Drug-loaded phase change microcapsule as well as preparation method and application thereof

Abstract

The invention discloses a drug-loaded phase change microcapsule as well as a preparation method and application thereof. The drug-loaded phase change microcapsule comprises a phase change material matrix and polyelectrolyte particles filled in the phase change material matrix, the phase change material matrix comprises a phase change material and a hydrophobic drug, and the polyelectrolyte particles comprise deacetylated chitosan, soluble polysaccharide and a hydrophilic drug. According to the drug-loaded phase change microcapsule disclosed by the invention, efficient co-encapsulation of hydrophilic drugs and hydrophobic drugs is realized, collaborative delivery of drugs with different dissolvability can be carried out, protection on core drug components is improved, the microcapsule can be kept complete in gastric juice, and drugs can be released in intestinal juice through pH response and bile salt mediated micellization, so that the drug-loaded phase change microcapsule has the advantages that the drug-loaded phase change microcapsule has a good application prospect. A good gastrointestinal sustained-release function can be achieved, and the biological accessibility of active drugs is remarkably improved.

Description

Technical Field

[0001] The present invention belongs to the technical field of drug delivery, and particularly relates to a drug-loaded phase change microcapsule, a preparation method thereof, and an application thereof. Background Art

[0002] The microencapsulation oral system can provide a unique carrier system for active ingredients. Different systems can specifically overcome the consumption of active ingredients in the complex gastrointestinal environment, and have characteristics such as precise delivery, responsive release, and synergistic effect of multiple active ingredients, becoming a research hotspot. Research shows that the intelligent combination of drugs helps to expand their applications in the fields of food, agriculture, and medicine. Therefore, it is of great significance to develop a microencapsulation oral system that can achieve the co-delivery of different active components. At present, the encapsulation technology for hydrophobic drugs is mainly based on ordered phase separation or self-assembly (for example: zein nanoparticles, liposomes, micelles, and O / W single emulsion methods, etc.), while the encapsulation of hydrophilic drugs is relatively difficult (the main encapsulation methods include gels, electrostatic complex coacervation, etc.). It is even more difficult to encapsulate components with different solubilities. Only complex methods such as microfluidic-phase separation method and multiple emulsion method can achieve this. However, both the microfluidic-phase separation method and the multiple emulsion method have limitations such as complex processes, insufficient stability, and sensitivity to system components, and it is difficult to fully meet the actual application requirements.

[0003] Therefore, it is of great significance to develop a new drug encapsulation strategy that is mild, efficient, and can achieve the co-delivery of components with different solubilities. Summary of the Invention

[0004] The purpose of the present invention is to provide a drug-loaded phase change microcapsule, a preparation method thereof, and an application thereof.

[0005] The technical solution adopted by the present invention is as follows:

[0006] A drug-loaded phase change microcapsule, which comprises a phase change material matrix and polyelectrolyte particles filled inside the phase change material matrix; the phase change material matrix comprises a phase change material and a hydrophobic drug; the polyelectrolyte particles comprise chitosan, soluble polysaccharide, and a hydrophilic drug.

[0007] Preferably, the phase change material is at least one of lauric acid, myristic acid, palmitic acid, and stearic acid.

[0008] Preferably, the hydrophobic drug is at least one of vitamin A, vitamin D, vitamin E, and vitamin K.

[0009] Preferably, the degree of deacetylation of the chitosan is 70% - 95%.

[0010] Preferably, the soluble polysaccharide is at least one of arabic gum, chondroitin sulfate, dextran sulfate, hyaluronic acid, alginate, carboxymethyl cellulose, and pectin.

[0011] Preferably, the hydrophilic drug is at least one of proanthocyanidins, tea polyphenols, vitamin C, vitamin B3, and glutathione.

[0012] Preferably, the mass ratio of the phase change material to the hydrophobic drug in the phase change material matrix is 1:0.1 - 0.2.

[0013] Preferably, the mass ratio of chitosan deacetylate, soluble polysaccharide, and hydrophilic drug in the polyelectrolyte particles is 1:0.1 - 1.5:0.1 - 3.0.

[0014] Preferably, the particle size of the polyelectrolyte particles is 400 nm - 900 nm.

[0015] Preferably, the particle size of the drug-loaded phase change microcapsules is 40 μm - 200 μm.

[0016] Preferably, the drug-loaded phase change microcapsules are spherical.

