Method for efficiently preparing narrow-distribution chitosan nanogel by utilizing self-oscillation pulse jet
By enhancing the oil-water mixing process through self-excited oscillation pulse jet technology, the problems of long preparation time and low efficiency in chitosan nanogel preparation have been solved. This has enabled the efficient, energy-saving, and safe preparation of chitosan nanogels with controllable particle size and narrow distribution, which are suitable for the encapsulation of drugs or nutrients.
Patent Information
- Application Number
- CN202411086503.5
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-08-08
- Publication Date
- 2026-02-10
AI Technical Summary
Existing methods for preparing chitosan nanogels suffer from problems such as long preparation time, low production efficiency, large particle size and wide distribution, making it difficult to achieve efficient, energy-saving, safe and economical preparation of uniform or narrowly distributed chitosan nanogels.
The oil-water mixing process in the suspension crosslinking method is enhanced by using self-excited oscillating pulse jet technology. Turbulence and cavitation effects are generated through the Helmholtz resonant cavity self-excited oscillating pulse jet device, which promotes the uniform mixing of chitosan droplets and crosslinking agent, forming nanoemulsions with ultrafine particle size and narrow distribution, thus enabling continuous operation and size control.
Chitosan nanogels with nanoscale particle size and narrow distribution were prepared, which are 40-80 times more energy efficient than traditional methods. The process is simple, easy to scale up, and can effectively encapsulate drugs or nutrients.
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Figure CN121489848A_ABST
Abstract
Description
TECHNICAL FIELD
[0001] The present application relates to a preparation method of nanogel, in particular to a method for efficiently preparing narrow-distribution chitosan nanogel by using self-excited oscillation pulsed jet flow. BACKGROUND
[0002] Chitosan, as a hydrophilic and positively charged linear amino weak alkaline polysaccharide, is often processed into a form of scaffold, microgel or nanogel in the fields of biology and medicine due to its excellent biocompatibility, degradability and bioadhesion, and is safe and non-toxic. Chitosan is used as a drug carrier to embed and load some valuable polypeptides, enzymes, vitamins, amino acids, tea polyphenols, insulin and anticancer drugs. At the same time, as a drug sustained-release carrier, uniform or narrow-distribution chitosan microgel or nanogel can significantly improve drug targeting, repeatability of drug effect and bioavailability of the drug. Therefore, the preparation of uniform or narrow-distribution chitosan microgel or nanogel has always been concerned in the industry.
[0003] In the field of pharmacy, the size of nanogel is defined between 1-1000 nm, which has large specific surface area effect and small volume effect, and the performance is more advantageous than that of microgel. At present, the suspension crosslinking method is a common method for preparing chitosan gel, which has the advantage of easy to realize the size and distribution control of the gel, that is, under the action of the added surfactant, the particle size and distribution (uniformity) of the dispersed phase droplets (water droplets) in the formed inverse (W / O) emulsion are important factors affecting the size and distribution of the subsequent crosslinked chitosan gel. Therefore, it is crucial to obtain uniform (narrow) distribution of chitosan nanogel by using appropriate means to strengthen the oil-water mixing process to obtain ultra-fine particle size and uniform (narrow) distribution of W / O emulsion droplets. The main process intensification methods for preparing W / O emulsion at present include mechanical stirring emulsification method, ultrasonic emulsification method, microfluidic emulsification method and membrane emulsification method. Among these methods, the mechanical stirring emulsification and ultrasonic emulsification equipment are simple and easy to operate; the chitosan gel prepared by microfluidic emulsification and membrane emulsification has narrow particle size distribution and controllable size. However, the microfluidic emulsification and membrane emulsification process is time-consuming and low in production efficiency, and the subsequent crosslinked chitosan gel prepared by mechanical stirring (homogenization) has a particle size of micrometer level (> 1.0 μm); although the ultrasonic emulsification can obtain W / O emulsion with narrow distribution, the energy efficiency is low, and it is difficult to control the size of the obtained chitosan gel in scale-up production, and the particle size distribution is often very wide; and the W / O emulsion obtained by mechanical stirring emulsification has very uneven particle size, and it is difficult to control the size of the subsequent crosslinked chitosan gel, and the particle size distribution is usually very wide, and the process energy consumption is high.
