CN113797177A - Quercetin oral sustained-release preparation modified by ionic emulsifier chitosan nanoparticles and preparation method thereof - Google Patents

Abstract

The invention relates to an ion emulsifier chitosan nanoparticle modified quercetin oral sustained-release preparation and a preparation method thereof, and specifically comprises the following steps: chitosan is used as a polymer nanoparticle carrier, and an anionic surfactant sodium dodecyl sulfate and chitosan with positive charges form a nano preparation wrapping quercetin by an ion crosslinking method, so that the solubility and the oral bioavailability of the quercetin in an aqueous solution are improved. In addition, the invention uses dextran-70 as a stabilizer to improve the stability of chitosan and sodium dodecyl sulfate anion-cation cross-linked encapsulated quercetin nanoparticles, and obtains a quercetin nanometer preparation with higher stability. The invention can improve the oral compliance of patients, and has small particle size, strong dispersibility and high stability, and simultaneously can enhance the solubility and stability of quercetin, prolong the action time of the drug effect, increase the activity of the drug, obviously improve the oral bioavailability, and the preparation process of the drug nano-particles is simple, the energy consumption is low, the toxicity is low and the safety is high.

Description

Quercetin oral sustained-release preparation modified by ionic emulsifier chitosan nanoparticles and preparation method thereof

Technical Field

The invention relates to a quercetin oral sustained-release preparation modified by an ionic emulsifier chitosan nanoparticle and a preparation method thereof, belonging to the technical field of quercetin nanometer oral sustained-release preparations.

Background

Quercetin is a natural polyhydroxy flavonoid compound, widely exists in melons, fruits, vegetables and various Chinese herbal medicines, has various biological activities and pharmacological actions such as anti-inflammation, anti-allergy, anti-free radical oxidation, anti-cancer, anti-HIV and the like, has the advantages of wide sources, low price, no toxic or side effect, high biocompatibility and the like, and can have great development value in clinical research and application. But the clinical application effect is not ideal due to the defects of low solubility, small internal activity, poor gastrointestinal absorption, low bioavailability and the like, thereby seriously limiting the application of the compound in the field of medicine. Therefore, a strategy for increasing the solubility and oral bioavailability of quercetin is urgently needed at present, so that the effective development and medical application values of quercetin resources are improved.

The nanometer technology is a very effective method for enhancing the solubility of the medicine and improving the curative effect, and compared with the traditional medicine, the nanometer preparation changes the pharmacokinetics, the tissue distribution and the internal pharmacological activity of the medicine by reducing the particle size, increasing the specific surface area, improving the solubility and the like so as to achieve the effects of reducing the adverse reaction and improving the medicine effect and the bioavailability. At present, researchers have conducted extensive research on quercetin nano-formulations, and have attempted to prepare various nano-formulations, such as quercetin nanocrystals, quercetin nanoliposomes, quercetin nanoemulsions, and the like. However, how to ensure the stability of the quercetin nanocrystals is still a difficult problem faced by researchers in the preparation process, and meanwhile, due to the defects of easy deterioration, poor stability, unsatisfactory controlled-release effect and the like of the quercetin nanoliposomes, the application of the quercetin nanocrystals in clinical practical treatment is limited. In addition, the quercetin nanoemulsion technology also has the defects of high pharmaceutical cost, short shelf life, influence on standard detection and the like.

The polymer nanoparticle drug carrying system is used for dissolving or dispersing drugs into nanoparticles, and the system is proved to be capable of improving drug solubility and biological activity by being used as a drug carrier at present, and has the advantages of stable drug carrying system, high drug encapsulation efficiency and the like. Among the drug carriers, polybutylcyanoacrylate and chitosan are attracting much attention due to their good biocompatibility and biodegradability, however, polybutylcyanoacrylate has the disadvantage of being expensive. Chitosan, as a natural polymer with biocompatibility and positive charge after ionization in solution, has good permeability and drug absorption enhancing performance, has been widely applied to form a carrier structure of a nano-composite, and can obviously improve the bioavailability of drugs, but chitosan is insoluble in water, and is difficult to form a stable nano-preparation by single use. Therefore, no report about preparing the polymer nano preparation for enhancing the oral bioavailability of the quercetin by a simple, safe and economic method is obtained so far.

