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CN-122005486-A - Temperature-sensitive core-shell structure microsphere loaded with active ingredients and preparation method thereof

CN122005486ACN 122005486 ACN122005486 ACN 122005486ACN-122005486-A

Abstract

The invention provides a temperature-sensitive core-shell structure microsphere loaded with active ingredients and a preparation method thereof. The preparation method comprises the steps of uniformly mixing bioactive molecules with sodium alginate solution, crosslinking to form a gel microsphere core layer loaded with the bioactive molecules, soaking the gel microsphere core layer in PNIPAM prepolymer aqueous solution, pre-adsorbing and carrying out ultraviolet irradiation crosslinking to obtain PNIPAM temperature-sensitive core-shell microspheres loaded with the bioactive molecules. The microsphere prepared by the invention has good temperature-sensitive responsiveness, and the PNIPAM shell layer endows the microsphere with obvious temperature-sensitive characteristic, and the microsphere has good safety, good biocompatibility, simple process and mild condition by taking SA and PNIPAM with excellent biocompatibility as main materials.

Inventors

  • MAO CUI
  • TAN HAIYING
  • LIANG XU
  • LIU SHUAI
  • SUN JIUXIAO
  • LIU XIAOHONG
  • PENG JIASHUN

Assignees

  • 中国制浆造纸研究院有限公司
  • 武汉纺织大学

Dates

Publication Date
20260512
Application Date
20260129

Claims (10)

  1. 1. The preparation method of the microsphere with the temperature-sensitive core-shell structure loaded with the active ingredients is characterized by comprising the following steps of: (1) Preparing a core layer, namely uniformly mixing bioactive molecules with a sodium alginate solution to form a mixed solution, then dripping the mixed solution into a cross-linking agent solution, standing and cross-linking for 30-45 minutes to form a gel microsphere core layer loaded with the bioactive molecules; (2) The shell construction method comprises the steps of adding an N-isopropyl acrylamide monomer, a cross-linking agent and a photoinitiator into water to obtain a prepolymer aqueous solution, cleaning a gel microsphere core layer obtained in the step (1), soaking the gel microsphere core layer in the prepolymer aqueous solution, pre-adsorbing for 3-12 hours under a light-proof condition, and irradiating with ultraviolet light with the wavelength of 365 nm for 0.5 min-24 hours to obtain the PNIPAM temperature-sensitive core-shell microsphere loaded with active molecules, wherein the ultraviolet light irradiation intensity is 10-40 mW/cm 2 .
  2. 2. The method for preparing a microsphere with a temperature-sensitive core-shell structure loaded with active ingredients according to claim 1, wherein the bioactive molecule in the step (1) is at least one of centella asiatica extract, hyaluronic acid and leonurus extract.
  3. 3. The method for preparing the microsphere with the temperature-sensitive core-shell structure loaded with the active ingredient according to claim 1, wherein the concentration of the sodium alginate solution in the step (1) is 0.5w/v% to 2.5w/v%.
  4. 4. The method for preparing the microsphere with the temperature-sensitive core-shell structure loaded with the active ingredients according to claim 1, wherein the mass ratio of the bioactive molecules in the step (1) to the sodium alginate solution is 0.5-1:3-5.
  5. 5. The preparation method of the active ingredient-loaded temperature-sensitive core-shell structure microsphere is characterized in that the concentration of the cross-linking agent solution in the step (1) is 1.5-3.0 w/v%, and the cross-linking agent is CaCl 2 or FeCl 3 .
  6. 6. The preparation method of the microsphere with the active ingredient-loaded temperature-sensitive core-shell structure, which is characterized in that the volume ratio of the mixed solution to the cross-linking agent solution in the step (1) is 1 (0.005-10), the dripping is carried out by adopting microfluidic injection, and the flow rate is 0.1 mL/min-100 mL/min.
  7. 7. The method for preparing the microsphere with the active ingredient-loaded temperature-sensitive core-shell structure according to claim 1, wherein the crosslinking agent in the step (2) is at least one of N, N '-methylenebisacrylamide, ethylene glycol methacrylate and triglyceryl methacrylate, and the photoinitiator is at least one of 2-hydroxy-4' - (2-hydroxyethoxy) -2-methylpropenone, 2-hydroxy-2-methyl-1-phenyl-1-propanone, hydroxycyclohexyl phenyl ketone and isopropylthioxanthone.
  8. 8. The method for preparing the microsphere with the active ingredient-loaded temperature-sensitive core-shell structure according to claim 1, wherein in the prepolymer aqueous solution in the step (2), the concentration of the N-isopropyl acrylamide monomer is 5-8%, the concentration of the cross-linking agent is 0.1-20%, and the concentration of the photoinitiator is 0.005-1%.
  9. 9. The method for preparing a microsphere with a temperature sensitive core-shell structure loaded with an active ingredient according to claim 1, wherein the ratio of the gel microsphere core layer to the prepolymer aqueous solution in the step (2) is 1 (0.01-2).
  10. 10. A temperature-sensitive core-shell structure microsphere prepared by the preparation method of claim 1, wherein the temperature-sensitive core-shell structure microsphere is provided with a calcium alginate/bioactive molecule composite gel core and a PNIPAM crosslinked polymer shell coated outside the core, and the particle size of the temperature-sensitive core-shell structure microsphere is 1.22-1750 μm.

