A starch-based colon dual-targeting microgel, and a preparation method and application thereof

Abstract

The application discloses starch-based colon double-targeting microgels, a preparation method and application thereof. The preparation method comprises the following steps: covalently connecting chondroitin sulfate to beta-cyclodextrin by EDC to prepare beta-cyclodextrin-chondroitin sulfate; encapsulating a hydrophobic bioactive substance in the hydrophobic cavity of the beta-cyclodextrin in the beta-cyclodextrin-chondroitin sulfate to prepare beta-cyclodextrin-chondroitin sulfate loaded with the bioactive substance; modifying dextrin by octenyl succinic anhydride to prepare modified dextrin; and making a first mixed reaction system comprising the beta-cyclodextrin-chondroitin sulfate loaded with the bioactive substance, the modified dextrin and sodium trimetaphosphate to have a crosslinking reaction to prepare starch-based colon double-targeting microgels. The starch-based colon double-targeting microgels have good encapsulation and protection effects on the bioactive substance, and have a targeting effect in the colon, so that the bioactive substance can be more effectively delivered.

Description

Technical Field

[0001] This invention belongs to the field of biomedical materials technology, specifically relating to a starch-based colon dual-targeting microgel, its preparation method, and its application. Background Technology

[0002] The colon, located at the end of the intestine, is the site where orally ingested substances are digested in the small intestine and cannot reach it. Utilizing the anti-digestive properties of materials can deliver bioactive substances to the colon, thus promoting colonic health. However, some colon-targeted delivery systems are composed of inorganic or synthetic materials, which have potential side effects. Therefore, developing colon-targeted delivery systems constructed from natural materials is essential.

[0003] Starch, as a natural macromolecular polysaccharide, possesses abundant resources, wide availability, low price, renewable nature, biodegradability, and good biocompatibility. Starch is a biopolymer composed of amylose and amylopectin, existing in granular form. Amylose is a linear macromolecule formed by D-glucose linked by α-(1-4)-glycosidic bonds, while amylopectin is a branched molecule containing (1-6)-glycosidic bonds linking α-D-glucose ions. Amylose can be converted into cyclodextrins under enzymatic action, exhibiting an internally hydrophobic and externally hydrophilic structure, making it an excellent encapsulation and delivery carrier for hydrophobic bioactive substances. Resistant starch, a substance that cannot be absorbed by the human small intestine, is an ideal material for constructing colon-targeted delivery systems. Resistant starch is generally classified into five categories: physically encapsulated starch (RS1), ungelatinized starch granules (RS2), retrograded starch (RS3), chemically modified starch (RS4), and starch-lipid complex (RS5). It not only has a low glycemic index, but can also be fermented by microorganisms in the colon, which is beneficial to human health.

[0004] Chondroitin sulfate, as a natural biomolecule, has a CD44 targeting effect. Grafting it onto the surface of a carrier can improve the targeting of bioactive substances. Encapsulating the targeting carrier in resistant starch-based microspheres can protect it from the influence of the gastric and small intestinal environment, effectively improving its targeting effect in the colon. Furthermore, resistant starch, as a prebiotic, can also effectively regulate intestinal health. Summary of the Invention

[0005] The main objective of this invention is to provide a starch-based colon dual-targeting microgel, its preparation method, and its application, in order to overcome the shortcomings of the prior art.

[0006] To achieve the aforementioned objectives, the technical solution adopted by this invention includes:

[0007] This invention provides a method for preparing a starch-based colon dual-targeting microgel, comprising:

[0008] β-Cyclodextrin-chondroitin sulfate was prepared by covalently linking chondroitin sulfate to β-cyclodextrin using 1-ethyl-(3-dimethylaminopropyl)carbodiimide.

[0009] Hydrophobic bioactive substances are encapsulated in the hydrophobic cavity of β-cyclodextrin in the β-cyclodextrin-chondroitin sulfate to obtain β-cyclodextrin-chondroitin sulfate loaded with bioactive substances.

[0010] Modified dextrin was prepared by modifying dextrin with octenyl succinic anhydride.

[0011] Furthermore, a cross-linking reaction is carried out on a first mixed reaction system containing the bioactive substances loaded with β-cyclodextrin-chondroitin sulfate, modified dextrin, and sodium trimetaphosphate to obtain a starch-based colonic dual-targeting microgel.

