WO2023151350A1 - Microsphère de gel composite chargée de curcumine à base d'amidon poreux de maïs réticulé, et son procédé de préparation - Google Patents
Microsphère de gel composite chargée de curcumine à base d'amidon poreux de maïs réticulé, et son procédé de préparation Download PDFInfo
- Publication number
- WO2023151350A1 WO2023151350A1 PCT/CN2022/135200 CN2022135200W WO2023151350A1 WO 2023151350 A1 WO2023151350 A1 WO 2023151350A1 CN 2022135200 W CN2022135200 W CN 2022135200W WO 2023151350 A1 WO2023151350 A1 WO 2023151350A1
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- Prior art keywords
- curcumin
- porous starch
- starch
- cross
- linked
- Prior art date
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- VFLDPWHFBUODDF-FCXRPNKRSA-N curcumin Chemical compound C1=C(O)C(OC)=CC(\C=C\C(=O)CC(=O)\C=C\C=2C=C(OC)C(O)=CC=2)=C1 VFLDPWHFBUODDF-FCXRPNKRSA-N 0.000 title claims abstract description 340
- 229920002472 Starch Polymers 0.000 title claims abstract description 318
- 235000019698 starch Nutrition 0.000 title claims abstract description 318
- 239000008107 starch Substances 0.000 title claims abstract description 317
- 239000004148 curcumin Substances 0.000 title claims abstract description 171
- 229940109262 curcumin Drugs 0.000 title claims abstract description 171
- 235000012754 curcumin Nutrition 0.000 title claims abstract description 170
- VFLDPWHFBUODDF-UHFFFAOYSA-N diferuloylmethane Natural products C1=C(O)C(OC)=CC(C=CC(=O)CC(=O)C=CC=2C=C(OC)C(O)=CC=2)=C1 VFLDPWHFBUODDF-UHFFFAOYSA-N 0.000 title claims abstract description 170
- 239000004005 microsphere Substances 0.000 title claims abstract description 88
- 240000008042 Zea mays Species 0.000 title claims abstract description 84
- 235000005824 Zea mays ssp. parviglumis Nutrition 0.000 title claims abstract description 84
- 235000002017 Zea mays subsp mays Nutrition 0.000 title claims abstract description 84
- 235000005822 corn Nutrition 0.000 title claims abstract description 84
- 239000002131 composite material Substances 0.000 title claims abstract description 59
- 238000002360 preparation method Methods 0.000 title claims abstract description 33
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 85
- 230000005684 electric field Effects 0.000 claims abstract description 63
- 238000003756 stirring Methods 0.000 claims abstract description 44
- XLOMVQKBTHCTTD-UHFFFAOYSA-N Zinc monoxide Chemical compound [Zn]=O XLOMVQKBTHCTTD-UHFFFAOYSA-N 0.000 claims abstract description 42
- 239000000203 mixture Substances 0.000 claims abstract description 34
- 238000001179 sorption measurement Methods 0.000 claims abstract description 33
- 239000000725 suspension Substances 0.000 claims abstract description 33
- 229920002134 Carboxymethyl cellulose Polymers 0.000 claims abstract description 31
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 30
- 239000001768 carboxy methyl cellulose Substances 0.000 claims abstract description 29
- 229920001661 Chitosan Polymers 0.000 claims abstract description 28
- 235000010948 carboxy methyl cellulose Nutrition 0.000 claims abstract description 28
- 239000008112 carboxymethyl-cellulose Substances 0.000 claims abstract description 28
- 150000001875 compounds Chemical class 0.000 claims abstract description 22
- 239000011787 zinc oxide Substances 0.000 claims abstract description 21
- 239000003431 cross linking reagent Substances 0.000 claims abstract description 16
- 229910021578 Iron(III) chloride Inorganic materials 0.000 claims abstract description 11
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 claims abstract description 11
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 claims abstract description 7
- 238000002156 mixing Methods 0.000 claims abstract description 4
- 239000000243 solution Substances 0.000 claims description 70
- 238000006243 chemical reaction Methods 0.000 claims description 45
- 239000008367 deionised water Substances 0.000 claims description 25
- 229910021641 deionized water Inorganic materials 0.000 claims description 25
- 102000004190 Enzymes Human genes 0.000 claims description 22
- 108090000790 Enzymes Proteins 0.000 claims description 22
- 229940088598 enzyme Drugs 0.000 claims description 22
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 21
- 238000006047 enzymatic hydrolysis reaction Methods 0.000 claims description 20
- 238000000034 method Methods 0.000 claims description 20
- 230000007071 enzymatic hydrolysis Effects 0.000 claims description 19
- 238000004132 cross linking Methods 0.000 claims description 18
- 235000013336 milk Nutrition 0.000 claims description 16
- 239000008267 milk Substances 0.000 claims description 16
- 210000004080 milk Anatomy 0.000 claims description 16
- 229920002261 Corn starch Polymers 0.000 claims description 14
- 102000004139 alpha-Amylases Human genes 0.000 claims description 14
- 108090000637 alpha-Amylases Proteins 0.000 claims description 14
- 229940024171 alpha-amylase Drugs 0.000 claims description 14
- 239000008120 corn starch Substances 0.000 claims description 14
- 238000001035 drying Methods 0.000 claims description 14
- 108010073178 Glucan 1,4-alpha-Glucosidase Proteins 0.000 claims description 12
- 102100022624 Glucoamylase Human genes 0.000 claims description 12
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 claims description 12
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 12
- 230000000694 effects Effects 0.000 claims description 12
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- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 11
- UGTZMIPZNRIWHX-UHFFFAOYSA-K sodium trimetaphosphate Chemical group [Na+].[Na+].[Na+].[O-]P1(=O)OP([O-])(=O)OP([O-])(=O)O1 UGTZMIPZNRIWHX-UHFFFAOYSA-K 0.000 claims description 11
- 230000007935 neutral effect Effects 0.000 claims description 8
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- 239000001103 potassium chloride Substances 0.000 claims description 6
- 235000011164 potassium chloride Nutrition 0.000 claims description 6
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- 239000000872 buffer Substances 0.000 claims description 4
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- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 4
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims description 4
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- BHZOKUMUHVTPBX-UHFFFAOYSA-M sodium acetic acid acetate Chemical group [Na+].CC(O)=O.CC([O-])=O BHZOKUMUHVTPBX-UHFFFAOYSA-M 0.000 claims description 4
