It includes, Valsartan is loaded by CD-MOF in composition.
Fig. 2: gas absorption is the results show that the specific surface area of potassium acetate CD-MOF is 996m2/ g, carrying medicine molar ratio is 1:
The near 307m of Langmuir specific surface area of 0.5 Valsartan CD-MOF composition (embodiment 11)2/ g, and carry medicine molar ratio and be
The Langmuir specific surface area of the Valsartan CD-MOF composition (embodiment 4) of 1:1.5 is almost nil, shows Valsartan by CD-
MOF load.
Fig. 3: infrared spectrogram display carry Valsartan neutrality micron order CD-MOF composition be different from Valsartan bulk pharmaceutical chemicals and
Neutral micron order CD-MOF and the physical mixture of both.Compare the object of CD-MOF, VAL/CD-MOF and CD-MOF and VAL
The map of mixture is managed, three samples are in 2926cm-1There is wider absorption band, the flexible of-CH- in CD-MOF can be attributed to
Vibrate (νCH).VAL due to itself amido bond and carbonyl presence, in 1731cm-1And 1600cm-1There is strong absorption at place, and (carbon oxygen is double
Key characteristic absorption) and 1445cm-1Locate ν(C=C)Aromatic ring vibration, CD-MOF do not have features above absorption;VAL/CD-MOF exists
1731cm-1(amido carboxyl) and 1445cm-1ν(C=C)Vibration obviously weakens or disappears in intensity, and physical mixture is still
In the presence of.The characteristic peak of VAL, which is blanked, shows that Valsartan is loaded by CD-MOF.
Fig. 4: powder x-ray diffraction the result shows that Valsartan in 13-15oWith 20-22oThere are two wide diffraction maximums;CD-MOF
With typical crystal structure.Corresponding CD-MOF diffraction maximum still has in Valsartan CD-MOF composition after load medicine, shows
Valsartan CD-MOF composition after carrying medicine is still crystal structure.
Embodiment 14: the preparation of Valsartan micron order potassium acetate CD-MOF composition capsule
Preparation process: weighing the load Valsartan micron order potassium acetate CD-MOF composition 10g of the preparation of embodiment 4, is added
10mL concentration is smooth -80 ethanol solution uniform wet of poly- sorb of 0.05mg/mL, with High Purity Nitrogen air-blowing 30min, crosses 30 mesh Shai Zhi
Grain, dry, whole grain fills capsule.And dissolution rate and dissolution rate are carried out in four kinds of different pH mediums with commercially available Valsartan capsule
Compare.
Dissolution determination: Rotating shaker is used, revolving speed 100rpm, 37 DEG C of temperature, four kinds of different mediums: pH6.8 phosphate is slow
Fliud flushing, pH4.5 acetate buffer, pH1.2 hydrochloric acid solution and each 1000mL of deionized water, 3,5,10,15,30,60,90,
120min takes a little, takes 5mL every time, with ultraviolet survey absorbance at 250nm.
The result shows that carrying the dissolution difference of Valsartan micron potassium acetate CD-MOF composition capsule (Fig. 5) in each medium
Lower than commercially available capsule (Fig. 6), dissolution rate of the commercially available capsule in pH1.2 and water is significantly improved, helps to improve Valsartan
Bioavilability.
Embodiment 15: rat vivo biodistribution availability
12 healthy male SD rats are purchased from Shanghai Laboratory Animal Research Institute, and weight is about 200 ± 20g, is randomly divided into 2
Group, every group 6, gastric infusion gives Valsartan CD-MOF composition (preparation of embodiment 6) respectively, original grinds Valsartan capsule 15mg/
Kg, in 0,0.08,0.25,0.5,0.75,1,1.5,2,3,4,8,12 with for 24 hours eye socket takes blood 0.3mL respectively.It will carry in Valsartan
Property micron order CD-MOF composition and original grind Valsartan capsule and carry out bioavilability comparison and evaluate.
It is dense using Valsartan in high performance liquid chromatography tandem mass spectrum (LC-MS/MS) analysis method measurement rat plasma sample
Degree.The pharmacokinetic parameters that 12 healthy male SD rats are calculated using DAS2.0 software, the results are shown in Table 2, compared with Valsartan group, figured silk fabrics
The mean relative bioavailability of Sha Tan/CD-MOF group is 149.3%, after showing that CD-MOF carries Valsartan, significantly improves figured silk fabrics
Sha Tan is in the intracorporal bioavilability of rat.Simultaneously using SPSS17.0 software to pharmacokinetic parameters (area under the drug-time curve
AUC0-24h, reach Cmax Cmax, peak time Tmax) analysis of t inspection statistics is carried out, the results show that two groups of AUC0-24h、CmaxAnd
TmaxSignificant difference is all had, bioavilability after Valsartan carries medicine by CD-MOF is further illustrated and is significantly improved.
