CN113372578A - preparation method of pH response type carboxymethyl chitosan/sodium alginate hydrogel spheres - Google Patents
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- C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
- C08J3/00—Processes of treating or compounding macromolecular substances
- C08J3/02—Making solutions, dispersions, lattices or gels by other methods than by solution, emulsion or suspension polymerisation techniques
- C08J3/03—Making solutions, dispersions, lattices or gels by other methods than by solution, emulsion or suspension polymerisation techniques in aqueous media
- C08J3/075—Macromolecular gels
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
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- A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
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- C08J3/00—Processes of treating or compounding macromolecular substances
- C08J3/24—Crosslinking, e.g. vulcanising, of macromolecules
- C08J3/246—Intercrosslinking of at least two polymers
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- C08J2305/00—Characterised by the use of polysaccharides or of their derivatives not provided for in groups C08J2301/00 or C08J2303/00
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Abstract
The invention belongs to the field of high-molecular polymer hydrogel, and relates to a preparation method of pH response type carboxymethyl chitosan/sodium alginate hydrogel spheres. The preparation method of the hydrogel spheres comprises the following steps: respectively stirring and dissolving carboxymethyl chitosan and sodium alginate in water at room temperature, filtering to remove insoluble substances, and performing ultrasonic degassing to respectively obtain transparent carboxymethyl chitosan and sodium alginate solutions; adding a certain amount of carboxymethyl chitosan solution into the sodium alginate solution, quickly stirring to form a uniform solution, and degassing; and dropwise adding the mixed solution into the cross-linking agent by using a 1mL disposable syringe, taking out the hydrogel spheres after solidification, and washing the hydrogel spheres with water. The invention can effectively reduce the release of protein in simulated gastric juice, has simple preparation process, safety, no toxicity, low price of raw materials, stable structure and good pH response characteristic, and has wide application prospect in the aspects of oral protein and water-soluble drug delivery.
Description
Technical Field
The invention belongs to the field of high-molecular polymer hydrogel, and relates to a preparation method of pH response type carboxymethyl chitosan/sodium alginate hydrogel spheres.
Background
The hydrogel is a hydrophilic macromolecular network polymer which can swell but does not dissolve in water, has good swelling performance, and is widely applied to the fields of medicine, agriculture and the like. The intelligent hydrogel with pH sensitivity can control the drug to release trace or even not release in the stomach and release in the intestinal tract, thereby achieving the purpose of protecting the drug sensitive to the gastric juice environment and having important research value in the field of oral drug delivery. Hydrogel prepared from natural raw materials is widely concerned because of the advantages of no toxicity, biodegradability, good biocompatibility and the like.
Carboxymethyl chitosan is a chitosan derivative of chitosan, has good water solubility and antibacterial property, is safe and nontoxic, and is widely applied to the fields of food preservation, health products, medicines, cosmetics and the like. Carboxymethyl chitosan contains-NH at the same time2Three active groups of-OH and-COOH show the property of amphoteric polyelectrolyte in solution, have specific isoelectric points, show obvious pH sensitivity, and are good pH sensitive controlled release carrier materials. Sodium alginate is an anionic polyelectrolyte polysaccharide from natural sources, can form gel by crosslinking carboxyl groups of sodium alginate by divalent cations, has good pH sensitivity, and is often used as a carrier material of acid-sensitive drugs.
The hydrogel prepared by utilizing sodium alginate and carboxymethyl chitosan has better pH sensitivity, but in the prior art, the cross-linking agents adopted in the preparation process are glutaraldehyde and CaCl2And genipin. The use of cross-linking agents such as glutaraldehyde can cause chemical residues that can affect health；CaCl2The intake of excessive calcium ions can also cause health effects; genipin is relatively expensive, which also limits its application.
Disclosure of Invention
In order to solve the technical problems, the invention aims to develop a more green method for preparing carboxymethyl chitosan/sodium alginate hydrogel spheres with pH sensitivity. The technical conception of the invention is as follows: sodium alginate is added into a carboxymethyl chitosan system, under an acidic environment, carboxymethyl chitosan can generate electrostatic interaction near the isoelectric point of the carboxymethyl chitosan to perform self-polymerization precipitation, and simultaneously, carboxyl of the sodium alginate can be protonated-COOH and-OH on the carboxymethyl chitosan can form hydrogen bond action under the acidic condition, so that hydrogel with a certain flexible three-dimensional network structure is formed.
