CN106110334B - A kind of preparation method of surface-functionalized medicine-carried elution microballoon - Google Patents
A kind of preparation method of surface-functionalized medicine-carried elution microballoon Download PDFInfo
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Abstract
The present invention announces a kind of preparation method of surface-functionalized medicine-carried elution microballoon, is related to biological medicine Material Field.The preparation method the following steps are included: (1) using carboxymethyl chitosan as raw material, polyethyleneglycol diglycidylether is crosslinking agent, by reverse phase micro suspension cross-linking method, the Crosslinked Carboxymethyl Chitosan Microsphere that partial size is mainly distributed on 300~400um is prepared；(2) the drying Crosslinked Carboxymethyl Chitosan Microsphere prepared is put into 2- acrylamide-2-methyl propane sulfonic aqueous solution and is impregnated, using ammonium ceric nitrate as initiator, 2- acrylamide-2-methyl propane sulfonic is made to be graft-polymerized in microsphere surface, microballoon is modified.Since the microsphere surface is by modification of graft, have a large amount of sulfonic acid group, can payload drug containing positive charge such as doxorubicin hydrochloride, be hopeful to prepare elution microballoon.
Description
Technical field
The present invention relates to a kind of preparation methods of biodegradable pharmaceutical carrier, are related to biomedicine field, more particularly to
A kind of preparation method of surface-functionalized medicine-carried elution microballoon.
Background technique
Primary carcinoma of liver is a kind of common malignant tumour, and morbidity and mortality are higher, the morbidity of global liver cancer
Rate shows an increasing trend year by year.China is global onset of liver cancer rate highest and dies of illness several most countries, the disease incidence of liver cancer at
Gastric cancer, the third-largest malignant tumour of lung cancer are only second to for the death rate.The disease seriously threatens the health of people, common treatment
Anti-tumor regimen is to use surgical excision, but for the tumor patient of middle and advanced stage, interventional therapy (ranscatheter
Arterial chemoembolization, TACE) it is more satisfactory therapeutic scheme.Interventional therapy is referred to through transcatheter arterial
Medicine-containing microsphere is inputted target tissue through conduit by Chemoembolization, block the feeding artery and slow release drug of tumour, thus
The local concentration for improving chemotherapeutics, reduces the toxic side effect of whole body.A series of clinical analysis show that TACE can be controlled effectively
Tumour growth processed extends patient survival.For the mid and late liver cancer patient for the excision that cannot perform the operation, TACE is preferred No operation
Treatment method.
Carboxymethyl chitosan (CCN) is the derivative of chitosan, is a kind of water soluble polymer, has from a wealth of sources, water
The advantages that dissolubility is good, antibiotic property is strong, because of its good biocompatibility and no cytotoxicity, and be widely used in cosmetics,
The industries such as food, medicine are concerned especially in terms of biological medicine material as pharmaceutical carrier.With carboxymethyl chitosan
There are reports as raw material preparation load medicine embolism microball for sugar, but carboxymethyl chitosan is used to prepare drug bearing microsphere still at present
Defective: first is that the crosslinking agent used has toxic action to cell, such as glutaraldehyde or crosslinking agent source are narrow, expensive,
Such as Geniposide；Two are a lack of suitable load medicine group, and the carboxyl in carboxymethyl chitosan is weakly ionized group, with positive charge drug
Active force is not strong, therefore drug loading rate is relatively low, and reaction speed is slow.
The elution microballoon of surface-functionalized medicine-carried can be oriented in the arteries around tumor tissues through interventional therapy, no
The nutrition supply to tumor tissues is only blocked, while discharging anti-tumor drug, with the liter of anticancer drug concentration in tumor tissues
Height plays inhibiting effect to tumour growth.Carboxymethyl chitosan microsphere can degrade in vivo, excrete with body metabolism.