Disclosure of Invention

Aiming at the defects in the prior art and the defects of the quercetin nanometer preparation in practical application, the invention provides the quercetin nanometer oral sustained-release preparation with the advantages of small particle size, strong dispersibility, good stability, slow drug release and the like, in order to solve the problem of low oral bioavailability of quercetin in practical application.

In order to solve the technical problems, the invention adopts the following technical scheme:

the polymer nanoparticle drug delivery system can effectively increase the solubility of quercetin in aqueous solution, and the sodium dodecyl sulfate used as a micelle initiator formed by polymerizing chitosan is an excellent anionic surfactant and can also enhance the solubility and gastrointestinal absorption penetrability of quercetin, thereby improving the solubility of quercetin in aqueous solution and increasing the oral bioavailability of quercetin. Meanwhile, dextran-70 is used as a stabilizer to improve the stability of the chitosan and sodium dodecyl sulfate anion-cation cross-linked coated quercetin nanoparticles, and finally the ionic emulsifier chitosan nanoparticle modified quercetin nano preparation with higher stability is obtained.

The preparation method of the ionic emulsifier chitosan nanoparticle modified quercetin oral sustained-release preparation provided by the invention comprises the following steps:

step one, weighing 0.3-0.6 g of chitosan, dissolving the chitosan in 40 ml of glacial acetic acid (0.8-1.1%) aqueous solution, stirring at a magnetic stirring speed of 800-1000 r/min at room temperature overnight, and filtering with a 0.45 micron filter membrane.

And step two, after filtering, adding 0.04-0.10 g of quercetin, carrying out ultrasonic treatment to fully dissolve the quercetin, and adjusting the pH of the solution to be slightly neutral (6.6-6.9) by using sodium hydroxide to obtain a mixed solution.

And step three, slowly dripping 40 ml of ultrapure water solution containing 0.3-0.6 g of emulsifier sodium dodecyl sulfate into the mixed solution prepared in the step two at the magnetic stirring speed of 900-1100 r/min, and maintaining the stirring speed for 1.5-2.5 hours at room temperature to preliminarily obtain the quercetin chitosan-loaded nano suspension.

And step four, slowly and dropwise adding the aqueous solution containing 20 milliliters of water of 0.8 to 1.1 grams of dextran-70 into the solution prepared in the step three, and stirring and reacting for 0.5 to 1 hour at 900 to 1100r/min to obtain the polymer-coated quercetin nanometer preparation with higher stability.

The encapsulation rate of the quercetin nano preparation obtained by the preparation method of the ionic emulsifier chitosan nano particle modified quercetin oral sustained-release preparation is 71.97-75.83%.

Due to the adoption of the technical scheme, the invention has the technical progress that:

the quercetin nano oral sustained-release preparation is in the form of milky white suspension or white freeze-dried powder, is spherical or ellipsoidal, has the particle size of less than 200 nanometers, has the dispersion index of 0.128-0.213 in ultrapure water and the electromotive force of-45.012-30.102 millivolts; the ionic emulsifier chitosan nanoparticle modified quercetin nanometer preparation has the nanoparticle encapsulation rate of 71.97-75.83%, can slowly release the drug for 72 hours, and has the advantages of small particle size, strong dispersibility, good stability and the like. The chitosan has good permeability enhancing performance, positive charges ionized from the chitosan in the solution interact with the anionic surfactant lauryl sodium sulfate through the charges of an ion crosslinking method to form a nanometer preparation capable of wrapping the quercetin, and the lauryl sodium sulfate can enhance the solubility of an active compound and the gastrointestinal absorption penetrability, so that the solubility of the quercetin in an aqueous solution and the bioavailability of oral absorption are improved. The dextran-70 is used as a stabilizer to improve the stability of the quercetin nanoparticles wrapped by chitosan and sodium dodecyl sulfate in an anion-cation crosslinking manner, so that the pharmacodynamic action time of the preparation is prolonged, the pharmacodynamic action is increased, and the bioavailability is increased.

