CN105326810A - Folic acid modified chitosan micro-capsule with reducing responsiveness and preparation method thereof - Google Patents
Folic acid modified chitosan micro-capsule with reducing responsiveness and preparation method thereof Download PDFInfo
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- CN105326810A CN105326810A CN201510736169.8A CN201510736169A CN105326810A CN 105326810 A CN105326810 A CN 105326810A CN 201510736169 A CN201510736169 A CN 201510736169A CN 105326810 A CN105326810 A CN 105326810A
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- 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
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/17—Amides, e.g. hydroxamic acids having the group >N—C(O)—N< or >N—C(S)—N<, e.g. urea, thiourea, carmustine
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- 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
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
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- 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
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/357—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
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- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
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- 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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
- A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
- A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
Abstract
The invention relates to a folic acid modified chitosan micro-capsule with reducing responsiveness and a preparation method thereof. The capsule wall is modified by folic acid and provided with a disulfide bond structure with reducing responsiveness, a chitosan crosslinking film modified by folic acid and compounds with sulfydryl or biomolecules is adopted as the capsule wall, and the oil phase loaded with hydrophobic drugs is adopted as a core material. Firstly, chitosan is modified by folic acid and the compounds with sulfydryl or the biomolecules, ultrasonic radiation is conducted on the oil phase loaded with the hydrophobic drugs and a chitosan water solution modified by the compounds with sulfydryl or the biomolecules, and the chitosan drug-loaded micro-capsule with the capsule wall provided with folic acid and the disulfide bond structure is obtained. The preparation method is rapid, easy and convenient, efficient, environmentally friendly and wide in material source, the product is pure and free of toxins, the drug loading capacity is large, the micro-capsule can be widely applied to covering the hydrophobic drugs, targeted conveyance of drugs is achieved through the targeting of folic acid, controllable release of the drugs is achieved through the reducing responsiveness of disulfide bonds, and good application prospects are achieved.
Description
Technical field
The present invention relates to a kind of bio-medical material, especially relate to a kind of microcapsule with reduction response and preparation method of modified with folic acid.
Background technology
Microcapsule is a kind of miniature vessel with particular geometric configuration of being made up of encystation material or packing material, due to the popularity of the particularity of its structure, the polytropy of performance and application, has significant application in fields such as agricultural, food and biological medicines.The material preparing microcapsule is varied, and the macromolecular material (PMMA, polylactic acid etc.) of mainly natural macromolecular material (protein, lipid etc.) or synthesis also can be inorganic compound (SiO
2, CaCO
3deng).Wherein, natural macromolecular material, owing to having good biocompatibility, avirulence and readily degradable, has important using value in the preparation of microcapsule.The method preparing microcapsule has a lot, according to encystation mechanism, three classes can be roughly divided into: Physical (spray drying method, air suspension, vacuum vapor deposition etc.), physical-chemical process (aqueous phase separation method, limonene method, squeezing and pressing method etc.) and chemical method (situ aggregation method, interfacial polymerization, molecule encapsulation method etc.).In recent years, there is again the technology of some new micro encapsulation, as surface grafting, matrix polymerization, LBL self-assembly etc.These technology are all the Microencapsulation Method based on chemical reaction, have structure-controllable, performance is adjustable, be easy to give the features such as various feature functionalitys.But more loaded down with trivial details, the consuming time length of these method operating process, and be easy to introduce impurity etc., which has limited their practical application.
The method utilizing ultrasonic radiation to prepare protein microcapsules is invented in the early 1990s by people such as the scientist Suslick of the U.S. the earliest, they utilize the ultrasonic radiation of high strength gas or water-fast liquid protein to be included, and are prepared into protein microcapsules.Because this method is simple to operate, efficient quick is environmental protection again, and the microcapsule obtained has good biocompatibility, has potential using value in fields such as targeted drug technology.Patent CN101953817B utilizes sonochemistry method to synthesize the microcapsule of a kind of year oil soluble material, and cyst material is protein or polymer.The preparation of modified with folic acid microcapsule had been reported in recent years, had potential application in fields such as drug targeting technology, but had no the report utilizing ultrasonic method preparation to have the chitosan microcapsules of reduction response modified with folic acid.
Summary of the invention
The object of the invention is to for above-mentioned the deficiencies in the prior art, provide a kind of efficiently succinct prepare modified with folic acid there is reduction response chitosan microcapsules;
The object of this invention is to provide a kind of preparation method with the chitosan microcapsules of reduction response of modified with folic acid.
Principle of the present invention: utilize high-strength ultrasonic in the catalytic action at oil/water interface, the sulfydryl that chitosan is modified is impelled to occur crosslinked, formed with the disulfide bond pattern containing reduction response and modified with folic acid structure and the cross linking membrane deposited, and will the oil phase embedding of hydrophobic drug be loaded with, formed with the cross linking membrane of the chitosan of sulfydryl modification for cyst wall, the oil phase being mounted with hydrophobic drug is the drug-loading microcapsule of core.Modified with folic acid there is reduction response chitosan microcapsules, the chitose crosslinked membrane through functionalization is cyst wall, and the oil phase being loaded with hydrophobic drug is capsule-core.