2. rat Internal pharmacokinetics parameter of table
Pharmacokinetic parameters | Valsartan CD-MOF composition | Valsartan capsule |
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 |
Note: the * p < 0.05 compared with Valsartan group;* p < 0.01.
Embodiment 16: beasle dog vivo biodistribution availability
For 12 healthy adult beasle dogs purchased from agricultural college, Shanghai Communications University teaching experiment practice field, weight is about 8~12kg, point
At 3 groups, every group 4 (half male and half female), using three periods, three cross-over experiment design, three groups of period 1 respectively take orally Valsartan/
CD-MOF composition capsule (A medicine, according to embodiment 4 prepare, be added Tween-80 ethanol solution granulation), Valsartan capsule (B medicine),
Valsartan/γ-CD clathrate capsule (C medicine);Three groups of second round takes orally B medicine, C medicine, A medicine respectively;Three groups of difference of period 3
Oral C medicine, A medicine, B medicine, the cleaning phase of period is 2 weeks every two weeks.Beasle dog fasting 12h, free water, 4h after medication before testing
Interior No Food or Drink, the tested unified meal of period feed.Being directly plugged into capsule when administration can be pharyngeal, and beasle dog is made to swallow and infuse automatically
Enter about 50mL clear water to send down, distinguishes forelimb in 0,0.25,0.5,1,1.5,2,2.5,3,3.5,4,6,8,10,12,24,36,48h
Inside venae subcutaneae takes blood 2mL.Using Determination of valsartan in human in LC-MS/MS analysis method measurement Dog Plasma sample.
Beasle dog Pharmacokinetic Results show (table 3), Valsartan/CD-MOF composition capsule and Valsartan γ-CD inclusion compound
Capsule is compared, average AUC0-48hImprove 47.3%, average CmaxImprove 42.2%;Valsartan/CD-MOF composition capsule with
Valsartan capsule is compared, average AUC0-48hImprove 59.8%, average CmaxImprove 119.1%.The above result shows that CD-MOF
After carrying Valsartan, compared with other two groups, Valsartan can be improved in the intracorporal bioavilability of beasle dog.
3 beasle dog Internal pharmacokinetics parameter of table
Pharmacokinetic parameters | Valsartan/CD-MOF | Valsartan | 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 |
Note: compared with Valsartan group*P < 0.05.
Embodiment 17: Valsartan/CD-MOF composition tablet
Preparation process: load Valsartan neutrality micron order CD-MOF composition in following prescriptions and each auxiliary material are weighed to mixing
It is uniformly mixed in machine, 12mm formed punch is selected to carry out the tabletting of powder direct pressure closing.
Prescription:
Dissolution measurement: using paddle method, and in revolving speed 100rpm, temperature is 37.0 ± 0.5 DEG C, and medium is 900mL deionized water,
It is taken a little 0.5,3,5,10,15,30,60min, takes 5mL every time, with 0.45 μm of membrane filtration, suitable multiple is diluted, in 250nm
Locate with ultraviolet survey absorbance (n=6).
As a result as shown in fig. 7, Valsartan micron order potassium acetate CD-MOF composition tablet 30min dissolves out 91%, and it is commercially available
The amount of dissolution of certain Valsartan tablet 30min is 58%.
Embodiment 18: Valsartan micron order potassium acetate CD-MOF composition-polishing
Weighing the micron order potassium acetate CD-MOF and 3.0g Valsartan for preparing in 7.0g embodiment 1, (cyclodextrin-metal is organic
The molar ratio of cyclodextrin and Valsartan in framework material is 1:1.5), ball mill (weight ratio of zirconium pearl and powder is 3:
1) 5,10 and 60min is ground respectively, obtains Valsartan micron order potassium acetate CD-MOF composition.Its solubilized multiple is followed successively by
32.2,32.5,38.9 times, being significantly higher than polishing, (molar ratio of cyclodextrin and Valsartan is 1:1.5, zirconium pearl and powder
Weight ratio is 3:1, grinds 60min) the Valsartan γ-CD composition (solubilized multiple be 4.5 times) of preparation.
The rate of dissolution for the composition that detection grinding 5min is obtained, as a result as shown in figure 8,10min dissolution 87.1%.
Simple drug Valsartan (weight ratio of zirconium pearl and powder is 3:1) 60min is ground in the same way, is increased
Molten multiple is 1.4 times.Rate of dissolution is as shown in figure 8,10min dissolution 4.8%.
Weigh 7.0g micron order potassium acetate CD-MOF and the 3.0g Valsartan (ring in cyclodextrin-metal-organic framework materials
The molar ratio of dextrin and Valsartan is 1:1.5), it is simply mixed, Valsartan micron order potassium acetate CD-MOF is obtained
Composition.Its solubilized multiple is 23.3 times.Rate of dissolution is as shown in figure 8,10min dissolves out 19.6%, compared to the combination of grinding
Object, rate of release are slower.
