CN110339170B - Resveratrol nano composite powder and preparation method thereof - Google Patents

Resveratrol nano composite powder and preparation method thereof Download PDF

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CN110339170B
CN110339170B CN201810285983.6A CN201810285983A CN110339170B CN 110339170 B CN110339170 B CN 110339170B CN 201810285983 A CN201810285983 A CN 201810285983A CN 110339170 B CN110339170 B CN 110339170B
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陈建峰
周警键
乐园
张志兵
王洁欣
唐辉
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Abstract

The invention discloses resveratrol nano composite powder and a preparation method thereof, wherein the nano composite powder consists of resveratrol, a surfactant, a polymer and an additive, wherein the resveratrol accounts for 40-60% of the total weight of the composite powder, the surfactant accounts for 10-20% of the total weight of the composite powder, the polymer accounts for 10-30% of the total weight of the composite powder, and the additive accounts for 10-30% of the total weight of the composite powder. The effective content of the active component resveratrol in the nano composite powder reaches 40-60%, the particle size is less than 200nm after the resveratrol is redispersed in water, and the particle size distribution dispersity index is less than 0.3; the resveratrol solubility of the nano composite powder reaches 82-98 percent after the nano composite powder is dissolved in the artificial intestinal juice for 30min, the inoxidizability is improved by nearly 10 percent compared with that of the raw material medicine, the bioavailability of the resveratrol is greatly improved, and the preparation method does not use organic solvents.

Description

Resveratrol nano composite powder and preparation method thereof
Technical Field
The invention relates to the technical field of medicines, in particular to resveratrol nano composite powder and a preparation method thereof.
Background
Resveratrol is a natural polyphenol substance with strong biological property, and mainly comes from plants such as grapes and giant knotweed. Its chemical name is 3,4 ', 5-trihydroxystilbene (3, 4', 5-trihydroxystilbene), and has both cis and trans conformations, and its molecular formula can be represented as C14H12O3The relative molecular weight is 228.25, the crystal particles are colorless and can be melted at 256-257 ℃ under normal pressure, and can be sublimated at 261 ℃, and the crystal particles are lipophilic and hydrophobic substances, and the dissolving capacity of the crystal particles in the following solvents is from strong to weak in sequence: acetone, ethanol, methanol, ethyl acetate, hexyl ether, chloroform.
Most polyphenols have antioxidant properties, and resveratrol is no exception. It can not only inhibit the oxidation of low density lipoprotein of human body, but also inhibit the peroxidation of membrane lipid, and reduce H: o: the product has antioxidant and free radical scavenging effects, and can be used for preventing Parkinson disease, Alzheimer disease, and viral hepatitis. Resveratrol also has the pathological effects of protecting cardiovascular system, regulating blood lipid metabolism, and inhibiting liver cirrhosis. In addition, resveratrol has anticancer effect, and can effectively inhibit cancer cell proliferation by acting on cytochrome P450. It is a new green anticancer drug following paclitaxel, and its therapeutic effect is published in the international top-grade journals such as Nature, Science, etc.
Resveratrol is poorly soluble in water, which means that the solubility of drug molecules in the aqueous phase of intestinal fluids is very low, resulting in only a small number of drug molecules being transported through the gastrointestinal tract, into the blood and finally to the organs and cells in the body to act. In other words, the low solubility of resveratrol in water greatly limits its bioavailability. Therefore, improving the solubility and dissolution rate of the poorly soluble drugs is the key to improving the bioavailability of the active ingredients. Rapid dissolution of the particles may be promoted due to the increased specific surface area and high wettability resulting from the reduced particle size of the particles. The increase in solubility can be explained by the Ostwald-Freundlich equation:
Figure BDA0001616003920000011
wherein S is1And S2Respectively, radius is r1And r2The solubility of the drug particles of (1) is surface tension, M is molecular weight, R is gas constant, ρ is solid density, and T is absolute temperature. It can be seen that the solubility of drug particles increases with decreasing particle radius, with other factors being constant.
The increase in dissolution rate can be explained by the Noyes-Whitney formula:
Figure BDA0001616003920000021
wherein dc/dt is the dissolution rate of the drug particles, D is the diffusion coefficient, A is the specific surface area of the particles, CSIs the saturation solubility of the drug, CXThe drug concentration, h is the diffusion distance.