The object of the invention is to be achieved through the following technical solutions
A kind of chitosan microcapsules with reduction response of modified with folic acid, by carrying out ultrasonic radiation to the oil phase being mounted with hydrophobic drug and the chitosan aqueous solution of modifying through folic acid and the compound containing sulfydryl or biomolecule, formed with the chitose crosslinked membrane of the modified with folic acid of disulfide bond crosslinking as cyst wall, to be loaded with the drug-loading microcapsule of oil phase for core of hydrophobic drug, the size of microcapsule is at 0.2-50 μm.
The described compound containing sulfydryl or biomolecule are sulfydryl alkanoic acid [HS-(CH
2)
n-COOH, alkyl number n>=1], 2-amino-5-mercaptobenzoic acid, 5-sulfydryl-1H-tetrazole-1-acetic acid, 2-mercaptonicotinic acid, mercapto succinic acid, 5-mercapto-tetrazole also-1-acetic acid, cysteine and derivant thereof or glutathion and derivant thereof.
Described hydrophobic drug is one or more in paclitaxel, lomustine, ginsenoside, camptothecine or silymarin medicine.
Described oil phase be biological medicine can various animal oil, vegetable oil, microbial grease, mineral oil, silicone oil, or other and the inconsistent nontoxic liquid state organics of water.
A preparation method with the chitosan of the microcapsule of reduction response for modified with folic acid, comprises the following steps:
A, in the acetic acid and sodium acetate buffer of pH=5.0, chitosan is dissolved and prepare certain density chitosan aqueous solution;
B, the compound containing sulfydryl or biomolecule and 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride and N-hydroxy-succinamide are dissolved with mol ratio 1:1:1, compound concentration is the aqueous solution of 0.1-1.0mg/ml, activation 20min;
C, be that 5:1-1:5 mixes above-mentioned two kinds of solution stirring and reacts 12 hours with volume ratio under nitrogen protection, the unreacted compound containing sulfydryl of centrifuge washing removing or biomolecule, obtain the chitosan aqueous solution containing sulfydryl modification repeatedly;
D, folic acid and 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride, N-hydroxy-succinamide are dissolved with mol ratio 1:2:2, compound concentration is the aqueous solution of 0.1-1.0mg/ml, lucifuge activation 1h;
Be chitosan aqueous solution and the folic acid activating solution of 5:1-1:5 mixing pH=5.0 with volume ratio under e, lucifuge, stirring reaction 12h, obtains the chitosan aqueous solution containing modified with folic acid;
F, according to the ratio mixing of 1:1-20:1 containing the chitosan aqueous solution of sulfydryl modification with containing the chitosan aqueous solution of modified with folic acid;
G, according to a certain volume measure above-mentioned mixed shell water solution and containing hydrophobic drug oil phase together be placed in ice-water bath mix homogeneously;
H, again ultrasonic probe is placed in oil-water two-phase interfaces place, under certain ultrasonic power, acts on a period of time;
I, to regulate after about pH to 9-10 carry out centrifuge washing to product for neutral to reactant liquor, the chitose crosslinked membrane with disulfide bond pattern obtained containing modified with folic acid is cyst wall, the drug-loading microcapsule being core with the oil phase containing hydrophobic drug.
Described ultrasound intensity is 100-900W, and ultrasonic time is 0.5-30min.
The concentration of described chitosan aqueous solution is 0.1-3.0mg/ml.
Described mixed shell water solution is 1:1-20:1 with the volume ratio of the oil phase containing hydrophobic drug.
Beneficial effect: the inventive method can by direct for folic acid load on the cyst wall of microcapsule, and by folate-targeted, the reduction response of disulfide bond is combined with the biocompatibility of chitosan, realizes targeting delivery and the controllable release of hydrophobic drug; Products pure is nontoxic, and drug loading is large, can be widely used in the coated of hydrophobic drug, the targeting of folic acid is utilized to realize the targeting delivery of medicine and utilize the reduction response of disulfide bond to realize the controllable release of medicine, preparation method is simple to operate, efficient quick, and not easily introduces impurity.
Detailed description of the invention:
Below in conjunction with embodiment, the present invention is described in further detail:
A kind of chitosan microcapsules with reduction response of modified with folic acid, by carrying out ultrasonic radiation to the oil phase being mounted with hydrophobic drug and the chitosan aqueous solution of modifying through folic acid and the compound containing sulfydryl or biomolecule, formed with the chitose crosslinked membrane of the modified with folic acid of disulfide bond crosslinking as cyst wall, to be loaded with the drug-loading microcapsule of oil phase for core of hydrophobic drug, the size of microcapsule is at 0.2-50 μm.
The described compound containing sulfydryl or biomolecule are sulfydryl alkanoic acid [HS-(CH
2)
n-COOH, alkyl number n>=1], 2-amino-5-mercaptobenzoic acid, 5-sulfydryl-1H-tetrazole-1-acetic acid, 2-mercaptonicotinic acid, mercapto succinic acid, 5-mercapto-tetrazole also-1-acetic acid, cysteine and derivant thereof or glutathion and derivant thereof.