- BRLQWZUYTZBJKN-UHFFFAOYSA-N Epichlorohydrin Chemical compound ClCC1CO1 BRLQWZUYTZBJKN-UHFFFAOYSA-N 0.000 claims description 3
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- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 claims description 2
- OTYBMLCTZGSZBG-UHFFFAOYSA-L potassium sulfate Chemical compound [K+].[K+].[O-]S([O-])(=O)=O OTYBMLCTZGSZBG-UHFFFAOYSA-L 0.000 claims description 2
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- 229920000609 methyl cellulose Polymers 0.000 claims 1
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- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
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- QCVGEOXPDFCNHA-UHFFFAOYSA-N 5,5-dimethyl-2,4-dioxo-1,3-oxazolidine-3-carboxamide Chemical compound CC1(C)OC(=O)N(C(N)=O)C1=O QCVGEOXPDFCNHA-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
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Classifications
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- A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
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- 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
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- A—HUMAN NECESSITIES
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- 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
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- A—HUMAN NECESSITIES
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- 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
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- 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
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- 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
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- 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
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- 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
Definitions
- the invention relates to the technical field of curcumin loading, in particular to a composite gel microsphere loaded with curcumin by cross-linked corn porous starch and a preparation method thereof.
- Curcumin bis- ⁇ , ⁇ -unsaturated ⁇ -diketone
- Curcuma longa L. a yellow-orange polyphenol derived from the rhizome of turmeric
- Curcumin is a rare pigment with a diketone structure in the plant kingdom.
- Curcumin is a fat-soluble molecule that has many health benefits such as reducing the risk of cancer, cardiovascular disease, chronic inflammation and metabolic disorders. Due to its unique physiological functions, it is widely used in many fields such as functional food and biomedicine. However, curcumin has the characteristics of poor water solubility, easy degradation, and low oral availability, which limit its application in food and pharmaceuticals.
- Porous starch refers to the modified starch in which microporous structures with a pore size of about 1 ⁇ m are distributed on the surface of starch granules. Compared with native starch, porous starch has larger porosity and specific surface area, better water absorption and oil absorption capacity, while retaining the original properties of starch such as non-toxic, harmless, degradable and good biocompatibility . Therefore, porous starch can be used as a wall material to embed active ingredients, protect the active ingredients, and achieve the effect of slow release or specific release of active ingredients.
- Hydrogel is a gel-like polymer formed by taking water or an aqueous medium as a dispersed phase, having a three-dimensional network structure after swelling, and being able to retain a large amount of solvent, and can be used as a drug carrier.
- natural polymer hydrogels are derived from animal and plant tissues in nature, such as chitosan extracted from shrimp shells, alginic acid extracted from kelp, etc.
- chitosan extracted from shrimp shells, alginic acid extracted from kelp, etc.
- a large number of studies have focused on the application of gels formed by chitosan, sodium alginate and carboxymethyl cellulose in the sustained and controlled release of drugs.
- the difference in the external environment such as the difference in pH value in the human body, will affect the effect of targeted drug release.
- the published curcumin embedding technology and curcumin gel loading technology mainly include: 1) Chinese invention patent 201510429922.9 discloses a method for preparing curcumin microcapsules with egg white powder as the wall material. As the core material, egg white powder and gelatin are used as the wall material, emulsifiers are added, and curcumin microcapsules are obtained by spray drying; however, the spray drying technology involved in this method has higher requirements for equipment and is relatively expensive. 2) Chinese invention patent application 202010546654.X discloses a preparation method of soybean lipophilic protein-curcumin complex, which uses thermal effect to induce the self-assembly of soybean lipophilic protein nanoparticles, and promotes the integration of soybean lipophilic protein nanoparticles and turmeric through ultrasound.
- the protein interaction improves the loading rate of soybean lipophilic protein; but the heat-induced technology used in this invention to process the structure of soybean lipophilic protein has higher requirements in the actual operation process, and the pH value in the reaction process needs to be strictly controlled, so that The system requirements for the reaction are higher.
- the object of the present invention is to provide a composite gel microsphere using cross-linked corn porous starch to load curcumin and a preparation method thereof, which can release curcumin in a targeted manner.
- the invention is mainly based on the cross-linking reaction of starch and the layer-by-layer self-assembly technology of hydrogel.
- the introduction of pulsed electric field increases the pore size and total pore volume of enzymatically hydrolyzed porous starch, thereby improving the adsorption properties of porous starch.
- the further increase of the pore size may lead to the collapse of the structure of some porous starches.
- the enzymatically hydrolyzed porous starch prepared with the assistance of the pulsed electric field was subjected to a cross-linking reaction, and the shear resistance and thermal stability of the porous starch were improved by cross-linking.
- the cross-linked porous starch is used as an adsorbent to physically adsorb the curcumin to obtain a curcumin/porous starch composite.
