CN106110334A - A kind of preparation method of surface-functionalized medicine-carried eluting microsphere - Google Patents
A kind of preparation method of surface-functionalized medicine-carried eluting microsphere Download PDFInfo
- Publication number
- CN106110334A CN106110334A CN201610650166.7A CN201610650166A CN106110334A CN 106110334 A CN106110334 A CN 106110334A CN 201610650166 A CN201610650166 A CN 201610650166A CN 106110334 A CN106110334 A CN 106110334A
- Authority
- CN
- China
- Prior art keywords
- microsphere
- carboxymethyl chitosan
- preparation
- carried
- medicine
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Classifications
-
- 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1617—Organic compounds, e.g. phospholipids, fats
-
- 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
-
- 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
-
- A—HUMAN NECESSITIES
- 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
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
- A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
-
- A—HUMAN NECESSITIES
- 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
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
-
- A—HUMAN NECESSITIES
- 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
- A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
-
- A—HUMAN NECESSITIES
- 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
- A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/56—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
- A61K47/61—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule the organic macromolecular compound being a polysaccharide or a derivative thereof
-
- 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
-
- 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1682—Processes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Abstract
The present invention announces the preparation method of a kind of surface-functionalized medicine-carried eluting microsphere, relates to biological medicine Material Field.This preparation method comprises the following steps: (1) is with carboxymethyl chitosan as raw material, polyethyleneglycol diglycidylether is cross-linking agent, by anti-phase micro suspension cross-linking method, prepare particle diameter and be mainly distributed on the Crosslinked Carboxymethyl Chitosan Microsphere of 300～400um；(2) the dry Crosslinked Carboxymethyl Chitosan Microsphere prepared is put in 2 acrylamide 2 methyl propane sulfonic acid aqueous solutions and soak, with ammonium ceric nitrate as initiator, make 2 acrylamide 2 methyl propane sulfonic acids be able to modification at microsphere surface glycerol polymerization, microsphere.Owing to this microsphere surface is by modification of graft, with substantial amounts of sulfonic acid group, can payload such as doxorubicin hydrochloride Han positive charge medicine, be hopeful to prepare eluting microsphere.
Description
Technical field
The present invention relates to the preparation method of a kind of biodegradable pharmaceutical carrier, relate to biomedicine field, particularly relate to
A kind of preparation method of surface-functionalized medicine-carried eluting microsphere.
Background technology
Primary hepatocarcinoma is a kind of common malignant tumor, and its M & M is the highest, the morbidity of whole world hepatocarcinoma
Rate is in the trend risen year by year.China is that whole world onset of liver cancer rate is the highest and die of illness several most country, and the sickness rate of hepatocarcinoma becomes
The third-largest malignant tumor of gastric cancer, pulmonary carcinoma it is only second to for mortality rate.Healthy, the common treatment of this disease serious threat people
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 refers to through transcatheter arterial
Chemoembolization, i.e. inputs target tissue through conduit by medicine-containing microsphere, blocks the feeding artery of tumor slow Slow release, thus
Improve the local concentration of chemotherapeutics, reduce the toxic and side effects of whole body.A series of clinical analysiss display TACE can be controlled effectively
Tumor growth processed, extends the survival of patients phase.For can not the mid and late liver cancer patient of excision, TACE is first-selected No operation
Therapeutic Method.
Carboxymethyl chitosan (CCN) is the derivant of chitosan, is a kind of water soluble polymer, has wide material sources, water
The advantages such as dissolubility is good, antibiotic property is strong, the biocompatibility good because of it and no cytotoxicity, and be widely used in cosmetics,
The industry such as food, medicine, particularly in terms of biological medicine material, receives much concern as pharmaceutical carrier.With carboxymethyl chitosan
Sugar prepares medicine carrying embolism microball as raw material, and there are reports, but carboxymethyl chitosan is used for preparing medicine carrying microballoons still at present
It is defective: one is that the cross-linking agent used has toxic action to cell, and such as glutaraldehyde, or cross-linking agent source is narrow, expensive,
Such as genipin；Two are a lack of suitable medicine carrying group, and the carboxyl in carboxymethyl chitosan is weakly ionized group, with positive charge medicine
Active force is not strong, and therefore drug loading rate is on the low side, and response speed is slow.
