CN107279134B

CN107279134B - PH-responsive drug-loaded Pickering emulsion and preparation method thereof

Info

Publication number: CN107279134B
Application number: CN201710381045.1A
Authority: CN
Inventors: 李嘉诚; 冯玉红; 林强; 余高波; 陈凯
Original assignee: Hainan University
Current assignee: Hainan University
Priority date: 2017-05-25
Filing date: 2017-05-25
Publication date: 2019-12-10
Anticipated expiration: 2037-05-25
Also published as: CN107279134A

Abstract

The invention provides a pH responsive drug-loaded Pickering emulsion and a preparation method thereof. Firstly, preparing sodium alginate modified silica nanoparticles, which are prepared from sodium alginate, formaldehyde, cyclohexyl isonitrile and fractal silica through a Ugi reaction, wherein the fractal silica is prepared by covalently assembling amino-terminated silica and aldehyde-terminated silica through layer-by-layer molecular imprinting, and repeatedly carrying out an imprinting process as required until the required number of silica layers is reached. The invention also provides a Pickering emulsion prepared by the nanoparticles. According to the invention, sodium alginate (Alg) is grafted to the surface of fractal SiO2 through an Ugi condensation reaction, so that a novel pH responsive Pickering emulsion can be prepared, the application of the trigger emulsion in a pesticide controlled release system is enriched, and the application of the Pickering emulsion in pesticide drug delivery is expanded.

Description

PH-responsive drug-loaded Pickering emulsion and preparation method thereof

Technical Field

The invention belongs to the technical field of sustained-release controlled release of medicines, and particularly relates to a pH-responsive medicine-carrying Pickering emulsion and a preparation method thereof.

Background

The Pickering emulsion is mainly stabilized by inorganic rigid particles or polymer soft particles with good surface wettability. These adsorbed particles hinder droplet coalescence by creating strong electrostatic repulsion, large steric hindrance, or high interfacial viscosity, resulting in emulsions that remain stable for many years (Pawar et al, 2011; tamber et al, 1993). A stable Pickering emulsion is widely used in various fields such as food, cosmetics, paints, pesticides and various industrial processes such as emulsion coalescence, metal cutting and cleaning and nanoparticle synthesis (Fang et al, 2015; Liu et al, 2006; Xiao et al, 2016). However, the reverse demulsification process also has critical applications in some industrial processes such as industrial extraction oil recovery (Rosen et al, 2012). Furthermore, emulsions which are temporarily stable, i.e. need to be stable within a certain time and must subsequently be broken (Zhu et al, 2015), such as stimuli-responsive emulsions (pH (Tu et al, 2014), temperature (zoppeeet al, 2012), redox (quasada et al, 2013), light irradiation (Tan et al, 2014) and magnetic field (Blanco et al, 2013)) which can interconvert stimuli through certain environmental factors between being stable and unstable, have gained increasing attention in recent years.

SiO ₂ has been extensively studied as a class of biomaterials and particulate emulsifiers for its unique functions including (i) controlled morphology, (ii) good chemical and thermal stability and high dispersibility in aqueous media, (iii) good diffusion barrier effect, (IV) excellent biocompatibility (the United states Food and Drug Administration (FDA) uses SiO ₂ as a Generally Recognized As Safe (GRAS) material), (v) tunable physical and chemical surfaces (Wibowo et al, 2016.) however, pure silica particles are highly hydrophilic and are not conducive to stabilizing Pickering emulsions as particulate emulsifiers.

Alginic acid acts as a natural pH-responsive polysaccharide. It is cheap, low in toxicity, good in biocompatibility (Lee et al, 2012), and has been widely studied in the food industry, as well as in the fields of environmental engineering, medicine, regenerative medicine, etc. (Li et al, 2011; lawrrie et al, 2007).

Pesticides are indispensable in modern agriculture. However, the utilization rate of traditional pesticides is only 20% -30%, which not only causes economic waste, but also causes great damage to the ecological environment (Song et al, 2014). Therefore, controlled release technology (such as controlled release amount, release time and release space) plays an important role in the development of new pesticide formulations. The application of the controlled release technology can greatly prolong the release time of the pesticide, reduce the total dosage of the pesticide and the application times, thereby obviously reducing the pesticide residue and the environmental pollution. Meanwhile, some traditional pesticides with high toxicity and low efficiency become novel pesticides with high efficiency, safety and economy through a slow release technology.

