CN114588129A - Curcumin-loaded composite gel microspheres prepared from crosslinked corn porous starch and preparation method of curcumin-loaded composite gel microspheres - Google Patents

Curcumin-loaded composite gel microspheres prepared from crosslinked corn porous starch and preparation method of curcumin-loaded composite gel microspheres Download PDF

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CN114588129A
CN114588129A CN202210118863.3A CN202210118863A CN114588129A CN 114588129 A CN114588129 A CN 114588129A CN 202210118863 A CN202210118863 A CN 202210118863A CN 114588129 A CN114588129 A CN 114588129A
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starch
curcumin
porous
corn
porous starch
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韩忠
罗秀儿
曾新安
蔡锦林
成军虎
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South China University of Technology SCUT
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/12—Ketones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/501—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
    • A61K9/5042—Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
    • A61K9/5047—Cellulose ethers containing no ester groups, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5089—Processes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
    • C08J9/00—Working-up of macromolecular substances to porous or cellular articles or materials; After-treatment thereof
    • C08J9/36—After-treatment
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P19/00—Preparation of compounds containing saccharide radicals
    • C12P19/04—Polysaccharides, i.e. compounds containing more than five saccharide radicals attached to each other by glycosidic bonds
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P19/00—Preparation of compounds containing saccharide radicals
    • C12P19/14—Preparation of compounds containing saccharide radicals produced by the action of a carbohydrase (EC 3.2.x), e.g. by alpha-amylase, e.g. by cellulase, hemicellulase
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
    • C08J2303/00—Characterised by the use of starch, amylose or amylopectin or of their derivatives or degradation products
    • C08J2303/02—Starch; Degradation products thereof, e.g. dextrin

Abstract

The invention discloses a composite gel microsphere of crosslinked corn porous starch loaded curcumin and a preparation method thereof. The composite gel microsphere is prepared by adding curcumin/crosslinked porous starch compound into a carboxymethyl cellulose solution, adding zinc oxide, and mixing and stirring uniformly in a water bath; dripping into ferric chloride or calcium chloride solution to form gel microspheres, transferring the gel microspheres into chitosan solution, stirring, and performing outer layer film wrapping treatment to obtain the chitosan microsphere; the curcumin/cross-linked porous starch compound is formed by adding cross-linked corn porous starch into a curcumin alcohol solution for adsorption; the cross-linked porous corn starch is obtained by adding a cross-linking agent into a porous corn starch suspension; the corn porous starch suspension is obtained by preparing corn porous starch through pulsed electric field assisted enzymolysis. The curcumin delivery system can effectively improve the stability of curcumin and achieve the effect of directional release to small intestine or colon, and is a very effective drug delivery system.

Description

Crosslinked corn porous starch loaded curcumin composite gel microsphere and preparation method thereof
Technical Field
The invention relates to curcumin load, in particular to a composite gel microsphere with curcumin loaded by cross-linked corn porous starch and a preparation method thereof; belongs to the field of food and drug industry.
Background
Curcumin (bis- α, β -unsaturated β -diketone) is a yellow-orange polyphenol derived from the rhizome of the plant Curcuma longa (Curcuma longa L.) and is a very rare pigment with a diketone structure in the plant world. Curcumin is a lipid soluble molecule that has many benefits to human health, such as reducing the risk of cancer, cardiovascular disease, chronic inflammation and metabolic disorders. Due to their unique physiological functions, they are widely used in various fields such as functional foods and biological medicines. However, curcumin has the characteristics of poor water solubility, easy degradation, low oral availability and the like, and the application of curcumin in food and pharmacy is limited. In order to improve the water solubility and stability of curcumin, protect curcumin from degradation and improve the bioavailability of curcumin, existing researches usually adopt the forms of emulsion, solid dispersion, nano delivery system and the like to embed curcumin, wherein the preparation of a novel biological delivery carrier, the design and preparation of a nano carrier material and the establishment of a sustained-release and controlled-release system are hot spots of curcumin researches in recent years.
The porous starch refers to modified starch with a microporous structure with the pore diameter of about 1 mu m distributed on the surface of starch granules. Compared with the original starch, the porous starch has larger porosity and specific surface area, better water absorption and oil absorption capacity, and simultaneously retains the original properties of the starch, such as no toxicity, no harm, degradability, good biocompatibility and the like. Therefore, the porous starch can be used as a wall material for embedding the active ingredients, protects the active ingredients and has the effect of slowly releasing or specifically releasing the active ingredients. However, the adsorption of active ingredients by pure porous starch as an adsorbent still has some defects, such as low entrapment rate of active ingredients, and resistance and high sensitivity of porous starch to shear and heat, which limits the application of the porous starch in embedding active ingredients to a certain extent.
The hydrogel is a gel polymer which takes water or an aqueous medium as a disperse phase, has a three-dimensional network structure after swelling, can retain a large amount of solvent and can be used as a drug carrier. The natural polymer hydrogel is derived from animal and plant tissues in nature, such as chitosan extracted from shrimp shell, alginic acid extracted from herba Zosterae Marinae, etc. In recent years, a great deal of research is focused on the application of gel formed by chitosan, sodium alginate, carboxymethyl cellulose and the like in the aspects of slow release and controlled release of drugs. However, in the process of controlled drug release by a single hydrogel, when the drug is released directionally, the targeted drug release effect can be affected by the difference of external environments, such as the difference of pH values in human bodies.
The technology for embedding curcumin and loading curcumin gel which is published mainly comprises the following steps: 1) the Chinese invention patent 201510429922.9 discloses a method for preparing curcumin microcapsules by taking egg white powder as a wall material, the method takes curcumin as a core material, egg white powder and gelatin as wall materials, an emulsifier is added, and curcumin microcapsules are obtained by spray drying; however, the spray drying technology involved in the method has high requirements on equipment and is relatively expensive. 2) Chinese invention patent application 202010546654.X discloses a preparation method of a soybean lipophilic protein-curcumin compound, which utilizes thermal effect to induce self-assembly of soybean lipoprotein nanoparticles, and promotes interaction of the soybean lipophilic protein nanoparticles and curcumin by ultrasound to improve the loading rate of the soybean lipophilic protein; however, the technology for thermally inducing the development of the soybean lipophilic protein structure used in the invention has higher requirements on the actual operation process, and the pH value in the reaction process needs to be strictly controlled, so that the system requirement of the reaction is higher.
Disclosure of Invention
In order to overcome the defects in the prior art, the invention aims to provide the composite gel microsphere using the crosslinked corn porous starch to load curcumin and the preparation method thereof, and the composite gel microsphere has the function of targeted release of curcumin.
