CN100553756C - A kind of preparation method of core-shell structure nano microcapsule - Google Patents

Abstract

A method for preparing nano-microcapsules with a core-shell structure is a nano-microcapsule with good dispersion, stable storage and slow-release effect and its preparation technology. The method uses polymer particles as a template, assembles polyelectrolytes with opposite charges on the surface of the template through layer-by-layer electrostatic self-assembly method, and then dissolves the template particles to obtain nanometer microcapsules with a core-shell structure. The wall thickness of the microcapsule can be precisely controlled at the nanometer scale, and the polyelectrolyte on the inner wall interacts with the drug, thereby encapsulating the drug into the microcapsule. The release rate of the encapsulated drug is controllable. The invention has the advantages of simple operation, good repeatability, effective control of drug release rate, and good application prospect in the field of slow-release drug packaging.

Description

A kind of preparation method of core-shell structure nano microcapsule

technical field

The invention specifically relates to a preparation method of a novel core-shell structure nano-microcapsule, in particular to a nano-microcapsule with good dispersibility, stable storage and slow-release effect and its preparation technology.

Background technique

Core-shell structure nanocapsules and porous materials formed by stacking core-shell structure nanocapsules are used in the field of catalysis, the packaging of sustained-release drugs, the simulation of artificial cells, the packaging and protection of biologically active macromolecules such as proteins, enzymes, and DNA, and as coatings. Various fields such as pigments or pigments have great potential value, and become one of the eye-catching directions in the field of materials research.

Template electrostatic self-assembly method is one of the main methods to prepare spherical shell structure nanocapsules. It combines the template method with the self-assembly process, and uses the electrostatic adsorption between anions and cations to adsorb opposite charges on the surface of the nanoparticle core to form a thin film, and then remove the core. Generally, a solvent can be used to dissolve the core. Thus, hollow particles are obtained, and the advantage is that the size of the core particle, the thickness and composition of the particle shell can be selected to meet different needs.

At present, there have been many studies on the application of empty-core nanocapsules in medicine at home and abroad. How to increase the drug loading and control the sustained release time has become the primary problem in the application of empty-core nanocapsules. Therefore, it is extremely challenging to find a drug carrier with high drug loading and adjustable sustained release performance.

The template electrostatic self-assembly method is used to prepare core-shell nanocapsules. The size of the microcapsules can be precisely controlled by the template, and the wall thickness can be controlled within the nanometer scale. Sustained release properties.

Contents of the invention

Technical problem: The purpose of the present invention is to provide a method for preparing nano-microcapsules with a core-shell structure, in which drugs are encapsulated in nano-microcapsules, which have a higher drug loading capacity and good drug sustained-release performance.

Technical scheme: The novel core-shell structure nano-microcapsule proposed by the present invention is to prepare melamine-formaldehyde resin (MF) nano-microspheres by dispersion polymerization; A layer of negatively charged polyelectrolyte is wrapped on the surface of the nanosphere; and then a layer of positively charged polyelectrolyte is wrapped on the surface of the MF nanosphere that has been wrapped with a layer of negatively charged polyelectrolyte by electrostatic adsorption; finally The MF as a template was removed by acid etching, and stable core-shell nanocapsules were prepared. The nano-microcapsule with core-shell structure has a nanometer scale.

The preparation method of the above-mentioned core-shell structure nano-microcapsules is as follows:

(1) Add 2 to 5 g of melamine and 4 to 10 ml of formaldehyde solution into a three-necked flask, and stir for 0.5 to 2 hours in a water bath at 40 to 70° C. to obtain a prepolymer methylol melamine. Then, 0.2-2.0 g of polyvinyl alcohol is dissolved in 50-150 g of ultrapure water under a water bath at 40-70° C., and the pH value of the solution is adjusted to 3-5 with acetic acid. Add the above-mentioned polyvinyl alcohol into the prepolymer methylol melamine, react in a water bath at 40-70°C for 0.5-1.0 hours, ultrasonically disperse at 40-70°C for 5-10 minutes, and quickly cool with ice water. Centrifuge the obtained product at 4000rpm, remove the supernatant, add ultrapure water to redisperse, and then centrifuge, repeat this process 3 to 5 times, dry in vacuum to obtain MF powder, and store at low temperature.