Described hydrophobic drug is one or more in paclitaxel, lomustine, ginsenoside, camptothecine or silymarin medicine.
Described oil phase be biological medicine can various animal oil, vegetable oil, microbial grease, mineral oil, silicone oil, or other and the inconsistent nontoxic liquid state organics of water.
A preparation method with the chitosan of the microcapsule of reduction response for modified with folic acid, comprises the following steps:
A, in the acetic acid and sodium acetate buffer of pH=5.0, chitosan is dissolved and prepare certain density chitosan aqueous solution;
B, the compound containing sulfydryl or biomolecule and 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride and N-hydroxy-succinamide are dissolved with mol ratio 1:1:1, compound concentration is the aqueous solution of 0.1-1.0mg/ml, activation 20min;
C, be that 5:1-1:5 mixes above-mentioned two kinds of solution stirring and reacts 12 hours with volume ratio under nitrogen protection, the unreacted compound containing sulfydryl of centrifuge washing removing or biomolecule, obtain the chitosan aqueous solution containing sulfydryl modification repeatedly;
D, folic acid and 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride, N-hydroxy-succinamide are dissolved with mol ratio 1:2:2, compound concentration is the aqueous solution of 0.1-1.0mg/ml, lucifuge activation 1h;
Be chitosan aqueous solution and the folic acid activating solution of 5:1-1:5 mixing pH=5.0 with volume ratio under e, lucifuge, stirring reaction 12h, obtains the chitosan aqueous solution containing modified with folic acid;
F, according to the ratio mixing of 1:1-20:1 containing the chitosan aqueous solution of sulfydryl modification with containing the chitosan aqueous solution of modified with folic acid;
G, according to a certain volume measure above-mentioned mixed shell water solution and containing hydrophobic drug oil phase together be placed in ice-water bath mix homogeneously;
H, again ultrasonic probe is placed in oil-water two-phase interfaces place, under certain ultrasonic power, acts on a period of time;
I, to regulate after about pH to 9-10 carry out centrifuge washing to product for neutral to reactant liquor, the chitose crosslinked membrane with disulfide bond pattern obtained containing modified with folic acid is cyst wall, the drug-loading microcapsule being core with the oil phase containing hydrophobic drug.
Described ultrasound intensity is 100-900W, and ultrasonic time is 0.5-30min.
The concentration of described chitosan aqueous solution is 0.1-3.0mg/ml.
Described mixed shell water solution is 1:1-20:1 with the volume ratio of the oil phase containing hydrophobic drug.
Embodiment 1
In the acetic acid and sodium acetate buffer of pH=5.0, chitosan is dissolved the chitosan aqueous solution preparing 0.1mg/ml; Cysteine hydrochloride and 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride and N-hydroxy-succinamide are dissolved with mol ratio 1:1:1, compound concentration is the aqueous solution of 0.1mg/ml, activation 20min; Be that the above-mentioned two kinds of solution stirring of 1:1 mixing react 12 hours under nitrogen protection with volume ratio, centrifuge washing removes unreacted cysteine hydrochloride repeatedly, obtains the chitosan aqueous solution containing sulfydryl modification; Folic acid and 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride, N-hydroxy-succinamide are dissolved with mol ratio 1:2:2, compound concentration is the aqueous solution of 0.1/ml, lucifuge activation 1h; Be chitosan aqueous solution and the folic acid activating solution of 5:1 mixing pH=5.0 with volume ratio under lucifuge, stirring reaction 12h, obtains the chitosan aqueous solution containing modified with folic acid; According to the chitosan aqueous solution of ratio mixing containing sulfydryl modification of 1:1 and the chitosan aqueous solution containing modified with folic acid; 5:1 measures above-mentioned mixed shell water solution and be placed in ice-water bath mix homogeneously together with the Oleum Glycines containing hydrophobic drug paclitaxel by volume; Again ultrasonic probe is placed in oil-water two-phase interfaces place, under the ultrasonic power of 100W, acts on 30min; Carry out centrifuge washing after regulating about pH to 9-10 to reactant liquor to product for neutral, the chitose crosslinked membrane with disulfide bond pattern obtained containing modified with folic acid is cyst wall, the drug-loading microcapsule being core with the oil phase containing hydrophobic drug.