- the pores of porous starch tend to cause early release of curcumin.
- natural polymer gel materials such as carboxymethyl cellulose, chitosan, etc., are coated on the surface of curcumin/porous starch, so that curcumin can be released to the small intestine and improve bioavailability.
- the drug-loaded microspheres formed by carboxymethylcellulose or chitosan cannot achieve the effect of curcumin sustained release.
- the microspheres formed by carboxymethyl cellulose will shrink in the gastric juice, unable to release curcumin, and disintegrate rapidly after entering the intestinal tract, resulting in the explosive release of the drug; chitosan microspheres expand rapidly in the gastric juice, and the drug is released quickly , nor can it play the role of targeted release. Therefore, using the layer-by-layer self-assembly mode, the curcumin/porous starch is embedded layer by layer, first embedded with carboxymethyl cellulose, and then the formed carboxymethyl cellulose microspheres are immersed in the chitosan solution Wrap a layer of chitosan. At the same time, the introduced zinc oxide can improve the mechanical properties and stability of the gel microspheres, and can also regulate the release rate of curcumin in the in vitro simulated release test.
- the preparation of corn porous starch assisted by pulsed electric field enzymolysis is to prepare corn starch and buffer solution into starch milk, and add a compound enzyme composed of ⁇ -amylase and glucoamylase, Water bath enzymatic hydrolysis for 1 ⁇ 2.5 h, stop the reaction, adjust the reactant to neutral, wash with water, wash with alcohol, dry, and crush to obtain porous starch; then mix the porous starch with water to form a uniform starch suspension, and stir evenly , add electrolyte solution, adjust the conductivity of the starch milk solution to 50 ⁇ 400 ⁇ S/cm, 20 ⁇ 60 pulsed electric field treatment in the pulsed electric field treatment chamber min, filtered, dried, crushed and sieved to obtain corn porous starch.
- a compound enzyme composed of ⁇ -amylase and glucoamylase Water bath enzymatic hydrolysis for 1 ⁇ 2.5 h, stop the reaction, adjust the reactant to neutral, wash with water, wash with alcohol, dry, and crush to obtain porous starch;
- the electric field intensity of the pulsed electric field is 5 ⁇ 20 kV/cm, and the pulse width is 5 ⁇ 100 ⁇ s, pulse frequency 500 ⁇ 2000 Hz;
- the electric field treatment solution is pumped into the pulse electric field treatment chamber through a peristaltic pump, and the flow rate is controlled at 50-200 mL/min;
- the electrolyte solution is one or both of potassium chloride solution and potassium sulfate solution, and the concentration of the electrolyte solution is 0.5 ⁇ 2 mol/L.
- the buffer is acetic acid-sodium acetate buffer or phosphate buffer
- the pH of the buffer is 4 ⁇ 5
- the mass fraction of native starch in the starch milk is 10 ⁇ 30%
- the enzyme activity of ⁇ -amylase The enzyme activity of glucoamylase is 5000-200000 U/mL
- the mass ratio of ⁇ -amylase to glucoamylase is 1:1 ⁇ 1:5
- the amount of compound enzyme added is the dry weight of starch 1.5-2.5%
- the temperature of enzymatic hydrolysis in water bath is 40 ⁇ 50°C.
- the cross-linked corn porous starch is prepared by the following method: mixing corn porous starch with deionized water to form a starch suspension, adding a cross-linking agent, adjusting the pH value of the system, and cross-linking reaction 0.5-2 After h, washing, filtering, drying, pulverizing, and sieving to obtain cross-linked porous starch.
- the cross-linking agent is one of sodium trimetaphosphate (STMP), phosphorus oxychloride (POCl 3 ), epichlorohydrin (EPCH) and sodium tripolyphosphate (STPP); adjust the pH of the system The value 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 amount of the crosslinking agent is the mass of the starch suspension. 5-20%; the cross-linking reaction is controlled by the water area, the temperature is 30-50 °C, the drying is 8-12 h in the blast dryer; the washing is washed 3-5 times with deionized water .
- STMP sodium trimetaphosphate
- POCl 3 phosphorus oxychloride
- EPCH epichlorohydrin
- STPP sodium tripolyphosphate
- the curcumin alcohol solution is formed by dissolving curcumin in ethanol, the concentration of curcumin is 1-3 mg/mL; the adsorption time is 0.5-2 h; cross-linked corn porous starch and turmeric Prime mass ratio 30:1 ⁇ 80:1.
- the mass fraction of the carboxymethyl cellulose solution is 0.5-5%, and the mass fraction of zinc oxide is 0-5%.
- the mass fraction of ferric chloride or calcium chloride solution is 1-5%
- the mass fraction of chitosan solution is 0.5-3%
- the rest is curcumin/cross-linked porous starch composite.
- the temperature of the water bath mixing and stirring is 30 ⁇ 50°C, and the stirring speed is 200 ⁇ 600°C. rpm, the stirring time is 0.5 ⁇ 2 h; the stirring time in the chitosan solution is 0.5 ⁇ 2 h h, the stirring rate is 200 ⁇ 600 rpm.