For a spherical particle, the specific surface area is calculated as follows:
Figure BDA0001616003920000022
wherein A is the specific surface area of the particles, d is the diameter of the spherical particles, and ρ is the solid density. As the diameter of the drug particles decreases, their specific surface area a increases and their saturation solubility increases, thus increasing the dissolution rate of the drug particles.
Chinese patent CN105126116 discloses a resveratrol nanoparticle, which is obtained by cross-linking reaction of polyethylene glycol monomethyl ether derivative, resveratrol derivative and dithiol monomer. The nano-particle size is within 200nm, and the water solubility is improved. However, the process is complex, the used organic solvent tetrahydrofuran is volatile and can threaten human health, and the auxiliary materials are high in price and are not easy to produce in a large scale and control cost.
Chinese patent CN104688715A discloses a resveratrol solid lipid nanoparticle and a preparation method thereof, and the resveratrol solid lipid nanoparticle prepared by the method has small particle size and high drug loading. However, the process requires a large amount of organic solvent.
Chinese patent CN101214225A discloses a preparation method of resveratrol nanoemulsion anticancer drug, the particle size of the nanoemulsion is within 100 nanometers, and the mobility of the nanoemulsion is good. However, creamy products are not conducive to storage and transportation.
Chinese patent CN102451179 discloses a resveratrol nano-dispersion and a preparation method thereof, wherein the preparation method is a solvent anti-solvent recrystallization method. The method selects inflammable and volatile absolute ethyl alcohol as a solvent, has high requirements on the safety and the sealing property of production equipment in the industrial amplification process, and has larger consumption of auxiliary materials, so that the content of the medicine in the nano dispersion is lower.
Chinese patent CN107029248 discloses a resveratrol solid dispersion and a method for increasing the solubility of resveratrol in red wine, wherein the solubility of resveratrol in red wine is increased to 240mg/100g in an amount of 200-. However, the method prepares the resveratrol solid dispersoid by drying the absolute ethyl alcohol, and the mass preparation is not easy.
Chinese patent CN102614127A discloses a resveratrol nano-dispersion and a preparation method thereof, the nano-dispersion prepared by the method comprises 1-20% of resveratrol as an active ingredient, 40-80% of auxiliary material and 5-40% of additive. Dispersing the nano dispersion into cold water can form transparent liquid, wherein the particle size of the resveratrol is less than 150 nm. Dissolving resveratrol in an organic solvent which can be mutually dissolved with water, dissolving a certain amount of auxiliary materials and additives in water, adding the resveratrol solution into the aqueous solution of the auxiliary materials and the additives to prepare a transparent mixed solution, and performing spray drying on the transparent mixed solution to obtain the nano-dispersion. The disadvantage of this dispersion is that: the active component resveratrol is only 1-20% in mass, and the viscosity of the nano dispersion is high, so that the powder flowability is poor.
Disclosure of Invention
The invention aims to solve the first technical problem of providing resveratrol nano composite powder. The weight of the active component resveratrol in the nano composite powder reaches 40-60%, the particle size is less than 200nm after the resveratrol is redispersed in water, and the particle size distribution dispersity index is less than 0.3; the resveratrol solubility of the nano composite powder reaches 82-98 percent after the nano composite powder is dissolved in the artificial intestinal juice for 30min, the inoxidizability is improved by nearly 10 percent compared with that of the raw material medicine, and the bioavailability of the resveratrol is greatly improved.
The second technical problem to be solved by the invention is to provide a preparation method of resveratrol nano-composite powder. The composite powder prepared by the method has the resveratrol mass of 40-60%, the particle size of less than 200nm and the particle size distribution dispersity index of less than 0.3.
In order to solve the first technical problem, the invention adopts the following technical scheme:
a resveratrol nano composite powder comprises resveratrol 40-60 wt%, surfactant 10-20 wt%, polymer 10-30 wt%, and additive 10-30 wt%.
As a further improvement of the technical scheme, the surfactant comprises one or more of beta-cyclodextrin, sodium dodecyl sulfate, water-soluble vitamins, poloxamer 188, poloxamer 407 and hydroxypropyl-beta-cyclodextrin.
As a further improvement of the technical scheme, the polymer comprises one or more of polyethylene glycol 4000, polyvinylpyrrolidone, polyethylene oxide, polyacrylamide, polysorbate-80, polysorbate 60 and polyoxyethylene sorbitan monolaurate.
As a further improvement of the technical scheme, the additive comprises one or more of mannitol, lactose, dextrin, modified starch, maltitol, xylitol, glucose and sucrose.