By 7.0g Valsartan and gamma cyclodextrin carry out simple physical mixing (molar ratio of cyclodextrin and Valsartan is 1:
1.5) Valsartan and gamma cyclodextrin composite, are prepared, the solubilized multiple of Valsartan and gamma cyclodextrin composite to Valsartan
It is 4.5 times.Rate of dissolution is as shown in figure 8,10min dissolution 24.8%.
Embodiment 19: Telmisartan CD-MOF composition
Weigh 1.944g γ-CD (1.5mmol), 0.672g KOH (12mmol) (nγ-CD:n KOH=1:8) and
1543.85mg (3mmol) Telmisartan is added 40mL pure water and makes it dissolve in 100mL conical flask, 50 DEG C of heating water bath stirrings
24mL anhydrous methanol is added in (300rpm) 1h, continues to stir 5min, is stored at room temperature 2h.It is centrifuged (4000rpm, 5min), precipitating is used
After methanol washs 3 times, it is dry to set 70 DEG C of air dry ovens.Measuring drugloading rate is 9.8%, and experiment measures Telmisartan in water
(25 DEG C) of saturation solubility are 0.117mg/mL, and the saturation solubility after CD-MOF load Telmisartan in water is
11.425mg/mL improves 98 times compared to the solubility in Telmisartan water.
Embodiment 20: Azilsartan potassium acetate nanometer CD-MOF composition
520mg Azilsartan is weighed in 50mL stuffed conical flask, 40mL dehydrated alcohol is added, sets 60 DEG C of heating water baths and stirs
Mixing makes complete drug dissolution, obtains Azilsartan ethanol solution (13mg/mL).1.2g potassium acetate nanometer CD-MOF is weighed to set
50mL stuffed conical flask, 60 DEG C, 400rpm, heating water bath stirs 4h.It is centrifuged (4000rpm, 5min), discards supernatant, take precipitating
Set oven drying.
Azilsartan/γ-CD inclusion compound: 8.45g γ-CD (dissolution of 10mL pure water) and 1.5g Azilsartan (10mL is weighed
Dehydrated alcohol dissolution), molar ratio CD: the diameter of half volume is added using planetary ball mill in Azilsartan=2:1
The grinding of 8mm zirconium pearl, after grinding 1h, oven drying after suspension revolving.
As a result: Azilsartan/CD-MOF drugloading rate is 22.77%, and carrying medicine molar ratio (AZL:CD) is 1:1.It obtains
Cyclodextrin/Azilsartan inclusion compound content of dispersion is 13.14%, carries medicine molar ratio (AZL:CD)=0.49:1.Azilsartan ring paste
The solubility of Azilsartan in water improves 9.4 times by inclusion compounds, Azilsartan/CD-MOF by Azilsartan in water
Solubility improves 339.7 times, and the solubilising power of CD-MOF is significantly higher than cyclodextrin encapsulated (36.1 times).
The preparation of Azilsartan CD-MOF physical mixture (PM): Azilsartan and acetic acid are weighed respectively according to medicine ratio is carried
Potassium nanoscale CD-MOF, is placed in a beaker, and is stirred mixing with glass bar, obtains physical mixture.
Azilsartan/CD-MOF composition characterization:
XRD result (a in Fig. 9) shows Azilsartan and CD-MOF has obvious characteristic diffraction maximum, carry after medicine XRD result without
Azilsartan diffraction maximum illustrates that existence form of the drug in CD-MOF is unformed.Equally, after γ-CD includes Azilsartan
The existence form of Azilsartan is also unformed.
FT-IR result (b in Fig. 9) shows Azilsartan in 1775cm-1And 1693cm-1There is the vibration of amido bond at place, respectively
For amido carboxyl and amidocarbonylation.After CD-MOF carries medicine, Azilsartan/CD-MOF amido carboxyl is subjected to displacement to 1770cm-1
And amidocarbonylation is subjected to displacement to 1646cm-1, illustrate that the strong interaction of CD-MOF and Azilsartan is the carboxylic of Azilsartan
Intermolecular hydrogen bonding occurs for the hydroxyl on base or carbonyl and CD-MOF.However then there is no positions for physical mixture (PM, embodiment)
It moves.And 1693cm on Azilsartan after γ-CD inclusion Azilsartan-1Place's amidocarbonylation is subjected to displacement to 1640cm-1, illustrate
The interaction position of γ-CD and Azilsartan is mainly the hydroxyl on amidocarbonylation and γ-CD.
Gas absorption (c in Fig. 9) shows that the langmuir specific surface area of CD-MOF is 996m2/ g, and there is certain hole
Diameter distribution, and carry after medicine in Azilsartan/CD-MOF then since the load specific surface area of drug declines.
DSC result (d in Fig. 9) shows that Azilsartan has melting endothermic peak at 205 DEG C, and it melts endothermic peak after carrying medicine
Disappear and physical mixture still remains, illustrate that existence of the Azilsartan in CD-MOF changes, in inclusion compound Ah
Identical variation similarly has occurred in Qi Shatan.