- the preparation method of the composite gel microsphere of described cross-linked corn porous starch load curcumin comprises the steps:
- Pulse electric field treatment of porous starch mix porous starch with water to form a uniform starch suspension, add electrolyte solution to adjust the conductivity of the starch emulsion solution, perform pulse electric field treatment in the pulse electric field treatment chamber, and treat the pulsed electric field. Porous starch, filtered, washed, dried, pulverized, sieved;
- curcumin-loaded composite gel microspheres Dissolve curcumin in ethanol to obtain curcumin alcohol solution, add it to cross-linked corn porous starch, stir to absorb curcumin, filter out unadsorbed curcumin, and obtain Curcumin/cross-linked porous starch complex;
- step 5) Add the curcumin/cross-linked porous starch compound prepared in step 4) to the carboxymethyl cellulose solution, add zinc oxide, mix and stir in a water bath; drop the mixture into ferric chloride or calcium chloride at a constant speed Gel microspheres are formed in the solution, and then the gel microspheres are filtered to remove the ungelled mixture, then the gel microspheres are transferred to the chitosan solution, and then the outer membrane is wrapped to obtain curcumin-loaded Composite gel microspheres.
- the concentration of hydrochloric acid is 1-3 mol/L
- the concentration of sodium hydroxide is 1-3 mol/L.
- the oil absorption rate of the cross-linked corn porous starch prepared by the invention can reach 90-110%, and has better shear resistance and degradation resistance.
- the oil absorption rate of untreated raw corn starch that is, the corn raw starch described in step 1) is only 50-60%; after the enzymatic hydrolysis process in step 1), the oil absorption rate of enzymatic hydrolyzed corn porous starch can be
- the oil absorption rate of the porous starch can reach 80-110% after pulse treatment in step 2) to enzymatically hydrolyze the porous starch.
- the enzymatic hydrolysis reaction can produce many micropores on the surface of raw corn starch, and also generate a hollow structure, so the specific surface area of porous starch is significantly increased compared with that of native starch. At the same time, the generated micropores can provide better adsorption sites for external substances, thereby improving the adsorption performance of porous starch.
- the further treatment of enzymatically hydrolyzed porous starch by pulsed electric field is based on the theory of charge polarization in macroscopic space. The electrolyte that runs through the surface and inside of the porous starch provides additional charges for the porous starch.
- the thermal stability of the cross-linked porous starch is improved, and the thermal decomposition temperature is increased by 2-8 °C compared with that of the uncross-linked porous starch.
- the cross-linking reaction increases the porous
- the tight structure will limit the movement of molecular chains, increase the resistance to decomposition, and further improve the thermal stability of cross-linked porous starch; at the same time, the swelling force of cross-linked porous starch is compared with that of porous starch Reduced by 0.5 ⁇ 1.5 g/g, this is because the cross-linking of starch molecules and cross-linking agent increases and strengthens the strength of hydrogen bonds, and the increase of hydrogen bond strength will limit the swelling ability of cross-linked porous starch.
- the cross-linked porous starch composite adsorbed with curcumin obtained in step 4) has a loading rate of curcumin of more than 60%, indicating that the cross-linked porous starch can be used as an effective adsorbent for curcumin.
- the curcumin-loaded composite gel microspheres obtained in step 4) can significantly improve the stability of curcumin, and can retain the activity of curcumin for a long time under light and a certain temperature.
- the outer layer of the gel microspheres is self-assembled layer by layer to form an inside-out carboxymethylcellulose-chitosan coating, which can effectively protect the stability of curcumin and also play a role in delaying drug release. , and at the same time protect curcumin and other drugs from being digested and absorbed in the stomach, and play the role of directional delivery to the small intestine. This is because the outer layer of the composite gel is wrapped with chitosan, which is an alkaline polysaccharide.
- Carboxymethylcellulose is an anionic cellulose ether substance, and its solubility will increase in an alkaline or weakly alkaline environment, so it can dissolve in the small intestine environment and release active substances such as curcumin for targeted release role.
- the present invention has the following advantages:
- the present invention uses pulsed electric field-assisted enzymatic hydrolysis to prepare porous starch, which can prepare porous starch with good adsorption properties in a relatively short period of time, which greatly reduces the reaction time of tens of hours required for chemical or enzymatic preparation. ;
- the present invention treats the porous starch prepared by enzymatic hydrolysis with pulse electric field, which can increase the pore size, specific surface area and pore volume of the enzymatic porous starch prepared in a short time, and effectively improve the pore-forming rate of porous starch, and then Improve the adsorption rate of porous starch.
- the present invention uses the cross-linking reaction to carry out cross-linking treatment on the prepared enzymatically hydrolyzed porous starch, which further improves the thermal stability of the porous starch, and the thermal decomposition temperature of the cross-linked porous starch after cross-linking is improved, and also To a certain extent, the adsorption of the cross-linked porous starch is improved, thereby improving the bioavailability of the cross-linked porous starch.
- the preparation method of the curcumin-loaded composite gel microspheres prepared by the layer-by-layer self-assembly method of the present invention is simple, the raw materials are cheap and easy to obtain, the required equipment is simple, and the selected raw materials are all non-toxic and harmless natural materials. Biodegradable and will not cause harm to the human body.
- the curcumin-loaded composite gel microspheres provided by the present invention have obvious stabilizing and protective effects on curcumin.
- the curcumin in the embedded curcumin composite gel microspheres The retention rate of is still greater than 50%, while the retention rate of unembedded procurcumin is less than 10%.
- the heat stability and light stability of curcumin after gelation are significantly improved compared with unembedded curcumin.
- Layer-by-layer self-assembly is a technology that uses the electrostatic interaction of opposite charges to repeatedly deposit on the surface of the colloidal matrix.
- the gelled layer-by-layer self-assembly of the active ingredient complex plays a role in the targeted release of curcumin, and this method can also be extended to other drug delivery systems.
- Fig. 1 is a diagram of the specific surface area and the average diameter of pores of porous starch without pulse treatment and after pulse treatment in Comparative Example 1 of the present invention.