Embodiment 2
In the acetic acid and sodium acetate buffer of pH=5.0, chitosan is dissolved the chitosan aqueous solution preparing 0.5mg/ml; By Mercaptoundecanoic acid [HS-(CH
2)
n-COOH, alkyl number n=10] and 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride and N-hydroxy-succinamide dissolve with mol ratio 1:1:1, compound concentration is the aqueous solution of 0.1mg/ml, activation 20min; Be that the above-mentioned two kinds of solution stirring of 1:5 mixing react 12 hours under nitrogen protection with volume ratio, centrifuge washing removes unreacted Mercaptoundecanoic acid repeatedly, obtains the chitosan aqueous solution containing sulfydryl modification; Folic acid and 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride, N-hydroxy-succinamide are dissolved with mol ratio 1:2:2, compound concentration is the aqueous solution of 1.0mg/ml, lucifuge activation 1h; Be chitosan aqueous solution and the folic acid activating solution of 2:1 mixing pH=5.0 with volume ratio under lucifuge, stirring reaction 12h, obtains the chitosan aqueous solution containing modified with folic acid; According to the chitosan aqueous solution of ratio mixing containing sulfydryl modification of 2:1 and the chitosan aqueous solution containing modified with folic acid; 1:2 measures above-mentioned mixed shell water solution and be placed in ice-water bath mix homogeneously together with the hydroxy silicon oil containing hydrophobic drug lomustine by volume; Again ultrasonic probe is placed in oil-water two-phase interfaces place, under the ultrasonic power of 300W, acts on 8min; Carry out centrifuge washing after regulating about pH to 9-10 to reactant liquor to product for neutral, the chitose crosslinked membrane with disulfide bond pattern obtained containing modified with folic acid is cyst wall, the drug-loading microcapsule being core with the oil phase containing hydrophobic drug.
Embodiment 3
In the acetic acid and sodium acetate buffer of pH=5.0, chitosan is dissolved the chitosan aqueous solution preparing 0.3mg/ml; By mercaptopropionic acid [HS-(CH
2)
n-COOH, alkyl number n=2] and 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride and N-hydroxy-succinamide dissolve with mol ratio 1:1:1, compound concentration is the aqueous solution of 1.0mg/ml, activation 20min; Be that the above-mentioned two kinds of solution stirring of 5:1 mixing react 12 hours under nitrogen protection with volume ratio, centrifuge washing removes unreacted mercaptopropionic acid repeatedly, obtains the chitosan aqueous solution containing sulfydryl modification; Folic acid and 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride, N-hydroxy-succinamide are dissolved with mol ratio 1:2:2, compound concentration is the aqueous solution of 0.5mg/ml, lucifuge activation 1h; Be chitosan aqueous solution and the folic acid activating solution of 2:1 mixing pH=5.0 with volume ratio under lucifuge, stirring reaction 12h, obtains the chitosan aqueous solution containing modified with folic acid; According to the chitosan aqueous solution of ratio mixing containing sulfydryl modification of 5:1 and the chitosan aqueous solution containing modified with folic acid; 1:5 measures above-mentioned mixed shell water solution and be placed in ice-water bath mix homogeneously together with the Oleum Arachidis hypogaeae semen containing hydrophobic drug ginsenoside by volume; Again ultrasonic probe is placed in oil-water two-phase interfaces place, under the ultrasonic power of 500W, acts on 6min; Carry out centrifuge washing after regulating about pH to 9-10 to reactant liquor to product for neutral, the chitose crosslinked membrane with disulfide bond pattern obtained containing modified with folic acid is cyst wall, the drug-loading microcapsule being core with the oil phase containing hydrophobic drug.
Embodiment 4
In the acetic acid and sodium acetate buffer of pH=5.0, chitosan is dissolved the chitosan aqueous solution preparing 1.0mg/ml; By mercaptohexadecanoic acid [HS-(CH
2)
n-COOH, alkyl number n=15] and 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride and N-hydroxy-succinamide dissolve with mol ratio 1:1:1, compound concentration is the aqueous solution of 0.2mg/ml, activation 20min; Be that the above-mentioned two kinds of solution stirring of 1:5 mixing react 12 hours under nitrogen protection with volume ratio, centrifuge washing removes unreacted mercaptohexadecanoic acid repeatedly, obtains the chitosan aqueous solution containing sulfydryl modification; Folic acid and 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride, N-hydroxy-succinamide are dissolved with mol ratio 1:2:2, compound concentration is the aqueous solution of 0.5mg/ml, lucifuge activation 1h; Be chitosan aqueous solution and the folic acid activating solution of 2:1 mixing pH=5.0 with volume ratio under lucifuge, stirring reaction 12h, obtains the chitosan aqueous solution containing modified with folic acid; According to the chitosan aqueous solution of ratio mixing containing sulfydryl modification of 10:1 and the chitosan aqueous solution containing modified with folic acid; 10:1 measures above-mentioned mixed shell water solution and be placed in ice-water bath mix homogeneously together with the olive oil containing hydrophobic drug camptothecine by volume; Again ultrasonic probe is placed in oil-water two-phase interfaces place, under the ultrasonic power of 300W, acts on 15min; Carry out centrifuge washing after regulating about pH to 9-10 to reactant liquor to product for neutral, the chitose crosslinked membrane with disulfide bond pattern obtained containing modified with folic acid is cyst wall, the drug-loading microcapsule being core with the oil phase containing hydrophobic drug.