SAXS result (Figure 10) display is after CD-MOF load Azilsartan, due to load of the Azilsartan in CD-MOF,
Especially occupying in the big empty cavity position of CD-MOF, scattered signal is obviously reduced at 1.6nm, and each scattering peak is displaced to High-Field,
Speculate that Azilsartan is loaded by CD-MOF, and occupied at the big cavity of CD-MOF, nanocluster is formed in situ.
Embodiment 21: Azilsartan rat vivo biodistribution availability experiment
By 8.45g γ cyclodextrin in 10mL pure water, 1.5g Azilsartan is dissolved in 10mL ethanol solution,
Molar ratio CD:AZL2:1, is added in planetary ball mill after two kinds of solvent mixing, the diameter 8mm of half volume is added
Pick pearl grinds 1h, and oven drying is after suspension revolving to get inclusion compound.Obtained cyclodextrin/Azilsartan inclusion compound content of dispersion
It is 13.14%, molar ratio (AZL:CD)=0.49:1.It is 9.4 times solubilized compared with azilsartan crude drug.
Healthy male SD rat 18 is taken, 3 groups, respectively azilsartan crude drug group, Azilsartan/CD- are randomly divided into
MOF group, Azilsartan/γ-CD inclusion compound group, every group 6.Rat Fast can't help water 12h before testing, and weigh, stomach-filling is given respectively
Medicine gives A Qisha prepared by azilsartan crude drug group, Azilsartan/CD-MOF group prepared by embodiment 20, embodiment 20
Smooth/γ-CD inclusion compound group 5mL/kg (Azilsartan dosage be 1mg/kg), 5min, 15min before administration and after administration,
30min, 1h, 1.5h, 2h, 4h, 8h, 12h, eye socket takes blood about 0.3mL respectively for 24 hours, and blood sample is set in the EP pipe of test tube of hepari, centrifugation
(4000rpm, 5min), separated plasma are set in -80 DEG C of refrigerators and are saved, and rat free water is allowed in experimentation.As a result: Ah
The absorption of Qi Shatan/CD-MOF is apparently higher than and is faster than Azilsartan/γ-CD inclusion compound and bulk pharmaceutical chemicals.Azilsartan/CD-MOF
AUC improves 9.7 times compared with azilsartan crude drug, and AUC improves 1.4 times compared with Azilsartan/γ-CD inclusion compound.
4 Azilsartan rat Internal pharmacokinetics parameter of table
Pharmacokinetic parameters | Azilsartan/CD-MOF | Azilsartan/γ-CD inclusion | Azilsartan crude drug |
AUC(0-12h)(mg/L*h) | 30.65±14.24 | 21.80±7.70 | 3.16±0.42 |
Tmax(h) | 1.50±1.30 | 0.90±0.42 | 6.67±2.07 |
Cmax(mg/L) | 2.63±1.02 | 2.06±0.41 | 0.19±0.01 |
Embodiment 22: it carries Valsartan different temperatures and investigates
Micron order potassium acetate CD-MOF is selected from embodiment 2, and the preparation method of reference implementation example 3 is respectively at 20,60 and 70 DEG C
Under the conditions of load medicine is carried out to Valsartan.Heating water bath speed of agitator is 400r/min, and the load medicine time is 2h, carries the centrifugation of medicine suspension
Precipitating is taken, 40 DEG C of vacuum drying prepare composition.As a result: 20, the drugloading rate under the conditions of 60 and 70 DEG C be respectively 22.9%,
28.8%, 29.3%, the molar ratio of CD-MOF and Valsartan is 1:1.0,1:1.4,1:1.4 in composition.
Embodiment 23: Valsartan different solvents are carried and are investigated
The preparation method of reference implementation example 3, select methanol, ethyl alcohol: methanol 1:1 mixed solvent, ethyl acetate are as load medicine
Solvent.Micron order potassium acetate CD-MOF is selected from embodiment 2, and carrying medicinal strip part is 40 DEG C, and Valsartan ethanol solution concentration is 250mg/
ML, heating water bath speed of agitator are 400r/min, and the load medicine time is 2h, carries medicine suspension centrifuging and taking precipitating, and 40 DEG C are dried in vacuo,
Prepare composition.As a result: methanol, methanol: the drugloading rate in ethyl alcohol 1:1 mixed solvent and ethyl acetate is respectively 26.4%,
24.5%, 22.37%, the molar ratio of CD-MOF and Valsartan is respectively 1:1.2,1:1.1,1:1.0 in composition.
