CN107279134B - A kind of pH-responsive drug-loaded Pickering emulsion and preparation method thereof - Google Patents

Abstract

The invention provides a pH-responsive drug-loaded Pickering emulsion and a preparation method thereof. First prepare a sodium alginate modified silica nanoparticle, which is prepared from sodium alginate, formaldehyde, cyclohexyl isonitrile and fractal silica through Ugi reaction, wherein the fractal silica is obtained by using layer by layer Molecularly imprinted is produced by covalently assembling amino-terminated silica and aldehyde-terminated silica, and repeating the imprinting process as needed until the desired number of silica layers is achieved. The invention also provides the Pickering emulsion prepared by using the nanoparticles. The present invention grafts sodium alginate (Alg) onto the surface of fractal SiO2 through the Ugi condensation reaction to prepare a novel pH-responsive Pickering emulsion, which enriches the application of trigger emulsions in pesticide controlled release systems and expands the use of Pickering emulsions for pesticides. drug delivery applications.

Description

A kind of pH-responsive drug-loaded Pickering emulsion and preparation method thereof

technical field

The invention belongs to the technical field of drug sustained release and controlled release, and in particular relates to a pH-responsive drug-loaded Pickering emulsion and a preparation method thereof.

Background technique

Pickering emulsions are 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 stable emulsions for many years (Pawar et al., 2011; Tambe et al., 1993). A stable Pickering emulsion is widely used in various fields, such as food, cosmetics, coatings, pesticides, and various industrial processes such as emulsion coalescence, metal cutting and cleaning, and synthesis of nanoparticles (Fang et al., 2015; Liu et al. al., 2006; Xiao et al., 2016). However, the opposite demulsification process also has crucial applications in some industrial processes such as industrial extraction and oil recovery (Rosen et al., 2012). Furthermore, emulsions that are transiently stable, that is, need to be stable for a specific time and then must be broken (Zhu et al., 2015), such as stimuli-responsive emulsions (pH (Tu et al., 2014), temperature (Zoppe et al., 2012), redox (Quesada et al., 2013), light irradiation (Tan et al., 2014) and magnetic field (Blanco et al., 2013)), it can be interconverted between stable and unstable through a certain environment In recent years, people have paid more and more attention to them.

_SiO2 has been extensively studied as a class of biomaterials and particle emulsifiers due to its unique features, including: (i) controllable morphology; (ii) good chemical and thermal stability and high dispersibility in aqueous media; (iii) good diffusion barrier effect; (iv) excellent biocompatibility (the U.S. Food and Drug Administration (FDA) recognized _SiO2 as a generally recognized as safe (GRAS) material); (v) tunable physical and chemical Surface (Wibowo et al., 2016). However, pure silica particles are highly hydrophilic, which is not conducive to stabilizing Pickering emulsions as a particle emulsifier. In addition, no carboxyl or amino groups exist on the surface of silica, so it cannot exhibit good pH response. Therefore, modified silica is imperative.

Alginic acid as a natural pH-responsive polysaccharide. It is cheap, low toxicity, and good biocompatibility (Lee et al., 2012), and has been widely studied in the food industry, as well as in the fields of environmental engineering, medicine, and regenerative medicine (Li et al., 2011; Lawrie 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 research and development of new pesticide formulations. The application of controlled release technology can greatly extend the release time of pesticides, reduce the total amount of pesticides used and the frequency of application, thereby significantly reducing pesticide residues and environmental pollution. At the same time, some traditional pesticides with high toxicity and low efficiency have become efficient, safe and economical new pesticides through slow release technology.

Contents of the invention

The purpose of the present invention is to overcome the deficiencies in the prior art, sodium alginate (Alg) is grafted onto SiO ₂ surface through Ugi condensation reaction. The pH-responsive Pickering emulsion with slow-release and controlled-release characteristics was prepared by using the particles.

The first aspect of the present invention is to provide a sodium alginate modified silica nanoparticle, which is prepared by Ugi reaction of sodium alginate, formaldehyde, cyclohexyl isonitrile and fractal silica, wherein the fractal Silica is prepared by covalently assembling amino-terminated silica and aldehyde-terminated silica using layer-by-layer molecular imprinting, repeating the imprinting process as needed until the desired number of silica layers is achieved.