The invention mainly relates to a layer-by-layer self-assembly technology based on starch crosslinking reaction and hydrogel. The introduction of the pulse electric field improves the aperture size and the total pore volume of the enzymolysis porous starch, thereby improving the adsorption property of the porous starch. However, the further increase in pore size may cause a phenomenon such as collapse of the structure of a part of the porous starch. In order to solve potential problems possibly brought by a pulse electric field, the enzymatic hydrolysis porous starch prepared by the aid of the pulse electric field is subjected to crosslinking reaction, and the shear resistance and the thermal stability of the porous starch are improved in a crosslinking mode. And then the crosslinked porous starch is used as an adsorbent to carry out physical adsorption on the curcumin so as to obtain the curcumin/porous starch compound. However, during the process of curcumin slow release, the pores of the porous starch easily lead the curcumin to be released in advance. In order to overcome the defect, the surface of the curcumin/porous starch is coated with natural high molecular gel materials, such as carboxymethyl cellulose, chitosan and the like, so that the curcumin can be released to the small intestine in a targeted manner, and the bioavailability is improved. However, the drug-loaded microspheres formed by only using carboxymethyl cellulose or chitosan cannot achieve the effect of slow release of curcumin. Microspheres formed by carboxymethyl cellulose can shrink in gastric juice and cannot release curcumin, and the microspheres rapidly disintegrate after entering intestinal tracts, so that the medicine is released by explosion; the chitosan microspheres can expand rapidly in gastric juice, and the drug can be released quickly, and cannot play a role in targeted release. Therefore, the curcumin/porous starch is embedded layer by utilizing a layer-by-layer self-assembly mode, the carboxymethyl cellulose is firstly used for embedding, and then the formed carboxymethyl cellulose microspheres are immersed into the chitosan solution to wrap a layer of chitosan. Meanwhile, the introduced zinc oxide can improve the mechanical property and stability of the gel microsphere, and can regulate and control the release rate of curcumin in an in-vitro simulated release test.
The purpose of the invention is realized by the following technical scheme:
adding the curcumin/crosslinked porous starch compound into a carboxymethyl cellulose solution, adding zinc oxide, and mixing and stirring uniformly in a water bath; dripping into ferric chloride or calcium chloride solution to form gel microspheres, transferring the gel microspheres into chitosan solution, stirring, and performing outer layer film wrapping treatment to obtain the chitosan microsphere; the curcumin/crosslinked porous starch compound is formed by adding crosslinked corn porous starch into a curcumin alcohol solution for adsorption; the cross-linked corn porous starch is obtained by adding a cross-linking agent into a corn porous starch suspension; the corn porous starch suspension is obtained by preparing corn porous starch through pulsed electric field assisted enzymolysis.
In order to further achieve the purpose of the invention, preferably, the preparation of the corn porous starch by pulsed electric field assisted enzymolysis is that corn raw starch and a buffer solution are prepared into starch milk, a complex enzyme consisting of alpha-amylase and diastase is added, water bath enzymolysis is carried out for 1-2.5 hours, the reaction is stopped, then a reactant is regulated to be neutral, and the porous starch is obtained by water washing, alcohol washing, drying and crushing; and then mixing the porous starch with water to form a uniform starch suspension, uniformly stirring, adding an electrolyte solution, adjusting the conductivity of the starch emulsion solution to 50-400 mu S/cm, treating in a pulsed electric field treatment chamber for 20-60 min, filtering, drying, crushing and sieving to obtain the corn porous starch.
Preferably, the electric field intensity of the pulse electric field is 5-20 kV/cm, the pulse width is 5-100 mus, and the pulse frequency is 500-2000 Hz; pumping the electric field treatment solution into a pulsed electric field treatment chamber by a peristaltic pump, and controlling the flow rate to be 50-200 mL/min; the electrolyte solution is one or two of a potassium chloride solution and a potassium sulfate solution, and the concentration of the electrolyte solution is 0.5-2 mol/L.
Preferably, the buffer solution is an acetic acid-sodium acetate buffer solution or a phosphate buffer solution, and the pH value of the buffer solution is 4-5; the mass fraction of native starch in the starch milk is 10-30%; the enzyme activity of the alpha-amylase is 3000-5000U/mL, and the enzyme activity of the saccharifying enzyme is 5000-; the mass ratio of the alpha-amylase to the saccharifying enzyme is 1: 1-1: 5; the adding amount of the complex enzyme is 1.5-2.5% of the dry mass of the starch; the temperature of the water bath enzymolysis is 40-50 ℃.
Preferably, the cross-linked porous corn starch is prepared by the following method: mixing porous corn starch with deionized water to prepare a starch suspension, adding a cross-linking agent, adjusting the pH value of the system, carrying out cross-linking reaction for 0.5-2 h, washing, filtering, drying, crushing, and sieving to obtain the cross-linked porous starch.
Preferably, the crosslinking agent is Sodium Trimetaphosphate (STMP), phosphorus oxychloride (POCl)3) One of Epichlorohydrin (EPCH) and Sodium Tripolyphosphate (STPP); the pH value of the adjusting system is adjusted by adding a mixture of sodium carbonate and sodium chloride, disodium hydrogen phosphate and sodium hydroxide; the mass fraction of the porous starch suspension in the starch suspension is 10-30%, and the dosage of the cross-linking agent is 5-20% of the mass of the starch suspension; the cross-linking reaction is controlled by a water area, the temperature is 30-50 ℃, and the drying is drying in a blast drier for 8-12 h; the washing is carried out 3-5 times by using deionized water.
Preferably, the curcumine alcohol solution is formed by dissolving curcumin in ethanol, and the concentration of the curcumin is 1-3 mg/mL; the adsorption time is 0.5-2 h; the mass ratio of the cross-linked corn porous starch to the curcumin is 30: 1-80: 1.
Preferably, according to the usage amount of the raw materials prepared by the composite gel microspheres loaded with curcumin by the crosslinked corn porous starch, the mass fraction of the carboxymethyl cellulose solution is 0.5-5%, the mass fraction of zinc oxide is 0-2%, the mass fraction of ferric chloride or calcium chloride solution is 1-5%, the mass fraction of the chitosan solution is 0.5-3%, and the balance is curcumin/crosslinked porous starch composite.
Preferably, the temperature of the water bath mixing and stirring is 30-50 ℃, the stirring speed is 200-600 rpm, and the stirring time is 0.5-2 h; the stirring time in the chitosan solution is 0.5-2 h, and the stirring speed is 200-600 rpm.
The preparation method of the composite gel microspheres loaded with curcumin by the crosslinked corn porous starch comprises the following steps:
1) preparing porous starch by enzymolysis: preparing corn starch and buffer solution into starch milk, and adding a complex enzyme consisting of alpha-amylase and saccharifying enzyme; performing water bath enzymolysis, adjusting the system to be neutral after the enzymolysis is finished, washing with water, washing with alcohol, drying, and crushing to obtain porous starch;
2) treating porous starch by using a pulsed electric field: mixing porous starch with water to form uniform starch suspension, adding electrolyte solution, adjusting the conductivity of the starch emulsion solution, performing pulsed electric field treatment in a pulsed electric field treatment chamber, filtering, washing, drying, pulverizing, and sieving the porous starch after the pulsed electric field treatment;
3) preparing cross-linked corn porous starch: adding a cross-linking agent into the porous starch suspension treated by the pulsed electric field, adjusting the pH value of a reaction system, uniformly stirring, carrying out water bath reaction, adjusting the pH value of the reaction system, stopping the reaction, washing, filtering, drying, crushing and sieving;
4) preparing curcumin-loaded composite gel microspheres: dissolving curcumin in ethanol to obtain curcumin solution, adding into crosslinked corn porous starch, stirring to adsorb curcumin, and filtering to remove unadsorbed curcumin to obtain curcumin/crosslinked porous starch compound;
5) adding the curcumin/crosslinked porous starch compound prepared in the step 4) into a carboxymethyl cellulose solution, adding zinc oxide, and mixing and stirring uniformly in a water bath; and dripping the mixture into a ferric chloride or calcium chloride solution at a constant speed to form gel microspheres, filtering the gel microspheres to remove the mixture which is not formed into gel, transferring the gel microspheres into a chitosan solution, and performing outer-layer film coating treatment to obtain the composite gel microspheres loaded with curcumin.