[0017] A method for preparing the drug-loaded phase change microcapsules as described above includes the following steps:

[0018] 1) Preparation of chitosan solution and polysaccharide-hydrophilic drug solution:

[0019] Preparation of chitosan solution: Dissolve chitosan deacetylate in acetic acid solution to obtain a chitosan solution;

[0020] Preparation of polysaccharide-hydrophilic drug solution: Dissolve soluble polysaccharide and hydrophilic drug in water to obtain a polysaccharide-hydrophilic drug solution;

[0021] 2) Add the polysaccharide-hydrophilic drug solution to the chitosan solution for electrostatic self-assembly, and then separate the product to obtain polyelectrolyte particles;

[0022] 3) Disperse the phase change material, polyelectrolyte particles, and hydrophobic drug in ethanol to obtain a stock solution;

[0023] 4) Add the stock solution to an aqueous surfactant solution for droplet splitting, then carry out phase change curing, and then separate the product to obtain the drug-loaded phase change microcapsules.

[0024] Preferably, in step 1), the dosage ratio of chitosan deacetylate to acetic acid solution is 1 mg - 2 mg:1 mL.

[0025] Preferably, the mass fraction of the acetic acid solution in step 1) is 1% - 3%.

[0026] Preferably, the preparation process of the chitosan solution in step 1) includes the following operations: dissolving deacetylated chitosan in an acetic acid solution, and then filtering it with a filter membrane having a pore size of 0.2 μm to 1.0 μm to obtain the chitosan solution.

[0027] Preferably, the dosage ratio of the soluble polysaccharide, hydrophilic drug, and water in step 1) is 1 mg to 2 mg: 1 mg to 4 mg: 1 mL.

[0028] Preferably, the volume ratio of the polysaccharide-hydrophilic drug solution to the chitosan solution in step 2) is 0.5 to 1.5:1.

[0029] Preferably, the polysaccharide-hydrophilic drug solution in step 2) is slowly added in the form of dropping.

[0030] Preferably, the electrostatic self-assembly in step 2) is carried out under light-shielded conditions at room temperature (25 °C ± 5 °C), and the time for electrostatic self-assembly is 15 min to 30 min.

[0031] Preferably, the electrostatic self-assembly in step 2) is carried out under stirring, and the stirring rate is 1000 rpm to 2000 rpm.

[0032] Preferably, the product separation method in step 2) is centrifugation, the centrifugal force is 9000 g to 10000 g, and the centrifugation time is 5 min to 10 min.

[0033] Preferably, the dosage ratio of the phase change material, polyelectrolyte particles, hydrophobic drug, and ethanol in step 3) is 0.6 mL to 1.5 mL: 0.01 g to 0.04 g: 50 mg to 200 mg: 1 mL.

[0034] Preferably, the dosage ratio of the surfactant to water in the surfactant aqueous solution in step 4) is 0.0005 g to 0.001 g: 1 mL.

[0035] Preferably, the surfactant in step 4) is at least one of Tween 20, Tween 60, and Tween 80.

[0036] Preferably, the stock solution in step 4) is slowly added in the form of dropping.

[0037] Preferably, the droplet splitting in step 4) is carried out at a temperature of 45 °C to 65 °C.

[0038] Preferably, the phase change curing in step 4) is carried out at a temperature of 0 °C to 4 °C, and the curing time is 5 min to 10 min.

[0039] A drug comprising the above-mentioned drug-loaded phase change microcapsules.

[0040] The beneficial effects of the present invention are as follows: The drug-loaded phase change microcapsules of the present invention achieve efficient co-encapsulation of hydrophilic drugs and hydrophobic drugs, enabling the synergistic delivery of drugs with different solubilities, enhancing the protection of the core drug components. The microcapsules can remain intact in gastric juice, while in intestinal juice, the drugs can be released through pH-responsive and bile salt-mediated micellization, exhibiting good gastrointestinal sustained-release function and significantly improving the bioaccessibility of the active drugs.

[0041] Specifically:

[0042] 1) The drug-loaded phase change microcapsules of the present invention adopt a co-encapsulation strategy for hydrophilic drugs and hydrophobic drugs based on the Marangoni effect and polyelectrolyte complex coacervates. By using a chitosan-soluble polysaccharide polyelectrolyte complex to encapsulate hydrophilic drugs and co-loading them with hydrophobic drugs in a phase change material, a composite microcapsule is constructed using the droplet self-splitting technology driven by surface tension gradient, solving the limitation of traditional delivery systems in the co-loading of multi-soluble active ingredients and achieving the simultaneous and efficient co-encapsulation of hydrophilic drugs and hydrophobic drugs.

[0043] 2) Compared with the traditional multiple emulsion method, the preparation method of the drug-loaded phase change microcapsules of the present invention shortens the preparation time from several hours to seconds and replaces mechanical energy input with chemical energy, providing an efficient and reliable solution for the multi-component synergistic delivery in the food and pharmaceutical fields.