[0004] Therefore, it is necessary to study new process strengthening means to improve / improve this process in order to overcome the shortcomings of the existing method, such as long time consumption, low production efficiency, large gel particle size and wide distribution, and to achieve the preparation of uniform or narrow distribution of chitosan nanogel in an efficient, energy-saving, safe and economical way. SUMMARY
[0005] The technical problem to be solved by the present application is to provide a method for efficiently preparing narrow-distribution chitosan nanogel by using self-excited oscillation pulse jet flow, which continuously acts on the oil-water mixed emulsion preparation process in the suspension crosslinking method, and the subsequent collision-mixing reaction process between chitosan molecules and crosslinking agent molecules in the dispersed phase emulsion droplets (water droplets), achieving continuous operation of the preparation process and the purpose of preparing uniform / narrow-distribution chitosan nanogel; The method is simple to operate, high in energy efficiency, low in cost, good in repeatability, and easy to control the size and distribution of chitosan nanogel.
[0006] The technical solution to solve the above technical problems is: a method for efficiently preparing narrow-distribution chitosan nanogel by using self-excited oscillation pulse jet flow, characterized by comprising the following steps: (1) Preparation of water phase I and water phase II: Dissolve the hydrophilic drug or nutrient in a chitosan solution with a concentration of 1.0-1.6% (w / v) as water phase I; The solvent used in the chitosan solution is an organic acid aqueous solution or an acidic buffer solution; The mass ratio of the hydrophilic drug or nutrient to chitosan is 1:1-30; Dissolve the crosslinking agent genipin in a 70-75% (v / v) ethanol aqueous solution as water phase II; The genipin dissolving concentration is 4.0-6.0% (w / v); (2) Preparation of oil phase: Dissolve the emulsifier in animal fat to form the oil phase; The emulsifier is one of polyglycerol ricinoleate, glycerol monooleate and alkylphenol polyoxyethylene (4) ether; The dissolving amount of the emulsifier is 4.0-6.0% (w / v) of the volume of animal fat; (3) Preparation of coarse emulsion I and coarse emulsion II: Add water phase I and water phase II prepared in step (1) to the oil phase of step (2) respectively, and stir at 40-60 ℃ to form coarse emulsion I and coarse emulsion II respectively; The volume ratio of water phase I, water phase II and oil phase is the same, both are 16-20% (v / v); The volume ratio of water phase I and water phase II used is 6-9:1; (4) Self-excited oscillation pulse jet flow reinforced mixing preparation of nanoemulsion: Under the same temperature as step (3) for preparing coarse emulsion I, the whole coarse emulsion I prepared in step (3) is treated by a self-excited oscillation pulse jet flow device for 15-30 min to obtain uniform nanoemulsion I; (5) The self-oscillating pulsating jet flow reinforced mixing preparation of nanogels: The whole crude emulsion II prepared in step (3) is added dropwise into the nanoemulsion I of step (4) at a speed of 0.9-3.0 L / h under the same temperature as that of step (4) and the uninterrupted self-oscillating pulsating jet flow device processing, the time is started when the crude emulsion II is added dropwise, and the continuous circulation processing is performed for 60-120 min, and finally the chitosan nanogels loaded with hydrophilic drugs or nutrients are obtained by centrifugation, washing and freeze-drying.
[0007] Further, the self-oscillating pulsating jet flow device comprises a Helmholtz resonator self-oscillating pulsating jet flow device, a tank and an oil pump, the Helmholtz resonator self-oscillating pulsating jet flow device is in communication with the tank and the oil pump respectively, and the tank and the oil pump are in communication to form a circulation loop.
[0008] Further, the upstream pressure of the Helmholtz resonator self-oscillating pulsating jet flow device is 0.50-1.0 MPa, and the downstream pressure is the ambient pressure.
[0009] Further, in step (1), the molecular weight of the chitosan is 800-5000 kDa, and the degree of deacetylation is 60-85%.
[0010] Further, in step (1), the organic acid is one of acetic acid, propionic acid, citric acid, tartaric acid, glutamic acid and monochloroacetic acid; the concentration of the aqueous organic acid solution is 1.0-5.0% (v / v); the acidic buffer solution is acetic acid-sodium acetate or citric acid-sodium citrate; the pH value of the acidic buffer solution is 2.5-4.0; and the hydrophilic drug or nutrient is a small molecule non-aromatic compound.
