CN105963278A - Preparation method of amycin controlled-release chitosan nano particles with pH/oxido-reduction dual response - Google Patents
Preparation method of amycin controlled-release chitosan nano particles with pH/oxido-reduction dual response Download PDFInfo
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- CN105963278A CN105963278A CN201610512675.3A CN201610512675A CN105963278A CN 105963278 A CN105963278 A CN 105963278A CN 201610512675 A CN201610512675 A CN 201610512675A CN 105963278 A CN105963278 A CN 105963278A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/51—Nanocapsules; Nanoparticles
- A61K9/5107—Excipients; Inactive ingredients
- A61K9/513—Organic macromolecular compounds; Dendrimers
- A61K9/5161—Polysaccharides, e.g. alginate, chitosan, cellulose derivatives; Cyclodextrin
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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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/51—Nanocapsules; Nanoparticles
- A61K9/5107—Excipients; Inactive ingredients
- A61K9/5115—Inorganic compounds
Abstract
The invention relates to a preparation method of amycin controlled-release chitosan nano particles with pH/oxido-reduction dual response. Thiolated chitosan, carboxymethyl chitosan, sodium tripolyphosphate, doxorubicin hydrochloride and hydrogen peroxide are taken as raw materials. The preparation method comprises the following steps: mixing a thiolated chitosans solution with a doxorubicin hydrochloride solution so as to obtain a solution I; mixing a carboxymethyl chitosan solution with a sodium tripolyphosphate solution so as to obtain a mixed solution II; dropwise adding the mixed solution I into the mixed solution II while stirring, controlling the dosage of carboxymethyl chitosan and thiolated chitosan, regulating the ph value of the solution to 6-8, performing ultrasonic blending, performing ion crosslinking and polymer condensing, then dropwise adding hydrogen peroxide into the system so as to finish oxidization crosslinking, performing room-temperature stirring reaction, separating products, and drying the products to obtain the amycin controlled-release chitosan nano particles with pH/oxido-reduction dual response. The amycin controlled-release chitosan nano particles with pH/oxido-reduction dual response is capable of escaping away from tumor cell endosome/lysosome, is capable of automatically regulating and controlling to realize cytoplast release based on unique microenvironments of tumor cells, improving the amycin medicine delivery efficiency and the medical effect, and has a favorable research and development application background in multiple aspects such as medicine and medical materials.
Description
Technical field
The present invention relates to the preparation method of the amycin controlled release chitosan nano that a kind of pH/ of having oxidoreduction double-bang firecracker is answered.
Background technology
Nano medication can realize that the targeted of chemotherapeutics is eased up On The Drug Release thus become the focus of research.Internal targeted delivery for medicine is spontaneous reply internal milieu and the feature of tumor microenvironment regulating medicine release, and pharmaceutical carrier needs possess the functional characteristic adapted with it.Tumor cell has the environmental characteristics (such as pH, reduction characteristic, temperature, enzyme etc.) of uniqueness, and environment sensitive carrier is by single or multiple environment characteristic response, and spontaneous control medicine is in correct space-time release.On the one hand, interior body/lysosomal interior environment is faintly acid (pH 4.5-6.5), and pH sensitive carrier based on groups such as ortho esters, hydrazone or acetals can disintegration release in interior body/lysosomal sour environment.If but medicine is at interior body/lysosome retention, the existence of sour environment and enzyme can cause medicines structure to destroy and inactivate, and needs medicine to escape from interior body/lysosome in time.O type carboxymethyl chitosan (CMCS), on the premise of retaining amino of chitosan group, strand has carboxylic group the most simultaneously so that it is become a kind of ampholyte.As pH < 4.8, the protonated amino on CMCS molecular skeleton, pH when 4.8-6.0, part carboxymethyl group deprotonation, CMCS reaches its isoelectric point, IP, as pH > 6, the amino of CMCS and carboxyl deprotonation.Therefore CMCS has pH response, in interior body/lysosomal sour environment, the adsorbable proton of carboxymethyl group of deprotonation, causes interior body/lysosome Permeation Swelling to disintegrate, it is achieved nanoparticle is escaped.On the other hand, the content of tumor cell matter GSH-PX activity (GSH) is apparently higher than normal structure, and making tumor cell matter is high reproducibility.Reduction sensitive carrier based on disulfide bond crosslinking, such as Chitosan-Thiolated Polymers, can disintegrate in Cytoplasm, makes medicine discharge at kytoplasm.PH/ oxidoreduction double-bang firecracker answers the drug-carrying nanometer particle can be in conjunction with the unique microenvironment of tumor tissues, and spontaneous regulating medicine is in correct space-time release.