- Fig. 2(a) is a data diagram of TG thermogravimetric analysis of porous starch in Comparative Example 2 of the present invention.
- Figure 2(b) is a data diagram of TG thermogravimetric analysis of cross-linked porous starch in Comparative Example 2 of the present invention
- Fig. 3 is the data graph of the loading rate of different kinds of starch adsorbing curcumin in Comparative Example 3 of the present invention.
- Fig. 4(a) is a full spectrum diagram of the surface photoelectron spectra of porous starch and cross-linked porous starch in Example 1 of the present invention.
- Fig. 4(b) is a phosphorus element spectrum of the surface photoelectron spectroscopy of the porous starch and the cross-linked porous starch in Example 1 of the present invention.
- Fig. 4(c) is the carbon element spectrum of the surface photoelectron spectrum after the porous starch peak fitting in Example 1 of the present invention.
- Fig. 4(d) is the carbon element spectrum of the surface photoelectron spectrum after the peak fitting of the cross-linked porous starch in Example 1 of the present invention.
- Fig. 5 is a scanning electron micrograph of gel microspheres loaded with curcumin in Example 1 of the present invention.
- Fig. 6 is the Fourier transform infrared spectrogram of each component in the curcumin-loaded gel microsphere of Example 1 of the present invention.
- Fig. 7 is a graph of in vitro release data of composite gel microspheres formed with different mass fractions of carboxymethylcellulose (CMC) in Example 1 of the present invention.
- Fig. 8 is a graph showing in vitro release data of composite gel microspheres formed with different mass fractions of nano zinc oxide particles (ZnO) in Example 2 of the present invention.
- Fig. 9 is a graph showing in vitro release data of composite gel microspheres formed from chitosan (Cs) solutions with different mass fractions in Example 3 of the present invention.
- the present invention first utilizes pulsed electric field assisted enzymatic hydrolysis to prepare corn porous starch, which can effectively reduce the time for preparing corn porous starch. To increase the adsorption and shear resistance of porous starch. Subsequently, the obtained cross-linked corn porous starch was used as a curcumin adsorbent to absorb the curcumin alcohol solution, centrifuged and filtered to remove the unadsorbed curcumin/porous starch complex, vacuum freeze-dried, and set aside.
- curcumin/porous starch mixture added to the carboxymethylcellulose solution dissolved in hot water, mix well, and add zinc oxide at the same time to improve the antibacterial, mechanical and stability of the hydrogel matrix, mix the mixed solution Uniformly, obtain the mixed solution that is mixed with curcumin/porous starch/zinc oxide/carboxymethyl cellulose. Then inject the mixed solution into the ferric chloride solution with a syringe, and stir evenly to obtain curcumin-loaded gel microspheres.
- the gel microspheres were filtered, and the unembedded substances were washed out with water, and then the gel was transferred to a chitosan solution for layer-by-layer self-assembly embedding to obtain the final composite gel microspheres loaded with curcumin. ball.
- the determination method of oil absorption rate of porous starch under different treatment conditions is as follows. Weigh the mass of a 10 mL centrifuge tube with 3 small glass beads in advance, record it as M 0 , and then add about 1g Porous starch was placed in a 10 mL centrifuge tube, weighed the mass M 1 of the centrifuge tube, then added 4 mL of corn oil, stirred well, and centrifuged at 8000 rpm/min for 15 min, poured off the supernatant, and centrifuged Invert the tube for 10 min to absorb the remaining floating oil, and weigh M 2 . Then the oil absorption rate OA of the porous starch to be measured can be calculated by the following formula:
- OA represents the oil absorption rate of the porous starch to be tested.
- the specific surface area, total pore volume and pore size distribution of starch samples were determined by low-temperature nitrogen adsorption method.
- the specific operation is as follows: a fully automatic gas adsorption analyzer is used for measurement. Before measurement, the starch sample is placed under vacuum conditions at 100 °C for 5 h to remove the air adsorbed on the surface of the starch sample. After the sample is cooled to room temperature, the low-temperature nitrogen adsorption test is carried out with high-purity nitrogen as the medium. The sample to be tested is placed in a fully automatic gas adsorption analyzer, and nitrogen is passed through for testing.
- the nitrogen adsorption amount of the sample to be tested is related to the specific surface area, total pore volume and pore size of the sample. As the test temperature increases, the nitrogen adsorbed by the starch is desorbed, and finally reaches an equilibrium state, and the adsorption-desorption curve and correlation test indicators. Afterwards, the specific surface area, pore volume pore size and pore size distribution of the test sample were calculated by BET method and BJH method.
- Preparation of corn porous starch by enzymatic hydrolysis using existing technology mix raw corn starch with acetic acid-sodium acetate buffer solution with a pH of 5.0, stir magnetically for 15 minutes to disperse the starch suspension evenly, and obtain 30wt% starch homogenate, then add 2% compound enzyme (mass percentage of compound enzyme and starch dry base) for enzymolysis reaction, the compound enzyme in the enzymolysis reaction is ⁇ -amylase and glucoamylase, the mass ratio of ⁇ -amylase and glucoamylase is 1:2 .
- the reaction was carried out in a constant temperature water bath at 50 °C, and the water bath reaction time was 1.5 h to obtain the enzymatically hydrolyzed porous starch milk.
- the reaction was terminated with 1 mol/L hydrochloric acid for 10 min, and then the reaction solution was adjusted to neutral with sodium hydroxide.
- the cornstarch milk after enzymolysis was washed with ethanol for 3 times, washed with water for 3 times, filtered with suction, and then dried with a blower dryer, the drying temperature was 45°C, the drying time was 12 h, and pulverized Sieve to obtain the porous starch in Comparative Example 1.