The preparation method of the quercetin nano oral sustained-release preparation provided by the invention has the advantages of simple preparation process, low cost, low requirement on preparation conditions, no generation of any toxic and harmful substances in the preparation process, contribution to industrialization, satisfaction of clinical application and very high application prospect.

Drawings

Fig. 1 is a flow chart of the preparation process of the quercetin nanometer oral sustained-release preparation.

FIG. 2 is a transmission electron microscope image of a quercetin nano oral sustained release preparation according to the present invention;

FIG. 3 is a Zeta potential diagram of a quercetin oral nano-formulation of sustained release formulation according to the present invention;

FIG. 4 is a UV scanning spectrum of a quercetin nano oral sustained release preparation according to the present invention;

FIG. 5 is a graph showing the in vitro release of a quercetin nano oral sustained release preparation according to the present invention;

FIG. 6 is a graph of the in vivo oral blood concentration-time curve (bioavailability) of a quercetin nano oral sustained release preparation according to the present invention;

Detailed Description

The present invention will be described in detail with reference to examples.

Example 1

Preparation method of ionic emulsifier chitosan nanoparticle modified quercetin oral sustained-release preparation

The preparation method comprises the following steps:

step one, 0.6 g of chitosan is weighed and dissolved in 40 ml of glacial acetic acid (1.1%) water solution, and the mixture is stirred at room temperature at a magnetic stirring speed of 1000r/min overnight and then filtered by a 0.45 micron filter membrane.

And step two, after filtering, adding 0.04 g of quercetin, carrying out ultrasonic treatment to fully dissolve the quercetin, and adjusting the pH of the solution to 6.9 by using sodium hydroxide to obtain a mixed solution.

And step three, slowly dripping 40 ml of ultrapure water solution containing 0.6 g of emulsifier sodium dodecyl sulfate into the mixed solution prepared in the step two at the magnetic stirring speed of 1100r/min, and maintaining the stirring speed for 2.5 hours at room temperature to preliminarily obtain the quercetin chitosan-loaded nano suspension.

And step four, slowly dropwise adding the aqueous solution containing 20 milliliters of water of 1.1 gram of dextran-70 into the solution prepared in the step three, stirring at 1100r/min for reaction for 1 hour, and then obtaining the chitosan-coated quercetin nanometer preparation with higher stability.

The preparation flow chart of the ionic emulsifier chitosan nanoparticle modified quercetin oral sustained-release preparation and the preparation method thereof is shown in fig. 1, and as shown in fig. 1, the preparation process is simple, easy to operate, green, low in energy consumption, and the used raw materials are economical and easy to obtain, so that the preparation process is easy to industrialize.

The observation result of the transmission electron microscope microscopic observation of the ionic emulsifier chitosan nanoparticle modified quercetin oral sustained-release preparation of the embodiment is shown in fig. 2, and fig. 2 is a transmission electron microscope image of the ionic emulsifier chitosan nanoparticle modified quercetin oral sustained-release preparation of the invention, which shows that the ionic emulsifier chitosan nanoparticle modified quercetin oral sustained-release preparation nanoparticle is spherical, and the particle size of the nanoparticle is 188.73 +/-5.26 nanometers. The encapsulation efficiency of QE was 75.83% as determined by high performance liquid chromatography.