The eluting microsphere of surface-functionalized medicine-carried can be in the arteries that interventional therapy guides around tumor tissues, no
Only block the nutrition supply to tumor tissues, discharge antitumor drug simultaneously, along with the liter of cancer therapy drug concentration in tumor tissues
Height, plays inhibitory action to tumor growth.Crosslinked Carboxymethyl Chitosan Resin can be degraded in vivo, excretes with body metabolism.
As medical material, the safety to human body is most important.The most originally synthesis carboxymethyl chitosan thromboembolism it is operated in
During microsphere, selected a kind of novel " green " surfactant, alkyl polyglucoside, APG for short 0810, it be by natural fatty alcohol and
Glucose synthesis, there is high surface, good ecological security and intermiscibility, be that internationally recognized " green " is functional
Surfactant.
Summary of the invention
For the preparation of current eluting microsphere and the defect of performance thereof, this patent has synthesized a kind of surface-functionalized medicine-carried and has washed
De-microsphere.First prepare Crosslinked Carboxymethyl Chitosan Resin, then dried microsphere is put into 2-acrylamide-2-methyl propane sulfonic
(AMPS) in aqueous solution, with cerium ion as initiator, make carboxymethyl chitosan glycoxidative, produce free radical, cause 2-third further
Acrylamide-2-methyl propane sulfonic acid (AMPS) is polymerized, thus microsphere surface is carried out graft modification, prepares surface-functionalized load
The eluting microsphere of medicine.Owing to the sulfonic group in 2-acrylamide-2-methyl propane sulfonic molecule is dense ionization group, hydrophilic pole
By force, this group is incorporated on carboxymethyl chitosan glycan molecule, Crosslinked Carboxymethyl Chitosan Resin can be greatly improved to drug adriamycin
Load factor；And the Crosslinked Carboxymethyl Chitosan Resin containing sulfonic acid group has no cytotoxicity, good biocompatibility, raw material sources
The advantage such as extensively.
The technical scheme preparing a kind of surface-functionalized medicine-carried eluting microsphere that the present invention provides, includes following step successively
Rapid:
1) Crosslinked Carboxymethyl Chitosan Microsphere is prepared, by carboxymethyl chitosan sugar aqueous solution and polyethyleneglycol diglycidylether
Mix homogeneously by a certain percentage, employs macromolecule crosslink agent during preparation, polyethyleneglycol diglycidylether (PEGDE), by it
Mix homogeneously with carboxymethyl chitosan solution, be added drop-wise in oil phase, by anti-phase micro suspension method, prepare carboxymethyl chitosan micro-
Ball.
2) Crosslinked Carboxymethyl Chitosan Microsphere is surface-functionalized, with ammonium ceric nitrate as initiator, by above-mentioned dried
Microsphere is immersed in 2-acrylamide-2-methyl propane sulfonic aqueous solution, makes 2-acrylamide-2-methyl propane sulfonic at microsphere surface
Glycerol polymerization.After reaction terminates, by microsphere with distilled water cyclic washing for several times, then lyophilization, obtain surface-functionalized load
Medicine eluting microsphere.
In described step 1) in, the preferred mass mark of carboxymethyl chitosan solution is 3%～4%, and Polyethylene Glycol two contracts
The degree of polymerization 2～8 of water glycerin ether, its consumption accounts for 1～5 times of carboxymethyl chitosan sugar weight, by the mixed solution magnetic agitation time
It is 15～30min.
Concrete, described step 1) in, oil phase is normal heptane, normal octane, paraffin oil or soybean oil, oil phase and the body of aqueous phase
Long-pending ratio is 3:1～6:1.
Concrete, described step 1) in, emulsifying agent is alkyl polyglucoside, APG for short 0810, and its consumption accounts for oil phase quality
0.5%～2%.
Concrete, described step 1) in, first emulsifying agent is joined in oil phase, after stirring 20min, then by carboxymethyl chitosan
Sugar is gradually dropped in oil phase with polyethyleneglycol diglycidylether mixture, and to control mixing speed be 200～500 revs/min
Clock.