It is most important to the safety of human body as medical material.Therefore this work is in synthesis carboxymethyl chitosan embolism
When microballoon, a kind of novel " green " surfactant is selected, alkyl glycosides, APG for short 0810, it is pure and mild by natural fat
Glucose synthesis, there is high surface, good ecological security and intermiscibility, be internationally recognized " green " functionality
Surfactant.
Summary of the invention
For current elution microballoon preparation and its defect of performance, this patent has synthesized a kind of surface-functionalized medicine-carried and has washed
De- microballoon.Carboxymethyl chitosan microsphere is made first, the microballoon after drying is then put into 2- acrylamide-2-methyl propane sulfonic
(AMPS) in aqueous solution, using cerium ion as initiator, keep carboxymethyl chitosan glycoxidative, generate free radicals, further cause 2- third
Acrylamide -2- methyl propane sulfonic acid (AMPS) polymerization prepares surface-functionalized carry to carry out graft modification to microsphere surface
The elution microballoon of medicine.Since the sulfonic group in 2- acrylamide-2-methyl propane sulfonic molecule is dense ionization group, hydrophily pole
By force, which is introduced on carboxymethyl chitosan glycan molecule, carboxymethyl chitosan microsphere can be greatly improved to drug adriamycin
Load factor；And the carboxymethyl chitosan microsphere containing sulfonic acid group has no cytotoxicity, good biocompatibility, raw material sources
The advantages that extensive.
The technical solution provided by the invention for preparing a kind of surface-functionalized medicine-carried elution microballoon, successively includes following step
It is rapid:
1) Crosslinked Carboxymethyl Chitosan Microsphere is prepared, by carboxymethyl chitosan sugar aqueous solution and polyethyleneglycol diglycidylether
It is mixed in a certain ratio uniformly, when preparation has used macromolecule crosslink agent, polyethyleneglycol diglycidylether (PEGDE), by it
It is uniformly mixed with carboxymethyl chitosan solution, is added drop-wise to oily Xiangli, by reverse phase micro suspension method, it is micro- to prepare carboxymethyl chitosan
Ball.
2) Crosslinked Carboxymethyl Chitosan Microsphere is surface-functionalized, using ammonium ceric nitrate as initiator, after above-mentioned drying
Microballoon is immersed in 2- acrylamide-2-methyl propane sulfonic aqueous solution, makes 2- acrylamide-2-methyl propane sulfonic in microsphere surface
It is graft-polymerized.After reaction, microballoon is washed for several times repeatedly with distilled water, then be freeze-dried, obtain surface-functionalized carry
Medicine elutes microballoon.
In the step 1), the preferred mass score of carboxymethyl chitosan solution is 3%~4%, and polyethylene glycol two contracts
The degree of polymerization 2~8 of water glycerin ether, dosage account for 1~5 times of carboxymethyl chitosan sugar weight, by the mixed solution magnetic agitation time
For 15~30min.
Specifically, oil is mutually normal heptane, normal octane, paraffin oil or soybean oil, the body of oil phase and water phase in the step 1)
Product is than being 3:1~6:1.
Specifically, in the step 1), emulsifier is alkyl glycosides, APG for short 0810, and dosage accounts for oily phase quality
0.5%~2%.
Specifically, in the step 1), emulsifier is first added to oily Xiangli, after stirring 20min, then by carboxymethyl chitosan
Sugar is gradually dropped oily Xiangli with polyethyleneglycol diglycidylether mixture, and controlling mixing speed is 200~500 revs/min
Clock.
Specifically, in the step 2), 2- acrylamide-2-methyl propane sulfonic dosage concentration are as follows: 0.1~1.5mol/L.
Specifically, initiator is ammonium ceric nitrate in the step 2), additional amount accounts for 2- acrylamide -2- methyl-prop sulphur
The 0.1%~2% of sour weight leads to N2Protection, reacts 8 hours under the conditions of 50 DEG C.