The Zeta potential distribution of the ionic emulsifier chitosan nanoparticle modified quercetin oral sustained-release preparation described in this example was measured by a Zeta potential analyzer, and the result is shown in fig. 3. Fig. 3 shows that 0.04 g of quercetin was fully dissolved in 100 ml of glacial acetic acid aqueous solution to obtain a solution, a blank nanoparticle solution prepared in the same preparation process as in this example without adding quercetin and an ionic emulsifier chitosan nanoparticle modified quercetin oral sustained release preparation solution prepared in this example were diluted ten times in three parts of samples, and 1 ml of the sample was respectively absorbed and injected into a sample cell of a Zeta potential analyzer for measurement. From the results, the Zeta potential of the quercetin oral sustained-release preparation modified by the ionic emulsifier chitosan nanoparticles prepared in the embodiment is about +36 mv, and the quercetin oral sustained-release preparation has good stability. The Zeta potential of the quercetin oral sustained-release preparation modified by the ionic emulsifier chitosan nanoparticles prepared by the embodiment is a positive value, so that the quercetin oral sustained-release preparation is easy to combine with intestinal cells with negative charges, the affinity of the nanoparticles and the intestinal cells is increased, and the preparation is easy to permeate the intestinal cells to enhance the oral absorption capacity.

The ionic emulsifier chitosan nanoparticle modified quercetin oral sustained-release preparation described in this example was subjected to a spectral measurement with an ultraviolet-visible light photometric analyzer, and the result is shown in fig. 4. Fig. 4 is a result of a spectrum measurement performed on three samples of a solution obtained by sufficiently dissolving 0.04 g of quercetin in 100 ml of a glacial acetic acid aqueous solution, a blank nanoparticle solution prepared in the same preparation process as in this example but without adding quercetin to the raw materials, and a quercetin oral sustained-release preparation solution modified with chitosan nanoparticles as an ionic emulsifier prepared in this example. The maximum absorption wavelength λ of quercetin is known_max374nm, the results of the uv scanning spectra of the three samples therefore show that: the ionic emulsifier chitosan nanoparticle modified quercetin oral sustained-release preparation prepared by the embodiment can effectively wrap quercetin, and the solubility and the oral bioavailability of the quercetin can be increased.

In this example, the measurement of the in vitro release condition of the obtained quercetin oral sustained-release preparation modified by the ionic emulsifier chitosan nanoparticle is as follows: taking Phosphate Buffer Solution (PBS) with the pH value of 7.4 as a release medium, accurately weighing 4 mg of quercetin reference substance solution, uniformly mixing with 20 ml of the release medium, uniformly mixing quercetin nano-preparation suspension with the release medium, then transferring the quercetin nano-preparation suspension with the total volume of 20 ml into a dialysis bag soaked by distilled water, fastening two ends of the dialysis bag, binding the dialysis bag on the pulp, respectively placing the dialysis bag into dissolution triangular flasks containing 250 ml of the release medium, and shaking at a constant speed in a constant-temperature (37 ℃) shaking table (120 r/min). Respectively sampling 2 ml of sample at set time, storing in a refrigerator at-4 deg.C, supplementing 2 ml of release medium solution after each sampling, centrifuging the sample at-4 deg.C for 15 min at 10000r/min by a high-speed low-temperature centrifuge, filtering 1 ml of supernatant with a 0.45-micron microporous membrane, measuring quercetin content in the sample at different time points by high performance liquid chromatography, sampling 20 microliters each time, measuring the peak area of quercetin, and calculating the concentration of quercetin according to a standard curve regression equation to obtain the percentage of accumulative released quercetin and drawing a drug release curve, wherein the experimental result is shown in figure 5, and the result analysis finds that the ionic emulsifier chitosan nanoparticles can slowly control the release of quercetin, and the release time is as long as 3 days, thereby effectively proving that the quercetin modified by the ionic emulsifier chitosan nanoparticles has the sustained and controlled release effect.