In order to solve the second technical problem, the invention adopts the following technical scheme:
a preparation method of the resveratrol nano-composite powder comprises the following steps:
s1, dissolving resveratrol in 0.1-1.0mol/L alkali solution, mixing thoroughly to dissolve it, preparing transparent resveratrol alkali solution of 5-15mg/mL at 10-40 deg.C, filtering with filter membrane to remove insoluble impurities;
s2, adding 0.1-1.0mol/L acid solution into the resveratrol alkali solution, mixing vigorously for reaction, keeping the temperature at 10-40 ℃, and precipitating resveratrol to form suspension;
s3, filtering the suspension under reduced pressure, and washing with deionized water for 2-3 times to obtain a filter cake;
s4, dispersing the filter cake in deionized water, adding a surfactant, a polymer and an additive in a prescribed amount, and then performing ultrasonic dispersion, high-speed stirring, high-speed grinding or high-pressure homogenization to uniformly disperse the mixture to obtain a nano suspension;
s5, spray drying the nanometer suspension to obtain resveratrol nanometer composite powder.
As a further improvement of the technical solution, in step S1, the alkali solution includes one or more of a potassium hydroxide solution, a barium hydroxide solution, a sodium bicarbonate solution, a sodium carbonate solution, a potassium carbonate solution, and a sodium bicarbonate solution.
As a further improvement of the technical scheme, the molar mass ratio of the effective components in the alkali solution and the acid solution is 1:1-1: 3.
Preferably, in step S2, the mixing reaction is performed under high-speed stirring, magnetic stirring or super-gravity mixing conditions.
The resveratrol nano-composite powder prepared by the invention is applied to preparing a medicinal preparation, wherein the medicinal preparation comprises capsules, tablets or oral liquid.
The resveratrol nano-composite powder prepared by the invention can be dispersed in deionized water to form stable and transparent dispersion liquid.
Any range recited herein is intended to include the endpoints and any number between the endpoints and any subrange subsumed therein or defined therein.
The starting materials of the present invention are commercially available, unless otherwise specified, and the equipment used in the present invention may be any equipment conventionally used in the art or may be any equipment known in the art.
Compared with the prior art, the invention has the following beneficial effects:
1) the mass of the resveratrol serving as an active ingredient in the resveratrol nano composite powder reaches 40-60 percent;
2) the grain diameter is less than 200nm, and the grain diameter distribution dispersity index is less than 0.3;
3) the nano composite powder can not be agglomerated;
4) the alcohol dissolution degree of the resveratrol reaches 82-98 percent after the nano composite powder is dissolved in the artificial intestinal juice for 30min, the inoxidizability is improved by nearly 10 percent compared with that of the raw material medicine, and the bioavailability of the resveratrol is greatly improved;
5) the preparation process is simple and feasible, the concentration of the acid-base solution used in the preparation process is low, the toxicity is low, and salts generated by neutralization are easy to dissolve in water and remove; organic solvents are not required; the dosage of the auxiliary materials is low, and the medicine content in the nano composite powder is higher; the preparation process can be continuous, the cost is low, and the large-scale industrial production is easy to realize.
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The following detailed description of embodiments of the invention is provided in connection with the accompanying drawings
FIG. 1 shows cis and trans isomers of resveratrol according to the invention;
FIG. 2 is a scanning electron micrograph of resveratrol nanosuspension prepared in example 4 of the invention
FIG. 3 is the dissolution curve of resveratrol composite powder prepared in examples 1-5 of the invention in artificial intestinal juice;
fig. 4 is a free radical scavenging curve of resveratrol composite powder and bulk drug prepared in example 4 of the invention;
fig. 5 is a graph showing the relationship between the drug concentration of resveratrol and the cell survival rate obtained in example 4 of the present invention.
Detailed Description
In order to more clearly illustrate the invention, the invention is further described below in connection with preferred embodiments. It is to be understood by persons skilled in the art that the following detailed description is illustrative and not restrictive, and is not to be taken as limiting the scope of the invention.
In order to solve the first technical problem, the invention adopts the following technical scheme:
a resveratrol nano composite powder comprises resveratrol 40-60 wt%, surfactant 10-20 wt%, polymer 10-30 wt%, and additive 10-30 wt%.