Wherein, the number of silicon dioxide layers of the fractal silicon dioxide is set according to needs, for example, it can be 1 layer, 2 layers, 3 layers or 4 layers.

The second aspect of the present invention is to provide 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, by using layer-by-layer molecular imprinting Covalent assembly of end-capped silica (Guan et al., 2009) and aldehyde-terminated silica (Shi et al., 2009) was performed, and the imprinting process was repeated as needed until the desired silica layer was achieved fractal silica; step 2, take the fractal silica prepared in step 1 and sodium alginate, formaldehyde, cyclohexyl isonitrile to prepare the sodium alginate modified silica nanoparticles by Ugi reaction .

Among them, amino-terminated silica (Guan et al., 2009) and aldehyde-terminated silica (Shi et al., 2009) can be prepared by published methods, and the present invention will not repeat them here.

The third aspect of the present invention is to provide a pH-responsive Pickering emulsion, which includes an oil phase and an aqueous phase, and uses the sodium alginate-modified silica nanoparticles described in the first aspect of the present invention as a stabilizer.

Preferably, the concentration of sodium alginate-modified silica nanoparticles dispersed in the water phase or oil phase is 2-20% (w/v), more preferably 5-15% (w/v). That is, when the sodium alginate-modified silica nanoparticles are dispersed in the water phase or the oil phase, the concentration is 1-20% (w/v), such as 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 5-15% (w/v). Because the lower the concentration of sodium alginate-modified silica nanoparticles, the number of particles adsorbed on the oil-water interface is not enough to stabilize the emulsion, and even the emulsion cannot be formed, and the oil-water two-phase layer is separated; the higher the concentration of sodium alginate-modified silica nanoparticles If it is high, it will easily lead to uneven dispersion of particles, and the system viscosity of dispersed particles is too high, which will affect the formation of emulsion.

Preferably, the oil phase includes a water-immiscible or slightly water-soluble solvent, and the solvent is preferably silicone oil, fatty esters, aromatic hydrocarbons, alkanes and alcohols with a C chain length of 6-16, and a C chain length of 6-16. Any one of 22-50 petroleum hydrocarbons or a mixture of at least two, more preferably fatty esters, any one or a mixture of at least two of alkanes or alcohols with a C chain length of 6-16 .

The oil phase can only be composed of water-immiscible or slightly water-soluble solvents, preferably, other soluble substances can be included in the oil phase, and the oil-soluble substances are selected from fat-soluble drugs, fat-soluble markers, Any one or a mixture of at least two of fat-soluble enzymes or fat-soluble proteins.

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

Preferably, the water phase further includes other water-soluble substances, and the water-soluble substances are any one or a mixture of at least two of salts, antibodies, proteins, polypeptides, drugs, enzymes, cytokines or sugars. The salts are sodium chloride, sodium acetate, potassium chloride, calcium chloride and the like.

Preferably, the volume ratio of the oil phase to the water phase is 1:20-20:1.

The fourth aspect of the present invention is to provide a method for preparing the pH-responsive Pickering emulsion as described in the third aspect of the present invention, characterized in that, the sodium alginate modified bismuth described in the first aspect of the present invention is used Silica nanoparticles are dispersed in the water phase, added to the oil phase, and sheared at a high speed.

A fifth aspect of the present invention provides a pH-responsive drug-loaded Pickering emulsion, which includes an oil phase and an aqueous phase, using the sodium alginate-modified silica nanoparticles described in claim 1 or 2 as a stabilizer, wherein , the drug is dissolved in the oil phase or the water phase.

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

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

Preferably, the water phase further includes other water-soluble substances, and the water-soluble substances are any one or a mixture of at least two of salts, antibodies, proteins, polypeptides, drugs, enzymes, cytokines or sugars. The salts are sodium chloride, sodium acetate, potassium chloride, calcium chloride and the like.

Preferably, the volume ratio of the oil phase to the water phase is 1:20-20:1.

The sixth aspect of the present invention is to provide a method for preparing the pH-responsive drug-loaded Pickering emulsion as described in the fifth aspect of the present invention, taking the sodium alginate modified silica described in the first aspect of the present invention The nanoparticles are dispersed in the water phase, added to the oil phase, and sheared at a high speed.