[0012] The present invention also provides a starch-based colon dual-targeting microgel prepared by the aforementioned preparation method, wherein the particle size of the starch-based colon dual-targeting microgel is 73.62–107.37 μm.

[0013] This invention also provides the application of the aforementioned starch-based colonic dual-targeting microgel in the preparation of colonic-targeted delivery bioactive substances.

[0014] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0015] (1) In this invention, EDC is used to mediate a specific esterification reaction between the primary hydroxyl group of β-cyclodextrin and the carboxyl group of chondroitin sulfate. The targeted delivery of bioactive substances is achieved by utilizing the targeting effect of chondroitin sulfate on CD44 receptor, and the grafting does not destroy the cyclic structure of β-cyclodextrin.

[0016] (2) The present invention uses ultrasound-assisted preparation of OSA-resistant dextrin, which can improve the grafting efficiency of OSA groups;

[0017] (3) The OSA-resistant dextrin gel matrix used in this invention can crosslink the hydroxyl groups of OSA-resistant dextrin and β-cyclodextrin to form microgels under the action of sodium trimetaphosphate; OSA-resistant dextrin can resist the digestion of enzymes in the small intestine and be fermented by microorganisms in the colon to release β-CD-CS loaded with bioactive substances, which has a passive targeting effect.

[0018] (4) The starch-based microgel prepared by this invention has a good protective effect on bioactive substances and has a dual targeting effect. Attached Figure Description

[0019] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are only some embodiments recorded in the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0020] Figure 1 This is a cumulative release diagram of free curcumin, Cur@β-CD-CS, and Cur@β-CD-CS in MPs prepared in Example 1 of this invention. Detailed Implementation

[0021] In view of the deficiencies of the prior art, the inventors of this case, through long-term research and extensive practice, have proposed the technical solution of this invention. The technical solution of this invention will be clearly and completely described below. Obviously, the described embodiments are only some, not all, of the embodiments of this invention. All other embodiments obtained by those skilled in the art based on the embodiments of this invention without creative effort are within the scope of protection of this invention.

[0022] Specifically, as one aspect of the technical solution of this invention, the preparation method of a starch-based colon dual-targeting microgel includes:

[0023] Chondroitin sulfate (CS) was covalently linked to β-cyclodextrin (β-CD) using 1-ethyl-(3-dimethylaminopropyl)carbodiimide (EDC) to prepare β-cyclodextrin-chondroitin sulfate (β-CD-CS);

[0024] Hydrophobic bioactive substances are encapsulated in the hydrophobic cavity of β-cyclodextrin in the β-cyclodextrin-chondroitin sulfate to obtain β-cyclodextrin-chondroitin sulfate loaded with bioactive substances (β-CD-CS loaded with bioactive substances).

[0025] Modified dextrin (OSA-resistant dextrin) was prepared by modifying dextrin with octenyl succinic anhydride.

[0026] Furthermore, a cross-linking reaction is carried out on a first mixed reaction system containing the bioactive substances loaded with β-cyclodextrin-chondroitin sulfate, modified dextrin, and sodium trimetaphosphate to obtain a starch-based colonic dual-targeting microgel.

[0027] In some preferred embodiments, the preparation method includes: dissolving chondroitin sulfate and β-cyclodextrin in water to form chondroitin sulfate solution and β-cyclodextrin solution, respectively; adding 1-ethyl-(3-dimethylaminopropyl)carbodiimide to the chondroitin sulfate solution; then adding the β-cyclodextrin solution and mixing and stirring; and reacting at a speed of 200-800 rpm and a temperature of 20-25°C for 30-60 min to obtain the β-cyclodextrin-chondroitin sulfate.

[0028] Furthermore, the chondroitin sulfate solution contains 0.5-2.0 wt% chondroitin sulfate.

[0029] Further, chondroitin sulfate and β-cyclodextrin were dissolved in water and stirred continuously at 4-6℃ and 200-800 rpm for 1-4 hours to prepare chondroitin sulfate solution and β-cyclodextrin solution, respectively.

[0030] Furthermore, EDC is added to the chondroitin sulfate solution to activate the carbonyl group, and the amount added is 0.1-0.2% of the chondroitin sulfate mass.

[0031] Furthermore, the β-cyclodextrin content in the β-cyclodextrin solution is 0.5-2.0 wt%.