[0044] 3) The preparation steps of the drug-loaded phase change microcapsules of the present invention are simple and easy to implement. The reaction can be completed under normal temperature and pressure conditions, significantly reducing energy consumption. The raw materials used are all natural bio-based materials, conforming to the concept of green chemistry, ensuring the biosafety and tissue compatibility of the final product. The process parameters in the preparation process are stable and controllable, and the production equipment has strong versatility, providing reliable technical support for industrial continuous production. BRIEF DESCRIPTION OF THE DRAWINGS

[0045] Figure 1 It is the preparation flow chart of the drug-loaded phase change microcapsules of the present invention.

[0046] Figure 2 It is the micrograph of the drug-loaded phase change microcapsules of Examples 1 - 5. DETAILED DESCRIPTION OF THE INVENTION

[0047] The present invention will be further explained and described below in conjunction with specific embodiments.

[0048] Example 1:

[0049] A kind of drug-loaded phase change microcapsule, and its preparation method is as follows (the preparation process is as Figure 1 shown):

[0050] 1) Preparation of chitosan solution and polysaccharide-hydrophilic drug solution:

[0051] Preparation of chitosan solution: Dissolve 7.5 mg of deacetylated chitosan (degree of deacetylation: 95%) in 5 mL of 1% acetic acid solution by mass, and then filter through a filter membrane with a pore size of 0.80 μm (to remove insoluble impurities) to obtain a chitosan solution (concentration: 1.5 mg / mL; denoted as Ch95 solution);

[0052] Preparation of polysaccharide-hydrophilic drug solution: Dissolve 7.5 mg of chondroitin sulfate and 10 mg of procyanidins in 5 mL of deionized water to obtain a polysaccharide-hydrophilic drug solution (concentration of chondroitin sulfate: 1.5 mg / mL, concentration of procyanidins: 2 mg / mL; denoted as CS / PA solution);

[0053] 2) Adjust the pH values of the Ch95 solution and the CS / PA solution to 3.0 respectively using 1 mol / L HCl solution or 1 mol / L NaOH solution. Then slowly drop 5 mL of the CS / PA solution into 5 mL of the stirred Ch95 solution. After adding, stir in the dark at room temperature for 30 min, with a stirring rate of 1500 rpm, centrifuge for 10 min (to remove free polysaccharides), with a centrifugal force of 10000 g, take the solid matter to obtain polyelectrolyte particles;

[0054] 3) Add 0.125 g of polyelectrolyte particles and 5 mL of ethanol to a high-speed shearer, shear for 2 min under the condition of a shear rate of 10000 rpm, then add 5 mL of lauric acid while stirring, with a stirring rate of 2000 rpm. Then take 200 μL of the dispersion and add 10 mg of vitamin D3 to obtain a stock solution;

[0055] 4) Dissolve 0.015 g of Tween 20 in 30 mL of deionized water, adjust the pH value to 5.0 using PBS buffer solution, then pour it into a glass petri dish with a diameter of 12 cm. Place the glass petri dish in a water bath at 50 °C and heat it, then slowly drop 10 μL of the stock solution. After adding, take out the glass petri dish, cool it at 4 °C for 10 min, filter, and take the solid matter to obtain the drug-loaded phase change microcapsules.

[0056] Example 2:

[0057] A drug-loaded phase change microcapsule, which is exactly the same as Example 1 except that in step 1), "deacetylated chitosan with a degree of deacetylation of 95%" is replaced with "deacetylated chitosan with a degree of deacetylation of 80%" in equal weight.

[0058] Example 3:

[0059] A drug-loaded phase change microcapsule, except that during preparation, "chondroitin sulfate" in step 1) is replaced with "gum arabic" in equal weight and "proanthocyanidins" in step 1) is replaced with "vitamin C" in equal weight, is otherwise exactly the same as Example 1.

[0060] Example 4:

[0061] A drug-loaded phase change microcapsule, except that during preparation, "lauric acid" in step 3) is replaced with "stearic acid" in equal volume, is otherwise exactly the same as Example 1.

[0062] Example 5:

[0063] A drug-loaded phase change microcapsule, except that during preparation, "vitamin D3" in step 3) is replaced with "vitamin E" in equal volume, is otherwise exactly the same as Example 1.

[0064] Performance test:

[0065] The drug-loaded phase change microcapsules of Examples 1 to 5 were placed in a drying cylinder and dried at room temperature. Then, an Olympus ix-53 bright-field microscope was used to observe the drug-loaded phase change microcapsules. The exposure was set manually and kept consistent. The obtained micrographs are as Figure 2 (shown as (a - e) for Examples 1 to 5 in sequence).