In order to realize the purpose of the invention, the following technical scheme is adopted:
the invention aims to provide a preparation method of pH response type carboxymethyl chitosan/sodium alginate hydrogel spheres, which comprises the following steps:
(1) mixing the carboxymethyl chitosan aqueous solution with the sodium alginate aqueous solution, and performing ultrasonic degassing to form a carboxymethyl chitosan/sodium alginate mixed solution;
(2) dropwise adding the carboxymethyl chitosan/sodium alginate mixed solution into acid liquor with the pH value of 2-3 for crosslinking reaction, taking out the hydrogel spheres after solidification, and washing the hydrogel spheres with water to obtain the pH-responsive carboxymethyl chitosan/sodium alginate hydrogel spheres.
Wherein, the dropwise adding manner in the step (2) includes, but is not limited to, the dropwise adding manner by using a 1mL disposable syringe.
Further, the acid solution is one or more of citric acid aqueous solution, acetic acid aqueous solution, malic acid aqueous solution, hydrochloric acid aqueous solution and phosphate buffer solution.
Further, the concentration of the acid liquor is 0.01M-0.1M.
Furthermore, the carboxymethyl chitosan in the carboxymethyl chitosan aqueous solution is a chitosan derivative, the carboxymethylation degree is more than or equal to 80%, and the mass concentration of the carboxymethyl chitosan in the carboxymethyl chitosan aqueous solution is 1-4%.
Further, the mass concentration of the sodium alginate in the sodium alginate aqueous solution is 0.5-1.5%.
Furthermore, in the carboxymethyl chitosan/sodium alginate mixed solution, the volume ratio of the carboxymethyl chitosan aqueous solution to the sodium alginate aqueous solution is 5: 1-1: 5.
Furthermore, the crosslinking reaction temperature is 10-30 ℃ (room temperature), and the curing time is 0.5-12 h.
Further, the carboxymethyl chitosan aqueous solution in the step (1) can be prepared by the following method: dissolving carboxymethyl chitosan in water, stirring rapidly to form uniform solution, filtering to remove insoluble substances, and ultrasonic degassing to obtain carboxymethyl chitosan water solution.
Further, the aqueous solution of sodium alginate solution in the step (1) may be prepared by: dissolving sodium alginate in water, rapidly stirring to form uniform solution, filtering to remove insoluble substances, and ultrasonic degassing to obtain sodium alginate solution water solution.
The second purpose of the invention is to provide the pH response type carboxymethyl chitosan/sodium alginate hydrogel sphere prepared by the method, wherein the diameter of the hydrogel sphere is 0.5-2.0 mm.
The third purpose of the invention is to provide an application of the pH response type carboxymethyl chitosan/sodium alginate hydrogel sphere in loading protein or water-soluble drugs.
The fourth purpose of the invention is to provide a preparation method of hydrogel loaded protein, adopting the method, mixing the protein and the carboxymethyl chitosan/sodium alginate mixed solution after the step (1) and before the step (2), and performing ultrasonic degassing to form a protein mixed solution;
and (3) replacing the carboxymethyl chitosan/sodium alginate mixed solution in the step (2) with the protein mixed solution to finally obtain the pH response type carboxymethyl chitosan/sodium alginate hydrogel spheres loaded with protein.
Further, the added protein is a protein solution or a protein solid, and the concentration of the protein relative to the protein mixed solution is 0.01-0.2% (w/w).
Furthermore, in the pH response type carboxymethyl chitosan/sodium alginate hydrogel sphere loaded with protein, the encapsulation rate of the hydrogel sphere to the protein is 50-99%, the hydrogel sphere has obvious pH response characteristics, the swelling ratio in simulated intestinal fluid at pH7.4 is 70-180, and the swelling ratio in simulated gastric fluid at pH3.0 is 1-7.
The invention has the beneficial effects that:
(1) the hydrogel ball obtained by the invention has good pH responsiveness, stable structure in simulated gastric fluid environment and good swelling performance in simulated intestinal fluid, can be widely applied to the fields of biomedical engineering, protein and water-soluble drug delivery, health food, intelligent drug controlled release and the like, and has good application prospect and potential application value.