Preferably, in the step 1), the concentration of the hydrochloric acid is 1-3 mol/L, and the concentration of the sodium hydroxide is 1-3 mol/L.
The oil absorption rate of the cross-linked porous corn starch prepared by the method can reach 90-110%, and the cross-linked porous corn starch has better shearing resistance and degradation resistance. The oil absorption rate of the untreated corn native starch (namely the corn native starch in the step 1) is only 50-60%; through the enzymolysis process in the step 1), the oil absorption rate of the enzymolyzed corn porous starch can reach 70-90%, and through the pulse treatment of the step 2), the oil absorption rate of the porous starch can reach 80-110%. This is because the enzymatic reaction can generate many micropores on the surface of the corn native starch, and at the same time, a hollow structure is generated, so that the specific surface area of the porous starch is significantly increased compared to the specific surface area of the native starch. Meanwhile, the generated micropores can provide better adsorption sites for external substances, so that the adsorption performance of the porous starch is improved. In addition, the further treatment of the enzymatic hydrolysis porous starch by the pulsed electric field is based on the charge polarization theory of the macroscopic space. The electrolyte penetrating through the surface and the interior of the porous starch provides extra charges for the porous starch, and the charges in the electrolyte can generate charge polarization under the action of an external electric field with certain strength, so that polarization energy is generated to act on the porous starch, the holes of the porous starch are further enlarged, the specific surface area of the porous starch is increased, and the adsorption performance of the porous starch is improved.
After the crosslinking reaction treatment in the step 3), the thermal stability of the crosslinked porous starch is improved, and the thermal decomposition temperature is increased by 2-8 ℃ compared with that of the uncrosslinked porous starch, because the compactness of the porous starch structure is increased by the crosslinking reaction, the movement of a molecular chain is limited by the compact structure, the decomposition resistance is increased, and the thermal stability of the crosslinked porous starch is further improved; meanwhile, compared with the expansive force of the porous starch, the expansive force of the crosslinked porous starch is reduced by 0.5-1.5 g/g, because the strength of hydrogen bonds is enhanced and is increased by crosslinking of starch molecules and a crosslinking agent, and the swelling capacity of the crosslinked porous starch is limited by the increase of the strength of the hydrogen bonds.
The load rate of the curcumin in the crosslinked porous starch compound adsorbed with the curcumin obtained in the step 4) can reach more than 60 percent, which shows that the crosslinked porous starch can be used as an effective adsorbent for the curcumin.
The curcumin-loaded composite gel microspheres obtained in the step 4) have the advantages that the stability of curcumin is remarkably improved, and the activity of curcumin can be maintained for a long time under illumination and a certain temperature. Meanwhile, the outer layer of the gel microsphere is a carboxymethyl cellulose-chitosan wrapping layer which is formed by self-assembling layer by layer from inside to outside, so that the stability of curcumin can be effectively protected, the effect of delaying the release of the medicine can be achieved, and medicines such as curcumin and the like are protected from being digested and absorbed in the stomach, and the effect of directionally conveying the curcumin to the small intestine is achieved. The reason is that the outer layer of the composite gel is wrapped by chitosan, the chitosan is basic polysaccharide, when the composite gel is in an acid environment such as gastric juice, amino groups of the chitosan are protonated, and a large number of cations increase the solubility of the chitosan by increasing polarity and electrostatic repulsion, so that the effect of dissolving the outer layer wrapping layer of the gel microsphere is achieved. The carboxymethyl cellulose belongs to anionic cellulose ether substances, and the solubility of the carboxymethyl cellulose is increased in an alkaline or weakly alkaline environment, so that the carboxymethyl cellulose can be dissolved in a small intestine environment to release active substances such as curcumin and the like, and the directional release effect is achieved.
Compared with the prior art, the invention has the following advantages:
1) the invention prepares the porous starch by using the pulsed electric field to assist enzymolysis, can prepare the porous starch with good adsorption property in a short time, and greatly reduces the reaction time of dozens of hours required by the preparation by a chemical method or an enzymolysis method;
2) the invention carries out the treatment of the pulse electric field aiming at the porous starch prepared by enzymolysis, can improve the aperture size, the specific surface area and the pore volume of the porous starch prepared by enzymolysis in a short time, effectively improves the pore-forming rate of the porous starch and further improves the adsorption rate of the porous starch.
3) According to the invention, the prepared enzymatic hydrolysis porous starch is subjected to crosslinking treatment by using crosslinking reaction, so that the thermal stability of the porous starch is further improved, the thermal decomposition temperature of the crosslinked porous starch after crosslinking is increased, and the adsorbability of the crosslinked porous starch is improved to a certain extent, thereby improving the bioavailability of the crosslinked porous starch.
4) The curcumin-loaded composite gel microsphere prepared by the layer-by-layer self-assembly method has the advantages of simple preparation method, cheap and easily-obtained raw materials, simple required equipment, non-toxic and harmless natural raw materials, biodegradability and no harm to human bodies.
5) The curcumin-loaded composite gel microsphere provided by the invention has an obvious stable protection effect on curcumin, and after 1 week of protection time, the retention rate of curcumin in the embedded curcumin composite gel microsphere is still more than 50%, and the retention rate of non-embedded pro-zingiberin is less than 10%. Meanwhile, the heat stability and the light stability of the curcumin after being gelled are obviously improved compared with the curcumin without being embedded. And in vitro simulated release experiments, the medicine shows good effect of directional release of small intestine and colon.
6) The invention utilizes the adsorption of porous starch to active ingredients, and then utilizes the layer-by-layer self-assembly technology to carry out the gelated layer-by-layer self-assembly of the porous starch/curcumin active ingredient compound, thereby playing the role of targeted curcumin release, and simultaneously, the method can also be extended to other drug delivery systems.
Drawings
FIG. 1 is a graph showing the specific surface area and the average diameter of pores of porous starch after no pulse treatment and pulse treatment in comparative example 1 of the present invention.
FIG. 2(a) is a data graph of TG thermogravimetric analysis of porous starch in comparative example 2 of the present invention.
Fig. 2(b) is data of TG thermogravimetric analysis of crosslinked porous starch in comparative example 2 of the present invention fig. 3 is a data of loading rate of curcumin adsorbed by different kinds of starch in comparative example 3 of the present invention.
FIG. 4(a) is a full spectrum of surface photoelectron spectroscopy of porous starch and crosslinked porous starch in example 1 of the present invention.
FIG. 4(b) is a phosphorus element spectrum of surface photoelectron spectrum of porous starch and crosslinked porous starch in example 1 of the present invention.
FIG. 4(c) is a spectrum of carbon element in a surface photoelectron spectrum after fitting the porous starch peak in example 1 of the present invention.
FIG. 4(d) is a carbon element spectrum of a surface photoelectron spectrum fitted with a peak of crosslinked porous starch in example 1 of the present invention.
Fig. 5 is a scanning electron microscope image of curcumin-loaded gel microspheres of example 1 of the present invention.
Fig. 6 is a fourier infrared spectrum of each component in the curcumin-loaded gel microspheres of example 1 of the present invention.
FIG. 7 is a graph of data for the in vitro release of composite gel microspheres formed from different mass fractions of carboxymethylcellulose (CMC) in example 1 of the present invention.
