CN110314240B - Valsartan cyclodextrin-metal organic framework composition and preparation method thereof - Google Patents
Valsartan cyclodextrin-metal organic framework composition and preparation method thereof Download PDFInfo
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Abstract
The application discloses a cyclodextrin-metal organic framework composition for improving valsartan solubility, which comprises the following components: (a) a cyclodextrin-metal organic framework material; and (b) valsartan mixed in the matrix material. According to the composition, after the valsartan and the cyclodextrin-metal organic framework material are mixed and ground, the solubility and the dissolution rate of the valsartan in water can be obviously improved, the problems of poor solubility and low oral bioavailability of the valsartan medicine are solved, the raw materials used for preparing the composition are cheap and easy to obtain, the use of organic solvents is avoided, the composition is green and safe, the steps are simple, medicine carrying operation is completed, and industrial production is facilitated.
Description
Technical Field
The application relates to a valsartan cyclodextrin-metal organic framework composition and a preparation method thereof.
Background
Hypertension is one of the most common cardiovascular diseases, not only directly endangering health, but also accelerating the process of atherosclerosis, and the rise of blood pressure is a major risk factor for cerebral apoplexy, coronary heart disease, heart failure and kidney diseases in Chinese population. The occurrence of cardiovascular and cerebrovascular diseases and the death rate of China are continuously increased, wherein the death rate of the heart and cerebral vascular diseases is 40 percent, and the hypertension is a general problem of health hazard.
The "sartan" type medicine, namely angiotensin II receptor Antagonist (ARB) type antihypertensive medicine, has been known for more than 10 years, has obvious antihypertensive effect and good tolerance, and especially clinical test and evidence-based evidence show that the medicine has unique curative effect and protective effect on cardiovascular diseases, becomes one of the most common antihypertensive medicines in clinic, causes clinical general attention, and has low incidence of adverse reactions such as dry cough, drug withdrawal rebound and postural hypotension after long-term application, and is recommended by WHO multiple treatment guidelines as a first-line antihypertensive medicine for patients with cardiovascular diseases and proteinuria. The sartan drugs are mainly BCS II drugs, and have poor solubility in water, so that the oral bioavailability of the sartan drugs is low. In order to improve the oral bioavailability of sartan drugs, the solubility of sartan drugs must be improved.
Valsartan is an angiotensin II receptor Antagonist (ARB) antihypertensive drug, has obvious antihypertensive effect and good tolerance since more than 10 years ago, and particularly has a unique curative effect and a protective effect on cardiovascular diseases as shown by clinical trials and evidence-based evidence, and is one of the most common antihypertensive drugs in clinic, and has been brought into clinical general attention, and has low occurrence rate of adverse reactions such as dry cough, withdrawal rebound and postural hypotension after long-term application, and has been recommended by WHO multiple treatment guidelines as a first-line antihypertensive drug for hypertensive patients with cardiovascular diseases and proteinuria. Valsartan is a BCS class ii drug with poor solubility in water, resulting in low oral bioavailability of valsartan. In order to increase the oral bioavailability of valsartan, the solubility of the valsartan drug must be increased.
Disclosure of Invention
The application aims to provide a valsartan cyclodextrin-metal organic framework composition and a preparation method thereof.
In a first aspect of the present application there is provided a valsartan cyclodextrin-metal organic framework composition comprising: (a) a cyclodextrin-metal organic framework material; and (b) valsartan mixed in the matrix material.
In the present application, valsartan is mixed with the framework material in two ways: clathrating valsartan molecules with cyclodextrin molecules; valsartan forms nanoclusters in the large cavity in the middle of the cyclodextrin-metal organic framework.
In another preferred embodiment, the metal ions in the cyclodextrin-metal organic framework material are selected from the group consisting of: li (Li) + 、Na + 、K + 、Rb + 、Cs + 、Mg 2+ 、Ag + 、Yb + 、Ba 2+ 、Sr 2+ 、Ca 2+ 、La 3+ 。
In another preferred example, the metal ion is Ca 2+ 、Na + Or K + Further preferably K + 。
In another preferred embodiment, the anions that form salts or bases with the metal ions include, but are not limited to, OH - 、NO 3 - 、CO 3 2- 、HCO 3 - 、CH 3 COO - 、SCN - 、C 6 H 5 COOH＝C 6 H 5 COO - 、Cl - 、Br - 、I - 、O 2 - 、S 2 - 、HS - 、HSO 4 - 、ClO - 、ClO 3 - 、MnO 4 - Preferably OH - 。
In another preferred example, the cyclodextrin-metal organic framework material is potassium hydroxide cyclodextrin-metal organic framework material, potassium carbonate cyclodextrin-metal organic framework material, potassium chloride cyclodextrin-metal organic framework material, potassium acetate cyclodextrin-metal organic framework material, preferably potassium acetate γ -cyclodextrin-metal organic framework material.