(2) in the NaCl solution that concentration is 0.3～0.6mol/L, and pH is 3～5, the negatively charged polyelectrolyte that concentration is 0.5～1.5mg/ml mixes with step (1) gained MF nanoparticle, Centrifuge to remove the supernatant, then add ultrapure water to redisperse the MF nanoparticles, then centrifuge to remove the supernatant, and wash repeatedly in this way to obtain the first layer of MF nanoparticles wrapped with negatively charged polyelectrolytes; ~0.6mol/L, NaCl solution with a pH of 3~5, add MF nanoparticles to a positively charged polyelectrolyte with a concentration of 0.5~1.5mg/ml, centrifuge to remove the supernatant, and repeat this with ultrapure water Wash to obtain the second layer of MF nanoparticles wrapped with positively charged polyelectrolytes; repeat the above process, and self-assemble the positively charged and negatively charged polyelectrolyte layers according to the expected number of layers to obtain core-shell structure nanoparticles, The MF as a template was removed by acid etching to obtain hollow nanocapsules.

(3) At a temperature of 20 to 70°C, the hollow nanocapsules obtained in step (2) are incubated for 0.5 to 3 hours in an aqueous drug solution with a pH value of 0.5 to 5 and a concentration of 0.01 to 100 mg/ml to make the drug Embedding in nanometer microcapsules to obtain drug-loaded nanometer microcapsules.

In the present invention, the negatively charged polyelectrolyte is sodium alginate (ALG); the positively charged polyelectrolyte is gelatin (GEL). Said medicine is nicardipine hydrochloride or olopatadine hydrochloride.

By changing the number of polyelectrolytic self-assembled layers and preparation conditions, the microstructure and thickness of the nanocapsule wall can be regulated at the nanometer scale, thereby improving drug loading and sustained release performance.

Beneficial effect: the advantage of the present invention is that a novel core-shell structure nano-capsule is prepared by template electrostatic self-assembly method, which not only has simple operation, good repeatability, uniform size of nano-microcapsule, but also its size can be adjusted through preparation conditions . The core-shell nanocapsule has high stability, uses non-toxic and biodegradable materials sodium alginate and gelatin as self-assembly materials, and has good biocompatibility.

Description of drawings

Figure 1 is a transmission electron microscope image of an empty-core nanocapsule,

Fig. 2 is the in vitro cumulative release curve of nicardipine hydrochloride.

Detailed ways

The following examples further illustrate the invention, but these examples are not intended to limit the invention.

Example 1

Add 2 g of melamine and 5 ml of formaldehyde solution into a three-necked flask, and stir for 30 min in a water bath at 50° C. to obtain a prepolymer methylol melamine. Then, 0.5 g of polyvinyl alcohol was dissolved in 100 g of ultrapure water under a water bath at 50° C., and the pH value of the solution was adjusted to 3.5 with acetic acid. Add the above polyvinyl alcohol into the prepolymer methylol melamine, react in a water bath at 50°C for 0.5 hours, then ultrasonically disperse at 50°C for 5 minutes, and quickly cool with ice water. Centrifuge the obtained product at 4000rpm, remove the supernatant, add ultrapure water to re-disperse, then centrifuge, repeat this process 3 times, dry in vacuum to obtain MF powder, and store at low temperature.

In 5ml of NaCl solution with a concentration of 0.3mol/L and a pH of 3.5, mix sodium alginate with a concentration of 0.5mg/ml and 1ml of a 5% MF nanoparticle suspension, centrifuge to remove the supernatant, and add Ultrapure water redisperses the MF nanoparticles, then centrifuges to remove the supernatant, and washes repeatedly in this way to obtain the first layer of MF nanoparticles wrapped with sodium alginate; MF nanoparticles were added to gelatin with a concentration of 0.5 mg/ml, and the supernatant was removed by centrifugation, and then washed repeatedly with ultrapure water to obtain the second layer of MF nanoparticles wrapped with gelatin; repeat the above process until the obtained MF/(ALG/GEL) ₄ core-shell nanoparticles.

Then add the core-shell nanoparticle into the hydrochloric acid solution with pH=1.2, react for 10 minutes, and remove the MF template. Repeatedly washing twice with hydrochloric acid solution with pH=1.2, centrifuging to remove the supernatant, washing with ultrapure water three times to obtain hollow nanocapsules. Figure 1 is a transmission electron microscope image of an empty-core nanocapsule.