[0011] Further, the hydrophilic drug is one or more of the antitumor drugs temozolomide, doxifluridine, thioguanine, tegafur and cytarabine, and the nutrient is one or more of vitamin B1, vitamin B3, vitamin B6, vitamin H and folic acid.
[0012] Further, in step (2), the animal fat is pig fat, beef fat, chicken fat and mutton fat.
[0013] Self-excited oscillation pulse jet flow is a new physical and chemical process intensification technology, and its generation principle is that when a continuous jet flow enters a resonance cavity at high speed, the fluid around the shear layer in the cavity chamber is entrained and generates various scale discrete vortices (in the form of vortex ring) through the exchange of momentum, heat and mass, and the fluid in the cavity chamber forms high-intensity turbulence (chaos) from the ordered state during pumping; when the discrete vortices reach the collision wall and interact with each other, pressure oscillation waves are generated in the collision area, the waves propagate upstream at the speed of sound, and new vortex pulsation is induced; if the pressure pulsation of the separation area and the collision area is opposite to each other, a circulation process of vortex flow disturbance-amplification-collision feedback-new vortex pulsation generation is formed; the process is repeated continuously to form a strong pulse (cavitation) jet flow. The multi-scale discrete vortices (entrainment), high-intensity turbulence, oscillation effect induced by collision feedback, and cavitation effect induced by bubble collapse provide an extremely superior physical and chemical environment for the intensification of physical and chemical processes. The present application uses self-excited oscillation pulse jet flow to intensify the mixing process to prepare narrow-distribution chitosan nanogel, and the main technical principles include: (1) based on the special structure of Helmholtz resonance cavity, the fluid generates entrainment, turbulence (chaos) and impact feedback in the cavity, forming an ordered vortex flow with concentrated intensity, and the liquid clusters oscillate back and forth near the impact surface, the residence time of two-phase fluid in the cavity is prolonged, the reaction probability of chitosan droplets and crosslinking agent droplets is increased, the reaction time is greatly shortened, and the production efficiency of chitosan nanogel is effectively improved; (2) the pulse cavitation effect generated by the self-excited oscillation pulse jet flow based on the Helmholtz resonance cavity is more intense than the conventional continuous jet cavitation effect, the cavitation field is wider and more uniform, the turbulent energy is greater, and the micro-mixing effect of the two phases is better, which promotes the oil-water two-phase mixing to generate W / O nanoemulsion with ultra-fine particle size and uniform distribution, which provides a nanoscale "template" reaction microsystem for obtaining chitosan nanogel with more uniform particle size and narrower distribution; (3) the double reverse emulsion coupled with the self-excited oscillation pulse jet flow mode, the dual action of the oscillation effect and the cavitation effect generated by the self-excited oscillation pulse jet flow promotes the suspended droplets (water droplets) in water phase II and water phase I to maintain ultra-fine particle size and uniform particle size distribution before collision, contact and reaction, which provides a favorable microenvironment for generating chitosan nanogel with ultra-fine particle size and narrow distribution when the two suspended droplets (water droplets) collide, contact and react.
[0014] The present application has the following beneficial effects: (1) The chitosan nanogel carrier prepared by the present application can embed various small molecule non-aromatic hydrophilic drugs or nutrients, such as antitumor drug temozolomide, deoxyfluorouridine, and nutrients vitamin B1, vitamin B3 and folic acid, etc.
[0015] (2) Compared with the micro-sized (>1.0 μm) chitosan micro-gel prepared by mechanical stirring, the chitosan gel prepared by the method has a nano-sized (<1.0 μm) particle size and a narrow distribution.
[0016] (3) The chitosan nanogel provided by the method has good dispersity, regular morphology, controllable size of 300-1000 nm, and controllable polydispersity index (PDI) of 0.25-0.70.
[0017] (4) The energy utilization rate of the method is 40-80 times higher than that of the mechanical stirring method, and is 2 orders of magnitude higher than that of the ultrasonic irradiation method based on a variable amplitude rod.