In another preferred embodiment, the cyclodextrin in the cyclodextrin-metal organic framework material is selected from the group consisting of: alpha-cyclodextrin, beta-cyclodextrin, gamma-cyclodextrin, hydroxypropyl-beta-cyclodextrin, sulfobutyl-beta-cyclodextrin, methyl-beta-cyclodextrin, carboxymethyl-beta-cyclodextrin.
In another preferred embodiment, the cyclodextrin is selected from the group consisting of: alpha-cyclodextrin, beta-cyclodextrin, gamma-cyclodextrin, and more preferably gamma-cyclodextrin.
In another preferred embodiment, the molar ratio of cyclodextrin-metal organic framework to valsartan in the composition is 1:0.2-1:2.
In another preferred embodiment, the molar ratio of cyclodextrin-metal organic framework to valsartan in the composition is 1:0.5-1:1.8.
In another preferred embodiment, the molar ratio of cyclodextrin-metal organic backbone to valsartan in the composition is preferably 1:1.5.
In another preferred embodiment, the composition further has one or more of the following features:
(1) The average grain diameter of the cyclodextrin-metal organic framework material is 5 nanometers-1000 micrometers;
(2) The drug loading of the composition is 5% -50%.
In another preferred embodiment, the cyclodextrin-metal organic framework material has an average particle size of 100-1000 nanometers (on the order of nanometers); or the cyclodextrin-metal organic framework material has an average particle size of 1-100 micrometers (micron order).
In another preferred embodiment, the composition has a drug loading of 10% to 45%.
In another preferred embodiment, the drug loading of the composition is further preferably 20% -40%.
The composition of the application has solubilization effect on valsartan, and improves the solubility of valsartan in water by 1-200 times, preferably 5-100 times, and more preferably 20-60 times.
According to pharmacokinetic data (AUC 0-t 、C max Etc.), the results show that valsartan CD-MOF can significantly improve the bioavailability of valsartan in rats.
In a second aspect of the present application, there is provided a method of preparing the composition of the first aspect, comprising the steps of:
and mixing and grinding valsartan and cyclodextrin-metal organic framework ring material to obtain the composition.
In another preferred embodiment, the feeding ratio of the cyclodextrin-metal organic framework material to valsartan is 1:0.2-1:2, preferably 1:0.4-1:1.8.
In another preferred embodiment, the cyclodextrin-metal organic framework material and valsartan are both in powder form.
In another preferred embodiment, the milling is performed using a ball mill. In another preferred embodiment, the ball mill is operated with zirconium beads having a diameter of 6-10mm, preferably 8 mm. In another preferred embodiment, the weight ratio of zirconium beads to (valsartan+cyclodextrin-metal organic framework material) is 15:1 to 1:1, preferably 10:1 to 3:1.
The grinding time is 1min-2h, preferably 5-80min.
In a third aspect of the application, there is provided a pharmaceutical composition comprising:
a composition according to the first aspect; and
a pharmaceutically acceptable carrier.
"pharmaceutically acceptable carrier" means: one or more compatible solid or liquid filler or gel materials which are suitable for human use and must be of sufficient purity and sufficiently low toxicity. "compatible" as used herein means that the components of the composition are capable of blending with and between the compounds of the present application without significantly reducing the efficacy of the compounds. Examples of pharmaceutically acceptable carrier moietiesCellulose and its derivatives (such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talcum, solid lubricant (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oil (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyalcohol (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifying agent Wetting agents (e.g., sodium lauryl sulfate), coloring agents, flavoring agents, stabilizing agents, antioxidants, preservatives, pyrogen-free water, and the like.