Concrete, described step 2) in, 2-acrylamide-2-methyl propane sulfonic consumption concentration is: 0.1～1.5mol/L.
Concrete, described step 2) in, initiator is ammonium ceric nitrate, and its addition accounts for 2-acrylamide-2-methyl-prop sulphur
The 0.1%～2% of acid weight, logical N2Protection, reacts 8 hours under the conditions of 50 DEG C.
Owing to containing-NH on carboxymethyl chitosan glycan molecule2Group, in alkalescence in water, therefore polyethylene glycol diglycidyl
Epoxide group in glycerin ether reacts open loop with the amino on carboxymethyl chitosan glycan molecule under base catalysis, gathers in anti-phase micro suspension
Under the conditions of conjunction, carboxymethyl chitosan is cross-linked to form microsphere.Prepared dry microspheres is put into 2-acrylamide-2-methyl propane sulfonic
Aqueous solution soaks 10 hours, adds ammonium ceric nitrate, carboxymethyl chitosan molecular moiety oxidized generation free radical, cause 2-third
Acrylamide-2-methyl propane sulfonic acid is polymerized, and is grafted to carboxymethyl chitosan glycan molecule up.According to as above mechanism, sulfonic acid group can have
It is grafted on microsphere surface to effect.
The present invention also provides for the application in chemotherapeutics carrier of a kind of surface-functionalized medicine-carried eluting microsphere.By micro-
The interaction of the negative charge of ball sulfonic acid surfactant group and the amino positive charge of doxorubicin hydrochloride molecule, improve drug loading rate and
Control release performance.
By such scheme, the present invention at least has the advantage that
1. use a kind of new macromolecule crosslink agent, nontoxic, cheap, be easily obtained.And owing to Polyethylene Glycol two contracts
Water glycerin ether belongs to oligomer, and for the little molecule of relative glutaraldehyde, gel " grid " space formed is bigger, it is easier to Ah is mould
Element molecule is diffused into inside microsphere, thus improves the carrying drug ratio of microsphere；
2. contain carboxyl and sulfonic acid group due to this microsphere, can strengthen and interact with antitumor drug amycin, because of
And the carrier load factor to medicine can be improved；
3. selected novel " green " emulsifying agent during synthesis microsphere, alkyl polyglucoside APG0810, it have high surface,
Good ecological security and intermiscibility, be internationally recognized " green " functional surfactant, micro-as emulsifying agent synthesis
Ball, it is ensured that the safety of product.
4. by homogeneous nucleation method, synthesizing eluting microsphere, method is simple, mild condition, and no coupling product produces,
Reaction is complete, products pure.
Described above is only the general introduction of technical solution of the present invention, in order to better understand the technological means of the present invention,
And can be practiced according to the content of description, after the following is presently preferred embodiments of the present invention and coordinating accompanying drawing to describe in detail such as.
Accompanying drawing explanation
Fig. 1 is the synthetic route of surface-functionalized medicine-carried eluting microsphere；
Fig. 2 is the infrared spectrum of rear carboxymethyl chitosan before modified, wherein a: Crosslinked Carboxymethyl Chitosan Resin before modified；B: change
Crosslinked Carboxymethyl Chitosan Resin after property；
Fig. 3 is the super depth-of-field microscope photo of surface-functionalized medicine-carried eluting microsphere in the present invention；
Fig. 4 is the microsphere accumulative release rate curve in PBS (pH 7.4) medium in the present invention.A: modified function of surface
Change medicine-carried eluting microsphere；B: unmodified carboxymethyl chitosan medicament-carrying microspheres.
Detailed description of the invention
Below in conjunction with the accompanying drawings and embodiment, the detailed description of the invention of the present invention is described in further detail.Hereinafter implement
Example is used for illustrating the present invention, but is not limited to the scope of the present invention.
Embodiment 1.