The resveratrol nano composite powder prepared by the invention has the active component resveratrol with the mass of 40-60%, the grain diameter of less than 200nm and the grain diameter distribution dispersity index of less than 0.3; the nano composite powder can not be agglomerated, the resveratrol solubility of the nano composite powder can reach 82-98 percent after the nano composite powder is dissolved in the artificial intestinal juice for 30min, the inoxidizability is improved by nearly 10 percent compared with that of the raw material medicine, and the bioavailability of the resveratrol is greatly improved.
In certain embodiments of the invention, the surfactant comprises one or more of beta-cyclodextrin, sodium lauryl sulfate, a water-soluble vitamin, poloxamer 188, poloxamer 407, and hydroxypropyl-beta-cyclodextrin. The surfactant has the functions of avoiding the agglomeration of drug particles and maintaining the stability of the dispersion liquid.
In certain embodiments of the invention, the polymer comprises one or more of polyethylene glycol 4000, polyvinylpyrrolidone, polyethylene oxide, polyacrylamide, polysorbate-80, polysorbate 60, polyoxyethylene sorbitan monolaurate. The polymer serves to avoid agglomeration of the drug particles.
In certain embodiments of the invention, the additive comprises one or more of mannitol, lactose, dextrin, modified starch, maltitol, xylitol, glucose, sucrose. The function of the additive is to enhance the water redispersibility of the dried powder.
The invention relates to a preparation method of resveratrol nano composite powder, which comprises the following steps:
s1, dissolving resveratrol in 0.1-1.0mol/L alkali solution, mixing thoroughly to dissolve it, preparing transparent resveratrol alkali solution of 5-15mg/mL at 10-40 deg.C, filtering with filter membrane to remove insoluble impurities;
s2, adding 0.1-1.0mol/L acid solution into the resveratrol alkali solution, mixing vigorously for reaction, keeping the temperature at 10-40 ℃, and precipitating resveratrol to form suspension;
s3, filtering the suspension under reduced pressure, and washing with deionized water for 2-3 times to obtain a filter cake;
s4, dispersing the filter cake in deionized water, adding a surfactant, a polymer and an additive in a prescribed amount, and then performing ultrasonic dispersion, high-speed stirring, high-speed grinding or high-pressure homogenization to uniformly disperse the mixture to obtain a nano suspension;
s5, spray drying the nanometer suspension to obtain resveratrol nanometer composite powder.
The preparation method of the resveratrol nano-composite powder does not use an organic solvent.
According to the preparation method of the resveratrol nano-composite powder, in the reaction crystallization process, crystal nuclei can be quickly formed by controlling the acid-base ratio, the crystallization temperature, the drug concentration, the acid-base solution concentration and the like, and the crystal growth is inhibited, so that resveratrol nano-particles with small particle size and uniform distribution are obtained; secondly, the resveratrol particles are reacted by adding proper auxiliary materials, so that the purposes of improving the particle solubility and inhibiting particle agglomeration are achieved; moreover, the spray drying technology is adopted, the drying speed is high, the drying strength is high, the heating time is short, the spray drying technology is suitable for thermosensitive substances, the agglomeration of medicine particles can be avoided while the spray drying technology is adopted, the product quality is high, the continuous operation can be realized, and the requirements of industrial large-scale production can be met. The dissolution rate and dissolution rate of the finally obtained nano composite powder in water are far higher than those of the bulk drugs, the oxidation resistance is enhanced, and the bioavailability of the resveratrol is greatly improved.
In certain embodiments of the present invention, in step S1, the alkaline solution includes one or more of a potassium hydroxide solution, a barium hydroxide solution, a sodium bicarbonate solution, a sodium carbonate solution, a potassium carbonate solution, and a sodium bicarbonate solution.
In certain preferred embodiments of the present invention, in step S1, the concentration of the basic solution is 0.1-0.9mol/L, or 0.1-0.8mol/L, or 0.1-0.7mol/L, or 0.1-0.6mol/L, or 0.1-0.5mol/L, or 0.1-0.4mol/L, or 0.1-0.3mol/L, or 0.1-0.2mol/L, or 0.3-1.0mol/L, or 0.3-0.9mol/L, or 0.3-0.8mol/L, or 0.3-0.7mol/L, or 0.3-0.6mol/L, or 0.3-0.5mol/L, or 0.3-0.4mol/L, or 0.5-1.0mol/L, or 0.5-0.9mol/L, or 0.5-0.5 mol/L, or 0.5-0.5 mol/, Or 0.7-1.0mol/L, or 0.7-0.9mol/L, or 0.7-0.8 mol/L.
In certain preferred embodiments of the present invention, the molar mass ratio of the effective components in the alkali solution and the acid solution is 1:1 to 1: 3.