In another preferred embodiment, the carrier is selected from the group consisting of: diluents, excipients, fillers, binders, wetting agents, disintegrants, absorption enhancers, surfactants, adsorption carriers, lubricants, or combinations thereof.
In another preferred embodiment, the pharmaceutical composition is formulated as a solid or liquid dosage form, preferably for oral administration. In another preferred embodiment, the solid dosage form includes capsules, tablets, pills, powders and granules. In another preferred embodiment, the liquid dosage form comprises a pharmaceutically acceptable emulsion, solution, suspension, syrup or tincture.
In another preferred example, the pharmaceutical composition is in the form of a capsule, tablet, granule.
In another preferred embodiment, the pharmaceutical composition further comprises a surfactant selected from the group consisting of: polysorbate-80, polysorbate-60, polyethylene glycol glycerol fatty acid ester, sorbitan fatty acid ester, and mixture of two or more.
It is understood that within the scope of the present application, the above-described technical features of the present application and technical features specifically described below (e.g., in the examples) may be combined with each other to constitute new or preferred technical solutions. And are limited to a space, and are not described in detail herein.
Drawings
FIG. 1 is a graph of dissolution rate for example 2.
Fig. 2 is an infrared spectrum of example 7.
FIG. 3 is a molecular simulation of valsartan loaded CD-MOF in example 11.
Detailed Description
The application provides a compound of cyclodextrin-metal organic framework for carrying valsartan, which is prepared by mixing and grinding valsartan and cyclodextrin-metal organic framework material, can remarkably improve the solubility and dissolution rate of valsartan in water, solves the problems of poor solubility of valsartan medicine and low oral absolute bioavailability, has low cost and easy obtainment of raw materials and solvents, simple steps and is beneficial to industrial production.
Cyclodextrin
Cyclodextrins are a generic term for a series of cyclic oligosaccharides produced from amylose by the action of glycosyltransferase, generally containing 6 to 12D-glucopyranose units. Of more interest and of practical importance are molecules containing 6, 7 and 8 glucose units, known as α, β -and γ -cyclodextrins, respectively. Cyclodextrins are ideal host molecules for the enzyme as found so far and are inherently characteristic of the enzyme model.
Metal organic framework material
Metal-organic frameworks (Metal-organic frameworks, MOFs) are crystalline materials in which inorganic Metal centers are connected by organic bridging ligands by means of coordination bonds to form an infinitely extending network-like structure. The MOFs have the potential application value in the fields of gas storage, catalysis, drug carriers and the like due to the ultrahigh porosity and the huge specific surface area of the MOFs and the structure of the MOFs consisting of inorganic and organic different components, so that the MOFs are diversified and adjustable in structure.
Cyclodextrin-metal organic framework materials
As used herein, the terms "Cyclodextrin-Metal-organic framework material (CD-MOF)", "Cyclodextrin-based Metal-organic framework material", "Cyclodextrin-Metal-organic framework compound" are used interchangeably to form a new crystal in an organic coordination manner with the first and second main group Metal ions in an aqueous solution using Cyclodextrin, which has the characteristics of being porous, having a large surface area, storing a gas, and the like. The green porous material can absorb some medicines with unstable structures, and the huge cavity can protect the medicines, so that the green porous material is possible to be used for commercial development, and is particularly suitable for human consumption because the cyclodextrin-metal organic framework is an edible derivative. The cyclodextrin is used as an organic ligand, and the metal ion is used as an inorganic metal center, so that a novel, high-safety and pharmaceutically acceptable cyclodextrin-metal organic framework, namely the CD-MOFs, can be formed.
As used herein, the term "alkaline cyclodextrin-metal organic framework material" is a cyclodextrin-metal organic framework material prepared from alkali metals and cyclodextrins, which is alkaline and which when dissolved in water to make a 10mg/mL aqueous solution has a pH of about 11-13.
As used herein, the terms "neutral cyclodextrin-metal organic framework material", "acidified cyclodextrin-metal organic framework material" are used interchangeably and refer to a near neutral cyclodextrin-metal organic framework material obtained by acidifying an alkaline cyclodextrin-metal organic framework material, which when dissolved in water to make a 10mg/mL aqueous solution has a pH of about 5 to 8. A preferred method of acidification treatment is as follows: weighing a certain amount of cyclodextrin-metal organic framework, placing the cyclodextrin-metal organic framework in ethanol, adding a certain amount of glacial acetic acid, shaking and incubating for a certain time at 25 ℃, and washing the obtained solid by using ethanol to obtain the nearly neutral cyclodextrin-metal organic framework.