[0066] It can be seen from Figure 2 that:

[0067] a) The surface of the drug-loaded phase change microcapsule of Example 1 is smooth, the internal structure is dense, presenting a regular spherical structure, and the particle size of the microcapsule is 40 μm to 100 μm;

[0068] b) The drug-loaded phase change microcapsule of Example 2 presents a relatively uniform spherical shape, the surface is smooth, the boundaries between the microcapsules are clear, and no surface overlap or adhesion phenomenon occurs. The particle size of the microcapsule is 50 μm to 150 μm;

[0069] c) The drug-loaded phase change microcapsule of Example 3 is roughly spherical, the surface is relatively smooth, and the edge part is slightly rough. Some small irregularities can be observed in certain areas. The particle size of the microcapsule is 50 μm to 150 μm;

[0070] d) The morphology of the drug-loaded phase change microcapsule of Example 4 is relatively complex and irregular, with wrinkles and depressions on the surface (caused by the fast solidification rate of stearic acid and the crystal form reconstruction during the cooling process). The particle size of the microcapsule is 50 μm to 100 μm;

[0071] e) The drug-loaded phase change microcapsules of Example 5 are regular spherical in shape, and the overall structure is similar to that of the drug-loaded phase change microcapsules of Example 1. The surface of the microcapsules is slightly rough (there are different interaction relationships between different embedded drugs and wall materials), and the particle size of the microcapsules is 50 μm to 200 μm.

[0072] In summary, it can be seen that the present invention can optimize the morphology and properties of the microcapsules by controlling the material characteristics and preparation conditions, so as to meet the different requirements of specific applications.

[0073] The above embodiments are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above embodiments. Any other changes, modifications, substitutions, combinations, and simplifications made without departing from the spirit and principle of the present invention shall be equivalent replacement methods and are all included in the protection scope of the present invention.

Claims

1. A drug-loaded phase change microcapsule, characterized in that The composition includes a phase change material matrix and polyelectrolyte particles filled inside the phase change material matrix; the composition of the phase change material matrix includes a phase change material and a hydrophobic drug; the composition of the polyelectrolyte particles includes chitosan, soluble polysaccharide, and a hydrophilic drug.

2. The drug-loaded phase change microcapsule according to claim 1, wherein: The phase change material is at least one of lauric acid, myristic acid, palmitic acid, and stearic acid.

3. The drug-loaded phase change microcapsule according to claim 1, wherein: The hydrophobic drug is at least one of vitamin A, vitamin D, vitamin E, and vitamin K.

4. The drug-loaded phase change microcapsule according to any one of claims 1 to 3, characterized in that: The soluble polysaccharide is at least one of gum arabic, chondroitin sulfate, dextran sulfate, hyaluronic acid, alginate, carboxymethyl cellulose, and pectin.

5. The drug-loaded phase change microcapsule according to any one of claims 1 to 3, characterized in that: The hydrophilic drug is at least one of proanthocyanidins, tea polyphenols, vitamin C, vitamin B3, and glutathione.

6. The drug-loaded phase change microcapsule according to any one of claims 1 to 3, characterized in that: The mass ratio of the phase change material to the hydrophobic drug in the phase change material matrix is 1:0.1 - 0.2; the mass ratio of chitosan, soluble polysaccharide, and hydrophilic drug in the polyelectrolyte particles is 1:0.1 - 1.5:0.1 - 3.

0.

7. The drug-loaded phase change microcapsule according to any one of claims 1 to 3, characterized in that: The particle size of the polyelectrolyte particles is 400 nm - 900 nm; the particle size of the drug-loaded phase change microcapsules is 40 μm - 200 μm.

8. A method for preparing a drug-loaded phase change microcapsule according to any one of claims 1 to 7, characterized in that, It includes the following steps: 1) Preparation of chitosan solution and polysaccharide-hydrophilic drug solution: Preparation of chitosan solution: Dissolve chitosan in acetic acid solution to obtain chitosan solution; Preparation of polysaccharide-hydrophilic drug solution: Dissolve soluble polysaccharide and hydrophilic drug in water to obtain polysaccharide-hydrophilic drug solution; 2) Add the polysaccharide-hydrophilic drug solution to the chitosan solution for electrostatic self-assembly, and then perform product separation to obtain polyelectrolyte particles; 3) Disperse the phase change material, polyelectrolyte particles, and hydrophobic drug in ethanol to obtain a stock solution; 4) Add the stock solution to an aqueous surfactant solution for droplet splitting, then perform phase change solidification, and then perform product separation to obtain the drug-loaded phase change microcapsules.

9. The preparation method according to claim 8, characterized in that: The electrostatic self-assembly in step 2) is carried out in the dark at room temperature, and the time of electrostatic self-assembly is 15 min - 30 min; the droplet splitting in step 4) is carried out at a temperature of 45°C - 65°C; the phase change solidification in step 4) is carried out at a temperature of 0°C - 4°C, and the solidification time is 5 min - 10 min.

10. A drug, characterized in that, It contains the drug-loaded phase change microcapsules described in any one of claims 1 - 7.

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