Disclosure of Invention

The invention aims to overcome the defects in the prior art, sodium alginate (Alg) is grafted to the surface of SiO ₂ to carry out an Ugi condensation reaction, and the pH responsive Pickering emulsion with the characteristics of slow release and controlled release is prepared by utilizing the particles.

The first aspect of the invention provides sodium alginate modified silica nanoparticles, which are prepared from sodium alginate, formaldehyde, cyclohexyl isonitrile and fractal silica through a Ugi reaction, wherein the fractal silica is prepared by covalently assembling amino-terminated silica and aldehyde-terminated silica through layer-by-layer molecular imprinting, and repeatedly carrying out an imprinting process as required until the required number of silica layers is reached.

The number of the silica layers of the fractal silica is set as required, and may be, for example, 1 layer, 2 layers, 3 layers, or 4 layers.

The second aspect of the present invention provides a method for preparing sodium alginate modified silica nanoparticles as described in the first aspect of the present invention, comprising the following steps: step 1, covalently assembling amino-terminated silica (Guan et al, 2009) and aldehyde-terminated silica (Shi et al, 2009) by using layer-by-layer molecular imprinting, and repeatedly performing an imprinting process as required until the number of required silica layers is reached to prepare fractal silica; and 2, carrying out Ugi reaction on the fractal silicon dioxide prepared in the step 1, sodium alginate, formaldehyde and cyclohexyl isonitrile to prepare the sodium alginate modified silicon dioxide nanoparticle.

The amino-terminated silica (Guan et al, 2009) and the aldehyde-terminated silica (Shi et al, 2009) can be prepared by the disclosed method, and the invention is not repeated herein.

The third aspect of the invention provides a pH-responsive Pickering emulsion, which comprises an oil phase and a water phase, and adopts the sodium alginate modified silica nanoparticles of the first aspect of the invention as a stabilizer.

Preferably, the concentration of the sodium alginate-modified silica nanoparticles dispersed in the aqueous phase or the oil phase is 2 to 20% (w/v), more preferably 5 to 15% (w/v). That is, when the sodium alginate-modified silica nanoparticles are dispersed in the aqueous phase or the oil phase, the concentration thereof is 1 to 20% (w/v), for example, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, or 19%, preferably 5 to 15% (w/v). Because the lower the concentration of the sodium alginate modified silica nanoparticles is, the number of particles adsorbed on an oil-water interface is not enough to stabilize an emulsion, even the emulsion cannot be formed, and an oil phase are layered; the higher the concentration of the sodium alginate modified silicon dioxide nanoparticles is, the nonuniform dispersion of the particles is easily caused, and the excessive viscosity of a system for dispersing the particles influences the formation of emulsion.

Preferably, the oil phase comprises a water-immiscible or sparingly water-soluble solvent, preferably any one or a mixture of at least two of silicone oils, fatty esters, aromatic hydrocarbons, alkanes and alcohols having a C chain length of 6 to 16, petroleum hydrocarbons having a C chain length of 22 to 50, more preferably any one or a mixture of at least two of fatty esters, alkanes having a C chain length of 6 to 16, or alcohols.

The oil phase may consist of only water-immiscible or sparingly water-soluble solvents, and preferably may contain other soluble substances selected from any one or a mixture of at least two of fat-soluble drugs, fat-soluble markers, fat-soluble enzymes, or fat-soluble proteins.

Preferably, the aqueous phase comprises any one of water, phosphate buffer, acetate buffer, citrate buffer or Tris buffer, or a mixture of at least two thereof.

Preferably, the water phase also comprises other water-soluble substances, and the water-soluble substances are any one or a mixture of at least two of salts, antibodies, protein polypeptide drugs and enzymes, cytokines or saccharides. The salt substances are sodium chloride, sodium acetate, potassium chloride, calcium chloride and the like.

Preferably, the volume ratio of the oil phase to the aqueous phase is from 1:20 to 20: 1.