(2) In the carboxymethyl chitosan/sodium alginate hydrogel spheres prepared by the method, sodium alginate and carboxymethyl chitosan are linear polysaccharides which are wide in source, low in price, safe and non-toxic, and the preparation process can complete a crosslinking reaction only by adding acid liquor, and the carboxymethyl chitosan/sodium alginate hydrogel spheres can be obtained by directly washing after solidification.
(3) The acid liquor is adopted to promote the crosslinking reaction of the carboxymethyl chitosan and the sodium alginate, and compared with the traditional crosslinking agent genipin, the acid liquor has lower cost, so that the production cost is reduced, and the application prospect is good; compared with the traditional cross-linking agent glutaraldehyde, the preparation process does not introduce a chemical cross-linking agent, is convenient to clean, and avoids the potential health hazard caused by chemical reagent residue; with the conventional crosslinking agent CaCl2Compared with the prior art, the preparation method does not need a high-concentration cross-linking agent in the preparation process, avoids the hidden health trouble caused by excessive intake of calcium ions, and has lower cost. On the other hand, the invention is compared with the traditional glutaraldehyde or CaCl2The cross-linking method is more green and environment-friendly, simple and universal in operation and easy to realize large-scale production.
(4) The invention is based on the characteristics of amphoteric electrolyte of carboxymethyl chitosan and the characteristic that the amphoteric electrolyte interacts with sodium alginate to form hydrogel under acidic condition (the prior art is not reported). The hydrogel spheres are dropwise added into acid liquor to form stable hydrogel spheres with a certain flexible spherical structure, and the interior of the hydrogel spheres presents a three-dimensional network porous structure.
(5) The present invention has the potential advantage of enabling efficient delivery of oral proteins: the entrapment rate of the hydrogel spheres to oral protein is 50-99%, and the hydrogel spheres have obvious pH response characteristics, so that the swelling ratio of the hydrogel spheres in simulated gastric fluid with the pH value of 3.0 is 1-7, and the swelling ratio of the hydrogel spheres in simulated intestinal fluid with the pH value of 7.4 is 70-180.
Drawings
FIG. 1 is a photograph of pH-responsive carboxymethyl chitosan/sodium alginate hydrogel spheres of example 3;
FIG. 2 is a surface electron microscope image of pH-responsive carboxymethyl chitosan/sodium alginate hydrogel spheres of example 3 after freeze-drying;
FIG. 3 is a cross-sectional electron micrograph of pH-responsive carboxymethyl chitosan/sodium alginate hydrogel spheres of example 3 after freeze-drying.
Detailed Description
The following examples further illustrate the present invention but are not to be construed as limiting the invention. Modifications and substitutions to methods, procedures, or conditions of the invention may be made without departing from the spirit and substance of the invention.
The embodiment of the invention adopts the following method to carry out performance test:
swelling property test method:
the pH responsiveness of the hydrogel microspheres is evaluated by measuring the swelling performance of the carboxymethyl chitosan/sodium alginate hydrogel spheres in a solution simulating the pH environment of the gastrointestinal tract. The appropriate amount of lyophilized hydrogel microspheres were placed in PBS solutions of different pH (pH3.0 or 7.4), incubated at room temperature (25 ℃) for 2 hours, the swollen hydrogel spheres were removed and excess surface water was removed with filter paper and weighed. Swelling ratio is adoptedThe swelling ratio (W) is calculated by the following formulas-Wd)/WdWherein W isdAnd WsThe weight of the hydrogel spheres after freeze-drying and the weight of the hydrogel spheres after swelling are respectively.
The method for testing the protein loading rate of hydrogel spheres comprises the following steps:
the protein-containing carboxymethyl chitosan/sodium alginate blend (1mL) was added dropwise to 40mL of the crosslinking solution. After sufficient cross-linking, the protein content of the supernatant was determined by Coomassie Brilliant blue. The total amount of protein embedded in the hydrogel microspheres was calculated by subtracting the residual amount of protein in the supernatant from the total amount of protein added. The loading rate was calculated according to the following formula:
loading rate (%) (mass of protein embedded in hydrogel spheres)/(mass of added protein) × 100
Test method of pH response performance:
the in-vitro slow release behavior of the protein-loaded carboxymethyl chitosan/sodium alginate hydrogel spheres is examined under the simulated gastrointestinal tract environment. PBS solutions (pH3.0 or 7.4) were chosen as the medium for in vitro slow release studies of proteins. An amount of lyophilized hydrogel spheres was first incubated in 4mL of SGF or PBS (pH3.0) for 2h (37 deg.C), then the hydrogel spheres were removed, the surface excess acidic solution was removed by filter paper and transferred to 8mL of PBS (pH 7.4) and incubation continued for 4h (37 deg.C). During incubation, at specific time points, 0.5mL of supernatant was aspirated for protein content determination, and equal amounts of PBS were added to maintain constant volume. The content of protein in the supernatant was determined by Coomassie brilliant blue method.