In the present invention, sodium alginate (Alg) is grafted onto the surface of fractal SiO2 through the Ugi condensation reaction, and a novel pH-responsive Pickering emulsion system can be prepared, which enriches the application of triggering emulsions in pesticide controlled release systems, and expands the use of Pickering emulsions for the controlled release of pesticides. Application in pesticide drug delivery.

Description of drawings

Figure 1 is a schematic diagram of the mechanism of grafting sodium alginate on the surface of _SiO2 .

Fig. 2 is the 1H NMR spectrum (a) and TGA spectrum (b) of Alg-SiO ₂ -x.

Figure 3 is the dynamic contact angle curve (a), potential and particle size curve (b) and contact line curve (c) of Alg-SiO ₂ .

Fig. 4 is different Alg-SiO ₂ 2-x structures to emulsion droplet morphology (a), the impact result of droplet size (c) and emulsification height (d), and different pH values to emulsion droplet morphology ( b), Results of the effect of droplet size (e) and emulsification height (f).

Fig. 5 is the change curve (a) of the apparent viscosity and shear rate of the emulsion with different pH values and the change curve (b) of the thixotropy of the emulsion with different pH values.

Fig. 6 is the strain scanning curve (a) of emulsions with different pH values and the dynamic oscillation frequency scanning curve (b) of emulsions with different pH values.

Figure 7 is the thermal stability curves of emulsions with different pH values.

Fig. 8 is the LCH sustained-release curve (a) of emulsions with different pH values and the Weibull model fitting curve (b) of emulsions with different pH values.

Detailed ways

The present invention will be further described below in combination with specific embodiments, so as to better understand the present invention.

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

First, amino-terminated silica (SiO ₂ -NH ₂ ) particles were prepared (Guan et al., 2009). The steps are as follows: add 1.0 g of hydrophilic silica and 10 mL of APTS to 50 mL of ethanol/water (v/v=3:1) at pH=3.6, and then reflux at 80° C. for 12 h. After the mixture was centrifuged, washed three times with ethanol and water respectively, and freeze-dried to obtain amino-terminated silica particles (SiO ₂ -NH ₂ ). Then prepare aldehyde-terminated silica particles (SiO ₂ -CHO) (Shi et al., 2009), the steps are as follows: after dispersing 0.5 g of the above particles in 30 mL (pH=8) of phosphate buffer solution, add 50 mL of 25% Ga. The reaction was stirred at room temperature for 12h. After the mixture was centrifuged, washed three times with ethanol and water respectively, and freeze-dried to obtain aldehyde-terminated silica particles. Finally, SiO ₂ -NH ₂ and SiO ₂ -CHO were covalently assembled by layer-by-layer molecular imprinting, and the imprinting process was repeated until the required number of silica layers was reached to obtain fractal silica. In this example, one layer of amino-terminated silica (SiO ₂ -1), two layers of amino-terminated silica (SiO ₂ -2) and four layers of amino-terminated silica (SiO ₂ -4) were finally synthesized. ).

Next, Alg-SiO ₂ -x was prepared by Ugi reaction (Yan et al., 2016). First, 1.696g of sodium alginate was dissolved in 80mL of water and stirred overnight. Next, adjust the pH of the solution to 3.6 with 0.5 mol/L HCl solution; then, add 0.195 g of formaldehyde, 0.5 g of the above fractal silica and 0.708 g of cyclohexylisonitrile to the solution in sequence, and stir and react at room temperature for 24 hours. Finally, the mixture was centrifuged, washed three times with pure water, and then freeze-dried to obtain the final product sodium alginate modified silica nanoparticles Alg-SiO ₂ -x (Alg-SiO ₂ -1, Alg-SiO ₂ -2 and Alg-SiO ₂ -4). The reaction mechanism diagram is shown in Figure 1.

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

(1) The Alg-SiO ₂ -x structure was characterized by a Bruker AV 400 NMR instrument. Their grafting ratios were measured by a TAQ600 thermogravimetric analyzer. The test conditions are as follows: temperature range: 30-800°C; heating rate: 10°C/min; nitrogen protection.