This example describes the measurement of the oral blood concentration-time curve (bioavailability) of an ionic emulsifier chitosan nanoparticle modified quercetin oral sustained-release preparation: adult healthy SD male rats 12 were prepared and divided into two groups on average: in both groups A and B, after fasting for 12 hours, blood was collected from the retro-orbital sinus as a blank control sample, and then, 1 ml of the drug solution was administered per 100 g of the weight of the rat to irrigate 12 rats. Wherein, group A is given 0.04 g quercetin fully dissolved in 100 ml glacial acetic acid (0.1%) aqueous solution, group B is given quercetin nanometer oral sustained release preparation solution prepared in this example, the gavage time is respectively recorded, 2 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, 14 hours, 16 hours, 18 hours, 20 hours, 22 hours and 24 hours after the gavage of two groups of rats, 0.5 ml blood is taken from retroorbital sinus of the rats and placed in a 5 ml anticoagulant-containing vacuum blood collection tube, then 3 ml formaldehyde is added to precipitate blood protein component, the mixture is swirled for 10 minutes, centrifuged for 10 minutes at 1000r/min, supernatant is filtered by a 0.45 micron filter membrane, 20 microliter of filtrate is precisely sucked by high performance liquid chromatography, and the concentration of quercetin in the filtrate is measured. And drawing blood concentration-time curves of the quercetin and the quercetin nano-preparation as shown in fig. 6, the result shows that the plasma peak concentration of the quercetin oral sustained-release preparation solution modified by the ionic emulsifier chitosan nano-particles is higher than the plasma peak concentration of the quercetin solution and the peak reaching time is prolonged, and meanwhile, the area under the blood concentration-time curve of the quercetin oral sustained-release preparation modified by the ionic emulsifier chitosan nano-particles is obviously larger than the area under the curve of the quercetin. The result proves that the ionic emulsifier chitosan nanoparticle modified quercetin oral sustained-release preparation can obviously improve the bioavailability of quercetin and can achieve the purpose of slowly and continuously orally taking the medicine for absorption.

Example 2

Preparation method of ionic emulsifier chitosan nanoparticle modified quercetin oral sustained-release preparation

The preparation method comprises the following steps:

step one, 0.3 g of chitosan is weighed and dissolved in 40 ml of glacial acetic acid (0.8%) water solution, and the mixture is stirred at the magnetic stirring speed of 800r/min at room temperature overnight and then filtered by a 0.45 micron filter membrane.

And step two, after filtering, adding 0.10 g of quercetin, carrying out ultrasonic treatment to fully dissolve the quercetin, and adjusting the pH of the solution to 6.6 by using sodium hydroxide to obtain a mixed solution.

And step three, slowly dripping 40 ml of ultrapure water solution containing 0.3 g of emulsifier sodium dodecyl sulfate into the mixed solution prepared in the step two at the magnetic stirring speed of 900r/min, and maintaining the stirring speed for 1.5 hours at room temperature to preliminarily obtain the quercetin chitosan-loaded nano suspension.

And step four, slowly dropwise adding the aqueous solution containing 20 milliliters of water of 0.8 gram of dextran-70 into the solution prepared in the step three, and stirring at 900r/min for reaction for 0.5 hour to obtain the chitosan-coated quercetin nanometer preparation with higher stability.

The particle size of the quercetin oral sustained-release preparation nanoparticles modified by the ionic emulsifier chitosan nanoparticles prepared in the embodiment is 162.31 +/-5.48 nanometers, the encapsulation rate is 71.97%, and the preparation flow chart, the transmission electron microscope chart, the Zeta potential chart, the ultraviolet scanning spectrogram, the in vitro release chart and the oral blood concentration-time curve (bioavailability) chart are similar to those in theembodiment 1.

Example 3

Preparation method of ionic emulsifier chitosan nanoparticle modified quercetin oral sustained-release preparation

The preparation method comprises the following steps:

step one, 0.4 g of chitosan is weighed and dissolved in 40 ml of glacial acetic acid (0.9%) water solution, and the mixture is stirred at the magnetic stirring speed of 900r/min at room temperature overnight and then filtered by a 0.45 micron filter membrane.

And step two, after filtering, adding 0.08 g of quercetin, carrying out ultrasonic treatment to fully dissolve the quercetin, and adjusting the pH of the solution to 6.7 by using sodium hydroxide to obtain a mixed solution.