The fourth aspect of the invention provides a preparation method of the pH-responsive Pickering emulsion according to the third aspect of the invention, which is characterized in that the sodium alginate-modified silica nanoparticles according to the first aspect of the invention are dispersed in a water phase, an oil phase is added, and high-speed shearing is performed to obtain the pH-responsive Pickering emulsion.

The fifth aspect of the invention provides a pH-responsive drug-loaded Pickering emulsion, which comprises an oil phase and an aqueous phase, and the sodium alginate-modified silica nanoparticles of claim 1 or 2 are used as a stabilizer, wherein the drug is dissolved in the oil phase or the aqueous phase.

Wherein, the medicament can be selected according to the actual requirement, and the invention does not limit the medicament. In one embodiment of the present invention, where lambda-cyhalothrin is used, the oil phase may be a toluene solution of lambda-cyhalothrin. The concentration of cyhalothrin in the toluene solution of cyhalothrin can be adjusted by those skilled in the art according to experience and needs, and the invention is not limited. Preferably, the concentration of the lambda-cyhalothrin in the toluene solution of lambda-cyhalothrin is 1-20% (w/v).

The sixth aspect of the invention provides a preparation method of the pH-responsive drug-loaded Pickering emulsion according to the fifth aspect of the invention, wherein the sodium alginate-modified silica nanoparticles according to the first aspect of the invention are dispersed in a water phase, and then added with an oil phase and cut at a high speed to obtain the sodium alginate-modified silica nanoparticles.

According to the invention, sodium alginate (Alg) is grafted to the surface of fractal SiO2 through Ugi condensation reaction, so that a novel pH-responsive Pickering emulsion system can be prepared, the application of a trigger emulsion in a pesticide controlled release system is enriched, and the application of the Pickering emulsion in pesticide drug delivery is expanded.

Drawings

FIG. 1 is a mechanism diagram of grafting sodium alginate on the surface of SiO ₂.

FIG. 2 shows 1H NMR spectrum (a) and TGA spectrum (b) of Alg-SiO ₂ -x.

FIG. 3 shows a dynamic contact angle curve (a), a potential and particle diameter curve (b), and a contact line curve (c) of Alg-SiO ₂.

FIG. 4 shows the results of the effect of different Alg-SiO ₂ 2-x structures on emulsion droplet morphology (a), droplet size (c) and emulsification height (d), and the effects of different pH values on emulsion droplet morphology (b), droplet size (e) and emulsification height (f).

FIG. 5 is a graph (a) showing the change of apparent viscosity and shear rate of emulsions with different pH values and a graph (b) showing the change of thixotropy of emulsions with different pH values.

FIG. 6 is a strain sweep (a) and a dynamic oscillation frequency sweep (b) for emulsions of different pH values.

FIG. 7 is a graph showing the thermal stability of emulsions at different pH.

FIG. 8 is a LCH release curve (a) for different pH emulsions and a Weibull model fit curve (b) for different pH emulsions.

Detailed Description

The invention will be better understood by reference to the following description taken in conjunction with the specific embodiments.

1. Sodium alginate grafted to the surface of SiO ₂ (Alg-SiO ₂)

Amino-terminated silica (SiO ₂ -NH ₂) particles were first prepared (Guan et al, 2009) by taking 1.0g of hydrophilic silica and 10mL of APTS and adding to 50mL of ethanol/water at pH 3.6 (v/v 3:1), refluxing at 80 ℃ for 12h, centrifuging the mixture, washing with ethanol and water three times each, freeze-drying to give amino-terminated silica particles (SiO ₂ -NH ₂), then aldehyde-terminated silica particles (SiO ₂ -CHO) (Shi et al, 2009) by taking 0.5g of the above particles and dispersing in 30mL (pH 8) of phosphoric acid buffer solution, adding 50mL of 25% GA., stirring at room temperature for 12h, centrifuging the mixture, washing with ethanol and water three times each, freeze-drying to give aldehyde-terminated silica particles, finally assembling SiO ₂ -NH ₂ and SiO ₂ -CHO layers by using molecular imprinting, repeating the imprinting process until the desired number of layers of amino-terminated silica (v/v) and SiO ₂ -amino-terminated silica (SiO 7335-SiO 2) in the final layer-amino-terminated silica double-terminated (SiO 7335-layer).