In certain preferred embodiments of the present invention, in step S2, the mixing reaction is performed under high speed stirring, magnetic stirring or super-gravity mixing conditions.
In some embodiments of the invention, the resveratrol nano-composite powder prepared by the invention is applied to preparation of a pharmaceutical preparation, wherein the pharmaceutical preparation comprises capsules, tablets or oral liquid.
In certain embodiments of the invention, the resveratrol nano-composite powder prepared by the invention can be dispersed in deionized water to form stable and transparent dispersion liquid.
Example 1
The preparation of resveratrol nano suspension comprises the following steps:
1) dissolving resveratrol in 1.0mol/L potassium hydroxide solution to obtain 15mg/mL transparent resveratrol alkali solution, stirring with magnetic stirrer to dissolve completely, filtering with filter membrane to remove insoluble impurities, and keeping temperature at 10 deg.C;
2) preparing 0.3mol/L sulfuric acid solution, controlling the acid-base molar ratio at 3:1 at the same temperature, adding a certain amount of acid solution into the resveratrol-base solution, stirring by using a magnetic stirrer, neutralizing with acid and base, and separating out resveratrol to form suspension;
3) filtering the suspension under reduced pressure, and washing with deionized water for 2-3 times to obtain a filter cake;
4) redispersing the filter cake in water, and adding the auxiliary materials according to the mass ratio of tween-80/beta-cyclodextrin/trehalose/resveratrol of 0.1/0.1/0.3/1; and carrying out ultrasonic dispersion to obtain a nanometer suspension.
Example 2
The preparation of resveratrol nano suspension comprises the following steps:
1) dissolving resveratrol in 0.5mol/L barium hydroxide solution to obtain 13mg/mL transparent resveratrol alkali solution, stirring with magnetic stirrer to dissolve completely, filtering with filter membrane to remove insoluble impurities, and keeping temperature at 20 deg.C;
2) preparing 0.5mol/L nitric acid solution, controlling the acid-base molar ratio at 2:1 at the same temperature, adding a quantitative acid solution into the resveratrol base solution, stirring by using a high-speed stirrer, wherein the rotating speed of a stirring paddle is 7000rpm, neutralizing the acid and the base, and separating out the resveratrol to form suspension;
3) filtering the suspension under reduced pressure, and washing with deionized water for 2-3 times to obtain a filter cake;
4) redispersing the filter cake in water, and adding the auxiliary materials according to the mass ratio of polyacrylamide/lauryl sodium sulfate/cane sugar/resveratrol of 0.2/0.1/0.2/1; stirring at high speed to disperse uniformly to obtain nanometer suspension.
Example 3
The preparation of resveratrol nano suspension comprises the following steps:
1) dissolving resveratrol in 0.3mol/L sodium bicarbonate solution to obtain 11mg/mL transparent resveratrol alkali solution, stirring with magnetic stirrer to dissolve completely, filtering with filter membrane to remove insoluble impurities at 30 deg.C;
2) preparing 0.7mol/L acetic acid solution, controlling the acid-base molar ratio at 1:1 at the same temperature, adding a quantitative acid solution into the resveratrol base solution, stirring by using a high-speed stirrer, wherein the rotating speed of a stirring paddle is 7000rpm, neutralizing the acid and the base, and separating out the resveratrol to form suspension;
3) filtering the suspension under reduced pressure, and washing with deionized water for 2-3 times to obtain a filter cake;
4) dispersing the filter cake in water, and adding the auxiliary materials according to the mass ratio of PEG-4000/hypromellose/lactose/resveratrol of 0.2/0.2/0.3/1; homogenizing under high pressure, and dispersing to obtain nanometer suspension.
Example 4
The preparation of resveratrol nano suspension comprises the following steps:
1) dissolving resveratrol in 0.1mol/L sodium hydroxide solution to obtain 9mg/mL transparent resveratrol alkali solution, stirring with magnetic stirrer to dissolve completely, filtering with filter membrane to remove insoluble impurities, and keeping temperature at 20 deg.C;
2) preparing 0.1mol/L hydrochloric acid solution, controlling the acid-base molar ratio at 1.5:1 at the same temperature, fully mixing a quantitative acid solution and a resveratrol alkali solution in a supergravity filled reactor, neutralizing the acid and the base, and separating out resveratrol to form suspension;
3) filtering the suspension under reduced pressure, and washing with deionized water for 2-3 times to obtain a filter cake;
4) redispersing the filter cake in water, and adding the auxiliary materials according to the mass ratio of polyvinylpyrrolidone K-30/poloxamer 188/mannitol/resveratrol of 0.1/0.1/0.5/1; and (4) carrying out high-speed grinding at the rotor rotating speed of 3000rpm to uniformly disperse the nano suspension to obtain the nano suspension.