Due to containing-NH on carboxymethyl chitosan glycan molecule2Group is in alkalescent, therefore polyethylene glycol diglycidyl in water
Epoxy group in glycerin ether reacts open loop with the amino on carboxymethyl chitosan glycan molecule under base catalysis, poly- in reverse phase micro suspension
Under the conditions of conjunction, carboxymethyl chitosan is cross-linked to form microballoon.Dry microspheres obtained are put into 2- acrylamide-2-methyl propane sulfonic
It is impregnated 10 hours in aqueous solution, ammonium ceric nitrate is added, carboxymethyl chitosan molecular moiety is oxidized generation free radical, causes 2- third
The polymerization of acrylamide -2- methyl propane sulfonic acid, is grafted to carboxymethyl chitosan glycan molecule up.According to mechanism as above, sulfonic acid group can have
It is grafted on microsphere surface to effect.
The present invention also provides a kind of application of surface-functionalized medicine-carried elution microballoon in chemotherapeutics carrier.By micro-
The interaction of the amino positive charge of the negative electrical charge and doxorubicin hydrochloride molecule of ball surface sulfonic acid group, improve drug loading rate and
Control release performance.
According to the above aspect of the present invention, the present invention has at least the following advantages:
It is nontoxic, cheap, be easily obtained 1. using a kind of new macromolecule crosslink agent.And since polyethylene glycol two contracts
Water glycerin ether belongs to oligomer, for opposite glutaraldehyde small molecule, it is bigger to be formed by gel " grid " space, it is easier to Ah mould
Plain molecule is diffused into inside microballoon, to improve the carrying drug ratio of microballoon；
2. it can be enhanced and interact with anti-tumor drug adriamycin since the microballoon contains carboxyl and sulfonic acid group, because
And carrier can be improved to the load factor of drug；
Selected novel " green " emulsifier when 3. synthesizing microballoon, alkyl glycosides APG0810, it with high surface,
Good ecological security and intermiscibility are internationally recognized " green " functional surfactants, and it is micro- to be used as emulsifier synthesis
Ball ensure that the safety of product.
4. by homogeneous nucleation method, synthesis elution microballoon, method is simple, mild condition, and no coupling product generates,
Fully reacting, products pure.
The above description is only an overview of the technical scheme of the present invention, in order to better understand the technical means of the present invention,
And can be implemented in accordance with the contents of the specification, it is presently preferred embodiments of the present invention below and cooperates attached drawing detailed description is as follows.
Detailed description of the invention
Fig. 1 is the synthetic route that surface-functionalized medicine-carried elutes microballoon；
Fig. 2 is the infrared spectrum of rear carboxymethyl chitosan before modified, wherein a: carboxymethyl chitosan microsphere before modified；B: change
Carboxymethyl chitosan microsphere after property；
Fig. 3 is the super depth-of-field microscope photo that surface-functionalized medicine-carried elutes microballoon in the present invention；
Fig. 4 is accumulative release rate curve of the microballoon in PBS (pH 7.4) medium in the present invention.A: modified function of surface
Change medicine-carried and elutes microballoon；B: unmodified carboxymethyl chitosan medicament-carrying microspheres.
Specific embodiment
With reference to the accompanying drawings and examples, specific embodiments of the present invention will be described in further detail.Implement below
Example is not intended to limit the scope of the invention for illustrating the present invention.
Embodiment 1.
1) preparation of carboxymethyl chitosan microsphere:
1.0g polyethyleneglycol diglycidylether is weighed, being added to 10ml concentration is in 4% carboxymethyl chitosan solution, often
The lower magnetic agitation 20min of temperature, is uniformly mixed the two.Measure 40ml normal heptane, be put into 250ml three-necked flask, then plus
Enter 0.27g (account for oily phase quality 1%) emulsifier APG0810, mechanical stirring, revolving speed 300rad/min.To be emulsified dose of dispersion
After uniformly, said mixture is gradually dropped in normal heptane, 30 DEG C of conditions emulsify side crosslinking below, and cross-linking reaction for 24 hours, is reacted
After, with the demulsification of a large amount of ethyl alcohol, cleaning microballoon, washs repeatedly for several times, finally microballoon is put into 35 DEG C of vacuum ovens and is done
The dry microspherulite diameter 24 hours, obtained is concentrated in 350um.