- Pulse electric field treatment of enzymatically hydrolyzed corn porous starch mix the porous starch with deionized water to form a uniform starch suspension, stir evenly with a magnetic force, and then add 1 mol/L potassium chloride electrolyte solution to adjust the conductivity of the starch milk solution to 150 ⁇ S/cm, using a peristaltic pump to pump into the pulse electric field treatment chamber, the actual treatment time of the pulse electric field is 30 min, the pulse electric field strength was 12 kV/cm, the pulse width was 40 ⁇ s, the pulse frequency was 1000 Hz, and the flow rate was 100 mL/min.
- the porous starch treated by the pulse electric field was filtered, washed three times with deionized water, dried in a blast drying oven for 12 h, crushed, and sieved to obtain the corn porous starch prepared by pulse electric field-assisted enzymatic hydrolysis in Comparative Example 1.
- the prepared enzymolyzed porous starch and the enzymolyzed porous starch after pulse treatment were tested for oil absorption, specific surface area and pore size. Obtained through the test of oil absorption rate, the oil absorption rate of enzymatic hydrolyzed porous corn starch in comparative example 1 reaches 76.16%, and the oil absorption rate of enzymolyzed porous corn starch after pulse reaches 88.35%; As shown in Figure 1, the enzymatic hydrolyzed porous corn starch The specific surface area is 4.174 cc/g, the average pore diameter is 8.271 nm, the specific surface area of the enzymatic hydrolyzed corn porous starch after pulse treatment is 5.056 cc/g, and the average pore diameter is 18.11 nm.
- the enzymolyzed corn porous starch obtained in Comparative Example 1 is cross-linked, and the porous starch is mixed with deionized water to form a starch suspension of 15% mass fraction, stirred evenly, and then 10wt% sodium trimetaphosphate is added as a cross-linking agent.
- Linking agent mass percentage of sodium trimetaphosphate and starch dry basis
- stirring reaction was carried out on a magnetic stirrer, and the speed of magnetic stirring was 400 rpm, water bath temperature is 40 °C, add 0.2 mL of sodium carbonate and 0.5 g of sodium chloride were dissolved in 20 mL of deionized water to adjust the pH value of the reaction system.
- the reaction time in the water bath was 1 h, and the reaction was terminated for 15 min. Dry for 12 h, pulverize, and sieve to obtain the cross-linked corn porous starch in Comparative Example 2.
- Adsorption rate (%) (m 2 -m 1 )/m 2 ⁇ 100
- m 1 is the mass of curcumin in the supernatant after centrifugation of the curcumin embedding solution
- m 2 is the mass of total curcumin added to the embedding, in mg.
- Preparation of porous corn starch by enzymatic hydrolysis mix raw corn starch with acetic acid-sodium acetate buffer solution with a pH of 5.0, and stir magnetically for 15 minutes to disperse the starch suspension evenly to obtain a 30wt% starch homogenate, then add 2%
- the compound enzyme mass percentage of the compound enzyme and starch dry base
- the compound enzyme is ⁇ -amylase and glucoamylase
- the mass ratio of ⁇ -amylase and glucoamylase is 1:2.
- the reaction was carried out in a constant temperature water bath at 50 °C, and the water bath reaction time was 1.5 h to obtain the enzymatically hydrolyzed porous starch milk.
- the reaction was terminated with 1 mol/L hydrochloric acid for 10 min, and then the reaction solution was adjusted to neutral with sodium hydroxide.
- the cornstarch milk after enzymolysis was washed with ethanol for 3 times, washed with water for 3 times, filtered with suction, and then dried with a blower dryer, the drying temperature was 45°C, the drying time was 12 h, and pulverized Sieve to obtain porous starch.
- Pulse electric field treatment of enzymatically hydrolyzed corn porous starch mix the porous starch with deionized water to form a uniform starch suspension, stir evenly with a magnetic force, and then add 1 mol/L potassium chloride electrolyte solution to adjust the conductivity of the starch milk solution to 150 ⁇ S/cm, using a peristaltic pump to pump into the pulse electric field treatment chamber, the actual treatment time of the pulse electric field is 30 min, the pulse electric field strength was 12 kV/cm, the pulse width was 40 ⁇ s, the pulse frequency was 1000 Hz, and the flow rate was 100 mL/min.
- the porous starch treated by the pulse electric field was filtered, washed three times with deionized water, dried in a blast drying oven for 12 h, crushed, and sieved to obtain the finished product.
- cross-link the corn porous starch prepared by pulse electric field-assisted enzymolysis obtained above, mix the porous starch and deionized water to form a starch suspension with a mass fraction of 15%, stir evenly, and then Add 10wt% sodium trimetaphosphate as cross-linking agent (sodium trimetaphosphate and starch dry basis mass percentage), carry out stirring reaction on magnetic stirrer, the speed of magnetic stirring is 400 rpm, water bath temperature is 40 °C, add 0.2 mL of sodium carbonate and 0.5 g of sodium chloride were dissolved in 20 mL of deionized water to adjust the pH value of the reaction system.
- sodium trimetaphosphate and starch dry basis mass percentage sodium trimetaphosphate and starch dry basis mass percentage
- the reaction time in the water bath was 1 h, and the reaction was terminated for 15 min. Dry for 12 h, crush and sieve to obtain cross-linked porous starch. In order to verify whether the cross-linked porous starch was successfully synthesized, it was tested by surface photoelectron spectroscopy.