Example 5
The preparation of resveratrol nano suspension comprises the following steps:
1) dissolving resveratrol in 0.7mol/L sodium carbonate solution to obtain 7mg/mL transparent resveratrol alkali solution, stirring with magnetic stirrer to dissolve completely, filtering with filter membrane to remove insoluble impurities, and keeping temperature at 20 deg.C;
2) preparing 1.0mol/L phosphoric acid solution, controlling the acid-base molar ratio at 2.5:1 at the same temperature, fully mixing a quantitative acid solution and a resveratrol base solution in a supergravity filled reactor, neutralizing the acid and the base, and separating out resveratrol to form suspension;
3) filtering the suspension under reduced pressure, and washing with deionized water for 2-3 times to obtain a filter cake;
4) redispersing the filter cake in water, and adding the auxiliary materials according to the mass ratio of tween-20/corn starch/glucose/resveratrol of 0.3/0.2/0.7/1; stirring at high speed to disperse uniformly to obtain nanometer suspension.
Comparative example 1
Resveratrol, polyvinylpyrrolidone K-30, poloxamer 188 and mannitol in the same amount as in example 4 were prepared according to the method of the example in the application document disclosed in Chinese patent CN102614127A,
1) weighing 2g of resveratrol raw material medicine, and dissolving the resveratrol raw material medicine in 60ml of absolute ethyl alcohol at room temperature to prepare resveratrol solution;
2) weighing 0.2g of polyvinylpyrrolidone K-30, 0.2g of poloxamer 188 and 1.0g of mannitol, and dissolving in 1000ml of deionized water at room temperature to obtain an auxiliary material aqueous solution; adding the resveratrol solution into the adjuvant water solution, stirring with a magnetic stirrer, and making colorless transparent mixture after two minutes.
Example 6
The particle size of the resveratrol nanosuspensions obtained in examples 1 to 5 and the mixed solution of comparative example 1 was measured, and the results are shown in Table 1 below
TABLE 1
Figure BDA0001616003920000091
As can be seen from the data in Table 1, the resveratrol nanosuspension prepared by the method can effectively reduce the particle size of resveratrol particles from micron level to nanometer level, greatly increase the specific surface area of the particles and control the particle size distribution of the particles in a smaller range; this will improve the dissolution rate of resveratrol in water to a great extent and improve its bioavailability. FIG. 2 is a SEM photograph of example 4.
Example 7
The method for preparing the resveratrol nano composite powder from the resveratrol nano suspension obtained in the embodiment 1-embodiment 5 comprises the following steps:
spray drying the resveratrol nano suspension, wherein the operation parameters are as follows: the air inlet temperature is 120 ℃, the air outlet temperature is 60 ℃, and the feeding flow rate is 20.0ml/min, so as to obtain the final resveratrol nano-composite powder.
Example 8 dissolution testing method of resveratrol composite powder
Figure BDA0001616003920000092
Figure BDA0001616003920000101
Dissolution testing method: a D-800 intelligent medicinal dissolution instrument is used, a II-type stirring paddle is selected, and the rotating speed is adjusted to be 100 rpm. Artificial intestinal juice (phosphate buffer) with pH of 6.8 was selected as dissolution medium, and the water bath temperature was 37 ℃. After the water bath temperature is raised to the set temperature, keeping the temperature constant and stable for two hours, putting the powder into a dissolution cup and starting timing, respectively sampling at 5min,10min,20min,30min,40min,50min,60min and 90min, and obtaining the dissolution percentage of the resveratrol at different moments by measuring the ultraviolet absorption value, wherein the result is shown in figure 3. As can be seen from the figure, the dissolution rate of the nano-composite powder obtained in example 4 can reach more than 98% within 5min, which is greatly improved compared with the bulk drug. The dissolution rates of the powders obtained in the other examples were also improved to a different extent than those of the bulk drugs.