Example 1
A preparation method of pH response type carboxymethyl chitosan/sodium alginate hydrogel spheres comprises the following specific steps:
(1) dissolving 1.0g carboxymethyl chitosan in 100mL water, rapidly stirring to form uniform carboxymethyl chitosan solution, filtering, removing insoluble substances, and ultrasonic degassing for 30 min;
(2) dissolving 0.6g of sodium alginate in 100mL of water, rapidly stirring to form a uniform sodium alginate solution, filtering, removing insoluble substances, and ultrasonically degassing for 30 min;
(3) mixing carboxymethyl chitosan solution and sodium alginate solution at a volume ratio of 1:1, rapidly stirring to form uniform carboxymethyl chitosan/sodium alginate mixed solution, and ultrasonic degassing for 30 min;
(4) and (3) dropwise adding the uniform mixed solution obtained in the step (3) into a citric acid solution with the concentration of 0.05M by using a 1mL disposable syringe for crosslinking at room temperature, taking out the cured hydrogel spheres after curing for 2 hours, and washing with water to obtain the pH-responsive carboxymethyl chitosan/sodium alginate hydrogel spheres.
Example 2
A preparation method of pH response type carboxymethyl chitosan/sodium alginate hydrogel spheres comprises the following specific steps:
(1) dissolving 4.0g carboxymethyl chitosan in 100mL water, rapidly stirring to form uniform carboxymethyl chitosan solution, filtering, removing insoluble substances, and ultrasonic degassing for 30 min;
(2) dissolving 1.5g of sodium alginate in 100mL of water, rapidly stirring to form a uniform sodium alginate solution, filtering, removing insoluble substances, and ultrasonically degassing for 30 min;
(3) mixing the carboxymethyl chitosan solution and the sodium alginate solution according to the volume ratio of 2:1, quickly stirring to form a uniform carboxymethyl chitosan/sodium alginate mixed solution, and ultrasonically degassing for 30 min;
(4) and (3) dropwise adding the uniform mixed solution obtained in the step (3) into a hydrochloric acid solution with the concentration of 0.02M by using a 1mL disposable syringe for crosslinking at room temperature, taking out the cured hydrogel spheres after curing for 1h, and washing with water to obtain the pH-responsive carboxymethyl chitosan/sodium alginate hydrogel spheres.
Example 3
A preparation method of pH response type carboxymethyl chitosan/sodium alginate hydrogel spheres comprises the following specific steps:
(1) dissolving 2.5g carboxymethyl chitosan in 100mL water, rapidly stirring to form uniform carboxymethyl chitosan solution, filtering, removing insoluble substances, and ultrasonic degassing for 30 min;
(2) dissolving 1.0g of sodium alginate in 100mL of water, rapidly stirring to form a uniform sodium alginate solution, filtering, removing insoluble substances, and ultrasonically degassing for 30 min;
(3) mixing carboxymethyl chitosan solution and sodium alginate solution at a volume ratio of 1:2, rapidly stirring to form uniform carboxymethyl chitosan/sodium alginate mixed solution, and ultrasonic degassing for 30 min;
(4) and (3) dropwise adding the uniform mixed solution obtained in the step (3) into an acetic acid aqueous solution with the concentration of 0.07M by using a 1mL disposable syringe for crosslinking at room temperature, taking out the cured hydrogel spheres after curing for 1h, and washing with water to obtain the pH-responsive carboxymethyl chitosan/sodium alginate hydrogel spheres.