[0032] Further, the mass ratio of 1-ethyl-(3-dimethylaminopropyl)carbodiimide to chondroitin sulfate is 0.1-0.2:100.

[0033] In some preferred embodiments, the preparation method includes: dissolving a hydrophobic bioactive substance in ethanol, and then mixing and reacting it with the β-cyclodextrin-chondroitin sulfate to obtain the β-cyclodextrin-chondroitin sulfate loaded with the bioactive substance.

[0034] Furthermore, the hydrophobic bioactive substance includes any one or a combination of two or more of curcumin, α-tocopherol, and resveratrol, but is not limited thereto.

[0035] In some preferred embodiments, the preparation method includes: dissolving octenyl succinic anhydride in ethanol and adding it dropwise to a dextrin solution at 40-60°C to form a second mixed reaction system, then subjecting the mixture to ultrasonic-assisted treatment at a power of 100-700W for 1-2 hours, while controlling the pH of the second mixed reaction system to 7-9, adjusting the pH of the obtained mixture to 5-6 after the reaction is complete, and then washing, centrifuging, and drying to obtain the modified dextrin.

[0036] Furthermore, the mass ratio of the octenyl succinic anhydride to dextrin is 0.01-0.05:1.

[0037] In some preferred embodiments, the preparation method includes: dispersing the β-cyclodextrin-chondroitin sulfate loaded with bioactive substances in a modified dextrin solution, adding sodium trimetaphosphate to form the first mixed reaction system, stirring at 500-1000 rpm for 20-40 min, and then heating at 40-50°C for 20-60 min to obtain the starch-based colon dual-targeting microgel.

[0038] Furthermore, the modified dextrin content in the modified dextrin solution is 10-20 wt%.

[0039] Furthermore, the mass ratio of the bioactive substance-loaded β-cyclodextrin-chondroitin sulfate to the modified dextrin is 0.05-0.2:1.

[0040] Furthermore, the mass ratio of sodium trimetaphosphate to modified dextrin is 5-15:100.

[0041] In some more specific embodiments, the preparation method of the starch-based colon dual-targeting microgel includes:

[0042] (1) Chondroitin sulfate and β-cyclodextrin were dissolved in deionized water, and 1-ethyl-(3-dimethylaminopropyl)carbodiimide (EDC) was added to covalently link chondroitin sulfate (CS) to β-cyclodextrin (β-CD), thereby further encapsulating the hydrophobic bioactive substance in the hydrophobic cavity of β-cyclodextrin to construct β-CD-CS loaded with bioactive substance;

[0043] (2) Dextrin was modified with octenyl succinic anhydride under ultrasonic assistance to obtain OSA-resistant dextrin;

[0044] (3) Add the β-CD-CS loaded with bioactive substances obtained in step (1) to the OSA-resistant dextrin solution obtained in step (2), and further crosslink with sodium trimetaphosphate to obtain starch-based colon dual-targeting microgel.

[0045] Further, in step (2), the preparation of OSA-resistant dextrin involves dissolving octenyl succinic anhydride in 3 times its mass of ethanol and adding it dropwise to the dextrin solution, controlling the temperature at 40-50℃, and maintaining the pH of the mixed reaction system at 7-9. After the octenyl succinic anhydride is added, the mixed system is subjected to ultrasonic treatment at 100-700W for 1-2 hours, during which the pH of the system is controlled at 7-9, to obtain the OSA-resistant dextrin. After the above reaction is completed, the pH of the obtained mixed system is adjusted to 5-6, and then washed, centrifuged, and dried.

[0046] Furthermore, in step (3), the OSA-resistant dextrin solution is prepared by heating at 80-100℃ for 15-30 min.

[0047] Furthermore, in step (3), the concentration of the OSA-resistant dextrin solution is 10%-20%.

[0048] Further, in step (3), β-CD-CS loaded with bioactive substances is dispersed in 10-20% OSA-resistant dextrin solution, and the mass ratio of β-CD-CS loaded with bioactive substances to OSA-resistant dextrin is 0.05-0.2. Then, 5-15% of the mass of OSA-resistant dextrin sodium trimetaphosphate is added to the mixing system, stirred at 500-1000 rpm for 20-40 min, heated at 40-50℃ for 30-60 min to form a large gel, and then crushed and sieved to obtain a gel with a uniform particle size.