Embodiment 5
In the acetic acid and sodium acetate buffer of pH=5.0, chitosan is dissolved the chitosan aqueous solution preparing 3.0mg/ml; By TGA [HS-(CH
2)
n-COOH, alkyl number n=1] and 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride and N-hydroxy-succinamide dissolve with mol ratio 1:1:1, compound concentration is the aqueous solution of 1.0mg/ml, activation 20min; Be that the above-mentioned two kinds of solution stirring of 1:3 mixing react 12 hours under nitrogen protection with volume ratio, centrifuge washing removes unreacted TGA repeatedly, obtains the chitosan aqueous solution containing sulfydryl modification; Folic acid and 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride, N-hydroxy-succinamide are dissolved with mol ratio 1:2:2, compound concentration is the aqueous solution of 1.0mg/ml, lucifuge activation 1h; Be chitosan aqueous solution and the folic acid activating solution of 1:3 mixing pH=5.0 with volume ratio under lucifuge, stirring reaction 12h, obtains the chitosan aqueous solution containing modified with folic acid; According to the chitosan aqueous solution of ratio mixing containing sulfydryl modification of 15:1 and the chitosan aqueous solution containing modified with folic acid; 20:1 measures above-mentioned mixed shell water solution and be placed in ice-water bath mix homogeneously together with the algal oil containing hydrophobic drug silymarin by volume; Again ultrasonic probe is placed in oil-water two-phase interfaces place, under the ultrasonic power of 600W, acts on 5min; Carry out centrifuge washing after regulating about pH to 9-10 to reactant liquor to product for neutral, the chitose crosslinked membrane with disulfide bond pattern obtained containing modified with folic acid is cyst wall, the drug-loading microcapsule being core with the oil phase containing hydrophobic drug.
Embodiment 6
In the acetic acid and sodium acetate buffer of pH=5.0, chitosan is dissolved the chitosan aqueous solution preparing 0.3mg/ml; 2-amino-5-mercaptobenzoic acid and 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride and N-hydroxy-succinamide are dissolved with mol ratio 1:1:1, compound concentration is the aqueous solution of 0.5mg/ml, activation 20min; Be that the above-mentioned two kinds of solution stirring of 5:3 mixing react 12 hours under nitrogen protection with volume ratio, centrifuge washing removes unreacted 2-amino-5-mercaptobenzoic acid repeatedly, obtains the chitosan aqueous solution containing sulfydryl modification; Folic acid and 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride, N-hydroxy-succinamide are dissolved with mol ratio 1:2:2, compound concentration is the aqueous solution of 0.6mg/ml, lucifuge activation 1h; Be chitosan aqueous solution and the folic acid activating solution of 2:1 mixing pH=5.0 with volume ratio under lucifuge, stirring reaction 12h, obtains the chitosan aqueous solution containing modified with folic acid; According to the chitosan aqueous solution of ratio mixing containing sulfydryl modification of 20:1 and the chitosan aqueous solution containing modified with folic acid; 20:1 measures above-mentioned mixed shell water solution and be placed in ice-water bath mix homogeneously together with the hydroxy silicon oil containing hydrophobic drug paclitaxel by volume; Again ultrasonic probe is placed in oil-water two-phase interfaces place, under the ultrasonic power of 900W, acts on 0.5min; Carry out centrifuge washing after regulating about pH to 9-10 to reactant liquor to product for neutral, the chitose crosslinked membrane with disulfide bond pattern obtained containing modified with folic acid is cyst wall, the drug-loading microcapsule being core with the oil phase containing hydrophobic drug.
Embodiment 7
In the acetic acid and sodium acetate buffer of pH=5.0, chitosan is dissolved the chitosan aqueous solution preparing 0.3mg/ml; 5-sulfydryl-1H-tetrazole-1-acetic acid and 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride and N-hydroxy-succinamide are dissolved with mol ratio 1:1:1, compound concentration is the aqueous solution of 0.1-1.0mg/ml, activation 20min; Be that the above-mentioned two kinds of solution stirring of 3:1 mixing react 12 hours under nitrogen protection with volume ratio, centrifuge washing removes unreacted 5-sulfydryl-1H-tetrazole-1-acetic acid repeatedly, obtains the chitosan aqueous solution containing sulfydryl modification; Folic acid and 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride, N-hydroxy-succinamide are dissolved with mol ratio 1:2:2, compound concentration is the aqueous solution of 0.3mg/ml, lucifuge activation 1h; Be chitosan aqueous solution and the folic acid activating solution of 1:1 mixing pH=5.0 with volume ratio under lucifuge, stirring reaction 12h, obtains the chitosan aqueous solution containing modified with folic acid; According to the chitosan aqueous solution of ratio mixing containing sulfydryl modification of 1:1 and the chitosan aqueous solution containing modified with folic acid; 5:1 measures above-mentioned mixed shell water solution and be placed in ice-water bath mix homogeneously together with the Oleum Glycines containing hydrophobic drug paclitaxel by volume; Again ultrasonic probe is placed in oil-water two-phase interfaces place, under the ultrasonic power of 500W, acts on 6min; Carry out centrifuge washing after regulating about pH to 9-10 to reactant liquor to product for neutral, the chitose crosslinked membrane with disulfide bond pattern obtained containing modified with folic acid is cyst wall, the drug-loading microcapsule being core with the oil phase containing hydrophobic drug.