[0018] (5) The preparation process provided by the method realizes continuous operation of the self-excited oscillation pulse jet flow reinforced W / O emulsion preparation process and the crosslinking reaction granulation process, and simplifies the operation process.
[0019] (6) The double reverse-phase emulsion coupled with the self-excited oscillation pulse jet flow mode avoids the problem that the particle size of the chitosan nanogel generated by the reaction is large and the distribution is wide due to the local violent reaction caused by the fact that the crosslinking agent droplet has a particle size too large to simultaneously contact a plurality of chitosan emulsion droplets (water droplets).
[0020] (7) The preparation method provided by the method is easy to adjust the size and distribution of the emulsion droplets of the water phase I and the water phase II by adjusting the operation conditions and structure parameters of the self-excited oscillation pulse jet flow, so as to realize the control of the size and distribution of the generated chitosan nanogel.
[0021] (8) The preparation process of the method is simple in operation, high in energy efficiency, good in repeatability, low in cost of the self-excited oscillation pulse jet flow device, easy to realize process control, and has the advantages of large-scale industrial application.
[0022] In the following, the technical features of the method for efficiently preparing chitosan nanogel with narrow distribution by using self-excited oscillation pulse jet flow according to the present application are further described in combination with the accompanying drawings and examples. BRIEF DESCRIPTION OF DRAWINGS
[0023] Figure 1 : The self-excited oscillation pulse jet flow device of the present application.
[0024] Figure 2 : The process flow block diagram of the method for efficiently preparing chitosan nanogel with narrow distribution by using self-excited oscillation pulse jet flow according to Example 1 of the present application.
[0025] Figure 3 : The SEM image of the chitosan nanogel prepared in Example 1 of the present application.
[0026] Figure 4 SEM image of chitosan gel prepared by mechanical stirring in Comparative Example 1 of Example 1.
[0027] Figure 5 SEM image of chitosan gel prepared by ultrasonic radiation based on an amplitude transformer, which is a comparative example 2 of Example 1.
[0028] Figure 6 SEM image of the chitosan nanogel prepared in Example 2 of this invention.
[0029] Figure 7 SEM image of chitosan gel prepared by mechanical stirring in Comparative Example 1 of Example 2.
[0030] Figure 8 SEM image of chitosan gel prepared by ultrasonic radiation based on an amplitude transformer, in Comparative Example 2 of Example 2.
[0031] Figure 9 SEM image of the chitosan nanogel prepared in Example 3 of this invention.
[0032] Figure 10 SEM image of chitosan gel prepared by mechanical stirring in Comparative Example 1 of Example 3.
[0033] Figure 11 SEM image of chitosan gel prepared by ultrasonic radiation based on an amplitude transformer, in Comparative Example 2 of Example 3.
[0034] In the diagram: 1-storage tank, 2-temperature controlled circulating cold tank, 3-valve I, 4-oil pump, 5-flow meter, 6-valve II, 7-valve III, 8-upstream pressure gauge, 9-Helmholtz resonant cavity self-excited oscillation pulse jet device, 10-downstream pressure gauge, 11-valve IV. Detailed Implementation
[0035] The self-excited oscillation pulse jet device used in various embodiments of the present invention (such as...) Figure 1 The system (shown) mainly includes: a Helmholtz resonant cavity self-excited oscillating pulse jet device 9, a storage tank 1, an oil pump 4, a flow meter 5, valves I3, II6, III7, and IV11, as well as an upstream pressure gauge 8 and a downstream pressure gauge 10 for monitoring the Helmholtz resonant cavity self-excited oscillating pulse jet device 9; wherein the inlet of the Helmholtz resonant cavity self-excited oscillating pulse jet device 9 is connected to the outlet of the oil pump 4, the outlet of the Helmholtz resonant cavity self-excited oscillating pulse jet device 9 is connected to the inlet of the storage tank 1, and the outlet of the storage tank 1 is connected to the inlet of the oil pump 4, forming a main circulation loop. The flow meter 5 is installed on the pipeline connecting the Helmholtz resonant cavity self-excited oscillating pulse jet device 9 and the oil pump 4.