[0049] Another aspect of the present invention provides a starch-based colonic dual-targeting microgel prepared by the aforementioned preparation method, wherein the particle size of the starch-based colonic dual-targeting microgel is 73.62–107.37 μm.

[0050] Furthermore, the starch-based colonic dual-targeting microgel provides excellent protection and targeted delivery of bioactive substances.

[0051] The resistant starch-based microgel in the starch-based colonic dual-targeting microgel of this invention enables the release of cyclodextrin carriers in the colon, and the chondroitin sulfate in the modified cyclodextrin enables the carriers to target colonic cells.

[0052] Another aspect of the present invention provides the application of the aforementioned starch-based colonic dual-targeting microgel in the preparation of colonic-targeted delivery bioactive substances.

[0053] The technical solution of the present invention will be further described in detail below with reference to several preferred embodiments and accompanying drawings. This embodiment is implemented on the premise of the technical solution of the invention, and provides detailed implementation methods and specific operation processes. However, the protection scope of the present invention is not limited to the following embodiments.

[0054] Unless otherwise specified, the experimental materials used in the examples below can be purchased from conventional biochemical reagent companies.

[0055] Example 1

[0056] (1) Prepare a 0.5% chondroitin sulfate solution and a 1% β-CD solution, and stir continuously at 4℃ and 500rpm for 2h to ensure sufficient hydration; add EDC to the chondroitin sulfate solution to activate the carbonyl group, the amount of which is 0.1% of the mass of chondroitin sulfate; then add the β-CD solution to the chondroitin sulfate solution and react at 500rpm for 60min. After the reaction is completed, wash and dry to obtain β-CD-CS; dissolve curcumin (Cur) in ethanol and add it dropwise to the β-CD-CS solution to prepare Cur@β-CD-CS.

[0057] (2) Dissolve octenyl succinic anhydride in 3 times its mass of ethanol and add it dropwise to the dextrin solution. Control the temperature at 50°C and maintain the pH of the mixed reaction system at 8. After the octenyl succinic anhydride is added, place the mixed system under 500W ultrasonic assisted treatment for 2 hours, during which the pH of the system is controlled at 8. After the above reaction is completed, adjust the pH of the obtained mixed system to 6, and then wash, centrifuge and dry to obtain OSA-resistant dextrin.

[0058] (3) Heat a 10% OSA-resistant dextrin solution at 90°C for 30 min, disperse Cur@β-CD-CS in the OSA-resistant dextrin solution, with a mass ratio of Cur@β-CD-CS to OSA-resistant dextrin of 0.1. Then add 10% of the mass of OSA-resistant dextrin with sodium trimetaphosphate to the mixture, stir at 500 rpm for 30 min, heat at 50°C for 30 min to form a large gel, pulverize and sieve to obtain starch-based colon dual-targeting microgels with uniform particle size (denoted as: Cur@β-CD-CS in MPs).

[0059] In addition, the applicant also prepared Cur@β-CD and Cur@β-CD-CS under the above conditions, and characterized them with Cur@β-CD-CS in MPs prepared in this embodiment. Table 1 shows the average particle size, ζ-potential, encapsulation efficiency and loading capacity of Cur@β-CD, Cur@β-CD-CS and Cur@β-CD-CS in MPs prepared in Example 1 of this invention; Table 2 shows the stability of Cur@β-CD, Cur@β-CD-CS and Cur@β-CD-CS in MPs prepared in Example 1 of this invention in the gastrointestinal tract. Figure 1 This is a cumulative release diagram of free curcumin, Cur@β-CD-CS, and Cur@β-CD-CS in MPs prepared in Example 1 of this invention.

[0060] Table 1. Characterization results of average particle size, ζ-potential, encapsulation efficiency, and loading capacity of Cur@β-CD, Cur@β-CD-CS, and Cur@β-CD-CS in MPs.

[0061]

[0062] Table 2. Stability of Cur@β-CD, Cur@β-CD-CS and Cur@β-CD-CS in MPs in the gastrointestinal tract

[0063]

[0064] Example 2

[0065] (1) Prepare a 1% chondroitin sulfate solution and a 2% β-CD solution, and stir continuously at 5℃ and 600 rpm for 3 h to ensure sufficient hydration; add EDC to the chondroitin sulfate solution to activate the carbonyl group, the amount of which is 0.2% of the mass of chondroitin sulfate; then add the β-CD solution to the chondroitin sulfate solution and react at 600 rpm for 40 min. After the reaction is completed, wash and dry to obtain β-CD-CS; dissolve curcumin in ethanol and add it dropwise to the β-CD-CS solution to prepare Cur@β-CD-CS.