Next, Alg-SiO ₂ -x (Yan et al, 2016) was prepared by Ugi reaction, firstly, 1.696g of sodium alginate was dissolved in 80mL of water and stirred overnight, secondly, the pH of the solution was adjusted to 3.6 with 0.5mol/L HCl solution, then 0.195g of formaldehyde, 0.5g of the above fractal silica and 0.708g of cyclohexyl isonitrile were sequentially added to the solution, stirred and reacted at room temperature for 24 hours, and finally, the mixture was centrifuged, washed three times with pure water, and then freeze-dried to obtain sodium alginate-modified silica nanoparticles Alg-SiO ₂ -x (Alg-SiO ₂ -1, Alg-SiO ₂ -2 and Alg-SiO ₂ -4) as the final products, the reaction mechanism is shown in fig. 1.

2. Characterization of Alg-SiO ₂ -x and surface Properties

(1) the Alg-SiO ₂ -x structure is characterized by a Bruker AV 400 nuclear magnetic resonance instrument, the grafting rate of the Alg-SiO ₂ -x structure is measured by a TA Q600 thermogravimetric analyzer, and the test conditions are that the temperature range is 30-800 ℃, the heating rate is 10 ℃/min and the nitrogen protection is performed.

Its ¹ H NMR spectrum is shown in FIG. 2 a.NMR data show that δ (ppm) ═ 5.08(C1H, G units) and 4.68(C1H, M units), but both are covered by a solvent peak (D ₂ O), 3.82(s,2H, N-C H ₂ -C ═ O),3.5(t,2H, C H ₂ -CH ₂ -CH ₂ -N-), 1.8-1.4 (t,11H, C6H11 for cyclohexyl), 1.2(s,2H, CH ₂ -C H ₂ -CH ₂ -N-),1.0(t,2H, CH ₂ -CH ₂ -C < u > H ₂ > -N-) (Yan et al, 2016).

The grafting yield (DS) of Alg-SiO ₂ -x is shown in FIG. 2b, with a slight decrease in the quality of unmodified SiO ₂ due to removal of surface adsorbed water, whereas the TGA curve of Alg-SiO ₂ -x has a distinct three-stage degradation process, the first stage at 40-160 ℃ due to loss of water bound to Alg-SiO ₂ -x, the second stage from 220 to 280 ℃ due to reduction of CO ₂ and water by elimination of the carboxyl groups on the Alg chain from the adjacent hydroxyl groups, and finally the entire Alg molecule is converted to CO ₂ and H ₂ O with a further increase in temperature in the third stage (Yang et al, 2013). The DS of Alg-SiO ₂ -x is calculated to be 24.6%, 26.8% and 28.8%, respectively.

(2) Zeta potential and mean particle size data for Alg-SiO ₂ -x were obtained by Zetasizer Nano ZS90 DLS measurements Alg-SiO ₂ -x water contact angle was measured by JC2000C1 contact angle measuring apparatus 5mg of Alg-SiO ₂ -x was dispersed in 10mL of pure water and the pH of the solution was adjusted from 2.0 to 9.0 using acetic acid followed by lyophilization.

the results are shown in FIG. 3 and Table 1, from FIG. 3a it can be seen that as DS goes from 24.6% to 28.8%, the contact angle increases and then decreases, indicating that too many hydrophilic Alg groups are present on the silica surface to be detrimental to the hydrophobic modification of silica, FIG. 3c indicates that as the pH goes from 6.2 to 2.0, the contact angle of the particles increases, primarily because the carboxyl groups on sodium alginate are protonated, decreasing the solubility of Alg, resulting in increased hydrophobicity of the particles, whereas as the pH goes from 6.2 to 8.0, the contact angle of the particles increases, possibly because uniformly dispersed particles favor the exposure of hydrophobic groups, increasing the hydrophobicity of the particles, when the pH goes to 9.0, the Na ⁺ shielding effect is not negligible, resulting in particle aggregation, hydrophobic groups are embedded, the contact angle is smaller, and the hydrophilicity of the particles increases.