Valsartan-loaded cyclodextrin-metal organic framework complex
As used herein, the terms "valsartan-loaded cyclodextrin-metal organic framework composition", "valsartan-loaded cyclodextrin-metal organic framework complex", "valsartan-loaded cyclodextrin-metal organic framework", "valsartan-loaded CD-MOF complex", "valsartan-loaded CD-MOF", "valsartan CD-MOF composition", "CD-MOF-loaded valsartan" are used interchangeably, and all refer to the samples obtained by mixing and grinding valsartan with cyclodextrin-metal organic framework material.
The application will be further illustrated with reference to specific examples. It is to be understood that these examples are illustrative of the present application and are not intended to limit the scope of the present application. The experimental procedures, which do not address the specific conditions in the examples below, are generally carried out under conventional conditions (e.g.those described in Sambrook et al, molecular cloning: A laboratory Manual (New York: cold Spring Harbor Laboratory Press, 1989)) or under conditions recommended by the manufacturer. Percentages and parts are weight percentages and parts unless otherwise indicated.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. In addition, any methods and materials similar or equivalent to those described herein can be used in the methods of the present application. The preferred methods and materials described herein are presented for illustrative purposes only.
General method
Valsartan content determination conditions: (1) ultraviolet spectrophotometry: the dissolution rate of the two-part valsartan capsule of the 2015 edition of Chinese pharmacopoeia is referred to, and the detection wavelength is 250nm. (2) High Performance Liquid Chromatography (HPLC): the content determination method of the valsartan capsule is established by referring to the Chinese pharmacopoeia 2015 edition. The column was Platisil ODS C18 (250X 4.6mm,5 μm); the mobile phase is acetonitrile-water-glacial acetic acid (500:500:1); the flow rate is 1.2mL/min; column temperature is 35 ℃; the detection wavelength is 230nm.
The method for measuring the solubility comprises the following steps: excess sample to be measured is weighed, placed in water, shaken by a shaker (25 ℃ C., 200 rpm) for three days, centrifugally filtered, and the concentration of valsartan in the solution is determined according to the valsartan content determination method. The solubility of the sample to be measured in water at 25℃is noted.
Solubilization fold: the solubility of the samples to be compared is compared with the solubility of valsartan starting material in water (25 ℃) (0.08 mg/mL).
The method for measuring and calculating the drug loading and drug loading molar ratio comprises the following steps: precisely weighing 5mg (m) 1 ) Placing the sample to be tested in a 100mL volumetric flask, and dissolving by pure water ultrasonicAfter filtration, the valsartan content is determined according to the valsartan content determination condition, and the mass m of the valsartan is calculated 2 。
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 body )
M Carrier body Is the molecular weight of the carrier, 435.52 is the molecular weight of valsartan.
Example 1
3000mL of purified water was weighed into a beaker, 97.3g of gamma-CD was added and stirred, 33.6g of KOH was added, and the mixture was sonicated to completely dissolve gamma-CD and KOH, thereby obtaining a mother liquor. The mother liquor was poured into a reaction kettle, the rotational speed was set at 300rpm, and the temperature was 50 ℃. 1800mL of methanol was added to the reactor, and after dissolution and clarification, 38.4g PEG20000 was added. Standing at room temperature overnight, centrifuging, removing supernatant, adding 0.4L absolute ethyl alcohol into the lower precipitate for dispersion, centrifuging, washing, adding 0.4L absolute ethyl alcohol and 20mL glacial acetic acid into the precipitate, stirring for neutralization, and centrifuging to remove supernatant. Finally, 0.4L of ethanol was added to the precipitate, and the precipitate was washed twice by centrifugation (4000 rpm,5 min). The washed precipitate was dried in a vacuum oven at 60℃for 4h. Thus obtaining the micron-sized potassium acetate cyclodextrin-metal organic framework, wherein the grain diameter is 1-10 microns.
