CN113521005A - Nanometer lipid particle carrier for delivering resveratrol drug and preparation method and application thereof - Google Patents
Nanometer lipid particle carrier for delivering resveratrol drug and preparation method and application thereof Download PDFInfo
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- CN113521005A CN113521005A CN202110715786.5A CN202110715786A CN113521005A CN 113521005 A CN113521005 A CN 113521005A CN 202110715786 A CN202110715786 A CN 202110715786A CN 113521005 A CN113521005 A CN 113521005A
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- 229940016667 resveratrol Drugs 0.000 title claims abstract description 80
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- 238000002360 preparation method Methods 0.000 title claims abstract description 16
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
- A61K31/05—Phenols
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- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
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Abstract
The invention provides a nano lipid particle carrier for delivering resveratrol drugs and a preparation method and application thereof. The nano lipid particle carrier takes phospholipid as a lipid carrier and cholesterol as a stabilizing agent, is used for encapsulating resveratrol drugs, is prepared into nano liposome particles, is used for improving the water solubility and stability of the drugs, further obtains the resveratrol oral drug with ideal bioavailability, takes the phospholipid as a main component of a cell membrane, can realize the effective encapsulation of water-soluble and liposoluble active drugs, has the functions of protection, carrying, slow release and the like on the active drugs, greatly improves the solubility of the resveratrol, has high encapsulation efficiency, is simple and easy to obtain, and is convenient to store.
Description
Technical Field
The invention belongs to the technical field of biomedicine, and particularly relates to a nano lipid particle carrier for delivering a resveratrol drug, and a preparation method and application thereof.
Background
In recent years, with the improvement of living standard, the health consciousness of people is gradually enhanced, and resveratrol related products with nutritional efficacy are gradually wondered and are concerned by a plurality of people.
Resveratrol (trans-resveratrol; trans-3, 5,4' -trihydroxycysteine) belongs to a class of polyphenols that occur naturally in grapes, red wine, peanuts and other peanut products. Recent studies have found that resveratrol has a wide range of biological effects including anti-inflammatory and neuroprotective properties and can protect against oxidative stress and cancer. A large amount of epidemiological and clinical evidence proves that the resveratrol has the effects of resisting bacteria and inflammation, resisting oxidation, protecting the liver, protecting the heart and cerebral vessels and the like.
However, the clinical role of resveratrol is limited, and in the clinical application of resveratrol, oral administration is the most important administration route, and the water solubility, membrane permeability and metabolic stability of the drug determine the oral bioavailability of small molecule drugs. Resveratrol, as a fat-soluble substance, has poor solubility in water (0.02-0.03 mg/mL), so the absorption rate by oral administration is extremely low, and its main active form trans-resveratrol has very poor stability under light and is easily isomerized into inactive cis-resveratrol. In recent years, scientists have conducted various pharmaceutical researches on the physical and chemical properties and metabolic stability of resveratrol: the existing animal experiment research shows that piperine can obviously improve the peak concentration (Cmax) and the area under the drug-time curve (AUC) of rat serum resveratrol. However, in human experiments, piperine can enhance the effect of resveratrol on cerebral blood flow, but cannot increase the bioavailability. The casein-resveratrol compound prepared from casein can improve the stability of resveratrol, prolong the shelf life of products and improve the water solubility of the products, but the affinity of the casein and the resveratrol is insufficient, so that the encapsulation efficiency is low. In the aspect of the preparation for increasing the water solubility of the resveratrol, Cyclodextrin (CD) has good solubilization effect on the resveratrol, and can improve the ultraviolet irradiation stability of the resveratrol to a certain extent, but cannot improve the pharmacokinetic behavior of the resveratrol.
The invention uses the lipid-based nanoparticles as the delivery carrier of the resveratrol drug, thereby obviously improving the water solubility of the drug and simultaneously ensuring the stability of the drug. It has been demonstrated that the use of nano-lipid particles as a carrier can improve the oral bioavailability and therapeutic potential of resveratrol.
Disclosure of Invention
The technical problem solved by the invention is as follows: the invention takes phospholipid as a lipid carrier and cholesterol as a stabilizer for encapsulating resveratrol drugs to prepare nano liposome particles so as to improve the water solubility and stability of the drugs and further obtain the resveratrol oral drug with ideal bioavailability.