2) preparation of surface-functionalized medicine-carried elution microballoon:
The carboxymethyl chitosan microsphere 50mg for weighing above-mentioned drying is put into the 2- acryloyl that 10ml concentration is 0.9mol/L
In amine -2- methyl propane sulfonic acid aqueous solution, magnetic agitation under room temperature after soaking 10h, is added 0.0186g ammonium ceric nitrate, leads to N2It protects
Shield, reacts 8 hours under the conditions of 50 DEG C.After reaction, by the modified multiple washing by soaking of microballoon distilled water, then vacuum is dry
It is dry, obtain medicine-carried elution microballoon.
Embodiment 2.
4% carboxymethyl chitosan solution in embodiment 1 is changed to 1% carboxymethyl chitosan solution, other dosages and its conjunction
It is same as Example 1 at process.
Embodiment 3.
4% carboxymethyl chitosan solution in embodiment 1 is changed to 2% carboxymethyl chitosan solution, other dosages and its conjunction
It is same as Example 1 at process.
Embodiment 4
4% carboxymethyl chitosan solution in embodiment 1 is changed to 3% carboxymethyl chitosan solution, other dosages and its conjunction
It is same as Example 1 at process.
Embodiment 5
4% carboxymethyl chitosan solution in embodiment 1 is changed to 5% carboxymethyl chitosan solution, other dosages and its conjunction
It is same as Example 4 at process.
Influence of the carboxymethyl chitosan of 1 various concentration of table to microballoon is prepared
Embodiment 6
The modified dry carboxymethyl chitosan microsphere 25mg of above-described embodiment 1 is weighed, being put into 10ml concentration is 2mg/ml
Doxorubicin hydrochloride solution in.Slowly concussion at room temperature, by using ultraviolet specrophotometer, in different time sections Detection wavelength
The concentration of Doxorubicin solution at 483nm, calculates the carrying drug ratio of microballoon, calculates the carrying drug ratio (LR) of microballoon according to the following formula:
LR (%)=WD/WS×100
W in formulaD--- the quality of drug, mg in microballoon
WS--- the quality of investment microballoon, mg
By calculating, modified carboxymethyl chitosan microsphere carrying drug ratio is 37.1%, and more unmodified microballoon improves
54.8%.
Embodiment 7
Unmodified carboxymethyl chitosan microsphere and modified carboxymethyl chitosan microsphere after a small amount of drying are taken respectively, are made
With Fourier infrared spectrograph is totally reflected, in 4000~500cm-1Wave-number range in carry out infrared absorption scanning, obtain infrared
Spectrogram.Fig. 2 is the infrared spectrum of rear carboxymethyl chitosan microsphere before modified, wherein a: unmodified carboxymethyl chitosan microsphere；B:
Modified carboxymethyl chitosan microsphere.
Embodiment 8
Modified partial size is chosen in the carboxymethyl chitosan microsphere of 350um, observes microballoon under super depth-of-field microscope respectively
Pattern.Fig. 3 is the super depth-of-field microscope photo that surface-functionalized medicine-carried elutes microballoon in the present invention.
Embodiment 9
Partial size is chosen in the modification drug bearing microsphere of 350um and unmodified drug bearing microsphere, 25mg is respectively weighed, is put into PBS (pH
7.4) it in buffer solution, then places it in thermostatic control oscillator vibration, temperature is controlled at 37 ± 0.5 DEG C, and fixed point measures on 5mL
Clear liquid, and the fresh medium of same volume is replenished in time, by UV spectrophotometer measuring buffer drug content, repeat
It operates 3 times and is averaged, calculate accumulative release rate of the different time sections in PBS (pH 7.4) medium.