[0036] The outlet of the oil pump 4 is also connected to the inlet of the storage tank 1 via a pipeline to form a bypass, and valve II 6 is installed on this pipeline. The main purpose of setting up the bypass is to facilitate the control of the flow rate of the main circuit and the upstream inlet pressure of the Helmholtz resonant cavity self-excited oscillation pulse jet device.
[0037] The storage tank 1 is provided with a temperature-controlled circulating cold tank 2 outside, and the Helmholtz resonant cavity self-excited oscillation pulse jet device 9 is a throttling element with a Helmholtz resonant cavity. Example 1
[0038] A method for efficiently preparing narrow-distribution chitosan nanogels using self-excited oscillating pulsed jets is illustrated in the process flow diagram below. Figure 2 As shown, it includes the following steps: (1) Preparation of aqueous phases I and II: Dissolve 5.0 g temozolomide in 0.6 L of 1.0% (w / v) chitosan (molecular weight 800 kDa, degree of deacetylation 85%) solution as aqueous phase I; the solvent used for chitosan solution is 5% (v / v) acetic acid.
[0039] 4.0 g of the crosslinking agent genipin was dissolved in 0.1 L of a 75% (v / v) aqueous ethanol solution to form aqueous phase II.
[0040] (2) Preparation of oil phase: 140.0 g of emulsifier polyglycerol ricinoleate was fully dissolved in 3.50 L of lard to form the oil phase.
[0041] (3) Preparation of crude emulsion I and II: 0.6 L of aqueous phase I and 0.1 L of aqueous phase II from step (1) were added to 3.0 L and 0.5 L of oil phase from step (2), respectively, and stirred at 45 °C to form crude emulsion I and crude emulsion II.
[0042] (4) Preparation of nanoemulsion by self-excited oscillation pulse jet: At 45 °C, the crude emulsion I from step (3) was circulated for 15 min using a self-excited oscillation pulse jet device with an upstream pressure of 0.60 MPa and a downstream pressure of ambient pressure to obtain a uniform nanoemulsion I.
[0043] (5) Preparation of nanogels by self-excited oscillating pulse jet: Under the condition of 45 °C and uninterrupted self-excited oscillating pulse jet device (upstream pressure is 0.60 MPa, downstream pressure is ambient pressure), crude emulsion II from step (3) was added dropwise to nanoemulsion I from step (4) at a rate of 1.5 L / h, and the process was continuously cyclically treated for 100 min (timing started when crude emulsion II was added dropwise). After centrifugation, alternating washing with petroleum ether and anhydrous ethanol 6 times, and freeze-drying, chitosan nanogels loaded with temozolomide were obtained.
[0044] Under the same material ratio, mechanical stirring (speed of 500 rpm) was used instead of the self-excited oscillating pulse jet in steps (4) and (5) as Comparative Example 1, and ultrasonic radiation based on a variable amplitude rod (ultrasonic power of 300W) was used instead of the self-excited oscillating pulse jet in steps (4) and (5) as Comparative Example 2. The physicochemical properties and energy efficiency comparison of the prepared chitosan gel are shown in Table 1.
[0045] Table 1
[0046] From Table 1 and Figures 3-5 It can be seen that the chitosan nanogel prepared by self-excited oscillating pulse jet enhancement exhibits good dispersibility, regular morphology, no adhesion, and ultra-fine gel size with a narrow distribution. The size of the obtained chitosan gel is 328.5 nm, and the PDI is 0.357. Under the same material ratio, the chitosan gels prepared by mechanical stirring and ultrasonic radiation based on an amplitude transformer have larger sizes (1279.3 nm and 892.6 nm, respectively) and PDIs (0.897 and 0.758, respectively). Both methods produce larger gels with wider distributions, and the ultrasonically radiated chitosan gel also exhibits irregular large gel fragments. These results indicate that the size and distribution of the gel obtained by self-excited oscillating pulse jet enhancement are significantly smaller or narrower than those obtained by mechanical stirring and ultrasonic radiation based on an amplitude transformer. In terms of energy utilization, self-excited oscillating pulse jet has a significant energy efficiency advantage in the preparation of chitosan nanogels. Its energy efficiency in the preparation of chitosan nanogels is significantly higher than that of mechanical stirring and ultrasonic radiation based on an amplitude transformer, which are 60.5 and 353.7 times higher, respectively. This result indicates that self-excited oscillating pulse jet can efficiently prepare chitosan nanogels with controllable size and uniform / narrow distribution. Example 2
[0047] A method for efficiently preparing narrow-distribution chitosan nanogels using self-excited oscillating pulsed jets includes the following steps: (1) Preparation of aqueous phases I and II: 10.0 g of deoxyfluorouridine was dissolved in 0.75 L of chitosan (molecular weight 1000 kDa, degree of deacetylation 82%) solution with a concentration of 1.2% (w / v) as aqueous phase I; the solvent used for the chitosan solution was 3% (v / v) acetic acid.