[0066] (2) Dissolve octenyl succinic anhydride in 3 times its mass of ethanol and add it dropwise to the dextrin solution. Control the temperature at 40°C and maintain the pH of the mixed reaction system at 7. After the octenyl succinic anhydride is added, place the mixed system under 700W ultrasonic assisted treatment for 1 hour, during which the pH of the system is controlled at 7. After the above reaction is completed, adjust the pH of the obtained mixed system to 6, and then wash, centrifuge and dry to obtain OSA-resistant dextrin.

[0067] (3) Heat a 15% OSA-resistant dextrin solution at 95°C for 30 min, disperse Cur@β-CD-CS in the OSA-resistant dextrin solution, with a mass ratio of Cur@β-CD-CS to OSA-resistant dextrin of 0.2, then add 5% of the mass of OSA-resistant dextrin and sodium trimetaphosphate to the mixture, stir at 600 rpm for 20 min, heat at 40°C for 30 min to form a large gel, pulverize and sieve to obtain starch-based colon dual-targeting microgels with uniform particle size.

[0068] Example 3

[0069] (1) Prepare a 0.5% chondroitin sulfate solution and a 2% β-CD solution, and stir continuously at 6℃ and 800rpm for 1h to ensure sufficient hydration; add EDC to the chondroitin sulfate solution to activate the carbonyl group, the amount of which is 0.1% of the mass of chondroitin sulfate; then add the β-CD solution to the chondroitin sulfate solution and react at 800rpm for 30min. After the reaction is completed, wash and dry to obtain β-CD-CS; dissolve curcumin in ethanol and add it dropwise to the β-CD-CS solution to prepare Cur@β-CD-CS.

[0070] (2) Dissolve octenyl succinic anhydride in 3 times its mass of ethanol and add it dropwise to the dextrin solution. Control the temperature at 60°C and maintain the pH of the mixed reaction system at 9. After the octenyl succinic anhydride is added, place the mixed system under 400W ultrasonic assisted treatment for 2 hours, during which the pH of the system is controlled at 9. After the above reaction is completed, adjust the pH of the obtained mixed system to 5, and then wash, centrifuge and dry to obtain OSA-resistant dextrin.

[0071] (3) Heat a 15% OSA-resistant dextrin solution at 100°C for 30 min, disperse Cur@β-CD-CS in the OSA-resistant dextrin solution, with a mass ratio of Cur@β-CD-CS to OSA-resistant dextrin of 0.05, then add 15% of the mass of OSA-resistant dextrin with sodium trimetaphosphate to the mixture, stir at 800 rpm for 40 min, heat at 40°C for 50 min to form a large gel, pulverize and sieve to obtain starch-based colon dual-targeting microgels with uniform particle size.

[0072] Example 4

[0073] (1) Prepare a 1% chondroitin sulfate solution and a 1% β-CD solution, and stir continuously at 4℃ and 700rpm for 3h to ensure sufficient hydration; add EDC to the chondroitin sulfate solution to activate the carbonyl group, the amount of which is 0.2% of the mass of chondroitin sulfate; then add the β-CD solution to the chondroitin sulfate solution and react at 700rpm for 50min. After the reaction is completed, wash and dry to obtain β-CD-CS; dissolve α-tocopherol in ethanol and add it dropwise to the β-CD-CS solution to prepare α-tocopherol@β-CD-CS.

[0074] (2) Dissolve octenyl succinic anhydride in 3 times its mass of ethanol and add it dropwise to the dextrin solution. Control the temperature at 50°C and maintain the pH of the mixed reaction system at 8. After the octenyl succinic anhydride is added, place the mixed system under 200W ultrasonic assisted treatment for 2 hours, during which the pH of the system is controlled at 8. After the above reaction is completed, adjust the pH of the obtained mixed system to 6, and then wash, centrifuge and dry to obtain OSA-resistant dextrin.