Summary of the invention
It is an object of the invention to provide the preparation method of the amycin controlled release chitosan nano that a kind of pH/ of having oxidoreduction double-bang firecracker is answered, using thio chitosan, carboxymethyl chitosan, sodium tripolyphosphate, doxorubicin hydrochloride, hydrogen peroxide is raw material, by ionomer, oxidation cross-linked, polymer agglomerates method, the load amycin chitosan nano answered of pH/ oxidoreduction double-bang firecracker of preparation can be escaped body/lysosome in tumor cell, spontaneous regulation and control realize kytoplasm release, and that improves amycin passs drug effect rate and drug effect.
The specific embodiment of the invention comprises the following steps.
(1) thio chitosan being dissolved in dilute acid soln, wherein dilute acid concentration is 1 mM, and thio chitosan concentration is 0.1%(w/v), the doxorubicin hydrochloride solution that concentration is 1 mg/mL is added in this solution, 30 mins are stirred at room temperature, control doxorubicin hydrochloride consumption, obtain mixed liquor one.
(2) carboxymethyl chitosan is dissolved in deionized water, carboxymethyl chitosan concentration is 0.1%(w/v), adding concentration in this solution is 0.2%(w/v) sodium tripolyphosphate solution, 30 mins are stirred at room temperature, control carboxymethyl chitosan and the consumption of sodium tripolyphosphate, obtain mixed liquor two.
(3) under agitation, being instilled by mixed liquor one in mixed liquor two, its addition is carboxymethyl chitosan and the mass ratio of thio chitosan is 1.5-2:1, and sodium tripolyphosphate and thio chitosan mass ratio are 0.1-0.5:1, rate of addition is 30 droplets/minute, regulation solution acid alkalinity, to pH6-8, is stirred at room temperature reaction 1 h, ultrasonic mixing, ultrasonic power 200 W, time 5 min, opens 2 s, stops 1 s.
(4) hydrogen peroxide that concentration is 30% is instilled in the system of step 3, hydrogen peroxide is 1:1 with the mol ratio of thio chitosan free sulfhydryl groups, reaction 2 hs are stirred at room temperature, 15000 revs/min of centrifugal 30 min separate product, it is dried to obtain solid product, i.e. there is the amycin controlled release chitosan nano that pH/ oxidoreduction double-bang firecracker is answered.
Thio chitosan used in the present invention is the conjugate that chitosan is formed by amido link, ester bond or amidino groups etc. with sulfhydryl compound, and thio chitosan molecular weight is 150 kDa, and substitution value scope is more than 150 μm ol/g;The molecular weight ranges of carboxymethyl chitosan is 150-1500 kDa, and deacetylation is more than 90%;Indication dilute acid soln can be that concentration is 1 mM hydrochloric acid or concentration is 1 mM acetic acid;The carboxymethyl chitosan of indication can be O-CMC, it is also possible to be CMC, and carboxymethyl chitosan substitution value scope is greater than 80%;Used product is carried out particle diameter and Zeta potential analysis, result shows, the particle diameter narrow distribution of the amycin controlled release chitosan nano that prepared pH/ oxidoreduction double-bang firecracker is answered, and mean diameter is at 150-250 nm, Zeta potential is-31--27 mv, and the envelop rate of doxorubicin hydrochloride is 54.9-70.7%.
