CN112315913A - Preparation method of selenium nano double-emulsion micro-preparation - Google Patents
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Abstract
The invention discloses a preparation method of a selenium nano double-emulsified micro-preparation with gastrointestinal tract slow release, nutrition supplement and cancer cell inhibition functions, which comprises the following steps: 1) preparing a W1 phase of the chitosan-selenium nano preparation by taking chitosan as a template; 2) adding the chitosan-selenium nano preparation W1 obtained in the step (1) into an O-phase container containing soybean oil-vitamin E, and carrying out high-pressure homogenization to form a W1/O colostrum-like liquid; 3) and (3) adjusting the pH of the W1/O colostrum-like liquid prepared in the step (2), and adding the adjusted pH into a W2 composite solution of a polysaccharide-whey protein stock solution to prepare a double-emulsion liquid. The invention adopts double emulsification technology to prepare a double emulsification oral delivery system with a core-shell structure. The selenium nano double-emulsion micro-preparation prepared by the method can effectively induce the apoptosis of HepG2 in vitro and inhibit the growth of tumors in vivo.
Description
Technical Field
The invention relates to a preparation method of a selenium nano double-emulsified micro-preparation with functions of slow release, nutrition supplement and cancer cell inhibition, and release control of the micro-preparation in gastrointestinal tract liquid and evaluation of cancer cell inhibition effect of the micro-preparation.
Background
Selenium (Selenium) is a trace nutrient element essential to human body, and has antioxidant, anticancer, and antibacterial effects. Most areas in China are in a selenium-deficient state, and because the effective dose and the toxic dose range of selenium are narrow, the surface modification of the selenium is a method commonly adopted at present by the micro-nano technology. The traditional nano selenium particles without surface modification have poor stability, and the controllability of the dosage and the release property of the nano selenium particles is influenced.
At present, the stability, the oxidation resistance and the like of the selenium nano preparation which is modified by a surface modifier are obviously improved. The chitosan-selenium nanometer preparation has special size and structure, can be effectively enriched at a tumor position in the systemic circulation process, simultaneously maintains the slow release of the medicine, reduces the toxic effect and the like, and is widely applied to the fields of nutrition and medicine at present. However, when applied to an oral preparation, the chitosan-selenium nanoparticles need to pass through the processes of oral cavity, esophagus, gastrointestinal tract and the like, and cannot realize accurate control of the positioned absorption and release of the digestive tract, and even have potential toxic effects.
Disclosure of Invention
Aiming at the problems that the chitosan-selenium preparation is applied to an oral delivery system for absorption and the release property cannot be accurately controlled, the whey protein with a natural cavity structure is compounded with food-grade Arabic gum with electronegativity, and the stability and the accurate release characteristic of a double-emulsion micro-nano capsule system with an Arabic gum-whey protein compound as a wall material and a chitosan-selenium nano preparation as a water-phase inner core are researched through simulation of in-vivo gastrointestinal fluid conditions; at the same time, the in vivo and in vitro antitumor properties of the chitosan-selenium system were evaluated.
The specific technical scheme of the invention is as follows:
a method for preparing a selenium nanometer double-emulsifying micro-preparation with gastrointestinal slow release, nutrition supplement and cancer cell inhibiting functions comprises the following steps:
(1) dissolving chitosan in acetic acid water solution, adding certain volume of selenious acid solution, and stirring and mixing for a period of time under continuous magnetic force.
(2) A certain volume of aqueous solution of Vc is slowly added into the mixture obtained in the step (1), and the mixture is continuously stirred, so that a W1 phase is obtained.
(3) Preparing corresponding stock solutions of Arabic gum and whey protein respectively, standing overnight, mixing the polysaccharide and the whey protein isolate stock solutions according to a certain volume ratio, and stirring by a constant light magnetic force to obtain a W2 phase.
(4) Mixing soybean oil, VE and PGPR in a certain proportion to prepare a mixed oil phase system required by a double-emulsification system.
(5) Slowly adding the chitosan-selenium nano preparation prepared in the step (2) into the mixed oil phase system prepared in the step (4) which is shearing at a high speed by adopting a high-speed shearing dispersion instrument, and carrying out high-pressure homogenization by adopting a high-pressure homogenizer to form primary emulsion of W1/O.
(6) Taking a certain mass of W1/O colostrum-like liquid prepared in the step (5), adjusting the pH value, and slowly adding the colostrum-like liquid into the polysaccharide-whey protein composite solution prepared in the step (3) which is subjected to high-speed shearing to prepare double-emulsion liquid.
(7) And (4) homogenizing the double emulsion prepared in the step (6) under high pressure to finally form the selenium micro-nano double-emulsion preparation with uniform W1/O/W2 particle size.