Description

Temperature-sensitive core-shell structure microsphere loaded with active ingredients and preparation method thereof Technical Field The invention relates to the technical field of drug carriers, in particular to a temperature-sensitive core-shell structure microsphere loaded with active ingredients and a preparation method thereof. Background Temperature-sensitive polymer materials such as poly-N-isopropyl acrylamide (PNIPAM) have great application potential in the fields of drug controlled release, tissue engineering and the like due to the characteristic of reversible transformation of hydrophilicity and hydrophobicity near a lower critical solution temperature (LCST, about 32-34 ℃). PNIPAM is combined with natural polymers with good biocompatibility (such as sodium alginate and SA), so that core-shell structure microspheres are constructed, and the microspheres can realize the release of temperature responsive drugs and protect active molecules by utilizing the good biocompatibility of SA and mild ion gel conditions. In the prior art, a one-step method or simple blending crosslinking is often adopted to prepare the temperature-sensitive microspheres, but the problems of poor structural uniformity, low encapsulation efficiency of active molecules, difficult compromise of temperature-sensitive response performance and structural strength and the like exist. In particular, there is still a need for improvement in how to precisely control the particle size of microspheres, to achieve stable construction of core-shell structures, and to ensure the activity of active molecules during the preparation process. Disclosure of Invention Therefore, the invention aims to provide a preparation method of the microsphere with the core-shell structure, which has controllable structure, high encapsulation efficiency and good temperature-sensitive responsiveness and is used for loading active molecules. In order to achieve the above purpose, the present invention provides the following technical solutions: the preparation method of the microsphere with the temperature-sensitive core-shell structure for loading the active ingredients comprises the following steps: (1) Preparing a core layer, namely uniformly mixing bioactive molecules with a sodium alginate solution to form a mixed solution, then dripping the mixed solution into a cross-linking agent solution, standing and cross-linking for 30-45 minutes to form a gel microsphere core layer loaded with the bioactive molecules; (2) The shell construction method comprises the steps of adding N-isopropyl acrylamide (NIPAM) monomers, a cross-linking agent and a photoinitiator into water to obtain a prepolymer aqueous solution, cleaning the gel microsphere core layer obtained in the step (1), soaking the gel microsphere core layer in the prepolymer aqueous solution, pre-adsorbing for 3-12 hours under a light-proof condition, and irradiating 45-min with ultraviolet light with the wavelength of 365 nm to obtain PNIPAM temperature-sensitive core-shell microspheres loaded with active molecules, wherein the ultraviolet light irradiation intensity is 10-40 mW/cm 2. Preferably, the bioactive molecule in the step (1) is at least one of centella asiatica extract (asiaticoside 80%, purchased from Guangzhou Haoxing fine chemical industry), hyaluronic acid, and herba Leonuri extract (food grade) leonurine, purchased from Guangxi biological technology). Preferably, the concentration of the sodium alginate solution in the step (1) is 0.5w/v% to 2.5w/v%. Preferably, the mass ratio of the bioactive molecules in the step (1) to the sodium alginate solution is 0.5-1:3-5. Preferably, the concentration of the cross-linking agent solution in the step (1) is 1.5w/v% -3.0 w/v%, and the cross-linking agent is CaCl 2 or FeCl 3. Preferably, the volume ratio of the mixed solution in the step (1) to the cross-linking agent solution is 1 (0.005-10), the dripping is carried out by microfluidic injection, and the flow rate is 0.1 mL/min-50 mL/min. Preferably, the cross-linking agent in the step (2) is at least one of N, N '-Methylene Bisacrylamide (MBA), ethylene glycol methacrylate and triglyceryl methacrylate, and the photoinitiator is at least one of 2-hydroxy-4' - (2-hydroxyethoxy) -2-methylpropenyl acetone (2659), 2-hydroxy-2-methyl-1-phenyl-1-acetone (1173), hydroxycyclohexyl phenyl ketone (184) and Isopropyl Thioxanthone (ITX). Preferably, in the prepolymer aqueous solution in the step (2), the concentration of the N-isopropyl acrylamide monomer is 5-8%, the concentration of the cross-linking agent is 0.1-10%, and the concentration of the photoinitiator is 0.005-1%. Preferably, the ratio of the gel microsphere core layer to the prepolymer aqueous solution in the step (2) is 1 (0.01-2). It is another object of the present invention to provide a temperature-sensitive core-shell structure microsphere prepared by the above method, wherein the particle size of the temperature-sensitive core-shell structure