The advantages such as the present invention has easy to operate, and preparing technique process is easy.Thio chitosan/carboxymethyl chitosan nano controlled release microgranule that the bag formed carries doxorubicin hydrochloride is spherical in shape.The significance of the present invention is that the nanoparticle formed has double responsiveness to oxidoreduction and pH, give carrier and tumor cell is passed the material behavior that the temporal characteristics of medicine adapts, can be based on tumor cell unique microenvironment, body/the lysosome destruction to medicine in escaping, effectively discharge in realizing kytoplasm, improve the transfer efficiency of medicine.In terms of the many such as medicine, medical material, there is good research and development application background.
Below in conjunction with subordinate list, chart and embodiment the present invention made and further illustrating.
Accompanying drawing explanation
The transmission electron microscope photo of the amycin controlled release chitosan nano that Fig. 1, pH/ oxidoreduction double-bang firecracker is answered.
The amycin controlled release chitosan nano that Fig. 2, pH/ oxidoreduction double-bang firecracker is answered is to oxidoreduction response drug release profiles.
The amycin controlled release chitosan nano that Fig. 3, pH/ oxidoreduction double-bang firecracker is answered is to pH response drug release profiles.
Detailed description of the invention
Below by embodiment the present invention made and being further elaborated with, but the present invention is not limited to these embodiments.
Embodiment
1
Weigh 2 mg thio chitosans, be dissolved in 2 mL
In the hydrochloric acid solution of 1 mM, instill 0.3 mL 1 mg/ml doxorubicin hydrochloride solution under agitation, obtain mixed liquor one, take the carboxymethyl chitosan that 3 mg molecular weight are 150 kDa to be dissolved in 3 mL deionized waters, instilling 0.1 mL concentration under agitation is 2%(w/v) sodium tripolyphosphate solution obtain mixed liquor two, mixed liquor one is added dropwise in mixed liquor two, rate of addition is 30 droplets/minute, by hydrochloric acid regulation acid-base value to pH 7.5, stirring reaction 1 h under room temperature, ultrasonic mixing, ultrasonic power 200 W, time 5 min, open 2 s, stop 1 s, drip 0.05 mL under agitation
The hydrogen peroxide of 30%, stirring reaction 2 h under room temperature, 15000 revs/min of centrifugal 30 min, remove supernatant, lyophilization i.e. obtains has the amycin controlled release chitosan nano that pH/ oxidoreduction double-bang firecracker is answered.
Embodiment
2
Weigh 2 mg thio chitosans, be dissolved in 2 mL
In the hydrochloric acid solution of 1 mM, instill 0.3 mL 1 mg/ml doxorubicin hydrochloride solution under agitation, obtain mixed liquor one, take the carboxymethyl chitosan that 4 mg molecular weight are 400 kDa to be dissolved in 4 mL deionized waters, instilling 0.2 mL concentration under agitation is 2%(w/v) sodium tripolyphosphate solution obtain mixed liquor two, mixed liquor one is added dropwise in mixed liquor two, rate of addition is 30 droplets/minute, by hydrochloric acid regulation acid-base value to pH 8.0, stirring reaction 1 h under room temperature, ultrasonic mixing, ultrasonic power 200 W, time 5 min, open 2 s, stop 1 s, drip 0.05 mL under agitation
The hydrogen peroxide of 30%, stirring reaction 2 h under room temperature, 15000 revs/min of centrifugal 30 min, remove supernatant, lyophilization i.e. obtains has the amycin controlled release chitosan nano that pH/ oxidoreduction double-bang firecracker is answered.
Embodiment
3
Weigh 2 mg thio chitosans, be dissolved in 2 mL
In the hydrochloric acid solution of 1 mM, instill 0.3 mL 1 mg/ml doxorubicin hydrochloride solution under agitation, obtain mixed liquor one, take the carboxymethyl chitosan that 3 mg molecular weight are 1500 kDa to be dissolved in 3 mL deionized waters, instilling 0.5 mL concentration under agitation is 2%(w/v) sodium tripolyphosphate solution obtain mixed liquor two, mixed liquor one is added dropwise in mixed liquor two, rate of addition is 30 droplets/minute, by hydrochloric acid regulation acid-base value to pH 6.0, stirring reaction 1 h under room temperature, ultrasonic mixing, ultrasonic power 200 W, time 5 min, open 2 s, stop 1 s, drip 0.05 mL under agitation
The hydrogen peroxide of 30%, stirring reaction 2 h under room temperature, 15000 revs/min of centrifugal 30 min, remove supernatant, lyophilization i.e. obtains has the amycin controlled release chitosan nano that pH/ oxidoreduction double-bang firecracker is answered.