The above is only a preferred embodiment of the present invention, it is not intended to restrict the invention, it is noted that for this skill
For the those of ordinary skill in art field, without departing from the technical principles of the invention, can also make it is several improvement and
Modification, these improvements and modifications also should be regarded as protection scope of the present invention.
Claims (3)
1. a kind of preparation method of surface-functionalized medicine-carried elution microballoon, it is characterized in that preparation is carried out in two steps:
1) prepare Crosslinked Carboxymethyl Chitosan Microsphere, by mass fraction range be 3%~4% carboxymethyl chitosan sugar aqueous solution with
Polyethyleneglycol diglycidylether is pre-mixed uniformly by a certain percentage, and mixed solution is added dropwise to containing emulsifier alkyl glycosides
The oily Xiangli of APG0810, the dosage of alkyl glycosides APG0810 account for the 0.5%~2% of oily phase quality, and oil is mutually normal heptane, oily phase
Volume ratio with water phase is that 3:1~6:1 is stirred to react under the conditions of 30 DEG C using reverse phase micro suspension cross-linking method, is prepared carboxymethyl
Chitosan microball, for several times by thus obtained microsphere ethyl alcohol, distillation water washing, vacuum drying；
2) Crosslinked Carboxymethyl Chitosan Microsphere is surface-functionalized, and the microballoon after above-mentioned drying is immersed in 2- acrylamide -2-
10h in methyl propane sulfonic acid aqueous solution, 2- acrylamide-2-methyl propane sulfonic concentration are 0.1~1.5mol/L, add ammonium ceric nitrate
For initiator, the additional amount of ammonium ceric nitrate accounts for the 0.1%~2% of 2- acrylamide-2-methyl propane sulfonic weight, leads to N2Protection,
50 DEG C are warming up to, 2- acrylamide-2-methyl propane sulfonic is made to be graft-polymerized in microsphere surface, reaction 8h after reaction will be micro-
Ball is washed for several times repeatedly with distilled water, then is freeze-dried, and the elution microballoon of surface-functionalized medicine-carried is finally obtained.
2. a kind of preparation method of surface-functionalized medicine-carried elution microballoon according to claim 1, it is characterised in that: institute
It states in step 1), the degree of polymerization 2~8 of polyethyleneglycol diglycidylether, dosage accounts for 1~5 times of carboxymethyl chitosan sugar weight,
Polyethyleneglycol diglycidylether is slowly dropped into carboxymethyl chitosan solution, the magnetic agitation time is 15~30min.
3. a kind of preparation method of surface-functionalized medicine-carried elution microballoon according to claim 1, it is characterised in that: institute
It states in step 2), emulsifier is first added to oily Xiangli, after stirring 20min, then carboxymethyl chitosan and polyethylene glycol two contracted
Water glycerol ether mixture is gradually dropped oily Xiangli, and controlling mixing speed is 200~500 revs/min.
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| CN201610650166.7A CN106110334B (en) | 2016-08-08 | 2016-08-08 | A kind of preparation method of surface-functionalized medicine-carried elution microballoon |
| PCT/CN2016/104511 WO2018028058A1 (en) | 2016-08-08 | 2016-11-04 | Preparation method for surface functionalized drug-loaded eluting microspheres |
| KR1020187007546A KR102083023B1 (en) | 2016-08-08 | 2016-11-04 | Method for preparing surface functionalized drug transportable eluted microspheres |
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| CN109464702B (en) * | 2019-01-14 | 2021-02-26 | 浙江瑞谷生物科技有限公司 | Alveolar bone repair material containing BMP-2 and preparation method and application thereof |
| DE102019107633A1 (en) | 2019-03-25 | 2020-10-29 | Sphera Technology Gmbh | Multi-component system and method for producing a multi-component system |
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| KR102083023B1 (en) | 2020-02-28 |
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