Fig. 8 is a graph of data on in vitro release of composite gel microspheres formed of different mass fractions of nano zinc oxide particles (ZnO) in example 2 of the present invention.
FIG. 9 is a graph of data on the in vitro release of microspheres of composite gels formed from solutions of different mass fractions of chitosan (Cs) in example 3 of the present invention.
Detailed Description
The present invention will be further described with reference to the drawings and examples, but the embodiments of the present invention are not limited thereto.
According to the invention, the corn porous starch is prepared by using the pulsed electric field assisted enzymolysis, so that the time for preparing the corn porous starch can be effectively reduced, and meanwhile, the prepared corn porous starch is subjected to crosslinking treatment by using a crosslinking agent to obtain the crosslinked corn porous starch, thereby playing a role in increasing the adsorbability and the shear resistance of the porous starch. And then, using the obtained cross-linked corn porous starch as a curcumin adsorbent, adsorbing a curcumin alcohol solution, carrying out centrifugation and filtration treatment, removing unadsorbed curcumin/porous starch compound, and carrying out vacuum freeze drying for later use. And then adding the curcumin/porous starch mixture into a hot water-dissolved carboxymethyl cellulose solution, uniformly mixing, simultaneously adding zinc oxide to improve the antibacterial property, the mechanical property and the stability of the hydrogel matrix, and uniformly mixing the mixed solution to obtain a mixed solution mixed with curcumin/porous starch/zinc oxide/carboxymethyl cellulose. And then injecting the mixed solution into an iron chloride solution by using an injector, and uniformly stirring to obtain the curcumin-loaded gel microspheres. And then, filtering the gel microspheres, washing out non-embedded substances, transferring the gel into a chitosan solution for embedding layer by layer in a self-assembly manner, and obtaining the final curcumin-loaded composite gel microspheres.
Measurement of oil absorption of porous starch: the method for measuring the oil absorption rate of the porous starch under different treatment conditions comprises the following specific steps of weighing the mass of a 10mL centrifuge tube filled with 3 small glass beads in advance, and marking the mass as M0Then, about 1g of porous starch is added into a 10mL centrifuge tube, and the mass M of the centrifuge tube is weighed1Adding 4mL of corn oil, stirring, centrifuging at 8000rpm/min for 15min, removing supernatant, inverting the centrifuge tube for 10min to remove residual oil, and weighing M2. The oil absorption OA of the porous starch to be detected can be calculated by the following formula:
OA＝(M2-M1)/(M1-M0)
in the formula: OA represents the oil absorption of the porous starch to be tested.
Determination of specific surface area and pore size of porous starch: and (3) determining the specific surface area, the total pore volume and the pore size distribution of the starch sample by using a low-temperature nitrogen adsorption method. The specific operation is as follows: and (3) measuring by using a full-automatic gas adsorption analyzer, and before measurement, placing the starch sample in a vacuum condition of 100 ℃ for degassing treatment for 5 hours to remove air adsorbed on the surface of the starch sample. And then, after the sample is cooled to room temperature, carrying out low-temperature nitrogen adsorption test by taking high-purity nitrogen as a medium, putting the sample to be tested into a full-automatic gas adsorption analyzer, and introducing nitrogen for testing. The nitrogen adsorption capacity of the sample to be tested is related to the specific surface area, the total pore volume, the pore diameter and the like of the sample, the nitrogen adsorbed by the starch is desorbed along with the rise of the test temperature, and finally the nitrogen is in an equilibrium state, so that an adsorption-desorption curve and related test indexes are obtained. Then, the specific surface area, the pore volume and the pore diameter and the pore size distribution of the test sample are calculated by using a BET method and a BJH method.
Comparative example 1:
preparing corn porous starch by adopting enzymolysis in the prior art: mixing corn starch and acetic acid-sodium acetate buffer solution with the pH value of 5.0, magnetically stirring for 15min to uniformly disperse the starch suspension to obtain 30 wt% of starch homogenate, and then adding 2% of complex enzyme (mass percentage of the complex enzyme and the starch dry base) to perform enzymolysis reaction, wherein the complex enzyme in the enzymolysis reaction is alpha-amylase and saccharifying enzyme, and the mass ratio of the alpha-amylase to the saccharifying enzyme is 1: 2. The reaction is carried out in a 50 ℃ constant-temperature water bath kettle, the water bath reaction time is 1.5h, the porous starch milk after enzymolysis is obtained, the reaction is stopped for 10min by 1mol/L hydrochloric acid, then the reaction solution is adjusted to be neutral by sodium hydroxide, the corn starch milk after enzymolysis is washed by ethanol for 3 times, washed by water for 3 times, filtered, and then dried by an air-blast drier, the drying temperature is 45 ℃, the drying time is 12h, and the porous starch in the comparative example 1 is obtained by crushing and sieving.
Treating and hydrolyzing the corn porous starch by using a pulsed electric field: mixing porous starch and deionized water to form uniform starch suspension, magnetically stirring uniformly, adding 1mol/L potassium chloride electrolyte solution, adjusting the conductivity of the starch emulsion solution to 150 mu S/cm, pumping into a pulsed electric field treatment chamber by using a peristaltic pump, wherein the actual treatment time of the pulsed electric field is 30min, the intensity of the pulsed electric field is 12kV/cm, the pulse width is 40 mu S, the pulse frequency is 1000Hz, and the flow rate is 100 mL/min. And (3) filtering the porous starch treated by the pulse electric field, washing the porous starch for 3 times by using deionized water, drying the porous starch in a forced air drying oven for 12 hours, crushing and sieving to obtain the corn porous starch prepared by the pulse electric field assisted enzymolysis in the comparative example 1.
And then carrying out oil absorption rate, specific surface area and pore size tests on the prepared enzymatic hydrolysis porous starch and the enzymatic hydrolysis porous starch after pulse treatment. The oil absorption rate test shows that the oil absorption rate of the enzymatic corn porous starch in the comparative example 1 reaches 76.16%, and the oil absorption rate of the pulsed enzymatic corn porous starch reaches 88.35%; as shown in FIG. 1, the specific surface area of the enzymatic corn porous starch is 4.174cc/g, the average diameter of the pores is 8.271nm, the specific surface area of the enzymatic corn porous starch after pulse treatment is 5.056cc/g, and the average diameter of the pores is 18.11 nm.
Comparative example 2:
and (2) performing crosslinking treatment on the enzymatic corn porous starch obtained in the comparative example 1, mixing the porous starch with deionized water to prepare 15% starch suspension by mass fraction, uniformly stirring, adding 10 wt% of sodium trimetaphosphate as a crosslinking agent (the mass percentage of the sodium trimetaphosphate to the dry basis of the starch), performing stirring reaction on a magnetic stirrer, wherein the magnetic stirring speed is 400rpm, the water bath temperature is 40 ℃, adding 0.2mL of sodium carbonate and 0.5g of sodium chloride into 20mL of deionized water, adjusting the pH value of the reaction system, performing water bath reaction for 1h, stopping the reaction for 15min, washing the reaction mixture with the deionized water for 3 times, drying in a forced air dryer for 12h, crushing, and sieving to obtain the crosslinked corn porous starch in the comparative example 2.
The thermal properties of the crosslinked porous starch and the uncrosslinked porous starch were tested by thermogravimetric analysis and the results are shown in fig. 2, where the maximum thermal decomposition temperature of the crosslinked porous starch in fig. 2(b) was 313.9 ℃ higher than the maximum thermal decomposition temperature of the uncrosslinked porous starch in fig. 2(a) by 310.9 ℃, indicating that the crosslinked porous starch has better thermal stability than the uncrosslinked porous starch.