Claims (2)
- null1. a preparation method with the amycin controlled release chitosan nano that pH/ oxidoreduction double-bang firecracker is answered,It is characterized in that 0.1%(w/v) thio chitosan solution and the doxorubicin hydrochloride solution of 1 mg/mL mix to obtain mixed liquor one,By sodium tripolyphosphate solution and the 0.1%(w/v of 0.2% (w/v)) carboxymethyl chitosan solution mix to obtain mixed liquor two,Under agitation,Mixed liquor one is instilled in mixed liquor two,Wherein,Carboxymethyl chitosan is 1.5-2:1 with the mass ratio of thio chitosan,Sodium tripolyphosphate and thio chitosan mass ratio are 0.1-0.5:1,Regulation solution acid alkalinity is to pH6-8,Ultrasonic mixing,The hydrogen peroxide of 30% it is added dropwise in above-mentioned system,Hydrogen peroxide is 1:1 with the mol ratio of thio chitosan free sulfhydryl groups,Stir under room temperature,Obtain stable bag and carry the nanometer disperse system of doxorubicin hydrochloride,Separate and be dried,I.e. obtain described product.
- 2. the preparation method of the amycin controlled release chitosan nano answered according to a kind of pH/ of the having oxidoreduction double-bang firecracker described in right 1, it is characterised in that thio chitosan is the conjugate that chitosan is formed by amido link, ester bond or amidino groups etc. with sulfhydryl compound.
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Cited By (6)
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CN108324680A (en) * | 2018-03-21 | 2018-07-27 | 武汉理工大学 | As segmented intestine targeted multiple response intelligent aqueous gel and preparation method thereof |
CN109908105A (en) * | 2018-12-30 | 2019-06-21 | 浙江中医药大学 | A kind of nano-complex of deoxycholic acid modification and its preparation and application |
CN113143867A (en) * | 2020-12-25 | 2021-07-23 | 武汉理工大学 | CMCS-DSP-IPI549 anti-tumor nano-delivery system and preparation method thereof |
CN113456611A (en) * | 2021-06-11 | 2021-10-01 | 淮阴工学院 | Double-response rapid controlled release nano-carrier and preparation method of nano-drug formed by nano-carrier |
CN114715994A (en) * | 2022-01-24 | 2022-07-08 | 南华大学 | PH response type nano iron-based slow release material, preparation method and application |
CN116919886A (en) * | 2023-07-21 | 2023-10-24 | 中国海洋大学 | Injectable photo-thermal hydrogel based on black pigment, and preparation method and application thereof |
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Cited By (9)
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CN108324680A (en) * | 2018-03-21 | 2018-07-27 | 武汉理工大学 | As segmented intestine targeted multiple response intelligent aqueous gel and preparation method thereof |
CN109908105A (en) * | 2018-12-30 | 2019-06-21 | 浙江中医药大学 | A kind of nano-complex of deoxycholic acid modification and its preparation and application |
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CN113143867A (en) * | 2020-12-25 | 2021-07-23 | 武汉理工大学 | CMCS-DSP-IPI549 anti-tumor nano-delivery system and preparation method thereof |
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CN113456611A (en) * | 2021-06-11 | 2021-10-01 | 淮阴工学院 | Double-response rapid controlled release nano-carrier and preparation method of nano-drug formed by nano-carrier |
CN114715994A (en) * | 2022-01-24 | 2022-07-08 | 南华大学 | PH response type nano iron-based slow release material, preparation method and application |
CN116919886A (en) * | 2023-07-21 | 2023-10-24 | 中国海洋大学 | Injectable photo-thermal hydrogel based on black pigment, and preparation method and application thereof |
CN116919886B (en) * | 2023-07-21 | 2024-01-30 | 中国海洋大学 | Injectable photo-thermal hydrogel based on black pigment, and preparation method and application thereof |
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