Wherein:
in the step (1), the molecular weight of the chitosan is 10 k-1000 k Da, the deacetylation degree is 60-99%, and the concentration of the chitosan is 0.1-10% (w/w); the proportion of the acetic acid aqueous solution is 0.01-5% (v glacial acetic acid \ v ultrapure water), the concentration of the selenious acid is 0.1-50 mM, the adding volume is 1-50 mL, and the stirring time is 0-48 h.
In the step (2), the concentration of the Vc aqueous solution is 0.1-80 mM, the volume of the Vc aqueous solution is 1-50 mL, the stirring time is 0-48 h, and the obtained chitosan-selenium nano system is stored at 4 ℃ before the subsequent steps are carried out.
In the step (3), the whey protein is whey protein isolate, the protein content is 97% (w/w), the concentration of the whey protein stock solution is 5-30% (w/w), and the prepared stock solution is allowed to stand overnight at 4 ℃. The concentration of the acacia gum stock solution is 0.5-5% (w/w). The ratio (p/w) of polysaccharide to whey protein is 0.01-0.2, and the pH of the solution is 6-8.
In the step (4), the volume fractions of the soybean oil, the VE and the PGPR are respectively 50-80%, 5-40% and 2-20%.
In the step (5), the high-speed shearing parameter is 5000-20000 rpm, and the time is 5-30 min. The high-pressure homogenizing parameter is 100-1000 bar, and the homogenizing time is 1-10 min.
In the step (6), the weight of the W1/O colostrum-like liquid is 1-10 g, and the pH value is adjusted to 6-8. The mass of the polysaccharide-whey protein mixed liquid is 60-100 g, the shearing parameter is 5000-25000 rpm, and the shearing time is 5-30 min.
In the step (7), the homogenizing condition is 50-250 bar, and the homogenizing time is 1-20 min.
The invention has the beneficial effects that: the invention adopts double emulsification technology to prepare a double emulsification oral delivery system with a core-shell structure. The chitosan-selenium nano system is used as an inner core, the soybean oil-vitamin E is used as an outer layer to coat the periphery of the inner core, the inner core is protected and modified, the absorption position of the inner core can be effectively controlled, and the absorption dose can be determined. In addition, the added vitamin E can enrich the nutritional effect of the preparation. Finally, whey protein-Arabic gum is used as an outermost layer inclusion material, so that the stability of the system is improved, spray drying treatment can be performed, the storage is facilitated, and the oral liquid can be used for oral administration. The selenium nano double-emulsifying micro-preparation prepared by the method can effectively induce the apoptosis of HepG2 in vitro and inhibit the dosage of tumor growth in vivo, and meanwhile, the selenium nano double-emulsifying micro-preparation can not cause the pathological changes of organs such as heart, liver, spleen, lung, kidney and the like in the in vivo process and has negligible side effect.
Preparation and basic characteristics of selenium micro-nano double-emulsion preparation
Particle size and potential of selenium micro-nano double-emulsion preparation
TABLE 1 particle size distribution and potential of Chitosan-selenium Nano-formulations and double emulsion formulations
The invention relates to a selenium micro-nano double-emulsion preparation for determining the sustained-release property of gastrointestinal fluid,
1. the vitamin E release rate of the selenium micro-nano double-emulsion preparation for gastric and small intestinal juice is simulated, and the vitamin E release rate is shown in figure 1.
2. The selenium release rate of the micro-nano double-emulsion preparation of selenium in gastric and small intestinal juice is simulated, and the figure 2 shows.
The selenium micro-nano preparation inhibits HepG2 cell activity in vivo and in vitro.
HepG2 cell activity assay, see figure 3.
2. Tumor volumes of HepG2 tumor-bearing mice at different dosing concentrations varied with time, see fig. 4.
Evaluation of side effects by H & E staining, see FIG. 5.
Drawings
Fig. 1 is a vitamin E release rate chart of a simulated gastric and small intestinal fluid selenium micro-nano double-emulsion preparation.
Fig. 2 is a selenium release rate chart of a simulated gastric and small intestinal fluid selenium micro-nano double-emulsion preparation.
FIG. 3 is a diagram showing the activity assay of HepG2 cells
FIG. 4 is a graph of tumor volume versus time for HepG2 tumor-bearing mice at various dosing concentrations.
FIG. 5 is a graph showing evaluation of side effects by the H & E staining method.
Fig. 6 is a flow chart of a preparation method of the selenium nano double-emulsified micro-preparation of the present invention.