1) preparation of Crosslinked Carboxymethyl Chitosan Resin:
Weighing 1.0g polyethyleneglycol diglycidylether, joining 10ml concentration is in 4% carboxymethyl chitosan solution, often
Lower magnetic agitation 20min of temperature, makes both mix homogeneously.Measure 40ml normal heptane, put in 250ml there-necked flask, then add
Entering 0.27g (accounting for the 1% of oil phase quality) emulsifying agent APG0810, mechanical agitation, rotating speed is 300rad/min.To be emulsified dose of dispersion
After Jun Yun, said mixture is gradually dropped in normal heptane, 30 DEG C of condition following emulsifying limit crosslinkings, cross-linking reaction 24h, reaction
After end, with a large amount of ethanol breakdowns of emulsion, cleaning microsphere, microsphere for several times, is finally put in 35 DEG C of vacuum drying ovens dry by cyclic washing
Dry 24 hours, the microspherulite diameter obtained concentrated at 350um.
2) preparation of surface-functionalized medicine-carried eluting microsphere:
Weigh above-mentioned dry Crosslinked Carboxymethyl Chitosan Resin 50mg, put into the 2-acryloyl that 10ml concentration is 0.9mol/L
In amine-2-methyl propane sulfonic acid aqueous solution, magnetic agitation, after invading bubble 10h under room temperature, add 0.0186g ammonium ceric nitrate, logical N2Protect
Protect, react 8 hours under the conditions of 50 DEG C.After reaction terminates, by modification microsphere distilled water repeatedly washing by soaking, then vacuum is done
Dry, obtain medicine-carried eluting microsphere.
Embodiment 2.
Make 4% carboxymethyl chitosan solution in embodiment 1 into 1% carboxymethyl chitosan solution, other consumptions and conjunction thereof
One-tenth process is same as in Example 1.
Embodiment 3.
Make 4% carboxymethyl chitosan solution in embodiment 1 into 2% carboxymethyl chitosan solution, other consumptions and conjunction thereof
One-tenth process is same as in Example 1.
Embodiment 4
Make 4% carboxymethyl chitosan solution in embodiment 1 into 3% carboxymethyl chitosan solution, other consumptions and conjunction thereof
One-tenth process is same as in Example 1.
Embodiment 5
Make 4% carboxymethyl chitosan solution in embodiment 1 into 5% carboxymethyl chitosan solution, other consumptions and conjunction thereof
One-tenth process is the same as in Example 4.
The impact on preparing microsphere of the carboxymethyl chitosan of table 1 variable concentrations
Embodiment 6
Weighing the dry Crosslinked Carboxymethyl Chitosan Resin 25mg that above-described embodiment 1 is modified, putting into 10ml concentration is 2mg/ml
Doxorubicin hydrochloride solution in.Slowly shake under room temperature, by using ultraviolet spectrophotometer, detect wavelength in different time sections
The concentration of Doxorubicin solution at 483nm, calculates the carrying drug ratio of microsphere, calculates the carrying drug ratio (LR) of microsphere according to the following formula:
LR (%)=WD/WS×100
W in formulaDThe quality of microsphere Chinese medicine, mg
WSPut into the quality of microsphere, mg
By calculating, modified Crosslinked Carboxymethyl Chitosan Resin carrying drug ratio is 37.1%, and more unmodified microsphere improves
54.8%.
Embodiment 7
Take a small amount of dried unmodified Crosslinked Carboxymethyl Chitosan Resin and modified Crosslinked Carboxymethyl Chitosan Resin respectively, make
With total reflection Fourier infrared spectrograph, 4000～500cm-1Wave-number range in carry out INFRARED ABSORPTION scanning, obtain infrared
Spectrogram.Fig. 2 is the infrared spectrum of rear Crosslinked Carboxymethyl Chitosan Resin before modified, wherein a: unmodified Crosslinked Carboxymethyl Chitosan Resin；B:
Modified Crosslinked Carboxymethyl Chitosan Resin.
Embodiment 8
Choose the modified particle diameter Crosslinked Carboxymethyl Chitosan Resin at 350um, under super depth-of-field microscope, observe microsphere respectively
Pattern.Fig. 3 is the super depth-of-field microscope photo of surface-functionalized medicine-carried eluting microsphere in the present invention.