Embodiment 24: different molar ratios-micron order potassium acetate CD-MOF
The preparation method of reference implementation example 3, setting Valsartan ethanol solution concentration be 100mg/mL, 150mg/mL and
200mg/mL, micron order potassium acetate CD-MOF are selected from embodiment 2.Heating water bath speed of agitator be 400r/min, carry the medicine time be
2h, carries medicine suspension centrifuging and taking precipitating, and 40 DEG C of vacuum drying prepare composition.As a result: micron order potassium acetate CD-MOF and figured silk fabrics are husky
Smooth molar ratio is that the drugloading rate of 1:10,1:15 and 1:20 are respectively 23.7%, 26.6%, 28.7%, CD- in composition
The molar ratio of MOF and Valsartan is respectively 1:1.1,1:1.2,1:1.4.
Embodiment 25: different molar ratios-micron order potassium hydroxide CD-MOF
The preparation method of reference implementation example 3, setting Valsartan ethanol solution concentration are 100mg/mL and 150mg/mL, micron
Grade potassium hydroxide CD-MOF is selected from embodiment 1.Heating water bath speed of agitator is 400r/min, and the load medicine time is 2h, carries medicine and is suspended
Liquid centrifuging and taking precipitating, 40 DEG C of vacuum drying, prepares composition.As a result: micron order potassium hydroxide CD-MOF feeds intake with Valsartan to rub
You are respectively 22.4%, 25.9% than the drugloading rate for being 1:10 and 1:15, mole score of CD-MOF and Valsartan in composition
It Wei not 1:1.0,1:1.2.
Embodiment 26: Irbesartan
1g Irbesartan raw material is weighed in 100mL conical flask, is added 50mL dehydrated alcohol (concentration 20mg/mL), sets
50 DEG C of water bath with thermostatic control magnetic agitations heat, and after complete drug dissolution, the micron order potassium acetate CD- in 1.16g embodiment 2 is added
MOF (the molar ratio 3:1 of drug and CD-MOF), heating stirring (300rpm) 4h.Supernatant is removed in centrifugation, and precipitating sets vacuum drying
Case is dry (50 DEG C, 5h).It weighs and carries medicine CD-MOF 5mg in 10mL volumetric flask, dissolved with pure water and be settled to scale.Centrifugation
Take supernatant ultraviolet spectrophotometry in medicament contg after (4000rpm, 5min).The results show that drugloading rate is 11.19%, group
Closing the molar ratio of CD-MOF and Irbesartan in object is respectively 1:0.4, and solubilized multiple is 339 times.
The molecular simulation of 27: γ CD-MOF of embodiment load Azilsartan
Distribution form of the Azilsartan in γ CD-MOF is mainly two states: a part be cyclodextrin molecular to Ah
The inclusion (a in Figure 11) of Qi Shatan;A part is that Azilsartan forms nanocluster (in Figure 11 in the big cavity of γ CD-MOF
b)。
Specifically: Azilsartan molecule tends to roll up first the hydrophobic sky that bicyclodextrin structure generates in γ CD-MOF
In chamber (docking free energy is -10.1kcal/mol), the hydrophobic part in Azilsartan just falls into the hydrophobic cavity of cyclodextrin
In, and hydrophilic segment then exists in the gap of bicyclodextrin pair.The characteristic at hydrophobic position in Azilsartan molecule is utilized, after
The Azilsartan molecule of continuous docking is docked in the big cavity of γ CD-MOF with different maximum system energies.6 Azilsartan molecules
By 6 cyclodextrin moleculars to inclusion, 3 Azilsartan molecules are carried in big cavity, γ CD-MOF and Valsartan in composition
The theoretical medicine molar ratio that carries be 1:1.
The molecular simulation and characterization of 28: γ CD-MOF of embodiment load Valsartan
Distribution form of the Valsartan in γ CD-MOF is mainly two states: a part is cyclodextrin molecular to figured silk fabrics sand
Smooth inclusion;A part is that Valsartan forms nanocluster in the big cavity of γ CD-MOF.Specifically: first Valsartan point
Son is more likely to roll up in the hydrophobic cavity that bicyclodextrin structure generates in γ CD-MOF (docking free energy -8.5kcal/
Mol), so that vacating hydrophilic cavity receives more valsartan molecules.In carboxyl and γ CD-MOF crystal gap in Valsartan
Hydroxyl and cyclodextrin in hydroxyl occur electrostatic interaction, generate hydrogen bond.Utilize hydrophilic site in valsartan molecule
With the characteristic at hydrophobic position, the valsartan molecule for continuing docking is docked to the big cavity of γ CD-MOF with different maximum system energies
In.Shown in Figure 12,6 valsartan molecules are by 6 cyclodextrin moleculars to inclusion, and 5 valsartan molecules are carried in big cavity, group
Closing the theoretical medicine molar ratio that carries of γ CD-MOF and Valsartan in object is 1:1.3.