[0048] 4.8 g of the crosslinking agent genipin was dissolved in 0.12 L of a 70% (v / v) aqueous ethanol solution to form aqueous phase II.
[0049] (2) Preparation of oil phase: 228.4 g of emulsifier glyceryl monooleate was fully dissolved in 5.44 L of mutton fat to form the oil phase.
[0050] (3) Preparation of crude emulsion I and II: 0.75 L of aqueous phase I and 0.12 L of aqueous phase II from step (1) were added to 4.69 L and 0.75 L of oil phase from step (2), respectively, and stirred at 50 °C to form crude emulsion I and crude emulsion II.
[0051] (4) Preparation of nanoemulsion by self-excited oscillation pulse jet: At 50 °C, the crude emulsion I from step (3) was circulated for 20 min using a self-excited oscillation pulse jet device with an upstream pressure of 0.50 MPa and a downstream pressure of ambient pressure to obtain a uniform nanoemulsion I.
[0052] (5) Preparation of nanogel by self-excited oscillation pulse jet enhancement: Under the condition of 50 °C and uninterrupted self-excited oscillation pulse jet device (upstream pressure is 0.50 MPa, downstream pressure is ambient pressure), crude emulsion II from step (3) was added dropwise to nanoemulsion I from step (4) at a rate of 2.0 L / h, and the process was continuously cyclically treated for 90 min (timing started when crude emulsion II was added dropwise). After centrifugation, alternating washing with petroleum ether and anhydrous ethanol 6 times, and freeze-drying, chitosan nanogel loaded with deoxyfluorouridine was obtained.
[0053] Under the same material ratio, mechanical stirring (900 rpm) was used instead of the self-excited oscillating pulse jet in steps (4) and (5) as Comparative Example 1 of Example 2, and ultrasonic radiation based on a variable amplitude rod (ultrasonic power 900W) was used instead of the self-excited oscillating pulse jet in steps (4) and (5) as Comparative Example 2 of Example 2. The physicochemical properties and energy efficiency comparison of the prepared chitosan gel are shown in Table 2.
[0054] Table 2
[0055] From Table 2 and Figures 6-8It can be seen that the chitosan nanogel prepared by self-excited oscillating pulse jet enhancement exhibits good dispersibility, regular morphology, no adhesion, and ultra-fine gel size with a narrow distribution. The size of the obtained chitosan gel is 307.2 nm, and the PDI is 0.343. Under the same material ratio, the chitosan gels prepared by mechanical stirring and ultrasonic radiation based on an amplitude transformer have larger sizes (828.6 nm and 754.7 nm, respectively) and PDIs (0.792 and 0.812, respectively). Both methods produce larger gels with wider distributions, and the ultrasonically radiated chitosan gel also exhibits irregular large gel fragments. These results indicate that the size and distribution of the gel obtained by self-excited oscillating pulse jet enhancement are significantly smaller or narrower than those obtained by mechanical stirring and ultrasonic radiation based on an amplitude transformer. In terms of energy utilization, self-excited oscillating pulse jet has a significant energy efficiency advantage in the preparation of chitosan nanogels. Its energy efficiency in the preparation of chitosan nanogels is significantly higher than that of mechanical stirring and ultrasonic radiation based on an amplitude transformer, which are 54.6 and 353.0 times higher, respectively. This result indicates that self-excited oscillating pulse jet can efficiently prepare chitosan nanogels with controllable size and uniform / narrow distribution. Example 3
[0056] A method for efficiently preparing narrow-distribution chitosan nanogels using self-excited oscillating pulsed jets includes the following steps: (1) Preparation of aqueous phases I and II: Dissolve 8.0 g of vitamin B1 in 0.8 L of chitosan (molecular weight 1200 kDa, degree of deacetylation 80%) solution with a concentration of 1.3% (w / v) as aqueous phase I; the solvent used for chitosan solution is 4% (v / v) acetic acid.