Embodiment 9
Choose particle diameter all at modified medicine carrying microballoons and the unmodified medicine carrying microballoons of 350um, respectively weigh 25mg, put into PBS (pH
7.4) in buffer solution, being then placed in water bath with thermostatic control agitator, temperature controls at 37 ± 0.5 DEG C, and fixed point measures on 5mL
Clear liquid, and supplement the fresh medium of same volume in time, by UV spectrophotometer measuring buffer drug content, repeat
Operate and average for 3 times, calculate the different time sections accumulative release rate in PBS (pH 7.4) medium.
The above is only the preferred embodiment of the present invention, is not limited to the present invention, it is noted that for this skill
For the those of ordinary skill in art field, on the premise of without departing from the technology of the present invention principle, it is also possible to make some improvement and
Modification, these improve and modification also should be regarded as protection scope of the present invention.
Claims (9)
1. a preparation method for surface-functionalized medicine-carried eluting microsphere, is characterized in that preparation is undertaken in two steps:
1) Crosslinked Carboxymethyl Chitosan Microsphere is prepared, by carboxymethyl chitosan sugar aqueous solution with polyethyleneglycol diglycidylether by one
Certainty ratio is pre-mixed uniformly, is added dropwise in the oil phase containing emulsifying agent by mixed solution, uses anti-phase micro suspension cross-linking method,
Under the conditions of 30 DEG C, stirring reaction, prepares Crosslinked Carboxymethyl Chitosan Resin, by thus obtained microsphere ethanol, distilled water wash for several times, and vacuum
It is dried.
2) Crosslinked Carboxymethyl Chitosan Microsphere is surface-functionalized, and above-mentioned dried microsphere is immersed in 2-acrylamide-2-
10h in methyl propane sulfonic acid aqueous solution, interpolation ammonium ceric nitrate is initiator, logical N2Protection, be warming up to 50 DEG C, make 2-acrylamide-
2-methyl propane sulfonic acid, in microsphere surface glycerol polymerization, reacts 8h, reacts after terminating, by microsphere with distilled water cyclic washing for several times,
Lyophilization again, finally obtains the eluting microsphere of surface-functionalized medicine-carried.
The preparation method of a kind of surface-functionalized medicine-carried eluting microsphere the most according to claim 1, it is characterised in that: institute
State step 1) in, the mass fraction scope of carboxymethyl chitosan solution is 1%～5%, and preferred mass mark is 3%～4%.
The preparation method of a kind of surface-functionalized medicine-carried eluting microsphere the most according to claim 1, it is characterised in that: institute
State step 1) in, the degree of polymerization 2～8 of polyethyleneglycol diglycidylether, its consumption accounts for 1～5 times of carboxymethyl chitosan sugar weight,
Being slowly dropped in carboxymethyl chitosan solution by polyethyleneglycol diglycidylether, the magnetic agitation time is 15～30min.
The preparation method of a kind of surface-functionalized medicine-carried eluting microsphere the most according to claim 1, it is characterised in that: institute
State step 1) in, oil phase is normal heptane, normal octane, paraffin oil or soybean oil, and oil phase is 3:1～6:1 with the volume ratio of aqueous phase.
The preparation method of a kind of surface-functionalized medicine-carried eluting microsphere the most according to claim 1, it is characterised in that: institute
State step 1) in, emulsifying agent is alkyl polyglucoside APG0810, and its consumption accounts for the 0.5%～2% of oil phase quality.
The preparation method of a kind of surface-functionalized medicine-carried eluting microsphere the most according to claim 1, it is characterised in that: institute
State step 2) in, first emulsifying agent is joined in oil phase, after stirring 20min, then carboxymethyl chitosan is contracted with Polyethylene Glycol two
Water glycerin ether mixture is gradually dropped in oil phase, and to control mixing speed be 200～500 revs/min.
The preparation method of a kind of surface-functionalized medicine-carried eluting microsphere the most according to claim 1, it is characterised in that: institute
State step 2) in, 2-acrylamide-2-methyl propane sulfonic concentration is: 0.1～1.5mol/L.