7.0g of the prepared micron-sized potassium acetate CD-MOF and 3.0g of valsartan (the molar ratio of cyclodextrin to valsartan in the cyclodextrin-metal organic framework material is 1:1.5) are weighed, and the mixture is ground for 5min by using a ball mill (the weight ratio of zirconium beads to powder is 3:1), so as to obtain the valsartan micron-sized potassium acetate CD-MOF composition. The solubilization multiple was 32.2 times. The dissolution rate is shown in FIG. 1, and the dissolution rate is 87.1% in 10 min.
The pure drug valsartan (weight ratio of zirconium beads to powder is 3:1) was ground in the same way for 60min with a solubilization multiple of 1.4. The dissolution rate is shown in FIG. 1, and the dissolution rate is 4.8% in 10 min.
Example 2
7.0g of the micron-sized potassium acetate CD-MOF prepared in example 1 and 3.0g of valsartan (the molar ratio of cyclodextrin to valsartan in the cyclodextrin-metal organic framework material is 1:1.5) are weighed and simply mixed to obtain the valsartan micron-sized potassium acetate CD-MOF composition. The solubilization multiple was 23.3 times. Dissolution rate as shown in fig. 1, dissolution rate was 19.6% in 10min and release rate was slower compared to the milled composition.
Example 3
The procedure of example 2 was used to prepare a valsartan and gamma cyclodextrin composition having a solubilization factor of 4.5 times for valsartan by simple physical mixing of 7.0g of valsartan and gamma cyclodextrin (molar ratio of cyclodextrin to valsartan 1:1.5). The dissolution rate is shown in FIG. 1, and the dissolution rate is 24.8% in 10 min.
Example 4
7.0g of gamma cyclodextrin and 3.0g of valsartan (molar ratio of gamma cyclodextrin to valsartan is 1:1.5) were weighed and ground for 60 minutes using a ball mill (weight ratio of zirconium beads to powder is 3:1), to obtain a valsartan and gamma cyclodextrin composition. The solubilization multiple was 5.7 times.
Example 5
7.0g of gamma cyclodextrin and 3.0g of valsartan (molar ratio of gamma cyclodextrin to valsartan is 1:1.5) were weighed and ground for 5min using a ball mill (weight ratio of zirconium beads to powder is 3:1), to obtain a valsartan and gamma cyclodextrin composition. The solubilization multiple was 4.8 times.
Example 6
7.0g of the micron-sized potassium acetate CD-MOF prepared in example 1 and 3.0g of valsartan (the molar ratio of cyclodextrin to valsartan in the cyclodextrin-metal organic framework material is 1:1.5) are weighed, and the mixture is ground for 10min by using a ball mill (the weight ratio of zirconium beads to powder is 3:1), so as to obtain the valsartan micron-sized potassium acetate CD-MOF composition. The solubilization multiple was 32.5 times. The dissolution rate is 57.8% after 10 min.
Example 7
7.0g of the micron-sized potassium acetate CD-MOF prepared in example 1 and 3.0g of valsartan (the molar ratio of cyclodextrin to valsartan in the cyclodextrin-metal organic framework material is 1:1.5) are weighed, and the mixture is ground for 60 minutes by using a ball mill (the weight ratio of zirconium beads to powder is 3:1), so as to obtain the valsartan micron-sized potassium acetate CD-MOF composition. The solubilization multiple was 38.9 times. The dissolution rate is 49.1% after 10 min.
Figure 2 infrared spectra show that valsartan microscale potassium acetate CD-MOF compositions are different from valsartan drug substance and microscale potassium acetate CD-MOF. Comparing the patterns of CD-MOF and VAL/CD-MOF, the two samples were at 2926cm -1 Has wider absorption band and can be attributed to the stretching vibration (v) of-CH-in CD-MOF CH ). Valsartan is characterized by the presence of self amide bond and carbonyl group at 1731cm -1 1600cm -1 With strong absorption (characteristic absorption of carbon-oxygen double bonds) at 1445cm -1 Treatment v (C＝C) The aromatic ring vibrates, and neither CD-MOF has the above characteristic absorption; valsartan/CD-MOF at 1731cm -1 (amidecarboxyl) 1445cm -1 ν (C＝C) The vibration is significantly reduced or eliminated in intensity. Elucidation the characteristic peaks of valsartan loaded by milling were masked indicating that valsartan was loaded by CD-MOF.