Embodiment 8
In the acetic acid and sodium acetate buffer of pH=5.0, chitosan is dissolved the chitosan aqueous solution preparing 0.5mg/ml; 2-mercaptonicotinic acid and 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride and N-hydroxy-succinamide are dissolved with mol ratio 1:1:1, compound concentration is the aqueous solution of 1.0mg/ml, activation 20min; Be that the above-mentioned two kinds of solution stirring of 2:1 mixing react 12 hours under nitrogen protection with volume ratio, centrifuge washing removes unreacted 2-mercaptonicotinic acid repeatedly, obtains the chitosan aqueous solution containing sulfydryl modification; Folic acid and 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride, N-hydroxy-succinamide are dissolved with mol ratio 1:2:2, compound concentration is the aqueous solution of 0.3mg/ml, lucifuge activation 1h; Be chitosan aqueous solution and the folic acid activating solution of 1:1 mixing pH=5.0 with volume ratio under lucifuge, stirring reaction 12h, obtains the chitosan aqueous solution containing modified with folic acid; According to the chitosan aqueous solution of ratio mixing containing sulfydryl modification of 1:1 and the chitosan aqueous solution containing modified with folic acid; 5:1 measures above-mentioned mixed shell water solution and be placed in ice-water bath mix homogeneously together with the Oleum Glycines containing hydrophobic drug paclitaxel by volume; Again ultrasonic probe is placed in oil-water two-phase interfaces place, under the ultrasonic power of 500W, acts on 6min; Carry out centrifuge washing after regulating about pH to 9-10 to reactant liquor to product for neutral, the chitose crosslinked membrane with disulfide bond pattern obtained containing modified with folic acid is cyst wall, the drug-loading microcapsule being core with the oil phase containing hydrophobic drug.
Embodiment 9
In the acetic acid and sodium acetate buffer of pH=5.0, chitosan is dissolved the chitosan aqueous solution preparing 0.1mg/ml; Mercapto succinic acid and 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride and N-hydroxy-succinamide are dissolved with mol ratio 1:1:1, compound concentration is the aqueous solution of 0.1mg/ml, activation 20min; Be that the above-mentioned two kinds of solution stirring of 1:1 mixing react 12 hours under nitrogen protection with volume ratio, centrifuge washing removes unreacted mercapto succinic acid repeatedly, obtains the chitosan aqueous solution containing sulfydryl modification; Folic acid and 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride, N-hydroxy-succinamide are dissolved with mol ratio 1:2:2, compound concentration is the aqueous solution of 0.3mg/ml, lucifuge activation 1h; Be chitosan aqueous solution and the folic acid activating solution of 1:1 mixing pH=5.0 with volume ratio under lucifuge, stirring reaction 12h, obtains the chitosan aqueous solution containing modified with folic acid; According to the chitosan aqueous solution of ratio mixing containing sulfydryl modification of 1:1 and the chitosan aqueous solution containing modified with folic acid; 5:1 measures above-mentioned mixed shell water solution and be placed in ice-water bath mix homogeneously together with the Oleum Glycines containing hydrophobic drug paclitaxel by volume; Again ultrasonic probe is placed in oil-water two-phase interfaces place, under the ultrasonic power of 500W, acts on 6min; Carry out centrifuge washing after regulating about pH to 9-10 to reactant liquor to product for neutral, the chitose crosslinked membrane with disulfide bond pattern obtained containing modified with folic acid is cyst wall, the drug-loading microcapsule being core with the oil phase containing hydrophobic drug.
Embodiment 10
In the acetic acid and sodium acetate buffer of pH=5.0, chitosan is dissolved the chitosan aqueous solution preparing 0.3mg/ml; By 5-mercapto-tetrazole also-1-acetic acid and 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride and N-hydroxy-succinamide dissolve with mol ratio 1:1:1, compound concentration is the aqueous solution of 0.1mg/ml, activation 20min; Be that the above-mentioned two kinds of solution stirring of 1:5 mixing react 12 hours under nitrogen protection with volume ratio, centrifuge washing removes unreacted 5-mercapto-tetrazole also-1-acetic acid repeatedly, obtains the chitosan aqueous solution containing sulfydryl modification; Folic acid and 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride, N-hydroxy-succinamide are dissolved with mol ratio 1:2:2, compound concentration is the aqueous solution of 0.3mg/ml, lucifuge activation 1h; Be chitosan aqueous solution and the folic acid activating solution of 1:1 mixing pH=5.0 with volume ratio under lucifuge, stirring reaction 12h, obtains the chitosan aqueous solution containing modified with folic acid; According to the chitosan aqueous solution of ratio mixing containing sulfydryl modification of 1:1 and the chitosan aqueous solution containing modified with folic acid; 5:1 measures above-mentioned mixed shell water solution and be placed in ice-water bath mix homogeneously together with the Oleum Glycines containing hydrophobic drug paclitaxel by volume; Again ultrasonic probe is placed in oil-water two-phase interfaces place, under the ultrasonic power of 500W, acts on 6min; Carry out centrifuge washing after regulating about pH to 9-10 to reactant liquor to product for neutral, the chitose crosslinked membrane with disulfide bond pattern obtained containing modified with folic acid is cyst wall, the drug-loading microcapsule being core with the oil phase containing hydrophobic drug.