The Zeta potential and mean particle size data for Alg-SiO ₂ -x are shown in Table 1 and FIG. 3b from Table 1 it can be seen that as DS increases, the particle potential increases and the particle size tends to decrease FIG. 3b shows that as the pH decreases from 6.2 to 4.0, the Alg-SiO ₂ -x particle size decreases, however, as the pH increases from 6.2 to 8.0, the Alg-SiO ₂ -x particle size decreases.

TABLE 1 particle size and potential of Alg-SiO ₂

3. Preparation of Pickering emulsion and evaluation of stability

20mg of Alg-SiO ₂ -x is dispersed in 10mL of pure water, 10mL of liquid paraffin is added, shearing and mixing are carried out at 25000rpm by using a FA25 high-speed shearing machine for 20min, and the stability of the emulsion is characterized by measuring the emulsion height, the emulsion droplet size and the morphology at certain time intervals (such as 0.5h, 12h, 24h, 72h and 168h) by using an optical microscope and a multiple light scattering instrument.

The results are shown in FIG. 4A, it can be seen from FIG. 4A that as the silica layer is increased from 1 to 4, the emulsification height is increased and then decreased, and the droplet size is decreased and then increased, indicating that Alg-SiO ₂ -2 has good emulsification compared to other particles, multiple light scattering instrument data (FIGS. 4c and 4d) indicate that as time is increased from 0.5h to 168h, the emulsification height of Alg-SiO ₂ -2 is the highest, the droplet size is the smallest, and the change is slow, further indicating that Alg-SiO ₂ -2 is the emulsifier with the best emulsification among all particles.

as can be seen from fig. 4b, as the pH increased from 2.0 to 8.0, the emulsification height increased and the droplet size decreased. As shown in fig. 4e, 4f, the emulsion with pH 8.0 emulsified the highest height, the smallest droplet size, and the slowest change with increasing time from 0.5h to 168h, further indicating that emulsion stability is related to pH. The emulsion with pH 9.0 had the highest initial emulsion height and after 30min, the emulsion height rapidly dropped to less than pH 8.0, showing extreme instability in a short time.

4. Pickering emulsion interfacial rheology test

⁺The effect of pH on the apparent viscosity and thixotropy of the emulsion was first studied using a shear stress controlled rheometer, as shown in FIG. 5. from FIG. 5a, it is known that the apparent viscosity of the emulsion decreases with increasing shear rate, showing typical shear thinning flow behavior. this result indicates that the emulsion is a pseudoplastic fluid. furthermore, at the same shear rate, as the pH of the emulsion increases from 2.0 to 6.2, the apparent viscosity of the emulsion increases. as the pH increases, more and more carboxylic acid groups deprotonate, the electrostatic repulsion within the molecule increases, and the Alg chains stretch and crosslink to form a three-dimensional network, increasing the stability of the emulsion.

Thixotropic properties as shown in figure 5b, thixotropic absolute values increased and then decreased as the pH increased from 2.0 to 9.0, and there was a maximum at pH 6.2, indicating that the emulsion formed a strong three-dimensional network structure at pH 6.2. This result is consistent with the apparent viscosity data in fig. 5 a.

The strain sweep test data is shown in fig. 6a and table 2. as the pH is increased from 2.0 to 6.2, the emulsion gamma _c increases, indicating that the stiffness and interfacial resistance of the emulsion increases due to the build-up of a three-dimensional network between the droplets, however, as the pH is increased from 6.2 to 9.0, the emulsion gamma _c decreases due to the disruption of the three-dimensional network as described above high G' and G "values indicate that the system has greater stiffness and the pH 6.2 emulsion has greater stiffness due to the build-up of the three-dimensional network η and tan δ _LVR are important parameters in measuring the emulsion storage stability η is greater and a smaller tan δ _LVR value indicates that the emulsion has better continuous stability and elastic behavior (Anvari et al, 2016).