Example 8
7.0g of the micron-sized potassium acetate CD-MOF prepared in example 1 and 3.0g of valsartan (the molar ratio of cyclodextrin to valsartan in the cyclodextrin-metal organic framework material is 1:1.5) are weighed, and the mixture is ground for 60 minutes by using a ball mill (the weight ratio of zirconium beads to powder is 10:1), so as to obtain the valsartan micron-sized potassium acetate CD-MOF composition. The solubilization multiple was 35.1 times.
Example 9
7.0g of the micron-sized potassium acetate CD-MOF prepared in example 1 and 3.0g of valsartan (the molar ratio of cyclodextrin to valsartan in the cyclodextrin-metal organic framework material is 1:0.5) are weighed, and the mixture is ground for 60 minutes by using a ball mill (the weight ratio of zirconium beads to powder is 3:1), so as to obtain the valsartan micron-sized potassium acetate CD-MOF composition. The solubilization multiple was 23.0 times.
Example 10
648mg of gamma-CD and 224mg of KOH are weighed, 20mL of pure water is added, and stirring is carried out until complete dissolution; pouring into a 50mL plastic centrifuge tube, and adding 12mL of anhydrous methanol; heating in a constant temperature water tank at 50deg.C for 20min. Adding 8mg/mL PEG20000, shaking uniformly; after standing for 1h, the mixture was centrifuged at 3500rpm for 5min, and the supernatant was removed. The precipitate was washed 3 times with 12mL of absolute ethanol and dried in vacuo to give potassium hydroxide CD-MOF.
7.0g of micron-sized potassium hydroxide CD-MOF and 3.0g of valsartan (the molar ratio of cyclodextrin to valsartan in the cyclodextrin-metal organic framework material is 1:1) are weighed, and the mixture is ground for 5min by using a ball mill (the weight ratio of zirconium beads to powder is 3:1), so as to obtain the valsartan micron-sized potassium acetate CD-MOF composition. The solubilization multiple was 53.9 times.
Example 11
Molecular simulation of CD-MOF-carried valsartan
The distribution of valsartan in gamma CD-MOF is mainly in two states: part of the cyclodextrin molecules comprise clathrates of valsartan; part of the valsartan forms nanoclusters in the large cavities of the gamma CD-MOF.
The method comprises the following steps: the first valsartan molecule is more prone to be condensed in the hydrophobic cavity created by the cyclodextrin structure in the γcd-MOF (free energy of docking-8.5 kcal/mol), thus freeing up a hydrophilic cavity to accept more valsartan molecules. The carboxyl group in valsartan electrostatically interacts with the hydroxyl group in the gaps of gamma CD-MOF crystals and the hydroxyl group in cyclodextrin to generate hydrogen bonds. By utilizing the characteristics of hydrophilic parts and hydrophobic parts in valsartan molecules, the valsartan molecules which are continuously butted are butted into large cavities of gamma CD-MOF with different system energies.
As shown in FIG. 3, 6 valsartan molecules are included by 6 cyclodextrin molecule pairs, 5 valsartan molecules are loaded in the large cavity, and the theoretical drug loading mole ratio of gamma CD-MOF to valsartan in the composition is 1:1.3.
Example 12
2000mL of pure water was taken in a 5000mL beaker, 64.9g of gamma-CD was weighed in the beaker, stirred, 22.4g of KOH was added to the beaker, and the gamma-CD and KOH were completely dissolved by ultrasound to prepare a mother liquor. The mother liquor was poured into a reaction vessel at a rotation speed of 300rpm and a temperature of 50℃1200mL of methanol was added to the reaction vessel followed by PEG20000 (8 mg/mL). Standing in cold water bath overnight. The supernatant was removed by centrifugation and the pellet was washed twice with 150mL ethanol and dried in a vacuum oven at 40℃for 12h. The grain diameter is 100-500 nanometers.
7.0g of the prepared nano-grade potassium acetate CD-MOF and 3.0g of valsartan (the molar ratio of cyclodextrin to valsartan in the cyclodextrin-metal organic framework material is 1:1.5) are weighed, and the nano-grade potassium acetate CD-MOF composition of valsartan is obtained by grinding for 5min by using a ball mill (the weight ratio of zirconium beads to powder is 3:1). The solubilization factor was 27.3 times.