Embodiment 11
In the acetic acid and sodium acetate buffer of pH=5.0, chitosan is dissolved the chitosan aqueous solution preparing 0.5mg/ml; Glutathion and 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride and N-hydroxy-succinamide are dissolved with mol ratio 1:1:1, compound concentration is the aqueous solution of 0.1mg/ml, activation 20min; Be that the above-mentioned two kinds of solution stirring of 1:5 mixing react 12 hours under nitrogen protection with volume ratio, centrifuge washing removes unreacted glutathion repeatedly, obtains the chitosan aqueous solution containing sulfydryl modification; Folic acid and 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride, N-hydroxy-succinamide are dissolved with mol ratio 1:2:2, compound concentration is the aqueous solution of 0.3mg/ml, lucifuge activation 1h; Be chitosan aqueous solution and the folic acid activating solution of 1:1 mixing pH=5.0 with volume ratio under lucifuge, stirring reaction 12h, obtains the chitosan aqueous solution containing modified with folic acid; According to the chitosan aqueous solution of ratio mixing containing sulfydryl modification of 1:1 and the chitosan aqueous solution containing modified with folic acid; 5:1 measures above-mentioned mixed shell water solution and be placed in ice-water bath mix homogeneously together with the Oleum Glycines containing hydrophobic drug camptothecine by volume; Again ultrasonic probe is placed in oil-water two-phase interfaces place, under the ultrasonic power of 500W, acts on 6min; Carry out centrifuge washing after regulating about pH to 9-10 to reactant liquor to product for neutral, the chitose crosslinked membrane with disulfide bond pattern obtained containing modified with folic acid is cyst wall, the drug-loading microcapsule being core with the oil phase containing hydrophobic drug.
Embodiment 12
In the acetic acid and sodium acetate buffer of pH=5.0, chitosan is dissolved the chitosan aqueous solution preparing 0.2mg/ml; Acetylcysteine and 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride and N-hydroxy-succinamide are dissolved with mol ratio 1:1:1, compound concentration is the aqueous solution of 1.0mg/ml, activation 20min; Be that the above-mentioned two kinds of solution stirring of 5:1 mixing react 12 hours under nitrogen protection with volume ratio, centrifuge washing removes unreacted acetylcysteine repeatedly, obtains the chitosan aqueous solution containing sulfydryl modification; Folic acid and 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride, N-hydroxy-succinamide are dissolved with mol ratio 1:2:2, compound concentration is the aqueous solution of 0.3mg/ml, lucifuge activation 1h; Be chitosan aqueous solution and the folic acid activating solution of 1:1 mixing pH=5.0 with volume ratio under lucifuge, stirring reaction 12h, obtains the chitosan aqueous solution containing modified with folic acid; According to the chitosan aqueous solution of ratio mixing containing sulfydryl modification of 1:1 and the chitosan aqueous solution containing modified with folic acid; 5:1 measures above-mentioned mixed shell water solution and be placed in ice-water bath mix homogeneously together with the hydroxy silicon oil containing hydrophobic drug paclitaxel by volume; Again ultrasonic probe is placed in oil-water two-phase interfaces place, under the ultrasonic power of 500W, acts on 6min; Carry out centrifuge washing after regulating about pH to 9-10 to reactant liquor to product for neutral, the chitose crosslinked membrane with disulfide bond pattern obtained containing modified with folic acid is cyst wall, the drug-loading microcapsule being core with the oil phase containing hydrophobic drug.
Claims (8)
1. the chitosan microcapsules with reduction response of a modified with folic acid, it is characterized in that, by carrying out ultrasonic radiation to the oil phase being mounted with hydrophobic drug and the chitosan aqueous solution of modifying through folic acid and the compound containing sulfydryl or biomolecule, formed with the chitose crosslinked membrane of the modified with folic acid of disulfide bond crosslinking as cyst wall, to be loaded with the drug-loading microcapsule of oil phase for core of hydrophobic drug, the size of microcapsule is at 0.2-50 μm.
2. according to the chitosan microcapsules with reduction response of a kind of modified with folic acid according to claim 1, it is characterized in that, the described compound containing sulfydryl or biomolecule are sulfydryl alkanoic acid [HS-(CH
2)
n-COOH, alkyl number n>=1], 2-amino-5-mercaptobenzoic acid, 5-sulfydryl-1H-tetrazole-1-acetic acid, 2-mercaptonicotinic acid, mercapto succinic acid, 5-mercapto-tetrazole also-1-acetic acid, cysteine and derivant thereof or glutathion and derivant thereof.