Comparative example 3:
to further verify the effect of enzymatic treatment alone and pulse treatment alone, as well as synergistic enzymatic and pulse treatment, and cross-linking treatment on the adsorption properties of the starch samples. In this comparative example, native corn starch after pulse treatment, porous enzymatic corn starch, porous starch after pulse treatment and crosslinked porous starch were used as carriers for adsorbing curcumin. Preparing 1mg/mL curcumin solution with anhydrous ethanol, and stirring until curcumin is completely dissolved in ethanol. Next, 5g of corn porous starch was added to 50mL of water, stirred well to make it a starch suspension, followed by addition of 50mL of a curcumine alcohol solution, (curcumin: porous starch 1:100) and packaging at 40 ℃ for 1 h. And centrifuging 3mL of curcumin/crosslinked porous starch compound solution at 5000rpm for 10min to remove non-embedded curcumin, collecting supernatant after centrifugation, measuring an absorbance at 425nm by using an ultraviolet spectrophotometer, and calculating the curcumin content in the supernatant according to the relation between the curcumin content and the absorbance at 425 nm. The precipitate was dried at 50 ℃ for 5h, then pulverized, sieved with a 80 mesh sieve and presented in a desiccator. The adsorption rate was calculated from the following formula:
adsorption rate (%) - (m)2-m1)/m2×100
Wherein m is1Is the mass m of curcumin in the supernatant after the curcumin embedded substance solution is centrifuged2Is the mass of total curcumin added to the inclusion in mg.
The results are shown in fig. 3, and the results show that the curcumin adsorption rate of the porous starch is increased by the synergistic effect of the pulse electric field and the crosslinking reaction, wherein the curcumin adsorption rate of the corn native starch is 56.78%, the curcumin adsorption rate of the enzymolysis corn porous starch is 59.44%, the curcumin adsorption rate of the enzymolysis corn porous starch after the pulse treatment is 60.82%, and the curcumin adsorption rate of the crosslinked corn porous starch is 61.11%.
Example 1
Preparing corn porous starch by enzymolysis: mixing corn starch and acetic acid-sodium acetate buffer solution with the pH value of 5.0, magnetically stirring for 15min to uniformly disperse the starch suspension to obtain 30 wt% of starch homogenate, and then adding 2% of complex enzyme (mass percentage of the complex enzyme and the starch dry base) to perform enzymolysis reaction, wherein the complex enzyme in the enzymolysis reaction is alpha-amylase and saccharifying enzyme, and the mass ratio of the alpha-amylase to the saccharifying enzyme is 1: 2. The reaction is carried out in a water bath kettle with the constant temperature of 50 ℃, the water bath reaction time is 1.5 hours, the porous starch milk after enzymolysis is obtained, the reaction is stopped for 10min by 1mol/L hydrochloric acid, then the reaction solution is adjusted to be neutral by sodium hydroxide, the corn starch milk after enzymolysis is washed by ethanol for 3 times, washed by water for 3 times, filtered by suction, and then dried by a blast drier, the drying temperature is 45 ℃, the drying time is 12 hours, and the porous starch is obtained by crushing and sieving.
Treating and enzymolyzing corn porous starch by using a pulsed electric field: mixing porous starch and deionized water to form uniform starch suspension, magnetically stirring uniformly, adding 1mol/L potassium chloride electrolyte solution, adjusting the conductivity of the starch emulsion solution to 150 mu S/cm, pumping into a pulsed electric field treatment chamber by using a peristaltic pump, wherein the actual treatment time of the pulsed electric field is 30min, the intensity of the pulsed electric field is 12kV/cm, the pulse width is 40 mu S, the pulse frequency is 1000Hz, and the flow rate is 100 mL/min. And filtering the porous starch treated by the pulse electric field, washing the porous starch for 3 times by using deionized water, drying the porous starch in a forced air drying oven for 12 hours, crushing and sieving to obtain a finished product.
Preparing cross-linked corn porous starch: and (2) carrying out cross-linking treatment on the obtained corn porous starch prepared by the pulsed electric field assisted enzymolysis, mixing the porous starch with deionized water to prepare 15% of starch suspension by mass fraction, uniformly stirring, adding 10 wt% of sodium trimetaphosphate as a cross-linking agent (the mass percentage of the sodium trimetaphosphate to the dry base of the starch), carrying out stirring reaction on a magnetic stirrer, wherein the magnetic stirring speed is 400rpm, the water bath temperature is 40 ℃, adding 0.2mL of sodium carbonate and 0.5g of sodium chloride into 20mL of deionized water, adjusting the pH value of a reaction system, carrying out the water bath reaction time to 1h, stopping the reaction for 15min, washing the reaction mixture for 3 times with the deionized water, drying in a blast drier for 12h, crushing and sieving to obtain the cross-linked porous starch. In order to verify whether the crosslinked porous starch is successfully synthesized, a surface photoelectron spectrum test is carried out, and the results are shown in fig. 4, wherein the surface photoelectron spectrum full spectrograms of the crosslinked porous starch and the porous starch, and the photoelectron spectrogram results of carbon elements, oxygen elements and phosphorus elements show that compared with the porous starch, the crosslinked porous starch generates a new C-O-P absorption peak in the carbon element photoelectron spectrogram and the oxygen element photoelectron spectrogram through crosslinking, which shows that the phosphorus element in the sodium trimetaphosphate is introduced into the crosslinked porous starch, and thus the successful progress of the crosslinking reaction is proved.
Preparing a curcumin/cross-linked corn porous starch compound: preparing 50mL of 1mg/mL curcumin solution by using absolute ethyl alcohol, and uniformly stirring until the curcumin is completely dissolved. Then, 5g of corn porous starch is added into 50mL of water and stirred uniformly to form starch suspension, then curcumin alcohol solution and the starch suspension are mixed, embedding is carried out at the rotating speed of 300rpm at 40 ℃, and shading treatment is carried out in the embedding process for 1 h. And centrifuging 3mL of curcumin/crosslinked porous starch compound solution at 5000rpm for 10min to remove non-embedded curcumin, collecting supernatant after centrifugation, measuring an absorbance at 425nm by using an ultraviolet spectrophotometer, and calculating the curcumin content in the supernatant according to the relation between the curcumin content and the absorbance at 425 nm. And then, carrying out suction filtration, water washing for 3 times, alcohol washing for 3 times, vacuum freeze drying the filtrate, then crushing, sieving by using a 80-mesh sieve, storing in a dryer in a dark place, and obtaining the curcumin/crosslinked porous starch compound.
Preparing the curcumin-loaded composite gel microspheres: respectively taking 1 percent, 2 percent, 3 percent and 4 percent of carboxymethyl cellulose dissolved in water according to the final mass percentage, dissolving the carboxymethyl cellulose in warm water at 50 ℃, then respectively taking 0.5 percent of zinc oxide and 0.5g of curcumin/crosslinked porous starch compound to dissolve in deionized water, fixing the volume to 100mL, and uniformly stirring. Pouring the mixture of zinc oxide and curcumin/crosslinked porous starch into carboxymethyl cellulose solution, mixing and stirring uniformly, and then injecting the mixed solution into FeCl with the mass fraction of 3% by using a syringe with the inner diameter of 10mm3In solution. Gel microspheres in FeCl3And (3) carrying out crosslinking reaction in the solution for 30min, filtering, washing, transferring the prepared microspheres wrapped with the carboxymethyl cellulose into 100mL of chitosan solution with the mass fraction of 1%, and carrying out reaction at normal temperature for 30min at 100rpm to obtain the curcumin-loaded composite gel microspheres.