Example 13
3000mL of pure water was weighed into a beaker, 97.3g of gamma-CD was added and stirred, 33.6g of sodium hydroxide was added, and the mixture was sonicated to completely dissolve gamma-CD and sodium hydroxide, thereby obtaining a mother liquor. The mother liquor was poured into a reaction kettle, the rotational speed was set at 300rpm, and the temperature was 50 ℃. 1800mL of methanol was added to the reactor, and after dissolution and clarification, 38.4g PEG20000 was added. After standing overnight at room temperature, the supernatant was removed, and the precipitate was washed twice with 100mL of ethanol and twice with 100mL of methanol, respectively. And drying the precipitate in a vacuum drying oven at 40 ℃ for 12 hours to obtain the micron-sized sodium hydroxide cyclodextrin metal organic framework. 7.0g of micron-sized sodium hydroxide cyclodextrin metal organic framework and 3.0g of valsartan (the molar ratio of cyclodextrin to valsartan in the cyclodextrin-metal organic framework material is 1:1) are weighed, and the mixture is ground for 5min by using a ball mill (the weight ratio of zirconium beads to powder is 3:1), so as to obtain the valsartan micron-sized sodium hydroxide cyclodextrin metal organic framework composition.
Example 14
3000mL of pure water was measured in a beaker, 97.3g of gamma-CD was added and stirred, 16.8g of calcium hydroxide was added, and the mixture was sonicated to completely dissolve gamma-CD and calcium hydroxide, thereby obtaining a mother liquor. The mother liquor was poured into a reaction kettle, the rotational speed was set at 300rpm, and the temperature was 50 ℃. 1800mL of ethanol was added to the reactor, and after dissolution and clarification, 38.4g PEG4000 was added. After standing overnight at room temperature, the supernatant was removed, and the precipitate was washed twice with 100mL of ethanol and twice with 100mL of ethanol, respectively. And drying the precipitate in a vacuum drying oven at 40 ℃ for 12 hours to obtain the micron-sized calcium hydroxide cyclodextrin metal organic framework. 7.0g of micron-sized calcium hydroxide cyclodextrin metal organic framework and 3.0g of valsartan (the molar ratio of cyclodextrin to valsartan in the cyclodextrin-metal organic framework material is 1:1) are weighed, and the mixture is ground for 5min by using a ball mill (the weight ratio of zirconium beads to powder is 3:1), so as to obtain the valsartan micron-sized calcium hydroxide cyclodextrin metal organic framework composition.
Example 15
In vivo bioavailability in rats
12 healthy male SD rats were purchased from Shanghai laboratory animal research center, weighing about 200+ -20 g, and were randomly divided into 2 groups of 6, each group being given with valsartan CD-MOF composition (prepared in example 1), 15mg/kg of primary culture capsules, and 0.3mL of blood was obtained from the orbitals at 0, 0.08, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 8, 12 and 24h, respectively. The bioavailability of valsartan-loaded neutral micron-sized CD-MOF compositions was compared and evaluated with primary-ground venturi capsules.
And (3) determining the valsartan concentration in the rat plasma sample by adopting a high performance liquid chromatography tandem mass spectrometry (LC-MS/MS) analysis method. The pharmacokinetic parameters of 12 healthy male SD rats are calculated by adopting DAS2.0 software, and the results are shown in Table 1, and compared with the metaplasia group, the average relative bioavailability of the valsartan/CD-MOF group is 149.3%, which indicates that after the CD-MOF carries the valsartan, the bioavailability of the valsartan in the rats is obviously improved. At the same time, SPSS17.0 software was used to determine pharmacokinetic parameters (area under the drug time curve AUC) 0-24h Peak concentration C max Peak time T max ) Statistical analysis of t-test showed AUC for both groups 0-24h 、C max T and T max All have significant differences, further showing that the bioavailability of valsartan is significantly improved after being loaded by CD-MOF.
TABLE 1 pharmacokinetic parameters in rats
| Pharmacokinetic parameters | Valsartan CD-MOF compositions | Generation Wen Jiaonang |
| AUC 0-24h (μg/mL·h) | 39.50±11.30 * | 17.75±23.02 |
| T max (h) | 0.36±0.35 | 0.39±0.31 |
| C max (μg/mL) | 9.56±1.75 ** | 5.04±1.38 |
Note that: comparison with the group of tokens * p＜0.05； ** p＜0.01。
All documents mentioned in this disclosure are incorporated by reference in this disclosure as if each were individually incorporated by reference. Further, it will be appreciated that various changes and modifications may be made by those skilled in the art after reading the above teachings, and such equivalents are intended to fall within the scope of the application as defined in the appended claims.