3. according to the chitosan microcapsules with reduction response of a kind of modified with folic acid according to claim 1, it is characterized in that, described hydrophobic drug is one or more in paclitaxel, lomustine, ginsenoside, camptothecine or silymarin medicine.
4. according to a kind of modified with folic acid described in right 1 have reduction response chitosan microcapsules, it is characterized in that, described oil phase be biological medicine can various animal oil, vegetable oil, microbial grease, mineral oil, silicone oil, or other and the inconsistent nontoxic liquid state organics of water.
5. a preparation method with the chitosan of the microcapsule of reduction response for modified with folic acid, is characterized in that, comprise the following steps:
A, in the acetic acid and sodium acetate buffer of pH=5.0, chitosan is dissolved and prepare certain density chitosan aqueous solution;
B, the compound containing sulfydryl or biomolecule and 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride and N-hydroxy-succinamide are dissolved with mol ratio 1:1:1, compound concentration is the aqueous solution of 0.1-1.0mg/ml, activation 20min;
C, be that 5:1-1:5 mixes above-mentioned two kinds of solution stirring and reacts 12 hours with volume ratio under nitrogen protection, the unreacted compound containing sulfydryl of centrifuge washing removing or biomolecule, obtain the chitosan aqueous solution containing sulfydryl modification repeatedly;
D, folic acid and 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride, N-hydroxy-succinamide are dissolved with mol ratio 1:2:2, compound concentration is the aqueous solution of 0.1-1.0mg/ml, lucifuge activation 1h;
Be chitosan aqueous solution and the folic acid activating solution of 5:1-1:5 mixing pH=5.0 with volume ratio under e, lucifuge, stirring reaction 12h, obtains the chitosan aqueous solution containing modified with folic acid;
F, according to the ratio mixing of 1:1-20:1 containing the chitosan aqueous solution of sulfydryl modification with containing the chitosan aqueous solution of modified with folic acid;
G, according to a certain volume measure above-mentioned mixed shell water solution and containing hydrophobic drug oil phase together be placed in ice-water bath mix homogeneously;
H, again ultrasonic probe is placed in oil-water two-phase interfaces place, under certain ultrasonic power, acts on a period of time;
I, to regulate after about pH to 9-10 carry out centrifuge washing to product for neutral to reactant liquor, the chitose crosslinked membrane with disulfide bond pattern obtained containing modified with folic acid is cyst wall, the drug-loading microcapsule being core with the oil phase containing hydrophobic drug.
6., according to the preparation method with the chitosan microcapsules of reduction response of a kind of modified with folic acid according to claim 5, it is characterized in that, described ultrasound intensity is 100-900W, and ultrasonic time is 0.5-30min.
7., according to the preparation method with the chitosan microcapsules of reduction response of a kind of modified with folic acid described in right 5, it is characterized in that, the concentration of described chitosan aqueous solution is 0.1-3.0mg/ml.
8., according to the preparation method with the chitosan microcapsules of reduction response of a kind of modified with folic acid described in right 5, it is characterized in that, described chitosan aqueous solution is 1:1-20:1 with the volume ratio of the oil phase containing hydrophobic drug.
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| CN106577645A (en) * | 2016-11-16 | 2017-04-26 | 武汉理工大学 | GSH (glutathione) responsive controlled-release nano-pesticide formulation and preparation method and application thereof |
| CN107096474A (en) * | 2017-05-11 | 2017-08-29 | 青岛大学 | A kind of method that the preparation and encapsulating material of organic microgel are realized in synchronization |
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| CN107375237A (en) * | 2017-09-08 | 2017-11-24 | 吉林大学 | Starch capsules with reduction response a kind of of modified with folic acid and preparation method thereof |
| CN108905915A (en) * | 2018-05-24 | 2018-11-30 | 江南大学 | The preparation method and its resulting materials of a kind of thio chitosan photochromic micro-encapsulation and application |
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| CN1557283A (en) * | 2004-01-18 | 2004-12-29 | 浙江大学 | Ternary composite microsphere formulation and its preparation method |
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| CN1557283A (en) * | 2004-01-18 | 2004-12-29 | 浙江大学 | Ternary composite microsphere formulation and its preparation method |
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| CN107096474A (en) * | 2017-05-11 | 2017-08-29 | 青岛大学 | A kind of method that the preparation and encapsulating material of organic microgel are realized in synchronization |
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| CN107375237A (en) * | 2017-09-08 | 2017-11-24 | 吉林大学 | Starch capsules with reduction response a kind of of modified with folic acid and preparation method thereof |
| CN108905915A (en) * | 2018-05-24 | 2018-11-30 | 江南大学 | The preparation method and its resulting materials of a kind of thio chitosan photochromic micro-encapsulation and application |
| CN110256705A (en) * | 2019-06-20 | 2019-09-20 | 中国科学院海洋研究所 | A kind of pH response type polymer film and preparation method thereof |
| CN110256705B (en) * | 2019-06-20 | 2021-12-17 | 中国科学院海洋研究所 | PH response type polymer film and preparation method thereof |
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