The obtained curcumin-loaded gel microspheres are subjected to shape and structure characterization, the shape of the dried curcumin-loaded gel microspheres is analyzed through a scanning electron microscope, and the result is shown in fig. 5, the surfaces of the formed gel microspheres are wrinkled, no obvious cavity structure is seen inside the gel microspheres, curcumin is uniformly mixed with viscous carboxymethyl cellulose in the embedding process, and the distribution condition of curcumin cannot be visually observed through a scanning electron microscope picture.
For gel microsphereAnd Fourier infrared spectrogram of each component, the result is shown in FIG. 6, firstly, the peak value is 3445cm in CMC and Cs-1And 3430cm-1Here, the hydroxyl peak became broader and shifted to a lower frequency of 3430cm in the ZnO @ CMC @ Cs microspheres-1Indicating the formation of hydrogen bonds between the carboxyl groups of CMC and the hydroxyl groups of Cs and-NH2And superposition of stretching vibrations of the-OH groups. Secondly, at 1580cm-1The peak intensity of carboxyl group is reduced at 1000cm-1～1200cm-1Extent of covalent bonding of the ferrite moiety, these phenomena being due to Fe3+Form ionic bonds with deprotonated carboxylate groups of the CMC. At 1400cm-1～1600cm-1The intensity of some small peaks is increased and is 1590cm-1A new absorption band was observed, which may be explained by the interaction of the amino group in Cs and the carboxyl group in CMC, forming a polyelectrolyte structure, and the formation of some new hydrogen bonds between chitosan and ZnO nanoparticles.
The prepared composite gel microspheres are subjected to an in-vitro digestion release test, and the in-vitro digestion release test is respectively carried out in simulated gastric fluid (SGF, pH 1.2), simulated small intestinal fluid (SIF, pH 6.8) and simulated colon fluid (SCF, pH 7.4) for 2 hours, 3 hours and 3 hours, and finally, the in-vitro release condition of the curcumin is judged by measuring the concentration of the curcumin in the digestion fluid.
The measurement shows that the adsorption rate of the cross-linked porous starch for adsorbing curcumin is 61.11%, the loading rate of the prepared gel microsphere loaded with curcumin is 56.88%, and the loading capacity is 5.69 mg/g. The thermal stability of the cross-linked porous starch was stable compared to the porous starch, as indicated by a maximum thermal decomposition temperature of 313.9 ℃ for the cross-linked porous starch, which was 310.4 ℃ above the maximum thermal decomposition temperature of the porous starch. In vitro digestion experiments show that the release rate of curcumin in simulated gastric juice (pH 1.2) is relatively low, and the release rates of microspheres formed by carboxymethylcellulose with the mass fraction of 1% to 4% in 2h are 12.02%, 9.36%, 6.56% and 6.36%, respectively, as shown in fig. 7. Subsequently, the cumulative 6h release achieved 69.15%, 75.86%, 80.35% and 73.65% in simulated intestinal fluid (pH 6.8) and simulated colonic fluid (pH 7.4), respectively.
Example 2
Preparing enzymolysis corn porous starch: preparing 30% of starch homogenate according to the method in the embodiment 1, adding 2% of complex enzyme (mass ratio of complex enzyme to dry starch basis) for enzymolysis reaction, wherein the mass ratio of alpha-amylase: the mass ratio of the saccharifying enzyme is 1:2, the stirring speed of the water bath is 500rpm, the temperature of the water bath is 50 ℃, the reaction time is 1.5h, the pH of the system is adjusted to be 1.2-1.5 by 1mol/L hydrochloric acid, the reaction is stopped for 10min, then the pH of the system is adjusted to be neutral by sodium hydroxide, and the reaction mixture is subjected to suction filtration, washing, drying, crushing, sieving and the like to obtain the porous starch.
Treating and enzymolyzing corn porous starch by using a pulsed electric field: mixing porous starch and deionized water to form uniform starch suspension, magnetically stirring uniformly, adding 1mol/L potassium chloride electrolyte solution, adjusting the conductivity of the starch emulsion solution to 150 mu S/cm, pumping into a pulsed electric field treatment chamber by using a peristaltic pump, wherein the actual treatment time of the pulsed electric field is 30min, the intensity of the pulsed electric field is 12kV/cm, the pulse width is 40 mu S, the pulse frequency is 1000Hz, and the flow rate is 100 mL/min. And filtering the porous starch treated by the pulse electric field, washing the porous starch for 3 times by using deionized water, drying the porous starch in a forced air drying oven for 12 hours, crushing and sieving to obtain a finished product.
Preparation of cross-linked porous starch: and (2) performing crosslinking treatment on the obtained corn porous starch prepared by the pulsed electric field assisted enzymolysis, preparing 15% mass fraction starch suspension from the porous starch and deionized water, adding 10% by mass of sodium trimetaphosphate as a crosslinking agent (sodium trimetaphosphate: starch dry basis mass ratio), stirring on a magnetic stirrer at the speed of 400rpm and the water bath temperature of 40 ℃, adding 0.2mL of sodium carbonate and 0.5g of sodium chloride into 20mL of deionized water, adjusting the pH value of the reaction system, performing water bath reaction for 1h, stopping the reaction for 15min, washing the reaction mixture with deionized water for 3 times, drying in a blast dryer for 12h, crushing, and sieving to obtain the crosslinked corn porous starch.
Preparation of curcumin-loaded composite gel microspheres: respectively dissolving 1%, 2%, 3% and 4% carboxymethyl cellulose dissolved in water in 50 deg.C warm water, and respectively taking final concentration of 05% of zinc oxide and 0.5g of curcumin/crosslinked porous starch compound are dissolved in deionized water, the volume is constant to 100mL, and the mixture is stirred uniformly. Pouring the mixture of zinc oxide and curcumin/crosslinked porous starch into carboxymethyl cellulose solution, mixing and stirring uniformly, and then injecting the mixed solution into FeCl with the mass fraction of 3% by using a syringe with the inner diameter of 10mm3In solution. Gel microspheres in FeCl3And (3) carrying out crosslinking reaction in the solution for 30min, filtering, washing, transferring the prepared microspheres wrapped with the carboxymethyl cellulose into 100mL of chitosan solution with the mass fraction of 1%, and carrying out reaction at normal temperature for 30min at 100rpm to obtain the curcumin-loaded composite gel microspheres.