[0057] 4.2 g of the crosslinking agent genipin was dissolved in 0.1 L of a 75% (v / v) aqueous ethanol solution as aqueous phase I.
[0058] (2) Preparation of oil phase: Dissolve 225.0 g of emulsifier alkylphenol polyoxyethylene (4) ether in 5.0 L of tallow to form the oil phase.
[0059] (3) Preparation of crude emulsion I and II: 0.8 L of aqueous phase I and 0.1 L of aqueous phase II from step (1) were added to 4.44 L and 0.56 L of oil phase from step (2), respectively, and stirred at 55 °C to form crude emulsion I and crude emulsion II.
[0060] (4) Preparation of nanoemulsion by self-excited oscillation pulse jet: At 55 °C, the crude emulsion I from step (3) was circulated for 20 min using a self-excited oscillation pulse jet device with an upstream pressure of 0.70 MPa and a downstream pressure of ambient pressure to obtain a uniform nanoemulsion I.
[0061] (5) Preparation of nanogel by self-excited oscillation pulse jet enhancement: Under the condition of 55 °C and uninterrupted self-excited oscillation pulse jet device (upstream pressure is 0.70 MPa, downstream pressure is ambient pressure), crude emulsion II from step (3) was added dropwise to nanoemulsion I from step (4) at a rate of 1.8 L / h, and the process was continuously cyclically treated for 120 min (timing started when crude emulsion II was added dropwise). After centrifugation, alternating washing with petroleum ether and anhydrous ethanol 6 times, and freeze-drying, chitosan nanogel loaded with vitamin B1 nutrient was obtained.
[0062] Under the same material ratio, mechanical stirring (1800 rpm) was used instead of the self-excited oscillating pulse jet in steps (4) and (5) as Comparative Example 1 of Example 3, and ultrasonic radiation based on a variable amplitude rod (ultrasonic power 600W) was used instead of the self-excited oscillating pulse jet in steps (4) and (5) as Comparative Example 2 of Example 3. The physicochemical properties and energy efficiency comparison of the prepared chitosan gel are shown in Table 3.
[0063] Table 3
[0064] From Table 3 and Figures 9-11 It can be seen that the chitosan nanogels prepared by self-excited oscillating pulse jet enhancement exhibit good dispersibility, regular morphology, no adhesion, and ultra-fine gel size with a narrow distribution. The size of the obtained chitosan gel is 287.5 nm, and the PDI is 0.362. Under the same material ratio, the chitosan gels prepared by mechanical stirring and ultrasonic radiation based on an amplitude transformer have larger sizes (786.7 nm and 687.5 nm, respectively) and PDIs (0.771 and 0.834, respectively). Both methods produce larger gels with wider distributions, and the ultrasonically radiated chitosan gel also exhibits irregular large gel fragments. These results indicate that the size and distribution of the gels prepared by self-excited oscillating pulse jet enhancement are significantly smaller or narrower than those prepared by mechanical stirring and ultrasonic radiation based on an amplitude transformer. In terms of energy utilization, self-excited oscillating pulse jet has a significant energy efficiency advantage in the preparation of chitosan nanogels. Its energy efficiency in enhancing the preparation of chitosan nanogels is significantly higher than that of mechanical stirring and ultrasonic radiation based on a variable amplitude rod, which are 44.6 and 318.8 times higher, respectively. This result indicates that self-excited oscillating pulse jet can efficiently prepare chitosan nanogels with controllable size and uniform / narrow distribution.