Its ¹ H NMR spectrum is shown in Fig. 2a. The NMR data are shown as follows: δ (ppm) = 5.08 (C1H, G unit) and 4.68 (C1H, M unit), but both are covered by the solvent peak (D ₂ O); 3.82 (s, 2H , NCH ₂ - C=O), 3.5(t,2H, CH ₂ -CH ₂ -CH ₂ -N-), 1.8–1.4(t,11H,C6H11 of cyclohexyl), 1.2(s,2H, CH ₂ -CH ₂ -CH ₂ -N-), 1.0(t,2H,CH ₂ -CH ₂ -CH ₂ -N-) (Yan et al., 2016).

The grafting ratio (DS) of Alg-SiO ₂ -x is shown in Fig. 2b, and the quality of unmodified SiO ₂ has slightly decreased due to the removal of surface-adsorbed water. However, the TGA curve of Alg-SiO ₂ -x has an obvious three-stage degradation process: the first stage is at 40-160°C, because of the loss of Alg-SiO ₂ -x bound water; the second stage is from 220 to 280°C, This is because the carboxyl on the Alg chain decreases based on the _deCO2 and water of the adjacent hydroxyl group; as the temperature rises again in the third stage, eventually the entire Alg molecule is converted into _CO2 and _H2O is removed (Yang et al ., 2013). Therefore, the calculated DSs of Alg-SiO ₂ -x are 24.6%, 26.8% and 28.8%, respectively.

(2) The Zeta potential and average particle size data of Alg-SiO ₂ -x were obtained by Zetasizer Nano ZS90 DLS measurement. The contact angle of Alg-SiO ₂ -x water phase was measured by JC2000C1 contact angle measuring instrument. Take 5 mg of Alg-SiO ₂ -x and disperse it in 10 mL of pure water, use acetic acid to adjust the pH value of the solution from 2.0 to 9.0, and then freeze-dry. Finally, after spreading the sample evenly on the glass slide, start the test. The water phase contact angle is calculated by the Young's equation that comes with the software.

The results are shown in Figure 3 and Table 1. It can be seen from Figure 3a that as the DS ranges from 24.6% to 28.8%, the contact angle first increases and then decreases, indicating that too many hydrophilic Alg groups on the surface of silica are not conducive to the hydrophobic modification of silica. Figure 3c shows that as the pH value decreased from 6.2 to 2.0, the contact angle of the particles increased, mainly because the carboxyl group on the alginate was protonated to reduce the solubility of Alg, resulting in enhanced hydrophobicity of the particles. However, when the pH value increased from 6.2 to 8.0, the contact angle of the particles increased. The possible reason is that the uniformly dispersed particles are conducive to the exposure of hydrophobic groups, which increases the hydrophobicity of the particles. When the pH value increased to 9.0, the Na ⁺ shielding effect could not be ignored, leading to particle aggregation, hydrophobic groups were embedded, the contact angle was smaller, and the particle hydrophilicity increased.

The zeta potential and average particle size data of Alg-SiO ₂ -x are shown in Table 1 and Fig. 3b. It can be seen from Table 1 that with the increase of DS, the particle potential increases and the particle size tends to decrease. Figure 3b shows that the Alg- _SiO2 -x particle size decreases as the pH value decreases from 6.2 to 4.0. However, the Alg-SiO ₂ -x particle size decreases as the pH value increases from 6.2 to 8.0.

Table 1 Particle size and potential of Alg- _SiO2

3. Preparation of Pickering emulsion and evaluation of its stability

Take 20mg of Alg-SiO ₂ -x and disperse in 10mL of pure water, then add 10ml of liquid paraffin, and use FA25 high-speed shearing machine to shear and mix at 25000rpm for 20min. The stability of the emulsion is characterized by measuring the emulsification height of the emulsion, the particle size and shape of the emulsion droplets within a certain time interval (such as 0.5h, 12h, 24h, 72h and 168h) through an optical microscope and a multiple light scattering instrument.

The result is shown in Figure 4. It can be seen from Figure 4a that as the silicon dioxide layer increases from 1 to 4, the emulsification height first increases and then decreases, and the droplet size first decreases and then increases, indicating that compared with other particles, Alg-SiO ₂ -2 has Good emulsification. The data of the multiple light scattering instrument (Figure 4c, 4d) shows that as the time increases from 0.5h to 168h, the emulsification height of Alg-SiO ₂ -2 is the highest, the droplet size is the smallest, and its change is slow, which further shows that Alg-SiO 2 -2 SiO ₂ -2 is the emulsifier with the best emulsifying effect among all particles.