TABLE 2 Strain Scan parameters for emulsions of different pH values

The viscous and elastic behavior of the emulsion can be tested by dynamic shaking experiments, all data are shown in fig. 6 b. In the frequency range tested, there is a tendency for the elastic (G ') and viscous (G') moduli to increase with increasing angular frequency (ω). Furthermore, the value of G 'is always greater than the value of G' in the frequency range tested, and in particular in the low frequency region, the two moduli are very different and close to each other in the high frequency region. This means that most of the energy is dissipated by elastic flow and the emulsion exhibits a gel-like behavior. In addition, stable emulsions at pH 6.2 exhibit higher storage modulus G' than other pH emulsions. This large storage modulus confirms that the emulsion forms a rigid volume-filled network structure that creates an O/W interface of the viscoelastic film that hinders emulsion coalescence, thereby stabilizing the emulsion.

The thermal stability of Pickering emulsions in shear or extrusion is shown in fig. 7, with pH 6.2 emulsion having a slight change in η in the range of 5 ℃ to 65 ℃ showing a good thermal stability (due to the presence of a stable three-dimensional network), whereas other emulsions have η values that increase with increasing temperature, indicating poor thermal stability. However, the η of pH 8.0 emulsions varies slightly over the range of 5 ℃ to 65 ℃, exhibiting a good thermal stability.

5. Preparation and controlled release of drug-loaded Pickering emulsion

The drug-loaded emulsion is prepared by dispersing 8mg of Alg-SiO ₂ -x in 6mL of effluent, then adding 2mL of 10% of high-efficiency cyhalothrin (LCH) toluene solution, and shearing and mixing for 20min at 25000rpm by adopting an FA25 high-speed shearing machine to prepare the drug-loaded emulsion with different pH values (2.0-9.0).

The drug release experiment of the drug-loaded emulsion is as follows: 5mL of the emulsion was added to a dialysis bag and dialyzed against 400mL of a 25% methanol solution. At predetermined time intervals (e.g., 10min, 20min, 1h, or 3h), the bag is removed and placed in a fresh volume of dialysate, and 5mL of the original dialysate is collected. This step was repeated until the end of dialysis.

The concentration of LCH was determined by 6890N Gas Chromatography (GC). The chromatographic conditions are as follows: an ECD detector; DB-1 quartz capillary column (30m × 0.25mm × 0.25 m); flow rate of carrier gas: 1 mL/min; column temperature: 250 ℃; the inlet and detector temperatures were 230 ℃ and 320 ℃ respectively. All tests were repeated twice. The cumulative release amount calculation formula is as follows:

F is the cumulative release, V _e is the volume per sample, V ₀ dialysate volume, C _i and C _n are the concentration of the i and n drug in the dialysate respectively M _ptx is the total mass of drug in the emulsion.

The Weibull model formula is as follows:

ln1n(1/(1-F))＝blnt+lna (2)

F and T are cumulative release amount and time, and a and b are constants.

Drug release data is shown in figure 8 a. The results show that the cumulative release rates of the emulsions from pH 2.0 to pH 9.0 are 27.8%, 99.7%, 87.3%, 40.5%, 13.5% and 51.3%, respectively. The reason is that the emulsion stability is increased and the cumulative release of the emulsion is reduced along with the change of the pH value, which indicates that the emulsion has sensitive pH responsiveness.

The results of the test data are shown in figure 8b, R ², b and the corresponding diffusion mechanism are shown in table 3, it is clear from table 3 that R ² for all samples is around 0.99, indicating that the samples are very compatible with the Weibull model, when the pH values are 2.0, 3.0, 8.0 and 9.0, the b values of the emulsions are below 0.75, demonstrating that their release follows Fickian diffusion, the release of an emulsion at pH 6.2 is a combined diffusion mechanism since b 0.8453, pH 4.0, appears to be a complex diffusion mechanism governing the release process.