In order to solve the technical problems, the invention provides a nano lipid particle carrier for delivering a resveratrol drug, wherein the nano lipid particle takes phospholipid as a lipid carrier and cholesterol as a stabilizer to encapsulate the resveratrol drug.
Preferably, the nano lipid particle carrier for delivering the resveratrol drug takes mannitol as a cryoprotectant.
Preferably, the mass ratio of cholesterol to lecithin is in the range of about 1:1 to about 1: 10.
Preferably, the encapsulated resveratrol drug to cholesterol mass ratio is in the range of about 1:2 to about 1:10, and the resveratrol drug to lecithin mass ratio is in the range of about 1:5 to about 1: 100.
Preferably, the diameter of the nano-lipid particle is from about 70 to about 500 nm.
The preparation method of the nano lipid particle carrier for delivering the resveratrol drug comprises the following steps:
(1) dissolving lecithin and cholesterol in a mixed solution of chloroform and methanol to obtain a solution I; (2) dissolving resveratrol in methanol to obtain solution II;
(3) mixing solution I and solution II, and performing rotary evaporation on the obtained solution to remove the organic solvent to obtain a yellow film;
(4) adding water, rotating to precipitate lipid film to obtain liposome emulsion, cooling the emulsion, ultrasonic treating, and freeze drying to obtain nanometer lipid particles.
The mass ratio of the lecithin to the cholesterol in the step (1) is 10: 1, chloroform-methanol volume ratio 2: 1, when the resveratrol is dissolved in the methanol in the step (2), the mass ratio of the resveratrol to the methanol is 1: 3.
after mixing the solution I and the solution II in step (3), the solvent was removed on a rotary evaporator at 51 ℃ and 150rpm and 500 mbar.
The invention has the beneficial effects that: the invention adopts natural phospholipid compounds to prepare the nano-scale vesicle with a bilayer structure, phospholipid is used as a main component of a cell membrane, and the structure can realize effective encapsulation of water-soluble and fat-soluble active medicaments and has the functions of protection, delivery, slow release and the like on the active medicaments. The nano liposome particles prepared by the invention greatly improve the solubility of resveratrol, have high encapsulation efficiency, are simple and easily obtained, are convenient to store, only use methanol and chloroform as organic solvents, have simple and convenient method and high repetition rate.
Drawings
FIG. 1 shows the layering state of the emulsion obtained by emulsifying the nano-liposome particles for delivering resveratrol drugs in water at room temperature for 48 hours, 7 days and 14 days
FIG. 2 is a graph showing the release profile of the nano-sized lipid particles of the present invention in simulated gastric fluid (SGF PH 1.2,0-2 hours) and simulated intestinal fluid (SIF PH 6.8,2-24 hours) when delivering resveratrol drugs
Detailed Description
Example 1 preparation of a Nanolipid particle Carrier for delivering resveratrol drugs according to the invention
Dissolving lecithin and cholesterol (in a mass ratio of 10: 1) in a mixed solution of chloroform and methanol (in a volume ratio of 2: 1) to obtain a solution I. Dissolving resveratrol in methanol (mass ratio of 1: 3) to obtain solution II. Solution I and solution II (volume ratio 3: 1) were added to a 250mL round bottom flask to give a pale yellow, slightly cloudy solution. The solvent was removed on a rotary evaporator (Heidolph, Hei-VAP Core) at 51 ℃ and 150rpm and 500mbar to give a pale yellow film. The flask was charged with 20mL of water. The liposome was rotated at 51 ℃ for 1 hour to precipitate a lipid film, thereby obtaining a liposome emulsion. This slightly cloudy emulsion was then cooled to 5 ℃ in an ice-water bath and sonicated with an ultrasonic homogenizer (Bandelin Sonopuls HD 2070) at 50% power intensity for 5 minutes. Freeze-drying the liposome to obtain nanometer lipid particles, and using mannitol as cryoprotectant.
Example 2 the use of nano-lipid particles as resveratrol carrier can significantly improve water solubility and stability
1. Water solubility analysis
Emulsifying 32.24mg of the prepared nano-lipid particles (containing 0.575mg of resveratrol) in 1150 mu L of water and carrying out ultrasonic treatment for 5 minutes to obtain a milk-like emulsion, wherein the total concentration of the resveratrol is 0.5mg/ml, and compared with the solubility (0.03mg/ml) of the resveratrol reported in the prior art, the solubility of the resveratrol is improved by 16 times.