It can be seen from Fig. 4b that as the pH value increased from 2.0 to 8.0, the emulsification height increased and the droplet size decreased. As shown in Figures 4e and 4f, as the time increases from 0.5h to 168h, the emulsification height of the emulsion at pH = 8.0 is the highest, the droplet size is the smallest, and the change is the slowest, which further shows that the stability of the emulsion is related to the pH value. The emulsion with pH=9.0 had the highest initial emulsification height, and after 30min, its emulsification height dropped rapidly to less than the emulsification height of pH=8.0, showing extreme instability in a short time.

4. Interfacial rheology test of Pickering emulsion

First, the effect of pH value on the apparent viscosity and thixotropy of the emulsion was studied using a shear stress-controlled rheometer, as shown in Figure 5. It can be seen from Figure 5a that the apparent viscosity of the emulsion decreases with the increase of the shear rate, showing a typical shear-thinning flow behavior. This result indicates that the emulsion is a pseudoplastic fluid. In addition, the apparent viscosity of the emulsion increases as the pH of the emulsion increases from 2.0 to 6.2 at the same shear rate. As the pH value increased, more and more carboxylic acid groups were deprotonated, the electrostatic repulsion within the molecule was enhanced, and the Alg chains were stretched and cross-linked to form a three-dimensional network, which improved the stability of the emulsion. However, as the pH value increased from 6.2 to 8.0, the apparent viscosity of the emulsion began to decrease, which may be due to the increase in the charge density of the particles with pH (Fig. loose. When the pH value was further increased to 9.0, the Na ⁺ shielding effect reduced the zeta potential, resulting in Alg chain curling and steric network disruption. Therefore, the viscosity of the emulsion is further reduced.

Thixotropic properties are shown in Figure 5b. As the pH value increases from 2.0 to 9.0, the absolute value of thixotropy first increases and then decreases, and there is a maximum value at pH = 6.2, indicating that the emulsion forms a strong three-dimensional network structure. This result is consistent with the apparent viscosity data in Figure 5a.

The strain sweep test data are shown in Fig. 6a and Table 2. As the pH value increased from 2.0 to 6.2, the _γc of the emulsion increased, which indicated that the stiffness and interfacial resistance of the emulsion increased due to the establishment of a three-dimensional network between droplets. However, when the pH value increased from 6.2 to 9.0, the γ _c of the emulsion decreased, which was due to the disruption of the three-dimensional network as described above. High G′ and G″ values indicate stronger stiffness of the system, and the pH=6.2 emulsion has stronger stiffness due to the three-dimensional network construction. η* and tanδ _LVR are important parameters to measure the storage stability of the emulsion. The η* value Larger and smaller tanδ _LVR values indicate that the continuous stability and elastic behavior of the emulsion are better (Anvari et al., 2016). Therefore, considering the above data, the pH=6.2 emulsion has better due to the formation of network structure consistent and resilient behavior.

Table 2 Strain sweep parameters of emulsions with different pH values

The viscous and elastic behavior of the emulsion can be tested by dynamic oscillation experiments, and all the data are shown in Fig. 6b. In the test frequency range, as the angular frequency (ω) increases, the elastic modulus (G′) and viscous modulus (G″) tend to increase. In addition, in the test frequency range, the G′ value is always greater than G ″ values, especially in the low frequency region, the two moduli are far apart, but close to each other in the high frequency. This means that most of the energy is dissipated by elastic flow and the emulsion exhibits a gel-like behavior. Furthermore, the stable emulsion at pH = 6.2 showed a higher storage modulus G' than the emulsions at other pH values. This large storage modulus confirms that the emulsion forms a rigid volume-filled network structure, which creates a viscoelastic film O/W interface that hinders emulsion coalescence and thus stabilizes the emulsion.

The thermal stability of the Pickering emulsion under shear or extrusion is shown in Figure 7. The η* value of the pH=6.2 emulsion changes slightly in the range of 5°C-65°C, showing a good thermal stability (because it is stable The three-dimensional network structure exists), on the contrary, the η* value of other emulsions increases and increases with temperature, indicating that the thermal stability is not good. However, the η* value of the pH=8.0 emulsion varied slightly in the range of 5°C–65°C, showing a good thermal stability.