Example 9 Oxidation resistance test of resveratrol nanocomposite powder
The oxidation resistance test method comprises the following steps: 4mg of DPPH reagent is accurately weighed and dissolved in 50mL of absolute ethyl alcohol to prepare a DPPH solution with the concentration of 0.08mg/mL, and the DPPH solution is put into a refrigerator for standby. Dissolving a certain amount of the resveratrol nano-composite powder prepared in the example 4 in an ethanol solution to prepare a drug sample solution with the resveratrol concentration of 1 mg/mL. A. the0Measurement of the value: adding 2mL of DPPH solution into a glass bottle, adding 1mL of anhydrous ethanol, mixing thoroughly, and performing ultraviolet spectrophotometry after 20minThe absorbance at 517nm is measured by a meter, namely the DPPH absorbance A without sample loading0。ArMeasurement of the value: respectively placing 20,40,60,120,180,240,300,400,500uL of sample liquid in a glass bottle, diluting to 3mL with anhydrous ethanol, mixing thoroughly, measuring the absorption value at 517nm after 20min, that is, the blank light absorption value A of the sampler。AsMeasurement of the value: respectively placing 20,40,60,120,180,240,300,400 and 500uL of sample liquid in a glass bottle, metering to 1mL with absolute ethyl alcohol, adding 2mLDPPH solution, mixing thoroughly, measuring the absorption value at the wavelength of 517nm after 20min, namely the blank light absorption value A of the samples. The oxidation resistance of the resveratrol can be quantitatively reflected by the numerical value of the free radical clearance rate Y, and the calculation formula is as follows:
Figure BDA0001616003920000102
the results are shown in FIG. 4. As can be seen from the figure, the radical clearance rate increases with increasing drug concentration. In the same treatment time, the radical clearance of the nano composite powder prepared in the example 4 is obviously higher than that of the bulk drug, which shows that the oxidation resistance and the biological activity of the nano composite powder are better than those of the bulk drug.
Example 10 cytotoxicity test of resveratrol nanocomposite powder
HepG2 cells were seeded in DMEM medium (Gibco) containing 10% newborn bovine serum at 37 ℃ with 5% CO2Subculturing under saturated humidity condition, taking cells in logarithmic growth phase for experiment, adjusting cell concentration to 4 × 104Perml, seeded in 96-well plates (200 uL/well) at 37 ℃ in 5% CO2Culturing for 24h in an incubator until the cells adhere to the wall; removing the original culture solution, adding culture medium containing resveratrol composite powder prepared in example 4 with different concentrations to treat cells, wherein each 3 holes are a small group; the plates were incubated at 37 ℃ in 5% CO2Conventionally culturing for 72h in a cell culture box; 4h before termination of the experiment, 20uL of 5mg/mL MTT solution was added to each well, the incubation was terminated, and the culture supernatant was carefully aspirated off the wells, 150uL DMSO was added to each well, and the mixture was shaken at room temperature for 10 min. Assay of wells on an enzyme-linked immunosorbent assayThe absorbance value (chosen wavelength 490nm) and the cell viability were calculated according to the following formula: cell survival rate (%) ═ asample/Acontrol) × 100% wherein A issampleAnd AcontrolRefer to the absorbance of the sample well and the blank control (with PBS added), respectively.
The results are shown in FIG. 5. The figure is a relation graph of the drug concentration and the cell survival rate of the bulk drug and the resveratrol nano-composite powder prepared in example 4. As can be seen in the figure, the survival rate of the liver cancer cells is reduced along with the increase of the concentration of the drug, and the resveratrol nano-composite powder prepared by the invention is superior to the bulk drug in terms of drug effect, and has more remarkable effect of inhibiting the proliferation of the liver cancer cells.
Example 11 preparation of resveratrol nanocomposite capsules
Adding a certain amount of flow aid and disintegrant into resveratrol nano composite powder, sterilizing the resveratrol composite powder, and granulating the resveratrol composite powder by a dry granulation method, wherein the working parameters are as follows: the minimum pinch roller interval, the rotating speed of feeding equipment is 10r/min, the rotating speed of the pinch rollers is 2r/min, the mesh diameter of a screen is 20 meshes, the granulation frequency is 1-5 times, the flowability of the resveratrol drug particles after granulation is good, and the resveratrol drug particles are filled into capsules by a capsule filling machine to obtain the resveratrol nano composite capsules. And packaging the resveratrol nano-composite capsule into a capsule tablet by using a capsule packaging machine. And (4) putting the packaged capsule tablets into a paper box, and storing in dark.