TABLE 3 Weibull model parameter comparison

The present invention synthesizes a pH-responsive silica (Alg-SiO2-x) by the Ugi reaction, whose structure, DS and surface properties are characterized by TGA, ¹ H NMR, DLS and contact angle measurements ¹ H NMR spectra confirm successful grafting, TGA calculates that Alg-SiO2-x has a DS of 24.6%, 26.8% and 28.8%, respectively, DLS and contact angle measurements show that as pH is decreased, the carboxyl groups on Alg chains are highly protonated, the modified nanoparticles exhibit superior surface and interfacial properties, rheological and multiple light scattering data show that as pH is increased from 2.0 to 6.2, emulsion stability increases due to the formation of a three-dimensional network by the extensional crosslinking of the polymer chains, as pH is increased from 6.2 to 8.0, the increase in particle charge density leads to an increase in interparticle repulsion, emulsion stability further increases, as pH is further increased to 9.0, particle charge decreases, leading to a decrease in emulsion stability, as pH is increased from 2.2 to 8.0, the increase in particle charge density, leading to an increase in the resulting in the particle charge density, which leads to an increase in the particle release rate from pH 2, which is found to 0.5, the pH-0.7, the pH-7H-7, the pH-7H release response of the weilbin the application of the vickl H-3-7H emulsion, the experiment, the pH-7H release model, the immediate release, the release of the drug-0H release, the dissolution of the drug-0H release, the drug-0H release, the drug loading process, the drug release, the drug loading H release, the drug release.

The embodiments of the present invention have been described in detail, but the embodiments are merely examples, and the present invention is not limited to the embodiments described above. Any equivalent modifications and substitutions to those skilled in the art are also within the scope of the present invention. Accordingly, equivalent changes and modifications made without departing from the spirit and scope of the present invention should be covered by the present invention.

Claims

1. A pH responsive Pickering emulsion is characterized by comprising an oil phase and a water phase, wherein sodium alginate modified silicon dioxide nanoparticles are used as a stabilizer; the sodium alginate modified silicon dioxide nanoparticle comprises: the sodium alginate, the formaldehyde, the cyclohexyl isonitrile and the fractal silicon dioxide are prepared through a Ugi reaction, wherein the fractal silicon dioxide is prepared by covalently assembling amino-terminated silicon dioxide and aldehyde-terminated silicon dioxide through layer-by-layer molecular imprinting, and repeatedly carrying out an imprinting process as required until the required silicon dioxide layer number is reached.

2. The pH-responsive Pickering emulsion of claim 1, wherein the number of silica layers of the fractal silica is 1, 2, or 4.

3. The pH-responsive Pickering emulsion according to claim 1 or 2, wherein the preparation method of the sodium alginate-modified silica nanoparticles comprises the following steps:

Step 1, covalently assembling amino-terminated silica and aldehyde-terminated silica by utilizing layer-by-layer molecular imprinting, and repeating the imprinting process as required until the number of required silica layers is reached to prepare fractal silica;

And 2, carrying out Ugi reaction on the fractal silicon dioxide prepared in the step 1, sodium alginate, formaldehyde and cyclohexyl isonitrile to prepare the sodium alginate modified silicon dioxide nanoparticle.

4. The pH-responsive Pickering emulsion of claim 1, wherein the concentration of sodium alginate-modified silica nanoparticles dispersed in the aqueous phase or the oil phase is 1-20% (w/v).

5. The pH-responsive Pickering emulsion of claim 1 or 4, wherein the volume ratio of the oil phase and the aqueous phase is from 1:20 to 20: 1.

6. A preparation method of the pH-responsive Pickering emulsion as claimed in any one of claims 1 to 5, characterized in that the sodium alginate-modified silica nanoparticles as claimed in claim 1 or 2 are dispersed in an aqueous phase, an oil phase is added, and high-speed shearing is carried out to obtain the pH-responsive Pickering emulsion.

7. a pH-responsive drug-loaded Pickering emulsion is characterized by comprising an oil phase and a water phase, wherein the sodium alginate modified silica nanoparticles of claim 1 or 2 are used as a stabilizer, and a drug is dissolved in the oil phase or the water phase.

8. The pH-responsive, drug-loaded Pickering emulsion of claim 7, wherein the oil phase is a toluene solution of lambda-cyhalothrin.

9. A preparation method of the pH-responsive drug-loaded Pickering emulsion as claimed in claim 7 or 8, characterized in that the sodium alginate-modified silica nanoparticles as claimed in claim 1 or 2 are dispersed in a water phase, an oil phase is added, and high-speed shearing is carried out to obtain the product.