Claims (17)
1. A valsartan cyclodextrin-metal organic framework composition, characterized in that the composition comprises: (a) a cyclodextrin-metal organic framework material; and (b) valsartan mixed in the matrix material;
wherein valsartan is mixed and ground with cyclodextrin-metal organic framework ring material to obtain the composition, valsartan is mixed with the framework material in two ways: clathrating valsartan molecules with cyclodextrin molecules; valsartan forms nanoclusters in a large cavity in the middle of a cyclodextrin-metal organic framework;
the molar ratio of the cyclodextrin-metal organic framework to the valsartan in the composition is 1:0.2-1:2;
the metal ion in the cyclodextrin-metal organic framework material is Ca 2+ 、Na + Or K + 。
2. The composition of claim 1, wherein the anion that forms a salt or base with the metal ion is selected from the group consisting of OH - 、NO 3 - 、CO 3 2- 、HCO 3 - 、CH 3 COO - 、SCN - 、C 6 H 5 COOH=C 6 H 5 COO - 、Cl - 、Br - 、I - 、O 2 - 、S 2 - 、HS - 、HSO 4 - 、ClO - 、ClO 3 - 、MnO 4 - 。
3. The composition of claim 1, wherein the cyclodextrin-metal organic framework material is selected from the group consisting of: potassium hydroxide cyclodextrin-metal organic framework material, potassium carbonate cyclodextrin-metal organic framework material, potassium chloride cyclodextrin-metal organic framework material, and potassium acetate cyclodextrin-metal organic framework material.
4. The composition of claim 1, wherein the cyclodextrin in the cyclodextrin-metal organic framework material is selected from the group consisting of: alpha-cyclodextrin, beta-cyclodextrin, gamma-cyclodextrin, hydroxypropyl-beta-cyclodextrin, sulfobutyl-beta-cyclodextrin, methyl-beta-cyclodextrin, carboxymethyl-beta-cyclodextrin.
5. The composition of claim 1, wherein the cyclodextrin in the cyclodextrin-metal organic framework material is selected from the group consisting of: alpha-cyclodextrin, beta-cyclodextrin, gamma-cyclodextrin.
6. The composition of claim 1, wherein the molar ratio of cyclodextrin-metal organic backbone to valsartan in the composition is from 1:0.5 to 1:1.8.
7. The composition of claim 1, wherein the composition has a drug loading of 5% to 50%.
8. The composition of claim 1, wherein the cyclodextrin-metal-organic framework material has an average particle size of 100 to 1000 nanometers; or the average particle size of the cyclodextrin-metal organic framework material is 1-100 microns.
9. The composition of claim 1, wherein the composition has a drug loading of 10% to 45%.
10. A process for preparing the composition of claim 1, comprising the steps of:
and mixing and grinding valsartan and cyclodextrin-metal organic framework ring material to obtain the composition.
11. The method of claim 10, wherein the milling is performed using a ball mill.
12. The method of claim 11, wherein the ball mill is operated with zirconium beads having a diameter of 6-10 mm.
13. The method of claim 12, wherein the weight ratio of zirconium beads to valsartan + cyclodextrin-metal organic framework material is from 15:1 to 1:1.
14. A pharmaceutical composition, comprising:
the composition of claim 1; and
a pharmaceutically acceptable carrier.
15. The pharmaceutical composition of claim 14, wherein the carrier is selected from the group consisting of: diluents, excipients, fillers, binders, wetting agents, disintegrants, absorption enhancers, surfactants, adsorption carriers, lubricants, or combinations thereof.
16. The pharmaceutical composition of claim 14, wherein the pharmaceutical composition is in the form of a capsule, tablet, granule.
17. The pharmaceutical composition of claim 14, further comprising a surfactant selected from the group consisting of: polysorbate-80, polysorbate-60, polyethylene glycol glycerol fatty acid ester, sorbitan fatty acid ester, and mixture of two or more.
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