Example 12 preparation of resveratrol nanocomposite tablets
Sterilizing the resveratrol composite powder. And tabletting by adopting a single-punch tablet machine, strictly weighing the mass of each tablet, and pressing one by one. The specific method comprises the following steps: the resveratrol composite powder and other auxiliary materials are weighed according to a formulated formula, and the total weight of the resveratrol composite powder and the auxiliary materials is 10 times of the mass of a single chip. And (3) sieving the mixed powder by a 100-mesh sieve for 3 times to fully mix the powder. Accurately weighing the mixed powder with the mass required by the single tablet, and packaging for later use. And tabletting the mixed powder by using a single-punch tablet machine to obtain the resveratrol composite tablet. And (3) filling the resveratrol composite tablet, labeling, inspecting and packaging.
Example 13 preparation of resveratrol NanoKol solution
Dissolving the prepared resveratrol composite powder in 1000 parts of purified water according to 50 parts by weight, adding 50 parts of white granulated sugar, 10 parts of honey and 2 parts of edible pectin according to a certain proportion, uniformly mixing, filtering by using a 200-mesh sieve to obtain oral liquid, and sequentially sterilizing, filling, capping, sealing, performing light inspection, packaging and eliminating defective products to obtain a finished product of the oral liquid.
It should be understood that the above-described embodiments of the present invention are merely examples for clearly illustrating the present invention, and are not intended to limit the embodiments of the present invention. Other variations and modifications will be apparent to persons skilled in the art in light of the above description. Not all embodiments are exhaustive. All obvious changes and modifications which are obvious to the technical scheme of the invention are covered by the protection scope of the invention.

Claims (7)

1. A preparation method of resveratrol nano composite powder is characterized in that the resveratrol nano composite powder consists of resveratrol, a surfactant, a polymer and an additive, wherein the resveratrol accounts for 40-60% of the total weight of the composite powder, the surfactant accounts for 10-20% of the total weight of the composite powder, the polymer accounts for 10-30% of the total weight of the composite powder, and the additive accounts for 10-30% of the total weight of the composite powder;
the preparation method comprises the following steps:
s1, dissolving resveratrol in 0.1-1.0mol/L alkali solution, mixing thoroughly to dissolve it, preparing transparent resveratrol alkali solution of 5-15mg/mL at 10-40 deg.C, filtering with filter membrane to remove insoluble impurities;
s2, adding 0.1-1.0mol/L acid solution into the resveratrol alkali solution, mixing vigorously for reaction, keeping the temperature at 10-40 ℃, and precipitating resveratrol to form suspension;
s3, filtering the suspension under reduced pressure, and washing with deionized water for 2-3 times to obtain a filter cake;
s4, dispersing the filter cake in deionized water, adding a surfactant, a polymer and an additive in a prescribed amount, and then performing ultrasonic dispersion, high-speed stirring, high-speed grinding or high-pressure homogenization to uniformly disperse the mixture to obtain a nano suspension;
s5, spray drying the nanometer suspension to obtain resveratrol nanometer composite powder.
2. The method for preparing resveratrol nano-composite powder according to claim 1, which is characterized in that: in step S1, the alkali solution includes one or more of a potassium hydroxide solution, a barium hydroxide solution, a sodium bicarbonate solution, a sodium carbonate solution, a potassium carbonate solution, and a sodium bicarbonate solution.
3. The method for preparing resveratrol nano-composite powder according to claim 1, which is characterized in that: the molar ratio of the effective components in the alkali solution and the acid solution is 1:1-1: 3.
4. The method for preparing resveratrol nano-composite powder according to claim 1, which is characterized in that: in step S2, the mixing reaction is performed under high-speed stirring, magnetic stirring or high-gravity mixing conditions.
5. The method for preparing resveratrol nano-composite powder according to claim 1, which is characterized in that: in step S4, the surfactant is selected from one or more of beta-cyclodextrin, sodium lauryl sulfate, water-soluble vitamins, poloxamer 188, poloxamer 407, and hydroxypropyl-beta-cyclodextrin.
6. The method for preparing resveratrol nano-composite powder according to claim 1, which is characterized in that: in step S4, the polymer is selected from one or more of polyethylene glycol 4000, polyvinylpyrrolidone, polyethylene oxide, polyacrylamide, polysorbate-80, polysorbate 60, and polyoxyethylene sorbitan monolaurate.
7. The method for preparing resveratrol nano-composite powder according to claim 1, which is characterized in that: in step S4, the additive is one or more selected from mannitol, lactose, dextrin, modified starch, maltitol, xylitol, glucose, and sucrose.
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