Claims
1. A method for efficiently preparing narrow-distribution chitosan nanogels using self-excited oscillating pulsed jets, characterized in that: Includes the following steps: (1) Preparation of aqueous phase I and aqueous phase II: The hydrophilic drug or nutrient is dissolved in a chitosan solution with a concentration of 1.0-1.6% (w / v) as aqueous phase I; the solvent used for the chitosan solution is an aqueous solution of organic acid or an acidic buffer solution; the mass ratio of the hydrophilic drug or nutrient to chitosan is 1:1-30. The crosslinking agent genipin is dissolved in a 70-75% (v / v) aqueous ethanol solution as aqueous phase II; the concentration of genipin is 4.0-6.0% (w / v). (2) Preparation of oil phase: The emulsifier is fully dissolved in the animal fat to form the oil phase; the emulsifier is one of polyglycerol ricinoleate, glyceryl monooleate and alkylphenol polyoxyethylene (4) ether; the amount of emulsifier dissolved is 4.0 to 6.0% (w / v) of the volume of the animal fat. (3) Preparation of crude emulsion I and crude emulsion II: Aqueous phase I and aqueous phase II prepared in step (1) are added to the oil phase in step (2) respectively, and stirred at 40-60 °C to form crude emulsion I and crude emulsion II respectively; the volume ratio of aqueous phase I, aqueous phase II to oil phase is the same, which is 16-20% (v / v); the volume ratio of aqueous phase I to aqueous phase II used is 6-9:1; (4) Preparation of nanoemulsion by self-excited oscillation pulse jet enhanced mixing: At the same temperature as the preparation of crude emulsion I in step (3), all the crude emulsion I prepared in step (3) is circulated for 15 to 30 min using a self-excited oscillation pulse jet device to obtain uniform nanoemulsion I. (5) Preparation of nanogel by self-excited oscillation pulse jet enhanced mixing: At the same temperature as the preparation of nanoemulsion I in step (4), and under the treatment of the uninterrupted self-excited oscillation pulse jet device, all the crude emulsion II prepared in step (3) is added dropwise to nanoemulsion I in step (4) at a rate of 0.9 to 3.0 L / h. Timing starts when crude emulsion II is added dropwise, and the continuous cycle treatment is carried out for 60 to 120 min. Finally, the chitosan nanogel loaded with hydrophilic drugs or nutrients is obtained by centrifugation, washing and freeze drying.
2. The method for efficiently preparing narrow-distribution chitosan nanogels using self-excited oscillating pulsed jet according to claim 1, characterized in that: The self-excited oscillating pulse jet device includes a Helmholtz resonant cavity self-excited oscillating pulse jet device, a storage tank, and an oil pump. The Helmholtz resonant cavity self-excited oscillating pulse jet device is connected to the storage tank and the oil pump respectively, and the storage tank and the oil pump are connected to form a circulation loop.
3. The method for efficiently preparing narrow-distribution chitosan nanogels using self-excited oscillating pulsed jet according to claim 2, characterized in that: The upstream pressure of the Helmholtz resonant cavity self-excited oscillation pulse jet device is 0.50–1.0 MPa, and the downstream pressure is ambient pressure.
4. The method for efficiently preparing narrow-distribution chitosan nanogels using self-excited oscillating pulsed jet according to claim 1, characterized in that: In step (1), the chitosan has a molecular weight of 800-5000 kDa and a degree of deacetylation of 60-85%.
5. The method for efficiently preparing narrow-distribution chitosan nanogels using self-excited oscillating pulsed jet according to claim 1, characterized in that: In step (1), the organic acid is one of acetic acid, propionic acid, citric acid, tartaric acid, glutamic acid, and monochloroacetic acid; the concentration of the aqueous solution of the organic acid is 1.0-5.0% (v / v); the acidic buffer solution is acetic acid-sodium acetate or citric acid-sodium citrate; the pH value of the acidic buffer solution is 2.5-4.0; and the hydrophilic drug or nutrient is a small molecule non-aromatic compound.
6. The method for efficiently preparing narrow-distribution chitosan nanogels using self-excited oscillating pulsed jet according to claim 1, characterized in that: The hydrophilic drug is one or more of the antitumor drugs temozolomide, deoxyfluorouridine, thioguanine, tegafur, and cytarabine, and the nutrient is one or more of vitamin B1, vitamin B3, vitamin B6, vitamin H, and folic acid.
7. The method for efficiently preparing narrow-distribution chitosan nanogels using self-excited oscillating pulsed jet according to claim 1, characterized in that: In step (2), the animal fats are lard, beef tallow, chicken fat and mutton fat.