- Curcumin/Crosslinked Porous Corn Starch Complex Formulated with Absolute Ethanol 1 mg/mL curcumin solution 50 mL, stir well until curcumin is completely dissolved. Subsequently, 5 g of corn porous starch was added to 50 mL of water, stirred evenly to make it into a starch suspension, then the curcuminol solution and the starch suspension were mixed, and embedded at a speed of 300 rpm at 40 °C. The embedding process was protected from light, and embedded for 1 h.
- curcumin/cross-linked porous starch complex takes 3 mL of curcumin/cross-linked porous starch complex solution and centrifuge at 5000 rpm for 10 min, to remove unembedded curcumin, collect the supernatant after centrifugation, then measure the absorbance at 425 nm with a UV spectrophotometer, and calculate the supernatant according to the relationship between the content of curcumin and the absorbance at 425 nm content of curcumin in.
- the curcumin/cross-linked porous starch complex is suction-filtered, washed 3 times with water, washed 3 times with alcohol, vacuum freeze-dried and filtered, then pulverized, sieved with 80 mesh sieves and stored in a desiccator in the dark. Obtain curcumin/cross-linked porous complex.
- curcumin-loaded composite gel microspheres take carboxymethyl cellulose with final mass percentages of 1%, 2%, 3% and 4% after being dissolved in water respectively, dissolve them in warm water at 50°C, and then Dissolve zinc oxide with a final concentration of 0.5% and curcumin/cross-linked porous starch composite with 0.5 g in deionized water, dilute to 100 mL, and stir evenly. Pour the mixture of zinc oxide and curcumin/cross-linked porous starch into the carboxymethyl cellulose solution, mix and stir evenly, and then use a syringe with a 10 mm inner diameter to inject the above mixture into the 3% FeCl3 solution by mass fraction .
- Gel microspheres were cross-linked in FeCl solution for 30 min, filtered, washed with water, and the prepared microspheres wrapped with carboxymethyl fibers were transferred to 100 mL of chitosan solution with a mass fraction of 1%, 100 rpm , and react at room temperature for 30 min to obtain composite gel microspheres loaded with curcumin.
- the resulting curcumin-loaded gel microspheres were characterized for their morphology and structure, and the morphology of the curcumin-loaded gel microspheres after drying was analyzed by scanning electron microscopy. The results are shown in Figure 5.
- the gel microspheres formed The surface of the glue microspheres was wrinkled, and there was no obvious cavity structure inside.
- the curcumin was mixed evenly with viscous carboxymethyl cellulose during the embedding process, and the scanning electron microscope image could not visually observe the curcumin. Distribution.
- SGF gastric fluid
- SIF simulated small intestinal fluid
- SCF simulated colonic fluid
- Preparation of enzymatically hydrolyzed corn porous starch configure 30% starch homogenate according to the method in Example 1, add 2% compound enzyme (weight ratio of compound enzyme to starch dry basis) for enzymolysis reaction, ⁇ -amylase: saccharification
- the mass ratio of the enzyme was 1:2
- the stirring rate of the water bath was 500 rpm
- the temperature of the water bath was 50 °C.
- the pH of the system was adjusted to 1.2-1.5 with 1 mol/L hydrochloric acid, and the reaction was terminated for 10 min.
- Sodium hydroxide is used to adjust the pH of the system to neutral, and the reaction mixture is suction filtered, washed, dried, pulverized, and sieved until porous starch is obtained.
- Pulse electric field treatment of enzymatically hydrolyzed corn porous starch mix the porous starch with deionized water to form a uniform starch suspension, stir evenly with a magnetic force, and then add 1 mol/L potassium chloride electrolyte solution to adjust the conductivity of the starch milk solution to 150 ⁇ S/cm, using a peristaltic pump to pump into the pulse electric field treatment chamber, the actual treatment time of the pulse electric field is 30 min, the pulse electric field strength was 12 kV/cm, the pulse width was 40 ⁇ s, the pulse frequency was 1000 Hz, and the flow rate was 100 mL/min.
- the porous starch treated by the pulse electric field was filtered, washed three times with deionized water, dried in a blast drying oven for 12 h, crushed, and sieved to obtain the finished product.
- curcumin-loaded composite gel microspheres take carboxymethyl cellulose with final mass percentages of 1%, 2%, 3% and 4% after being dissolved in water respectively, dissolve them in warm water at 50°C, and then Dissolve zinc oxide with a final concentration of 0.5% and curcumin/cross-linked porous starch composite with 0.5 g in deionized water, dilute to 100 mL, and stir evenly. Pour the mixture of zinc oxide and curcumin/cross-linked porous starch into the carboxymethyl cellulose solution, mix and stir evenly, and then use a syringe with a 10 mm inner diameter to inject the above mixture into the 3% FeCl3 solution by mass fraction .
- Gel microspheres were cross-linked in FeCl solution for 30 min, filtered, washed with water, and the prepared microspheres wrapped with carboxymethyl fibers were transferred to 100 mL of chitosan solution with a mass fraction of 1%, 100 rpm , and react at room temperature for 30 min to obtain composite gel microspheres loaded with curcumin.
- curcumin-loaded composite gel microspheres take 0%, 0.25%, 0.50% and 1.00% zinc oxide nanoparticles by mass fraction, dissolve them in a certain volume of warm water at 50°C, and then take 3% Carboxymethyl cellulose and 0.5 g of curcumin/cross-linked porous starch complex were dissolved in a certain volume of deionized water, and the volume was adjusted to 100 ml, and stirred evenly. Pour the mixture of zinc oxide and curcumin/cross-linked porous starch into the carboxymethyl cellulose solution, mix and stir evenly, and then use a syringe with a 10 mm inner diameter to inject the above mixture into the 3% FeCl3 solution by mass fraction .