Detailed Description
A method for preparing a selenium nanometer double-emulsification micro-preparation with slow release property, nutrition supplement and cancer cell inhibition function comprises the following steps:
1) preparing a W1 phase of the chitosan-selenium nano preparation by taking chitosan as a template;
2) adding the chitosan-selenium nano preparation W1 obtained in the step (1) into an O-phase container containing soybean oil-vitamin E, and carrying out high-pressure homogenization to form a W1/O colostrum-like liquid;
3) and (3) adjusting the pH of the W1/O colostrum-like liquid prepared in the step (2), and adding the adjusted pH into a W2 composite solution of a polysaccharide-whey protein stock solution to prepare a W1/O/W2 double emulsion.
Example 1 preparation of chitosan-selenium (W1 phase) according to the invention
In-situ reduction of H by Vc2SeO3Dissolving 0.01-10 g of chitosan gum in 50mL of ultrapure water, stirring by a magnetic stirrer at the rotating speed of 100-1000 r/min for 0-48 h, slowly adding 1-50 mL of 0.1-50 mM/L selenious acid solution, reacting for 1h, adding 1-50 mL of 1-100 mmol/L Vc solution, and fully stirring until the solution becomes bright orange-red. And then, the orange red solution is subjected to constant volume of 100-500 mL, is continuously and fully stirred for 1-36 h, and is stored in a refrigerator at the temperature of-20-10 ℃.
Example 2 preparation of selenium micro-nano double emulsion formulation of the invention
1. Preparing a whey protein stock solution with the concentration of 1-30% (w/w): the whey protein powder was dissolved in water, magnetically stirred at room temperature for 2 hours, and then allowed to stand overnight at 4 ℃ to ensure complete dissolution and hydration. The next day, the mixture was allowed to equilibrate to room temperature and heated in a water bath at 80 ℃ for 30min to fully denature the mixture. Preparing 0.5-5% (w/w) acacia gum solution. The concentrations of the prepared whey protein isolate and pectin stock solution are respectively 10% and 2%.
2. Preparation of polysaccharide-protein mixed system: mixing polysaccharide and whey protein isolate solution according to a certain volume ratio and continuously stirring by a gentle magnetic force, wherein the whey protein isolate concentration in a final mixing system is fixed at the mixing mass ratio of Arabic gum to whey protein.
Preparation of W1\ O phase emulsion: in the first step, 10-50 mL of the chitosan-selenium nano preparation prepared in the first example is slowly added into the mixed oil phase undergoing high-speed shearing by using a high-speed shearing disperser. Wherein the volume fraction of the soybean oil is 50-80%, the vitamin E5-40%, the PGPR 2-20%, and the shearing parameter is 5000-20000 rpm for 5-30 min. And homogenizing the mixed emulsion by a high-pressure homogenizer to form a primary emulsion (W1/O phase), wherein the homogenization parameter is 100-1000 bar and is 1-10 min.
4, preparation of W1\ O \ W2 double-emulsified micro-nano preparation: and secondly, taking 1-10 g of W1\ O colostrum-like liquid, adjusting the pH value to 6-8, and slowly adding the mixture into 60-100 g of Arabic gum-whey protein complex solution (W2 phase) which is subjected to high-speed shearing, wherein the shearing parameter is 5000-25000 rpm and the time is 5-30 min. The obtained double emulsion is homogenized by a high-pressure homogenizer to form W1\ O \ W2 double-emulsified microcapsules. The homogenizing condition is 50-250 bar and 1-20 min.
Example 3: the selenium micro-nano double-emulsion preparation of the invention has the characteristic of gastric and small intestinal juice release properties
1. Selenium micro-nano double-emulsion preparation physical and chemical property determination
The Particle size and potential of the double emulsion formulations were determined by dynamic light scattering using a Delsa Nano Particle Analyzer (CA53878Beckman Coulter Inc, USA). The test temperature was 25 ℃ and the measurement was repeated at least 3 times per sample.
2. Release characteristics of selenium micro-nano double-emulsion preparation in stomach and intestinal juice
Gastric juice system was prepared by adjusting the solution to pH1.2 with HCl and NaOH solutions while adding 0.1% (w/v) pepsin.
The intestinal juice system was prepared using phosphate buffered saline containing 1% (w/v) of pancreatic digestive enzymes.
The system is 100mL, wherein the double emulsion preparation comprises digestive tract liquid which is 1: and (3) continuously oscillating the mixture for 6 hours at 37 ℃ under the condition of a constant temperature oscillator, sampling 1mL of the mixture every 1 hour, and determining the content of the selenium element by adopting ICP-MS (inductively coupled plasma-mass spectrometry).