At a temperature of 30°C, add the obtained 50 μl hollow nanocapsule solution to 10 ml of nicardipine hydrochloride aqueous solution with a pH value of 1.0 and a concentration of 0.04 mg/ml and incubate for 1 hour to embed nicardipine hydrochloride into the nanocapsules. In the capsule, the drug-loaded nano-microcapsules are obtained.

The drug-loaded nano-microcapsules were dispersed with a little ultrapure water, placed in a dialysis bag, and a phosphate buffer solution with a pH of 6.8 was used as a release medium at a temperature of 30°C to conduct a drug release experiment. And pure nicardipine hydrochloride was placed in a dialysis bag for a control experiment. Figure 2 is the cumulative release curve of nicardipine hydrochloride in vitro.

Example 2

Same as Example 1, but the release medium was changed to hydrochloric acid solution at pH = 1.2. The prepared nano-capsules with core-shell structure can release less than 10% of the drug loading in the first 2 hours in the release medium of hydrochloric acid solution with pH=1.2. Figure 2 is the cumulative release curve of nicardipine hydrochloride in vitro.

Example 3

Same as Example 1, but the nicardipine hydrochloride solution was changed to pH 5.0 and the concentration was 50 mg/ml.

Example 4

Same as Example 1, but the drug loading temperature was changed to 60°C.

The structure and properties of the core-shell nanocapsules prepared in Examples 3 and 4 above are the same or similar to those of Example 1, and both have good sustained-release properties.

Claims (4)

1. a preparation method of core-shell structure nano-microcapsules, characterized in that the method may further comprise the steps: 1) Add 2-5g melamine and 4-10ml formaldehyde solution into a three-necked flask, stir in a water bath at 40-70°C for 0.5-2 hours to obtain prepolymer methylol melamine; then add 0.2-2.0g polyvinyl alcohol , dissolved in 50-150g ultrapure water in a water bath at 40-70°C, and adjusted the pH of the solution to 3-5 with acetic acid; After reacting in a water bath at ℃ for 0.5 to 1.0 hours, ultrasonically disperse at 40 to 70 ℃ for 5 to 10 minutes, and quickly cool in ice water; centrifuge the obtained product at 4000 rpm, remove the supernatant, add ultrapure water to redisperse, and centrifuge again , repeat this process 3 to 5 times, vacuum dry to obtain MF powder, and store at low temperature; 2) In a NaCl solution with a concentration of 0.3 to 0.6 mol/L and a pH of 3 to 5, mix the negatively charged polyelectrolyte with a concentration of 0.5 to 1.5 mg/ml and the MF powder described in step 1), and centrifuge Remove the supernatant, add ultrapure water to redisperse the MF nanoparticles, then centrifuge to remove the supernatant, and wash repeatedly in this way to obtain the first layer of MF nanoparticles wrapped with negatively charged polyelectrolytes; 0.6mol/L, pH 3~5 NaCl solution, add MF nanoparticles to positively charged polyelectrolyte with a concentration of 0.5~1.5mg/ml, centrifuge to remove the supernatant, and then wash repeatedly with ultrapure water , to obtain the second layer of MF nanoparticles wrapped with positively charged polyelectrolytes; repeat the above process, and self-assemble the positively charged and negatively charged polyelectrolyte layers according to the expected number of layers, to obtain core-shell structure nanoparticles, by The method of acid etching removes MF as a template to obtain hollow nanocapsules; 3) At a temperature of 20-70°C, incubate the hollow nanocapsules obtained in step 2) in an aqueous drug solution with a pH value of 0.5-5 and a concentration of 0.01-100 mg/ml for 0.5-3 hours to embed the drug into nano-microcapsules to obtain drug-loaded nano-microcapsules. 2. The preparation method of the core-shell nanocapsule according to claim 1, characterized in that the negatively charged polyelectrolyte is sodium alginate. 3. The preparation method of the core-shell nanocapsule according to claim 1, characterized in that the positively charged polyelectrolyte is gelatin. 4. The preparation method of the core-shell nano-microcapsule according to claim 1, characterized in that the applicable medicine of the microcapsule is nicardipine hydrochloride or olopatadine hydrochloride.

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