[0075] (3) Heat a 10% OSA-resistant dextrin solution at 90°C for 15 min, disperse α-tocopherol@β-CD-CS in the OSA-resistant dextrin solution, with a mass ratio of α-tocopherol@β-CD-CS to OSA-resistant dextrin of 0.1, then add 10% of the mass of OSA-resistant dextrin with sodium trimetaphosphate to the mixture, stir at 700 rpm for 30 min, heat at 50°C for 30 min to form a large gel, pulverize and sieve to obtain starch-based colon dual-targeting microgels with uniform particle size.

[0076] Example 5

[0077] (1) Prepare a 2% chondroitin sulfate solution and a 1% β-CD solution, and stir continuously at 400 rpm for 4 h at 4 °C to ensure sufficient hydration; add EDC to the chondroitin sulfate solution to activate the carbonyl group, the amount of which is 0.2% of the mass of chondroitin sulfate; then add the β-CD solution to the chondroitin sulfate solution and react at 400 rpm for 50 min. After the reaction is completed, wash and dry to obtain β-CD-CS; dissolve resveratrol in ethanol and add it dropwise to the β-CD-CS solution to prepare Res@β-CD-CS.

[0078] (2) Dissolve octenyl succinic anhydride in 3 times its mass of ethanol and add it dropwise to the dextrin solution. Control the temperature at 50°C and maintain the pH of the mixed reaction system at 9. After the octenyl succinic anhydride is added, place the mixed system under 700W ultrasonic assisted treatment for 1 hour, during which the pH of the system is controlled at 9. After the above reaction is completed, adjust the pH of the obtained mixed system to 6, and then wash, centrifuge and dry to obtain OSA-resistant dextrin.

[0079] (3) Heat a 20% OSA-resistant dextrin solution at 100°C for 30 min, disperse Res@β-CD-CS in the OSA-resistant dextrin solution, with a mass ratio of Res@β-CD-CS to OSA-resistant dextrin of 0.2, then add 8% of the mass of OSA-resistant dextrin with sodium trimetaphosphate to the mixture, stir at 400 rpm for 40 min, heat at 50°C for 60 min to form a large gel, pulverize and sieve to obtain starch-based colon dual-targeting microgels with uniform particle size.

[0080] Example 6

[0081] (1) Prepare a 1% chondroitin sulfate solution and a 0.5% β-CD solution, and stir continuously at 5℃ and 800rpm for 3h to ensure sufficient hydration; add EDC to the chondroitin sulfate solution to activate the carbonyl group, the amount of which is 0.2% of the mass of chondroitin sulfate; then add the β-CD solution to the chondroitin sulfate solution and react at 800rpm for 30min. After the reaction is completed, wash and dry to obtain β-CD-CS; dissolve curcumin in ethanol and add it dropwise to the β-CD-CS solution to prepare Cur@β-CD-CS.

[0082] (2) Dissolve octenyl succinic anhydride in 3 times its mass of ethanol and add it dropwise to the dextrin solution. Control the temperature at 60°C and maintain the pH of the mixed reaction system at 8. After the octenyl succinic anhydride is added, place the mixed system under 600W ultrasonic assisted treatment for 2 hours, during which the pH of the system is controlled at 8. After the above reaction is completed, adjust the pH of the obtained mixed system to 6, and then wash, centrifuge and dry to obtain OSA-resistant dextrin.

[0083] (3) Heat a 15% OSA-resistant dextrin solution at 80°C for 20 min, disperse Cur@β-CD-CS in the OSA-resistant dextrin solution, with a mass ratio of Cur@β-CD-CS to OSA-resistant dextrin of 0.15, then add 9% of the mass of OSA-resistant dextrin and sodium trimetaphosphate to the mixture, stir at 800 rpm for 30 min, heat at 60°C for 20 min to form a large gel, pulverize and sieve to obtain starch-based colon dual-targeting microgels with uniform particle size.

[0084] In summary, the starch-based colonic dual-targeting microgel obtained by the above-described technical solution of this invention utilizes the targeting effect of chondroitin sulfate on the CD44 receptor to achieve targeted delivery of bioactive substances, and the grafting does not disrupt the cyclic structure of β-cyclodextrin; the OSA-resistant dextrin matrix can protect the bioactive substances, preventing premature release in the stomach and small intestine. The method for preparing the starch-based colonic dual-targeting microgel of this invention is simple to operate, low in cost, and effectively improves the targeting of bioactive substances.