Example 4 evaluation of the efficacy of the chitosan-selenium nano-preparation of the invention in inhibiting the tumor growth of HepG2 tumor-bearing mice
Balb/c nude mice 18 days change in body weight
Using 15 balb/c nude mice, injecting 5X 10 subcutaneous injection into right shoulder 6500 mu L of mLHepG2 cell sap, and the size of the tumor to be detected is 75-150 mm3In time, intratumoral injection is used for administration.
Of (2) cells
2. Change in tumor volume
The digital vernier caliper is adopted, measurement is carried out once every 2 days, the same position needs to be measured in each measurement, and the tightness of the caliper is the same. The tumor volume was determined by the formula:
tumor volume
Wherein l is the major diameter of the tumor, and w is the major diameter of the tumor.
3. Evaluation of side effects-H & E staining of Heart, liver, spleen, Lung, Kidney
Paraffin is adopted for fixing, slicing (the thickness is 2-4 mu m), and then microscopic examination is carried out after a series of staining.
The above embodiments describe the technical solutions of the present invention in detail. It will be clear that the invention is not limited to the described embodiments. Based on the embodiments of the present invention, those skilled in the art can make various changes, but any changes equivalent or similar to the present invention are within the protection scope of the present invention.
Claims (7)
1. A preparation method of a selenium nano double-emulsified micro preparation with gastrointestinal tract slow release, nutrition supplement and cancer cell inhibition functions is characterized by comprising the following steps:
1) preparing a W1 phase of the chitosan-selenium nano preparation by taking chitosan as a template;
2) adding the chitosan-selenium nano preparation W1 obtained in the step (1) into an O-phase container containing soybean oil-vitamin E, and carrying out high-pressure homogenization to form a W1/O colostrum-like liquid;
3) and (3) adjusting the pH of the W1/O colostrum-like liquid prepared in the step (2), and adding the adjusted pH into a W2 composite solution of a polysaccharide-whey protein stock solution to prepare a double-emulsion liquid.
2. The method according to claim 1, wherein the chitosan is dissolved in the aqueous solution of acetic acid in step 1), the selenious acid solution is added, and the aqueous solution of vitamin c is added; the molecular weight of the chitosan is 3 k-1000 k Da, the deacetylation degree is 60-99%, and the concentration of the chitosan is 0.1-10% (w/w); the volume fraction of the acetic acid is 0.01-1%, and the proportion of the acetic acid aqueous solution is 0.01-5% of v glacial acetic acid \ v ultrapure water; the concentration of the selenious acid solution is 0.1-50 mM, the concentration of the Vc aqueous solution is 0.1-80 mM, and the stirring time is 0-48 h; the ratio of the selenious acid to the vitamin C is 1: 1-1: 5; the formulated W1 phase was stored at 4 ℃.
3. The method according to claim 1, wherein in the step 2), the volume fractions of the soybean oil, VE and PGPR in the O phase are 50% to 80%, 5% to 40% and 2% to 20%, respectively, the O phase is stirred at a high speed by the O compatilizer, the shearing parameter is 5000 to 20000rpm, and the time is 5 to 30 min; the high-pressure homogenization parameter is 100-1000 bar, and the homogenization time is 1-10 min.
4. The method according to claim 1, wherein in the step 3), the whey protein is whey protein isolate, the protein content is 97% (w/w), the concentration of the whey protein stock solution is 5-30% (w/w), and the prepared stock solution is left to stand at 4 ℃ overnight; the polysaccharide stock solution is gum arabic stock solution, the concentration of the gum arabic stock solution is 0.5% -5% (w/w), and the ratio (p/w) of gum arabic to whey protein is 0.01-0.2; the mass of the W1/O primary emulsion is 1-10 g, and the pH value is adjusted to 6-8; the mass of the polysaccharide-whey protein mixed solution is 60-100 g, the composite solution is stirred at a high speed, the shearing parameter is 5000-25000 rpm, and the shearing time is 5-30 min.
5. The method of claim 1, wherein the double emulsion prepared in step 3) is further homogenized under high pressure for 1-20 min under 50-250 bar, and finally forms the selenium micro-nano double-emulsified micro-preparation with uniform W1/O/W2 particles.
6. The selenium nanoemulsifying miniformulation of claim 1, wherein vitamin E in phase O and the chitosan-selenium miniformulation in phase W1 both have gastrointestinal sustained release properties, and the amount released increases dynamically over time.
7. The selenium nanoemulsifying micro-formulation of claim 6, wherein the micro-formulation is in the form of particles with a particle size range of 116.84 ± 2.77nm and a surface potential of 46.04 ± 1.25 mV.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN114288412A (en) * | 2021-12-28 | 2022-04-08 | 山西农业大学 | Preparation method and application of chitosan-nano selenium particle hydrosol |
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