Preparation of curcumin-loaded composite gel microspheres: respectively taking 0%, 0.25%, 0.50% and 1.00% of zinc oxide nanoparticles by mass fraction, dissolving in warm water at 50 ℃ with a certain volume, respectively taking 3% of carboxymethyl cellulose and 0.5g of curcumin/crosslinked porous starch compound, dissolving in deionized water with a certain volume, fixing the volume to 100ml, and uniformly stirring. Pouring the mixture of zinc oxide and curcumin/crosslinked porous starch into carboxymethyl cellulose solution, mixing and stirring uniformly, and then injecting the mixed solution into FeCl with the mass fraction of 3% by using a syringe with the inner diameter of 10mm3In solution. Gel microspheres in FeCl3And (3) carrying out crosslinking reaction in the solution for 30min, filtering, washing, transferring the prepared microspheres wrapped with the carboxymethyl cellulose into a chitosan solution with the mass fraction of 1%, and carrying out reaction at normal temperature for 30min at 100rpm to obtain the curcumin-loaded composite gel microspheres. Then, the prepared composite gel microspheres were subjected to in vitro digestion release tests for 2 hours, 3 hours, and 3 hours in simulated gastric fluid (SGF, pH 1.2), simulated small intestinal fluid (SIF, pH 6.8), and simulated colon fluid (SCF, pH 7.4), respectively. And finally, determining the adsorption rate of the crosslinked porous starch for adsorbing the curcumin, the loading rate of the composite gel microspheres for loading the curcumin and the in-vitro release condition of the composite gel microspheres.
The measurement shows that the adsorption rate of the cross-linked porous starch for adsorbing curcumin is 61.11%, the loading rate of the prepared gel microsphere loaded with curcumin is 56.88%, and the loading capacity is 5.69 mg/g. The thermal stability of the cross-linked porous starch is more stable than that of the porous starch, and is characterized in that the maximum thermal decomposition temperature of the cross-linked porous starch is 313.9 ℃ and is higher than the maximum thermal decomposition temperature of the porous starch by 310.4 ℃. In vitro digestion experiments show that the release rate of curcumin in simulated gastric juice (pH 1.2) is relatively low, and within 2h, the release rates of microspheres formed by zinc oxide nanoparticles with the mass fraction of 0% to 1.00% are 7.52%, 5.76%, 5.39% and 5.06%, respectively, as shown in fig. 8. Subsequently, the cumulative 6h release in simulated small intestine fluid (pH 6.8) and simulated colon fluid (pH 7.4) reached 79.35%, 74.83%, 73.67% and 68.15%, respectively.
Example 3
Preparing enzymolysis corn porous starch: preparing 30% of starch homogenate according to the method in the embodiment 1, adding 2% of complex enzyme (mass ratio of complex enzyme to dry starch basis) for enzymolysis reaction, wherein the mass ratio of alpha-amylase: the mass ratio of the saccharifying enzyme is 1:2, the stirring speed of the water bath is 500rpm, the temperature of the water bath is 50 ℃, the reaction time is 1.5h, the pH of the system is adjusted to be 1.2-1.5 by 1mol/L hydrochloric acid, the reaction is stopped for 10min, then the pH of the system is adjusted to be neutral by sodium hydroxide, and the reaction mixture is subjected to suction filtration, washing, drying, crushing, sieving and the like to obtain the porous starch.
Treating and enzymolyzing corn porous starch by using a pulsed electric field: mixing porous starch and deionized water to form uniform starch suspension, magnetically stirring uniformly, adding 1mol/L potassium chloride electrolyte solution, adjusting the conductivity of the starch emulsion solution to 150 mu S/cm, pumping into a pulsed electric field treatment chamber by using a peristaltic pump, wherein the actual treatment time of the pulsed electric field is 30min, the intensity of the pulsed electric field is 12kV/cm, the pulse width is 40 mu S, the pulse frequency is 1000Hz, and the flow rate is 100 mL/min. And filtering the porous starch treated by the pulse electric field, washing the porous starch for 3 times by using deionized water, drying the porous starch in a forced air drying oven for 12 hours, crushing and sieving to obtain a finished product.
Preparation of cross-linked porous starch: and (2) performing crosslinking treatment on the obtained corn porous starch prepared by the pulsed electric field assisted enzymolysis, preparing 15 mass percent of starch suspension from the porous starch and deionized water, adding 10 mass percent of sodium trimetaphosphate as a crosslinking agent (sodium trimetaphosphate: starch dry basis mass ratio), stirring on a magnetic stirrer at the speed of 400rpm and the water bath temperature of 40 ℃, adding 0.2mL of sodium carbonate and 0.5g of sodium chloride into 20mL of deionized water, adjusting the pH value of the reaction system, performing water bath reaction for 1h, stopping the reaction for 15min, washing the reaction mixture for 3 times with deionized water, drying in a forced air dryer for 12h, crushing, and sieving to obtain the crosslinked corn porous starch.
Preparation of curcumin-loaded composite gel microspheres: respectively dissolving 3% of carboxymethyl cellulose, 0.5% of zinc oxide and 0.5g of curcumin/crosslinked porous starch compound in deionized water with a certain volume, fixing the volume to 100mL, and uniformly stirring. Mixing, injecting the mixture into FeCl with a mass fraction of 3% with a syringe with an inner diameter of 10mm3In solution. Gel microspheres in FeCl3And (3) carrying out crosslinking reaction in the solution for 30min, filtering, washing, transferring the prepared microspheres wrapped with the carboxymethyl cellulose into chitosan solution with the mass fraction of 0.25%, 0.5%, 1% and 1.25%, and carrying out reaction at 100rpm at normal temperature for 30min to obtain the curcumin-loaded composite gel microspheres. Then, the prepared composite gel microspheres were subjected to in vitro digestion release tests for 2 hours, 3 hours, and 3 hours in simulated gastric fluid (SGF, pH 1.2), simulated small intestinal fluid (SIF, pH 6.8), and simulated colon fluid (SCF, pH 7.4), respectively. And finally, determining the adsorption rate of the crosslinked porous starch for adsorbing the curcumin, the loading rate of the composite gel microspheres for loading the curcumin and the in-vitro release condition of the composite gel microspheres.
The measurement shows that the adsorption rate of the cross-linked porous starch for adsorbing curcumin is 61.11%, the loading rate of the prepared gel microspheres is 56.88%, and the loading capacity is 5.69 mg/g. The thermal stability of the cross-linked porous starch is more stable than that of the porous starch, and is characterized in that the maximum thermal decomposition temperature of the cross-linked porous starch is 313.9 ℃ and is higher than the maximum thermal decomposition temperature of the porous starch by 310.4 ℃. In vitro digestion experiments show that the release rate of curcumin in simulated gastric juice (pH 1.2) is relatively low, and the release rates of microspheres formed by chitosan solution with the mass fraction of 0.25% to 1.00% are 5.26%, 6.16%, 7.33% and 8.62% within 2h respectively, as shown in fig. 9. Subsequently, the cumulative 6h release in simulated small intestine fluid (pH 6.8) and simulated colon fluid (pH 7.4) reached 79.06%, 79.56%, 75.75% and 72.17%, respectively.
The method utilizes the pulsed electric field to assist in preparing the enzymatic corn porous starch, and can efficiently prepare the corn porous starch with high adsorbability and drug-loading property; meanwhile, the layer-by-layer self-assembly technology of the hydrogel can effectively improve the stability and targeted release property of the curcumin. Therefore, the invention aims at the preparation of porous starch and the preparation of hydrogel to construct an effective drug delivery system, and has important significance for the increasing market demand of people. The invention carries out pulse electric field treatment on the corn porous starch obtained by enzymolysis, and compared with the porous starch obtained by direct enzymolysis, the pulse electric field can effectively shorten the enzymolysis time and obtain higher adsorbability and drug loading rate. The porous starch/curcumin compound adsorbed with curcumin is subjected to composite gelatinization treatment of carboxymethyl cellulose and chitosan, so that the stability of curcumin can be effectively improved, and the effect of directional release is achieved, and the curcumin-carrying porous starch/curcumin compound is a very effective drug carrying system.