Figure 13: X-ray small-angle scattering (SAXS) the result shows that: CD-MOF is typical body centred cubic crystal, and long-range has
Sequence has preferable periodical.(Valsartan/CD-MOF1:1.5 of embodiment 4 and Valsartan/CD- of embodiment 11 after load medicine
MOF1:0.5), Prague Valsartan/CD-MOF long period (2.2nm) is consistent with CD-MOF, but due to drug molecule
Skeleton into CD-MOF causes halfwidth to increase.When Valsartan/CD-MOF is 1:0.5, position of the CD-MOF at each peak
It sets and does not invent aobvious displacement, when Valsartan/CD-MOF is 1:1.5,1.6nm empty cavity position is due to by drug on (200) crystal face
Molecule seizing signal is obviously reduced.
Figure 14: solid-state nmr as the result is shown: CD-MOF carry medicine after (Valsartan/CD-MOF1:1.5 of embodiment 4 and implementation
Valsartan/CD-MOF1:0.5 of example 11) overall signal line width dramatically increases, particularly with high drug load VAL/CD-MOF (1:
1.5), Valsartan phenyl ring (C12-23) split sub-signal disappearance, the upper glycosidic bond (C of CD-MOF4) line width obviously increases, illustrate drug with
Exist between CD-MOF carrier compared with strong interaction.Valsartan molecule is in a constrained environment and is highly likely to enter double γ-
CD molecule centering.CD-MOF hydroxyl (C after load medicine6) punished to high field offset, VAL/CD-MOF1:0.5 and 1:1.5 in 57.5ppm
It Pian Yi not 1.9ppm and 1.7ppm;Correspondingly, carboxylic of the Valsartan at 170-180ppm in VAL/CD-MOF1:0.5 and 1:1.5
Base (C10) from splitting swarming become a broad peak, show that the hydroxyl of the carboxyl of Valsartan and CD-MOF may pass through shape in drug incorporation
It interacts at hydrogen bond.The alkyl chain (8-36ppm) after medicine for Valsartan is carried, VAL/CD-MOF1:0.5 is here
Significant changes occur for line style and intensity, and signal is similar to the line style of Valsartan in VAL/CD-MOF1:1.5, shows Valsartan
Molecular moiety is gathered in the formation nanocluster big cavity among CD-MOF Nei.
Embodiment 29: Irbesartan
3000mL pure water is measured in beaker, 97.3g γ-CD stirring is added, adds 33.6g KOH, ultrasound makes γ-
CD and KOH are completely dissolved, and mother liquor is made.Mother liquor is poured into reaction kettle, setting revolving speed is 300rpm, temperature 50 C.Again to anti-
Addition 1800mL methanol in kettle is answered, 38.4g PEG20000 is added after dissolution clarification.It is centrifuged after being stored at room temperature overnight, removes supernatant,
Into lower sediment thing be added 0.4L dehydrated alcohol dispersion, carry out centrifuge washing, then into precipitating be added 0.4L dehydrated alcohol and
20mL glacial acetic acid, stirring neutralize, centrifugation removal supernatant.0.4L ethyl alcohol is finally added into precipitating, is centrifuged (4000rpm, 5min)
Twice of washing.Precipitating after washing is placed in 60 DEG C of vacuum ovens dry 4h.Up to micron order potassium acetate cyclodextrin-metal
Organic backbone, partial size are 1-10 microns.
Weigh 4.29g Irbesartan raw material and 14.93g micron order potassium acetate CD-MOF (cyclodextrin-metal organic framework material
The molar ratio of cyclodextrin and Irbesartan in material is 1:1), it mixes well, is fed intake grinding, made with the ratio of molar ratio 1:1
With ball mill (weight ratio of zirconium pearl and powder is 3:1), 5,15,20min are ground respectively.Sample after weighing grinding respectively
5mL pure water is added in 10mL centrifuge tube in 20mg (excess), and be vortexed (1000rpm) 1min immediately, and 0.22 μm of membrane filtration is used
Ultraviolet spectrophotometry surveys saturation solubility.The results show that saturation solubility of the Irbesartan raw material in pure water is 8.4 μ g/
ML, Irbesartan and CD-MOF be co-mulled and made into 5,15, saturation solubility is respectively 145.2,153.4,193.8 μ g/mL after 20min,
It is 17.3,18.3,23.1 times solubilized respectively.
30 Azilsartan of embodiment
Weigh micron order potassium acetate CD-MOF prepared by 7.0g embodiment 29 and 3.0g Azilsartan (cyclodextrin-metal
The molar ratio of cyclodextrin and Azilsartan in organic framework material is 1:1), use the ball mill (weight of zirconium pearl and powder
Ratio is 3:1) grinding 5min, obtain Azilsartan micron order potassium acetate CD-MOF composition.Its solubilized multiple is 25.4 times.
The mixture of embodiment 31 Valsartan and cyclodextrin
7.0g gamma cyclodextrin and 3.0g Valsartan (molar ratio of gamma cyclodextrin and Valsartan is 1:1.5) are weighed,
60min, 5min are ground respectively using ball mill (weight ratio of zirconium pearl and powder is 3:1), obtain Valsartan and gamma ring paste
Smart composition, solubilized multiple are respectively 5.7 times, 4.8 times.