And step three, slowly dripping 40 ml of ultrapure water solution containing 0.4 g of emulsifier sodium dodecyl sulfate into the mixed solution prepared in the step two at the magnetic stirring speed of 900r/min, and maintaining the stirring speed for 1.5 hours at room temperature to preliminarily obtain the quercetin chitosan-loaded nano suspension.

And step four, slowly dropwise adding the aqueous solution containing 20 milliliters of water of 0.9 gram of dextran-70 into the solution prepared in the step three, and stirring and reacting for 0.5 hour at 1000r/min to obtain the chitosan-coated quercetin nanometer preparation with higher stability.

The particle size of the ionic emulsifier chitosan nanoparticle modified quercetin oral sustained-release preparation nanoparticle prepared in the embodiment is 172.56 +/-4.83 nanometers, the encapsulation rate is 73.57%, and the preparation flow chart, the transmission electron microscope chart, the Zeta potential chart, the ultraviolet scanning spectrogram, the in vitro release chart and the oral blood concentration-time curve (bioavailability) chart are similar to those in theembodiment 1.

Example 4

Preparation method of ionic emulsifier chitosan nanoparticle modified quercetin oral sustained-release preparation

The preparation method comprises the following steps:

step one, 0.5 g of chitosan is weighed and dissolved in 40 ml of glacial acetic acid (1.0%) water solution, and the mixture is stirred at the magnetic stirring speed of 900r/min at room temperature overnight and then filtered by a 0.45 micron filter membrane.

And step two, after filtering, adding 0.06 g of quercetin, carrying out ultrasonic treatment to fully dissolve the quercetin, and adjusting the pH of the solution to 6.8 by using sodium hydroxide to obtain a mixed solution.

And step three, slowly dripping 40 ml of ultrapure water solution containing 0.5 g of emulsifier sodium dodecyl sulfate into the mixed solution prepared in the step two at the magnetic stirring speed of 900r/min, and maintaining the stirring speed for 2 hours at room temperature to preliminarily obtain the quercetin chitosan-loaded nano suspension.

And step four, slowly dropwise adding the aqueous solution containing 20 milliliters of water of 0.10 gram of dextran-70 into the solution prepared in the step three, stirring at 1000r/min for reaction for 1 hour, and then obtaining the chitosan-coated quercetin nanometer preparation with higher stability.

The particle size of the ionic emulsifier chitosan nanoparticle modified quercetin oral sustained-release preparation nanoparticle prepared in the embodiment is 179.62 +/-4.67 nanometers, the encapsulation rate is 74.92%, and the preparation flow chart, the transmission electron microscope chart, the Zeta potential chart, the ultraviolet scanning spectrogram, the in vitro release chart and the oral blood concentration-time curve (bioavailability) chart are similar to those in theembodiment 1.

Example 5

Preparation method of ionic emulsifier chitosan nanoparticle modified quercetin oral sustained-release preparation

The preparation method comprises the following steps:

step one, 0.5 g of chitosan is weighed and dissolved in 40 ml of glacial acetic acid (1.0%) water solution, and the mixture is stirred at the magnetic stirring speed of 800r/min at room temperature overnight and then filtered by a 0.45 micron filter membrane.

And step two, after filtering, adding 0.08 g of quercetin, carrying out ultrasonic treatment to fully dissolve the quercetin, and adjusting the pH of the solution to 6.7 by using sodium hydroxide to obtain a mixed solution.

And step three, slowly dripping 40 ml of ultrapure water solution containing 0.4 g of emulsifier sodium dodecyl sulfate into the mixed solution prepared in the step two at the magnetic stirring speed of 900r/min, and maintaining the stirring speed for 2 hours at room temperature to preliminarily obtain the quercetin chitosan-loaded nano suspension.

And step four, slowly dropwise adding the aqueous solution containing 20 milliliters of water of 0.9 gram of dextran-70 into the solution prepared in the step three, stirring at 1100r/min for reaction for 0.5 hour, and then obtaining the chitosan-coated quercetin nanometer preparation with higher stability.