The embodiments of the present invention are not limited to the embodiments, and any other changes, modifications, substitutions, combinations, and simplifications which do not depart from the spirit and principle of the present invention should be construed as equivalents and are included in the scope of the present invention.

Claims (10)

1. The composite gel microspheres loaded with curcumin by crosslinked corn porous starch are characterized in that curcumin/crosslinked porous starch composite is added into a carboxymethyl cellulose solution, zinc oxide is added, and the materials are mixed and stirred uniformly in a water bath; dripping into ferric chloride or calcium chloride solution to form gel microspheres, transferring the gel microspheres into chitosan solution, stirring, and performing outer layer film wrapping treatment to obtain the chitosan microsphere; the curcumin/cross-linked porous starch compound is formed by adding cross-linked corn porous starch into a curcumin alcohol solution for adsorption; the cross-linked porous corn starch is obtained by adding a cross-linking agent into a porous corn starch suspension; the corn porous starch suspension is obtained by preparing corn porous starch through pulsed electric field assisted enzymolysis.
2. The composite gel microsphere with curcumin supported by crosslinked corn porous starch as claimed in claim 1, wherein the preparation of the corn porous starch by pulsed electric field assisted enzymolysis is that corn native starch and buffer solution are prepared into starch milk, a composite enzyme consisting of alpha-amylase and glucoamylase is added, water bath enzymolysis is carried out for 1-2.5 h, the reaction is terminated, then the reactant is adjusted to be neutral, and the porous starch is obtained by water washing, alcohol washing, drying and crushing; and then mixing the porous starch with water to form uniform starch suspension, stirring uniformly, adding an electrolyte solution, adjusting the conductivity of the starch emulsion solution to 50-400 mu S/cm, treating in a pulsed electric field treatment chamber for 20-60 min, filtering, drying, crushing and sieving to obtain the corn porous starch.
3. The crosslinked porous corn starch curcumin-loaded composite gel microsphere as claimed in claim 2, wherein the electric field strength of the pulse electric field is 5-20 kV/cm, the pulse width is 5-100 μ s, and the pulse frequency is 500-2000 Hz; pumping the electric field treatment solution into a pulsed electric field treatment chamber by a peristaltic pump, and controlling the flow rate to be 50-200 mL/min; the electrolyte solution is one or two of a potassium chloride solution and a potassium sulfate solution, and the concentration of the electrolyte solution is 0.5-2 mol/L.
4. The crosslinked porous corn starch curcumin-loaded composite gel microsphere as claimed in claim 2, wherein the buffer is an acetic acid-sodium acetate buffer or a phosphate buffer, and the pH value of the buffer is 4-5; the mass fraction of native starch in the starch milk is 10-30%; the enzyme activity of the alpha-amylase is 3000-5000U/mL, and the enzyme activity of the saccharifying enzyme is 5000-; the mass ratio of the alpha-amylase to the saccharifying enzyme is 1: 1-1: 5; the adding amount of the complex enzyme is 1.5-2.5% of the dry mass of the starch; the temperature of the water bath enzymolysis is 40-50 ℃.
5. The crosslinked porous corn starch curcumin-loaded composite gel microspheres of claim 1, wherein the crosslinked porous corn starch is prepared by the following method: mixing porous corn starch with deionized water to prepare a starch suspension, adding a cross-linking agent, adjusting the pH value of the system, carrying out cross-linking reaction for 0.5-2 h, washing, filtering, drying, crushing, and sieving to obtain the cross-linked porous starch.
6. The crosslinked porous corn starch curcumin-loaded composite gel microsphere of claim 5, wherein said crosslinking agent is one of sodium trimetaphosphate, phosphorus oxychloride, epichlorohydrin and sodium tripolyphosphate; the pH value of the adjusting system is adjusted by adding a mixture of sodium carbonate and sodium chloride, disodium hydrogen phosphate and sodium hydroxide; the mass fraction of the porous starch suspension in the starch suspension is 10-30%, and the dosage of the cross-linking agent is 5-20% of the mass of the starch suspension; the cross-linking reaction is controlled by a water area, the temperature is 30-50 ℃, and the drying is drying in a blast drier for 8-12 h; the washing is carried out 3-5 times by using deionized water.
7. The crosslinked porous corn starch curcumin-loaded composite gel microsphere as claimed in claim 1, wherein the curcumin alcohol solution is formed by dissolving curcumin in ethanol, and the concentration of the curcumin is 1-3 mg/mL; the adsorption time is 0.5-2 h; the mass ratio of the cross-linked corn porous starch to the curcumin is 30: 1-80: 1.
8. The crosslinked porous corn starch loaded curcumin composite gel microsphere as claimed in claim 1, wherein the mass fraction of the carboxymethyl cellulose solution is 0.5-5%, the mass fraction of zinc oxide is 0-2%, the mass fraction of the ferric chloride or calcium chloride solution is 1-5%, the mass fraction of the chitosan solution is 0.5-3%, and the balance is curcumin/crosslinked porous starch composite, based on the raw material usage amount of the crosslinked porous corn starch loaded curcumin composite gel microsphere.
9. The crosslinked porous corn starch-curcumin-loaded composite gel microsphere as claimed in claim 1, wherein the temperature of water bath mixing and stirring is 30-50 ℃, the stirring speed is 200-600 rpm, and the stirring time is 0.5-2 h; the stirring time in the chitosan solution is 0.5-2 h, and the stirring speed is 200-600 rpm.
10. The preparation method of the crosslinked porous corn starch curcumin-loaded composite gel microspheres according to any one of claims 1 to 9, is characterized by comprising the following steps:
1) preparing porous starch by enzymolysis: preparing corn starch and buffer solution into starch milk, and adding a complex enzyme consisting of alpha-amylase and saccharifying enzyme; performing water bath enzymolysis, adjusting the system to be neutral after the enzymolysis is finished, washing with water, washing with alcohol, drying, and crushing to obtain porous starch;
2) treating porous starch by using a pulsed electric field: mixing porous starch with water to form uniform starch suspension, adding electrolyte solution, adjusting the conductivity of the starch emulsion solution, performing pulsed electric field treatment in a pulsed electric field treatment chamber, filtering, washing, drying, pulverizing, and sieving the porous starch after the pulsed electric field treatment;
3) preparing cross-linked corn porous starch: adding a cross-linking agent into the porous starch suspension treated by the pulsed electric field, adjusting the pH value of a reaction system, uniformly stirring, carrying out water bath reaction, adjusting the pH value of the reaction system, stopping the reaction, washing, filtering, drying, crushing and sieving;
4) preparing curcumin-loaded composite gel microspheres: dissolving curcumin in ethanol to obtain curcumin solution, adding into crosslinked corn porous starch, stirring to adsorb curcumin, and filtering to remove unadsorbed curcumin to obtain curcumin/crosslinked porous starch compound;
5) adding the curcumin/crosslinked porous starch compound prepared in the step 4) into a carboxymethyl cellulose solution, adding zinc oxide, and mixing and stirring uniformly in a water bath; and dripping the mixture into a ferric chloride or calcium chloride solution at a constant speed to form gel microspheres, filtering the gel microspheres to remove the mixture which is not formed into gel, transferring the gel microspheres into a chitosan solution, and performing outer-layer film coating treatment to obtain the composite gel microspheres loaded with curcumin.
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