The appearance of the hydrogel spheres prepared in the embodiments 1 to 3, the surface appearance of the hydrogel spheres after freeze-drying and the cross-sectional appearance of the hydrogel spheres after freeze-drying are characterized, wherein the hydrogel spheres prepared in the embodiment 3 are taken as an example, and the characterization results are shown in fig. 1 to 3. As shown in FIG. 1, the freshly prepared hydrogel spheres of example 3 are regular spheres having a diameter of about 1.2mm and are white in color; as shown in fig. 2, the surface of the freeze-dried hydrogel spheres appeared to be in a wrinkled state and had a dense structure; as shown in fig. 3, the hydrogel microspheres have a typical three-dimensional network structure of gel inside. The diameter of the pH response type carboxymethyl chitosan/sodium alginate hydrogel sphere prepared by the invention is 0.5-2.0 mm.
The hydrogel spheres prepared in the embodiments 1 to 3 are subjected to swelling property tests, and the results show that the pH-responsive carboxymethyl chitosan/sodium alginate hydrogel spheres obtained by the invention have good pH responsiveness, relatively stable structure in simulated gastric juice environment and good swelling property in simulated intestinal juice. Taking the pH-responsive carboxymethyl chitosan/sodium alginate hydrogel spheres prepared in example 3 as an example, the swelling ratio in a simulated gastric acid environment with pH3 is only 1.61, while the swelling ratio in a simulated intestinal fluid with pH7.4 is 137.
Example 4
Practical application of pH response type carboxymethyl chitosan/sodium alginate hydrogel sphere loaded with bovine serum albumin
(1) Dissolving 1.5g carboxymethyl chitosan in 100mL water, rapidly stirring to form uniform carboxymethyl chitosan solution, filtering, removing insoluble substances, and ultrasonic degassing for 30 min;
(2) dissolving 1.0g of sodium alginate in 100mL of water, rapidly stirring to form a uniform sodium alginate solution, filtering, removing insoluble substances, and ultrasonically degassing for 30 min;
(3) mixing carboxymethyl chitosan solution and sodium alginate solution at a volume ratio of 1:2, rapidly stirring to form uniform carboxymethyl chitosan/sodium alginate mixed solution, and ultrasonic degassing for 30 min;
(4) adding bovine serum albumin into the carboxymethyl chitosan/sodium alginate mixed solution in the step (3) to ensure that the final concentration of protein is 0.07% (w/w), fully mixing to form a uniform transparent solution, and performing ultrasonic degassing for 10 min;
(5) and (3) dropwise adding the uniform mixed solution obtained in the step (4) into 0.05M acetic acid aqueous solution by using a 1mL disposable syringe at room temperature for crosslinking, curing for 1.5h, taking out the cured hydrogel spheres, and washing with water to obtain the pH-responsive carboxymethyl chitosan/sodium alginate hydrogel spheres loaded with bovine serum albumin.
The results of the experiment showed that the bovine serum albumin loading of the hydrogel spheres prepared in example 4 was 83.8%.
The release rate of the bovine serum albumin in the simulated gastric fluid environment with the pH value of 3 is less than 10 percent, and the bovine serum albumin can be completely released within 3.5 hours along with the gradual disintegration of the microspheres in the simulated intestinal fluid environment with the pH value of 7.4.
Example 5
Practical application of pH response type carboxymethyl chitosan/sodium alginate hydrogel spheres loaded with lactoferrin
(1) Dissolving 2.0g carboxymethyl chitosan in 100mL water, rapidly stirring to form uniform carboxymethyl chitosan solution, filtering, removing insoluble substances, and ultrasonic degassing for 30 min;
(2) dissolving 1.0g of sodium alginate in 100mL of water, rapidly stirring to form a uniform sodium alginate solution, filtering, removing insoluble substances, and ultrasonically degassing for 30 min;
(3) mixing carboxymethyl chitosan solution and sodium alginate solution at a volume ratio of 1:2, rapidly stirring to form uniform carboxymethyl chitosan/sodium alginate mixed solution, and ultrasonic degassing for 30 min;
(4) preparing a lactoferrin solution, adding 100 mu L of the lactoferrin solution into the carboxymethyl chitosan/sodium alginate mixed solution in the step (3) to enable the final concentration of lactoferrin to be 0.1% (w/w), fully mixing to form a uniform transparent solution, and ultrasonically degassing for 10 min;
(5) and (3) dropwise adding the uniform mixed solution obtained in the step (4) into a citric acid solution with the concentration of 0.04M by using a 1mL disposable syringe for crosslinking at room temperature, taking out the cured hydrogel spheres after curing for 3 hours, and washing with water to obtain the pH-responsive carboxymethyl chitosan/sodium alginate hydrogel spheres loaded with lactoferrin.