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

The drug-loaded emulsion was prepared as follows: 8 mg of Alg-SiO ₂ -x was dispersed in 6 mL of effluent water, then 2 mL of 10% lambda-cyhalothrin (LCH) toluene solution was added, and the FA25 high-speed shearing machine was used to shear and mix at 25,000 rpm for 20 min , to prepare drug-loaded emulsions with different pH values (2.0-9.0).

The drug release experiment of the drug-loaded emulsion is as follows: take 5mL of the emulsion and put it into a dialysis bag, put it into 400ml of 25% methanol solution for dialysis. At predetermined time intervals (such as 10min, 20min, 1h or 3h), the dialysis bag is taken out and put into a new dialysate, and 5mL of the original dialysate is collected. Repeat this step until the end of dialysis.

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

F is the cumulative release amount, _Ve is the volume of each sample, V is the volume of the _dialysate , C _i and C _n are the concentrations of the i-th and n-th drugs 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 and time, a and b are constants.

The sustained drug release data are shown in Figure 8a. The results showed that the cumulative release rate of the emulsion was 27.8%, 99.7%, 87.3%, 40.5%, 13.5% and 51.3% when the pH value increased from 2.0 to 9.0. The reason is that as the pH value changes, the stability of the emulsion increases, and the cumulative release of the emulsion decreases, indicating that the emulsion has a sensitive pH response.

According to the test data, the fitting curve of Weibull model is shown in Fig. 8b. R ² , b and the corresponding diffusion mechanisms are presented in Table 3. It can be seen from Table 3 that the R ² of all samples is around 0.99, indicating that the samples fit the Weibull model very well. When the pH values were 2.0, 3.0, 8.0 and 9.0, the b values of the emulsions were all lower than 0.75, proving that their release followed Fickian diffusion. The release of the emulsion at pH=6.2 belongs to the combined diffusion mechanism because b=0.8453. The emulsion with pH=4.0 showed that the complex diffusion mechanism dominates the release process.

Table 3 Comparison of Weibull model parameters

The present invention synthesizes pH-responsive silicon dioxide (Alg-SiO2-x) through Ugi reaction. Its structure, DS and surface properties were characterized by TGA, ¹ H NMR, DLS and contact angle measurement. The ¹ H NMR spectrum confirmed that the grafting was successful. The DSs of Alg-SiO2-x calculated by TGA are 24.6%, 26.8% and 28.8%, respectively. DLS and contact angle measurement data indicated that the carboxyl groups on the Alg chain were highly protonated with decreasing pH, and the modified nanoparticles exhibited excellent surface and interfacial properties. Rheological and multiple light scattering data show that as the pH value increases from 2.0 to 6.2, the emulsion stability increases due to the stretching and crosslinking of polymer chains to form a three-dimensional network; as the pH value increases from 6.2 to 8.0, the particle charge density increases. increase, leading to an increase in the electrostatic repulsion between particles, and further increase in the stability of the emulsion. However, as the pH was further increased to 9.0, the particle charge decreased, resulting in a decrease in emulsion stability. In the pesticide release test, the cumulative release rate of the drug was 27.8%, 99.7%, 87.3%, 40.5%, 13.5% and 53.1% when the pH value increased from 2.0 to 9.0, indicating that the emulsion drug release process has a sensitive pH value Responsiveness. In addition, at 240min, the drug release of the pH=4.0 emulsion can reach 87.3% instantaneously. The release kinetic data of LCH can be fitted by Weibull model. As the pH value changed from 2.0 to 9.0, the release mechanism of LCH experienced Fickian to complex and then combined and finally returned to Fickian diffusion mechanism. Studies have shown that Alg-SiO2-x particles have good prospects in the application of pH-responsive drug-loaded emulsions.

The specific embodiments of the present invention have been described in detail above, but they are only examples, and the present invention is not limited to the specific embodiments described above. For those skilled in the art, any equivalent modifications and substitutions to the present invention are also within the scope of the present invention. Therefore, equivalent changes and modifications made without departing from the spirit and scope of the present invention shall fall within the scope of the present invention.

Claims (9)

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.