The particle size of the ionic emulsifier chitosan nanoparticle modified quercetin oral sustained-release preparation nanoparticles prepared in the embodiment is 171.83 +/-5.82 nanometers, the encapsulation rate is 74.11%, and the preparation flow chart, the transmission electron microscope chart, the Zeta potential chart, the ultraviolet scanning spectrogram, the in vitro release chart and the oral blood concentration-time curve (bioavailability) chart are similar to those in theembodiment 1.

The foregoing is a detailed description of the invention with reference to specific embodiments, and the practice of the invention is not to be construed as limited thereto. Various modifications and changes may be made by those skilled in the art without departing from the spirit and scope of the invention, and any such modifications, equivalents, improvements, etc. are intended to be included within the scope of the invention.

Claims (8)

1. A preparation method of an ionic emulsifier chitosan nanoparticle modified quercetin oral sustained-release preparation is characterized by comprising the following steps: chitosan is used as a polymer nanoparticle carrier, anionic surfactant sodium dodecyl sulfate and chitosan with positive charges form a nanometer preparation capable of wrapping quercetin through charge interaction particles by an ion crosslinking method, and dextran-70 is used as a stabilizer to improve the stability of chitosan and sodium dodecyl sulfate anion-cation crosslinking wrapped quercetin nanoparticles.

2. The method for preparing the quercetin oral sustained-release preparation modified by the ionic emulsifier chitosan nanoparticles according to claim 1, wherein the preparation method comprises the following steps:

step one, weighing chitosan, dissolving the chitosan in glacial acetic acid water solution, magnetically stirring the chitosan at room temperature overnight, and filtering the mixture by using a filter membrane.

And step two, after filtering, adding quercetin, carrying out ultrasonic treatment to fully dissolve the quercetin, and adjusting the pH of the solution to be slightly neutral by using sodium hydroxide to obtain a mixed solution.

And step three, slowly dripping the ultrapure water solution containing the emulsifier sodium dodecyl sulfate into the mixed solution prepared in the step two under the magnetic stirring, and preliminarily obtaining the quercetin chitosan-loaded nano suspension after maintaining the stirring speed for a certain time at room temperature.

And step four, slowly dropwise adding the aqueous solution of the dextran-70 into the solution prepared in the step three, and magnetically stirring to react for a certain time to obtain the chitosan-coated quercetin nanoparticles with higher stability.

3. The oral administration sustained-release preparation of quercetin as claimed in claim 2, wherein the amount of chitosan in step one is 0.3-0.6 g, the amount of glacial acetic acid aqueous solution is 40 ml, the content of glacial acetic acid is 0.8-1.1%, the magnetic stirring rate is 800-1000 r/min, and the pore size of the filter membrane is 0.45 μm.

4. The oral sustained-release quercetin preparation according to claim 2, wherein the amount of quercetin in step two is 0.04-0.10 g, and the pH of the solution is 6.6-6.9 after adjusting the pH of the solution to be slightly neutral with sodium hydroxide.

5. The oral administration sustained-release preparation of quercetin as claimed in claim 2, wherein the ionic emulsifier chitosan nanoparticle modified quercetin solution is prepared by the steps of adding 0.3-0.6 g sodium dodecyl sulfate into 40 ml ultrapure water solution, stirring with magnetic force at 900-1100 r/min for 1.5-2.5 hr.

6. The oral sustained release formulation of claim 2, wherein the aqueous solution of dextran-70 in step four is 20 ml aqueous solution containing 0.8-1.1 g dextran-70, the magnetic stirring rate is 900-1100 r/min, and the stirring time is maintained at the magnetic stirring rate for 0.5-1 hr.

7. An oral sustained-release formulation of quercetin modified with chitosan nanoparticles as an ionic emulsifier, characterized by comprising a drug and a nanoformulation component comprising an oral sustained-release formulation of quercetin modified with chitosan nanoparticles as an ionic emulsifier according to any one of claims 1 to 8.

8. The use of an ionic emulsifier chitosan nanoparticle modified quercetin sustained release formulation according to any one of claims 1 to 8 for improving the oral bioavailability of quercetin.

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