Embodiment 32
Weighing micron order potassium acetate CD-MOF and 3.0g Valsartan prepared by 7.0g embodiment 29, (cyclodextrin-metal has
The molar ratio of cyclodextrin and Valsartan in machine framework material is respectively 1:1.5,1:0.5), use ball mill (zirconium pearl and powder
The weight ratio of body is respectively 10:1,3:1) grinding 60min, Valsartan micron order potassium acetate CD-MOF composition is obtained, solubilising
Multiple is 35.1 times, 23.0 times.
Embodiment 33
It weighs 648mg γ-CD and 224mg KOH, is added 20mL pure water, stirring is to being completely dissolved;Pour into 50mL plastics from
In heart pipe, 12mL anhydrous methanol is added;It is put into 50 DEG C of heating 20min in constant temperature water tank.8mg/mL PEG20000 concussion is added to shake
It is even;5min is centrifuged with 3500rpm after standing 1h, outwells supernatant.System is dried in vacuo after washing precipitating 3 times with 12mL dehydrated alcohol
It is standby to obtain potassium hydroxide CD-MOF.
7.0g micron order potassium hydroxide CD-MOF and 3.0g Valsartan are weighed (in cyclodextrin-metal-organic framework materials
The molar ratio of cyclodextrin and Valsartan is 1:1), 5min is ground using ball mill (weight ratio of zirconium pearl and powder is 3:1),
Obtain Valsartan micron order potassium acetate CD-MOF composition.Its solubilized multiple is 53.9 times.
Embodiment 34
It takes 2000mL pure water in 5000mL large beaker, weighs 64.9g γ-CD in large beaker, stir, then into beaker
22.4g KOH is added, ultrasound is completely dissolved γ-CD and KOH, and mother liquor is made.Mother liquor is poured into reaction kettle, revolving speed
300rpm when temperature 50 C, 1200mL methanol is added into reaction kettle, adds PEG20000 (8mg/mL).It is quiet in cold bath
It sets overnight.Supernatant is removed in centrifugation, and precipitating uses twice of 150mL ethanol washing respectively, the dry 12h in 40 DEG C of vacuum ovens.Grain
Diameter is 100-500 nanometers.
Weigh nanoscale potassium acetate CD-MOF prepared by 7.0g and 3.0g Valsartan (cyclodextrin-metal organic framework material
The molar ratio of cyclodextrin and Valsartan in material is 1:1.5), it uses ball mill (weight ratio of zirconium pearl and powder is 3:1)
5min is ground, Valsartan nanoscale potassium acetate CD-MOF composition is obtained.Its solubilized multiple is 27.3 times.
Embodiment 35
3000mL pure water is measured in beaker, 97.3g γ-CD stirring is added, adds 33.6g sodium hydroxide, ultrasound makes
γ-CD and sodium hydroxide are completely dissolved, and mother liquor is made.Mother liquor is poured into reaction kettle, setting revolving speed is 300rpm, temperature 50
℃.1800mL methanol is added into reaction kettle again, 38.4g PEG20000 is added after dissolution clarification.Be stored at room temperature overnight after from
The heart removes supernatant, and precipitating uses twice of 100mL ethanol washing respectively, then is washed twice with 100mL methanol.It is deposited in 40 DEG C of vacuum
Dry 12h is in drying box to get micron sodium hydroxide cyclodextrin metal organic framework.Weigh 7.0g microns of sodium hydroxide rings
Dextrin metal organic framework and 3.0g Valsartan (mole of cyclodextrin and Valsartan in cyclodextrin-metal-organic framework materials
Ratio is 1:1), using ball mill (weight ratio of zirconium pearl and powder is 3:1) grinding 5min, obtain Valsartan micron order hydrogen-oxygen
Change sodium cyclodextrin metal organic framework composition.
Embodiment 36
3000mL pure water is measured in beaker, 97.3g γ-CD stirring is added, adds 16.8g calcium hydroxide, ultrasound makes
γ-CD and calcium hydroxide are completely dissolved, and mother liquor is made.Mother liquor is poured into reaction kettle, setting revolving speed is 300rpm, temperature 50
℃.1800mL ethyl alcohol is added into reaction kettle again, 38.4g PEG4000 is added after dissolution clarification.It is centrifuged after being stored at room temperature overnight,
Supernatant is removed, precipitating uses twice of 100mL ethanol washing respectively, then with twice of 100mL ethanol washing.It is deposited in 40 DEG C of vacuum drying
Dry 12h is in case to get micron order calcium hydroxide cyclodextrin metal organic framework.Weigh 7.0g micron order calcium hydroxide cyclodextrin
Metal organic framework and the 3.0g Valsartan (molar ratio of cyclodextrin and Valsartan in cyclodextrin-metal-organic framework materials
Valsartan micron order calcium hydroxide is obtained using ball mill (weight ratio of zirconium pearl and powder is 3:1) grinding 5min for 1:1)
Cyclodextrin metal organic framework composition.