2. Stability analysis
32.24mg of the nano-lipid particles (containing 0.575mg of resveratrol) obtained by the preparation are emulsified in 1150 mu L of water and ultrasonically treated for 5 minutes, the obtained emulsion is placed at room temperature without shading, and the appearance change is observed, so that the result shows that no obvious change exists within 7 days.
The nano-lipid particles were left at room temperature without shading, and samples of the nano-particles were taken at predetermined times (24 hours, 7 days, 1 month) and subjected to particle size and particle size distribution analysis, Zeta potential analysis, encapsulation efficiency analysis, as shown below, 2.1 to 2.3, with the results shown in table 1.
2.1 particle size and particle size distribution analysis
The size and polydispersity index (PDI) of the obtained lipid nanoparticles were measured by Dynamic Light Scattering (DLS) at 25 ℃ using zetasizer nano-ZS90(Malvern Instruments ltd., Worcestshire, UK). The lyophilized nanoparticles were redispersed in pure water and diluted appropriately and stirred for 10 minutes. Measurements were performed in triplicate (three readings were taken).
2.2Zeta potential analysis
Zeta potential of the prepared sample of the nano-lipid particles was measured to evaluate its surface charge and stability. The Zeta potential of the nanoparticles was evaluated by measuring the electrophoretic mobility of the particles at 25 ℃ using a Zetasizer Nano-ZS90(Malvern Instruments Ltd., Worcestershire, UK). The sample was prepared by re-dispersing the lyophilized nanoparticles in pure water as a dispersion medium. Measurements were repeated three times for each sample.
2.3 Encapsulation Efficiency (EE) assay
2mL of the liposome emulsion prepared in example 1 was taken and passed through a centrifugal filter (C)
Ultra-2 mL, MWCO 3K,4000g centrifuge,40 min). The filtrate was collected, and the absorbance was measured at 306nm using an ultraviolet visible spectrometer (VWR UV3100-PC), and the concentration of uncoated resveratrol was calculated from the calibration chart. The envelope efficiency EE was calculated according to the following formula and is listed in table 1.
Table 1: the average diameter, the polydispersity index, the Zeta potential and the encapsulation efficiency of the resveratrol nano liposome particles.
The stability analysis shows that the resveratrol nano-liposome particles prepared by the invention have good stability in the conventional environment and have no obvious change within 1 month. The encapsulation efficiency of resveratrol in nanoliposomes is very high (over 80%), indicating that it is preferentially partitioned into liposomes. The developed nanoparticles may be considered physically stable because the absolute value of the Zeta potential is about 26mV, so electrostatic repulsion between particles may avoid flocculation and aggregation of nanoparticles. Furthermore, the polydispersity index was 0.2, indicating that the dispersion profile is acceptable with low drift. The nanoparticles have an average diameter of 190nm and are suitable for oral administration and gastrointestinal absorption, and negatively charged nanoparticles can interact with intestinal cells and readily penetrate through intestinal barriers.
Example 3 the application of the composite nano-preparation in anti-aging and wrinkle-removing in the prior art is different from the nano-lipid particles as resveratrol carrier in the invention
The prior art provides an anti-aging wrinkle-removing compound nano preparation, a preparation method and application thereof (application number is 202010155534). the nano preparation contains hydroxypropyl tetrahydropyrane triol, retinol retinoic acid ester and soybean isoflavone as active ingredients, and shows obvious anti-aging and wrinkle-removing effects. The difference between the double-core nano preparation and the application thereof in the prior art and the nano lipid particles used as resveratrol carriers in the invention is as follows:
example 4A curcumin lipid carrier in the prior art is distinguished from the nano-lipid particles described in the present invention as resveratrol carriers
The prior art provides a curcumin lipid carrier and a preparation method thereof (application No. 200810155819), wherein the curcumin lipid carrier contains curcumin with a therapeutically effective dose; a lipid; proper amount of surfactant, cosurfactant and additive. The preparation has good effects of protecting neurons after cerebral ischemia reperfusion of experimental animals, maintaining the integrity of a blood brain barrier and preventing and treating cerebral edema after stroke. However, the differences between the curcumin lipid carrier and the nano lipid particles as resveratrol carriers in the invention are as follows:
example 5 in vitro Release study of Nanosomal particles
In vitro release experiments were performed using Simulated Gastric Fluid (SGF) and intestinal fluid (SIF) in a 37 ℃ water bath containing 0.5% Tween80 to increase water solubility. Nanoliposome particles containing 3mg resveratrol, pre-dispersed in 5ml of water, were added to a 10.000MWCO dialysis cartridge (Thermoscientific, Rockford, Ill., USA). The capsule was placed in a vessel containing 500ml of sgf (pH 1.2, 37 ℃) with magnetic stirring. After 2 hours in SGF, the cassette was placed in another container containing 500mL SIF (pH 6.8, 37 ℃). Samples were collected at predetermined times (10min,20min,30min,1h,2h, 3h,4h,6h,9h,12h,16h,24h) and filtered with a 0.45 μm membrane filter (Thermo, Chino, CA, USA) before quantification. The amount of resveratrol released from the formulation was quantified by HPLC. Calibration curves for free resveratrol were plotted in water containing 0.5% Tween80 at pH values of 1.2 and 6.8, in the range of 0.05-6. mu.g/ml. The results are shown in fig. 2, and fig. 2 shows the release of resveratrol from liposome nanoparticles, i.e. the cumulative percentage of drug released versus time. Within the first 2 hours, at SGF (PH 1.2), approximately 30% of the loaded resveratrol was released. Then, after 6 hours (at SIF), the release was more than 70% of the total resveratrol content. After 12 hours from the start of the experiment, almost all of the encapsulated resveratrol was released from the nanoparticles.
The results show that the resveratrol drug is still released from the nanoliposome particles in simulated intestinal fluid after culturing in SIF for 9 hours. Under the environment of in vitro simulated gastric juice and intestinal juice, the invention has sustained release effect on resveratrol, is beneficial to improving the bioavailability and is more convenient for oral administration.
The foregoing shows and describes the general principles, essential features, and advantages of the invention. It will be understood by those skilled in the art that the present invention is not limited to the embodiments described above, which are described in the specification and illustrated only to illustrate the principle of the present invention, but that various changes and modifications may be made therein without departing from the spirit and scope of the present invention, which fall within the scope of the invention as claimed. The scope of the invention is defined by the appended claims and equivalents thereof.
Claims (9)
1. A nano lipid particle carrier for delivering a resveratrol drug is characterized in that the nano lipid particle takes phospholipid as a lipid carrier and cholesterol as a stabilizer to encapsulate the resveratrol drug.
2. The nano lipid particle carrier for delivering the resveratrol drug according to claim 1, wherein the nano lipid particle carrier for delivering the resveratrol drug uses mannitol as a cryoprotectant.
3. The nano-lipid particle carrier for delivering resveratrol drugs according to claim 1, wherein the mass ratio of cholesterol and lecithin is in the range of about 1:1 to about 1: 10.
4. The nano-lipid particle carrier for delivering a resveratrol drug according to claim 1, wherein the encapsulated resveratrol drug to cholesterol mass ratio is in the range of about 1:2 to about 1:10, and the resveratrol drug to lecithin mass ratio is in the range of about 1:5 to about 1: 100.
5. The nano-lipid particle carrier for delivering resveratrol drugs according to claim 1, wherein the nano-lipid particle diameter is about 70 to about 500 nm.
6. The preparation method for preparing the nano lipid particle carrier for delivering the resveratrol drug in claim 1 comprises the following steps:
(1) dissolving lecithin and cholesterol in a mixed solution of chloroform and methanol to obtain a solution I; (2) dissolving resveratrol in methanol to obtain solution II;
(3) mixing solution I and solution II, and performing rotary evaporation on the obtained solution to remove the organic solvent to obtain a yellow film;
(4) adding water, rotating to precipitate lipid film to obtain liposome emulsion, cooling the emulsion, ultrasonic treating, and freeze drying to obtain nanometer lipid particles.
7. The method according to claim 6, wherein the mass ratio of lecithin to cholesterol in the step (1) is 10: 1, chloroform-methanol volume ratio 2: 1, when the resveratrol is dissolved in the methanol in the step (2), the mass ratio of the resveratrol to the methanol is 1: 3.
8. the process of claim 6, wherein the solvent is removed on a rotary evaporator at 51 ℃, 150rpm and 500mbar after mixing solution I and solution II in step (3).
9. The use of the nano-lipidic particles for delivering resveratrol drugs according to claim 1 for preparing resveratrol oral drugs.
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