[0085] In addition, the inventors of this case also conducted experiments with other raw materials and conditions listed in this specification, referring to Examples 1 to 6, and similarly obtained starch-based colonic dual-targeting microgels.

[0086] It should be understood that the technical solutions of the present invention are not limited to the specific embodiments described above. Any technical modifications made to the technical solutions of the present invention without departing from the spirit and scope of the claims are within the scope of protection of the present invention.

Claims

1. A method for preparing a starch-based colon dual-targeting microgel, characterized in that... include: β-Cyclodextrin-chondroitin sulfate was prepared by covalently linking chondroitin sulfate to β-cyclodextrin using 1-ethyl-(3-dimethylaminopropyl)carbodiimide. A hydrophobic bioactive substance is encapsulated within the hydrophobic cavity of β-cyclodextrin in the β-cyclodextrin-chondroitin sulfate to obtain β-cyclodextrin-chondroitin sulfate loaded with bioactive substance; wherein the hydrophobic bioactive substance is selected from any one or a combination of two or more of curcumin, α-tocopherol, and resveratrol. Modified dextrin was prepared by modifying dextrin with octenyl succinic anhydride. Furthermore, a cross-linking reaction is carried out on a first mixed reaction system containing the bioactive substances loaded with β-cyclodextrin-chondroitin sulfate, modified dextrin, and sodium trimetaphosphate to obtain a starch-based colon dual-targeting microgel; the particle size of the starch-based colon dual-targeting microgel is 73.62–107.37 μm.

2. The preparation method according to claim 1, characterized in that... include: Chondroitin sulfate and β-cyclodextrin were dissolved in water to form chondroitin sulfate solution and β-cyclodextrin solution, respectively. Then, 1-ethyl-(3-dimethylaminopropyl)carbodiimide was added to the chondroitin sulfate solution, followed by the β-cyclodextrin solution. The mixture was stirred and reacted at 200-800 rpm and 20-25°C for 30-60 min to obtain the β-cyclodextrin-chondroitin sulfate solution.

3. The preparation method according to claim 2, characterized in that: The chondroitin sulfate solution contains 0.5-2.0 wt% chondroitin sulfate. And / or, the β-cyclodextrin content in the β-cyclodextrin solution is 0.5-2.0 wt%; And / or, the mass ratio of 1-ethyl-(3-dimethylaminopropyl)carbodiimide to chondroitin sulfate is 0.1-0.2:

100.

4. The preparation method according to claim 1, characterized in that... include: The hydrophobic bioactive substance was dissolved in ethanol and then mixed with the β-cyclodextrin-chondroitin sulfate to prepare the β-cyclodextrin-chondroitin sulfate loaded with the bioactive substance.

5. The preparation method according to claim 1, characterized in that... include: Octenyl succinic anhydride was dissolved in ethanol and added dropwise to the dextrin solution at 40-60°C to form a second mixed reaction system. Then, the mixture was ultrasonically assisted for 1-2 hours at a power of 100-700W, while the pH of the second mixed reaction system was controlled at 7-9. After the reaction was completed, the pH of the resulting mixture was adjusted to 5-6, and then washed, centrifuged, and dried to obtain the modified dextrin.

6. The preparation method according to claim 5, characterized in that: The mass ratio of octenyl succinic anhydride to dextrin is 0.01-0.05:

1.

7. The preparation method according to claim 1, characterized in that... include: The β-cyclodextrin-chondroitin sulfate loaded with bioactive substances was dispersed in a modified dextrin solution, and sodium trimetaphosphate was added to form the first mixed reaction system. The mixture was stirred at 500-1000 rpm for 20-40 min, and then heated at 40-50℃ for 20-60 min to obtain the starch-based colon dual-targeting microgel.

8. The preparation method according to claim 7, characterized in that: The modified dextrin solution contains 10-20 wt% modified dextrin. And / or, the mass ratio of the bioactive substance-loaded β-cyclodextrin-chondroitin sulfate to modified dextrin is 0.05-0.2:1; And / or, the mass ratio of sodium trimetaphosphate to modified dextrin is 5-15:

100.

9. A starch-based colonic dual-targeting microgel prepared by any one of claims 1-8.

10. The use of the starch-based colonic dual-targeting microgel of claim 9 in the preparation of colonic-targeted delivery bioactive substances.

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