All references mentioned in the present invention is incorporated herein by reference, independent just as each document
It is incorporated as with reference to such.In addition, it should also be understood that, after reading the above teachings of the present invention, those skilled in the art can
To make various changes or modifications to the present invention, such equivalent forms equally fall within model defined by the application the appended claims
It encloses.
Claims (10)
1. a kind of drug cyclodextrin-metal organic framework composition, which is characterized in that the composition includes: (a) cyclodextrin-
Metal-organic framework materials;And (b) it is carried on the framework material or mixed drug, wherein the drug is sand
Smooth class drug.
2. composition as described in claim 1, which is characterized in that the metal in the cyclodextrin-metal-organic framework materials
Ion is selected from the group: Li+、Na+、K+、Rb+、Cs+、Mg2+、Cd2+、Sn2+、Ag+、Yb+、Ba2+、Sr2+、Ca2+、Pb2+、La3+;And/or
Cyclodextrin in the cyclodextrin-metal-organic framework materials is selected from the group: alpha-cyclodextrin, beta-cyclodextrin, γ-ring paste
Essence, hydroxypropyl-β-cyclodextrin, Sulfobutyl ether β _ cyclodextrin, methyl-B-cyclodextrin, carboxymethyl-beta-cyclodextrin.
3. composition as described in claim 1, which is characterized in that the composition cyclodextrin-metal organic framework with
The molar ratio of the drug is 1:0.2-1:2.
4. composition as described in claim 1, which is characterized in that the drugloading rate of the composition is 5%-50%.
5. composition as described in claim 1, which is characterized in that the sartans be olmesartan medoxomil, Olmesartan,
Irbesartan, Telmisartan, Valsartan, Losartan Potassium, Losartan, candesartan Cilexetil, Candesartan, eprosartan, A Qisha
Smooth or two or more composition.
6. a kind of preparation method of composition as described in claim 1, which is characterized in that the preparation method includes will be described
The step of cyclodextrin-metal-organic framework materials obtain the composition after mixing with drug solution.
7. a kind of preparation method of composition as described in claim 1, which is characterized in that the preparation method includes will be described
Drug mixes with the cyclodextrin-metal-organic framework materials and is ground the step of obtaining the composition.
8. a kind of preparation method of composition as described in claim 1, which is characterized in that the preparation method includes following step
It is rapid:
(i) cyclodextrin, metal ion source are dissolved in the water and are prepared into the first solution, the drug is mixed into system with organic solvent
At the second solution;
(ii) the second solution is added in the first solution and carries out being mixed to get mixture;
(iii) solid collection and drying are carried out to get the composition to the mixture.
9. a kind of pharmaceutical composition, which is characterized in that described pharmaceutical composition includes:
Composition as described in claim 1;With
Pharmaceutically acceptable carrier.
10. pharmaceutical composition as claimed in claim 9, which is characterized in that described pharmaceutical composition be capsule, tablet,
Granula.
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CN111671736A (en) * | 2020-06-18 | 2020-09-18 | 辽宁大学 | Metal organic framework-based drug carrier, preparation method thereof and application thereof in oral drug carrier |
CN112546240A (en) * | 2020-12-14 | 2021-03-26 | 中国药科大学 | Cyclodextrin metal organic framework composition for improving dissolution of indometacin |
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CN101732270A (en) * | 2010-01-17 | 2010-06-16 | 鲁南制药集团股份有限公司 | Dispersing tablet of valsartan and preparation method thereof |
WO2017165618A1 (en) * | 2016-03-24 | 2017-09-28 | Panaceanano, Inc. | Compositions containing cyclodextrin-based metal organic frameworks |
CN107837401A (en) * | 2016-09-19 | 2018-03-27 | 中国科学院上海药物研究所 | Cyclodextrin metal-organic framework materials complex microsphere and preparation method thereof |
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CN101732270A (en) * | 2010-01-17 | 2010-06-16 | 鲁南制药集团股份有限公司 | Dispersing tablet of valsartan and preparation method thereof |
WO2017165618A1 (en) * | 2016-03-24 | 2017-09-28 | Panaceanano, Inc. | Compositions containing cyclodextrin-based metal organic frameworks |
CN107837401A (en) * | 2016-09-19 | 2018-03-27 | 中国科学院上海药物研究所 | Cyclodextrin metal-organic framework materials complex microsphere and preparation method thereof |
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CN111671736A (en) * | 2020-06-18 | 2020-09-18 | 辽宁大学 | Metal organic framework-based drug carrier, preparation method thereof and application thereof in oral drug carrier |
CN112546240A (en) * | 2020-12-14 | 2021-03-26 | 中国药科大学 | Cyclodextrin metal organic framework composition for improving dissolution of indometacin |
CN112546240B (en) * | 2020-12-14 | 2022-08-30 | 中国药科大学 | Cyclodextrin metal organic framework composition for improving dissolution of indometacin |
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