The test results showed that the hydrogel spheres prepared in example 5 had a lactoferrin loading of 96.7% and a release rate of less than 10% in a simulated gastric environment at pH3. And the protein can be completely released within 4 hours along with the gradual disintegration of the microspheres in the simulated intestinal fluid environment with the pH of 7.4, which shows that the hydrogel spheres prepared by the invention have the potential of realizing the high-efficiency delivery of the oral protein.
By adjusting preparation parameters, the encapsulation rate of the pH response type carboxymethyl chitosan/sodium alginate hydrogel spheres to protein is 50-99%, and the pH response type carboxymethyl chitosan/sodium alginate hydrogel spheres have obvious pH response characteristics: the swelling ratio in simulated gastric fluid at pH3.0 is 1-7, and the swelling ratio in simulated intestinal fluid at pH7.4 is 70-180. Therefore, the invention can effectively reduce the release of protein in simulated gastric juice. The hydrogel spheres prepared by the invention have good application prospect and potential application value in the fields of biomedical engineering, protein and water-soluble drug delivery, health food, intelligent controlled release of drugs and the like.
Claims (10)
1. A preparation method of pH response type carboxymethyl chitosan/sodium alginate hydrogel spheres is characterized by comprising the following steps:
(1) mixing the carboxymethyl chitosan aqueous solution with the sodium alginate aqueous solution, and performing ultrasonic degassing to form a carboxymethyl chitosan/sodium alginate mixed solution;
(2) dropwise adding the carboxymethyl chitosan/sodium alginate mixed solution into acid liquor with the pH value of 2-3 for crosslinking reaction, taking out the hydrogel spheres after solidification, and washing the hydrogel spheres with water to obtain the pH-responsive carboxymethyl chitosan/sodium alginate hydrogel spheres.
2. The method for preparing pH-responsive carboxymethyl chitosan/sodium alginate hydrogel spheres of claim 1, wherein the acid solution is one or more of citric acid aqueous solution, acetic acid aqueous solution, malic acid aqueous solution, hydrochloric acid aqueous solution and phosphate buffer solution.
3. The preparation method of the pH-responsive carboxymethyl chitosan/sodium alginate hydrogel sphere according to claim 1, wherein the carboxymethyl chitosan in the carboxymethyl chitosan aqueous solution is a chitosan derivative, the carboxymethylation degree is not less than 80%, and the mass concentration of the carboxymethyl chitosan in the carboxymethyl chitosan aqueous solution is 1-4%.
4. The method for preparing pH-responsive carboxymethyl chitosan/sodium alginate hydrogel spheres of claim 3, wherein the mass concentration of sodium alginate in the sodium alginate aqueous solution is 0.5-1.5%.
5. The preparation method of the pH-responsive carboxymethyl chitosan/sodium alginate hydrogel sphere according to claim 4, wherein the volume ratio of the carboxymethyl chitosan aqueous solution to the sodium alginate aqueous solution in the carboxymethyl chitosan/sodium alginate mixed solution is 5: 1-1: 5.
6. The method for preparing pH-responsive carboxymethyl chitosan/sodium alginate hydrogel spheres of claim 2, wherein the concentration of the acid solution is 0.01-0.1M.
7. The method for preparing pH-responsive carboxymethyl chitosan/sodium alginate hydrogel spheres as claimed in any one of claims 1 to 6, wherein the crosslinking reaction temperature is 10-30 ℃ and the curing time is 0.5-12 h.
8. The pH-responsive carboxymethyl chitosan/sodium alginate hydrogel sphere prepared by the method of any one of claims 1 to 7, wherein the diameter of the hydrogel sphere is 0.5 to 2.0 mm.
9. The use of the pH responsive carboxymethyl chitosan/sodium alginate hydrogel spheres of claim 8 for loading protein or water soluble drugs.
10. A preparation method of hydrogel loaded protein is characterized in that the method of any one of claims 1 to 8 is adopted, after the step (1) and before the step (2), the protein and carboxymethyl chitosan/sodium alginate mixed solution are mixed, and ultrasonic degassing is carried out to form a protein mixed solution;
replacing the carboxymethyl chitosan/sodium alginate mixed solution in the step (2) with the protein mixed solution to finally obtain the pH response type carboxymethyl chitosan/sodium alginate hydrogel spheres loaded with protein.
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