- SGF gastric fluid
- SIF simulated small intestine fluid
- SCF
- the microparticles formed by zinc oxide nanoparticles with a mass fraction of 0% to 1.00% The ball release rates were 7.52%, 5.76%, 5.39% and 5.06%, respectively.
- Preparation of enzymatically hydrolyzed corn porous starch configure 30% starch homogenate according to the method in Example 1, add 2% compound enzyme (weight ratio of compound enzyme to starch dry basis) for enzymolysis reaction, ⁇ -amylase: saccharification
- the mass ratio of the enzyme was 1:2
- the stirring rate of the water bath was 500 rpm
- the temperature of the water bath was 50 °C.
- the pH of the system was adjusted to 1.2-1.5 with 1 mol/L hydrochloric acid, and the reaction was terminated for 10 min.
- Sodium hydroxide is used to adjust the pH of the system to neutral, and the reaction mixture is suction filtered, washed, dried, pulverized, and sieved until porous starch is obtained.
- Pulse electric field treatment of enzymatically hydrolyzed corn porous starch mix the porous starch with deionized water to form a uniform starch suspension, stir evenly with a magnetic force, and then add 1 mol/L potassium chloride electrolyte solution to adjust the conductivity of the starch milk solution to 150 ⁇ S/cm, using a peristaltic pump to pump into the pulse electric field treatment chamber, the actual treatment time of the pulse electric field is 30 min, the pulse electric field strength was 12 kV/cm, the pulse width was 40 ⁇ s, the pulse frequency was 1000 Hz, and the flow rate was 100 mL/min.
- the porous starch treated by the pulse electric field was filtered, washed three times with deionized water, dried in a blast drying oven for 12 h, crushed, and sieved to obtain the finished product.
- the reaction time in the water bath was 1 h, and the reaction was terminated for 15 min.
- the reaction mixture was washed 3 times with deionized water, dried in a blast dryer for 12 h, pulverized, and sieved. , to obtain cross-linked corn porous starch.
- SGF gastric fluid
- SIF simulated small intestine
- the invention utilizes pulsed electric field to assist in the preparation of enzymatically hydrolyzed corn porous starch, which can efficiently prepare corn porous starch with high adsorption and drug loading; meanwhile, the layer-by-layer self-assembly technology of hydrogel can effectively improve the stability and target of curcumin. toward release. Therefore, the present invention is aimed at the preparation of porous starch and the preparation of hydrogel to construct an effective drug delivery system, which is of great significance to the growing market demand of people.
- the invention performs pulse electric field treatment on the corn porous starch obtained by enzymolysis.
- the pulse electric field can effectively reduce the time of enzymolysis, and simultaneously obtain higher adsorption and drug loading rate.
- Carboxymethyl cellulose and chitosan composite gelation treatment of porous starch/curcumin complex with curcumin can effectively improve the stability of curcumin and achieve the effect of directional release. It is a kind of Very effective drug delivery system.
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Abstract
Microsphère de gel composite chargée de curcumine à base d'amidon poreux de maïs réticulé. Un procédé de préparation de la microsphère de gel composite consiste : à ajouter un composé de curcumine/amidon poreux réticulé dans une solution de carboxyméthylcellulose, à ajouter de l'oxyde de zinc, à bien mélanger et à agiter dans un bain d'eau, à ajouter goutte à goutte le mélange dans une solution de chlorure ferrique ou de chlorure de calcium afin de former des microsphères de gel, puis à transférer les microsphères de gel dans une solution de chitosane, à agiter, et à effectuer un traitement d'enduction de film de couche externe. Le composé de curcumine/amidon poreux réticulé est formé en ajoutant de l'amidon poreux de maïs réticulé dans une solution d'alcool de curcumine et en effectuant une adsorption, l'amidon poreux de maïs réticulé est obtenu en ajoutant un agent de réticulation dans une suspension d'amidon poreux de maïs, et la suspension d'amidon poreux de maïs est obtenue à partir d'amidon poreux de maïs préparé au moyen d'une enzymolyse assistée par champ électrique pulsé. La microsphère de gel composite chargée de curcumine à base d'amidon poreux de maïs réticulé peut améliorer la stabilité de la curcumine, et libérer de manière directionnelle la curcumine dans l'intestin grêle ou le côlon.
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CN117643576A (zh) * | 2024-01-30 | 2024-03-05 | 江西滕王阁药业有限公司 | 一种含盐酸赖氨酸和葡萄糖颗粒的制备方法 |
CN117643637A (zh) * | 2024-01-25 | 2024-03-05 | 中国农业大学 | 一种提高姜黄素生物可及性的控制释放载体及其制备方法 |
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CN114588129A (zh) * | 2022-02-08 | 2022-06-07 | 华南理工大学 | 交联玉米多孔淀粉负载姜黄素的复合凝胶微球及其制备方法 |
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CN117643576A (zh) * | 2024-01-30 | 2024-03-05 | 江西滕王阁药业有限公司 | 一种含盐酸赖氨酸和葡萄糖颗粒的制备方法 |
CN117643576B (zh) * | 2024-01-30 | 2024-04-16 | 江西滕王阁药业有限公司 | 一种含盐酸赖氨酸和葡萄糖颗粒的制备方法 |
CN117771183A (zh) * | 2024-02-27 | 2024-03-29 | 深圳大佛药业股份有限公司 | 一种盐酸羟甲唑啉喷雾剂及其制备方法 |
CN117771183B (zh) * | 2024-02-27 | 2024-05-03 | 深圳大佛药业股份有限公司 | 一种盐酸羟甲唑啉喷雾剂及其制备方法 |
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