The preparation method of a kind of surface-functionalized medicine-carried eluting microsphere the most according to claim 1, it is characterised in that: institute
State step 2) in, initiator is ammonium ceric nitrate, and addition accounts for the 0.1%～2% of 2-acrylamide-2-methyl propane sulfonic weight.
9. the surface-functionalized medicine-carried eluting microsphere application in preparing chemotherapeutics carrier, it is characterised in that by micro-
The interaction of the negative charge of ball sulfonic acid surfactant group and the amino positive charge of doxorubicin hydrochloride molecule, improve drug loading rate and
Control release performance.
Priority Applications (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610650166.7A CN106110334B (en) | 2016-08-08 | 2016-08-08 | A kind of preparation method of surface-functionalized medicine-carried elution microballoon |
| KR1020187007546A KR102083023B1 (en) | 2016-08-08 | 2016-11-04 | Method for preparing surface functionalized drug transportable eluted microspheres |
| PCT/CN2016/104511 WO2018028058A1 (en) | 2016-08-08 | 2016-11-04 | Preparation method for surface functionalized drug-loaded eluting microspheres |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610650166.7A CN106110334B (en) | 2016-08-08 | 2016-08-08 | A kind of preparation method of surface-functionalized medicine-carried elution microballoon |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN106110334A true CN106110334A (en) | 2016-11-16 |
| CN106110334B CN106110334B (en) | 2019-11-15 |
Family
ID=57257628
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201610650166.7A Active CN106110334B (en) | 2016-08-08 | 2016-08-08 | A kind of preparation method of surface-functionalized medicine-carried elution microballoon |
Country Status (3)
| Country | Link |
|---|---|
| KR (1) | KR102083023B1 (en) |
| CN (1) | CN106110334B (en) |
| WO (1) | WO2018028058A1 (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108264612A (en) * | 2018-02-25 | 2018-07-10 | 温岭汉德高分子科技有限公司 | A kind of preparation method of chitosan-poly- 2- acrylamide-2-methylpro panesulfonic acid sodium copolymers for monocrystalline silicon making herbs into wool |
| CN109464702A (en) * | 2019-01-14 | 2019-03-15 | 浙江瑞谷生物科技有限公司 | Alveolar bone repairing material and its preparation method and application containing BMP-2 |
| CN112168787A (en) * | 2020-09-24 | 2021-01-05 | 山东瑞安泰医疗技术有限公司 | Functional degradable drug eluting microsphere and preparation method thereof |
| CN112316199A (en) * | 2020-11-16 | 2021-02-05 | 江南大学 | Modified carboxymethyl chitosan microsphere and preparation method and application thereof |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE102019107633A1 (en) | 2019-03-25 | 2020-10-29 | Sphera Technology Gmbh | Multi-component system and method for producing a multi-component system |
| CN110508259B (en) * | 2019-09-03 | 2022-02-15 | 晋江瑞碧科技有限公司 | Preparation method of copper ion imprinted composite magnetic hollow microsphere |
| DE102020124955A1 (en) | 2020-09-24 | 2022-03-24 | Sphera Technology Gmbh | Electronic unit with an integrated circuit and method for its production |
| CN114191410A (en) * | 2021-11-15 | 2022-03-18 | 深圳北航新兴产业技术研究院 | Preparation method of diagnosis and treatment integrated amphiphilic microsphere sustained-release microspheres |
| CN114481616A (en) * | 2022-03-11 | 2022-05-13 | 四川三联新材料有限公司 | Preparation method of chitosan-based membrane composite material for heating cigarettes |
Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102462664A (en) * | 2010-11-18 | 2012-05-23 | 华侨大学 | Sulfonyl sulfhydryl chitosan interventional chemoembolization slow-release microsphere and preparation method thereof |
| CN103304417A (en) * | 2012-03-15 | 2013-09-18 | 江南大学 | Preparation method and application of amphiphatic copolymer modified chitosan compound |
| CN103977458A (en) * | 2014-05-28 | 2014-08-13 | 南京弗来明医疗器械有限公司 | Polyhydroxyl polymer embolized microsphere and preparation process thereof |
| CN104258474A (en) * | 2014-10-15 | 2015-01-07 | 江南大学 | Embolic microspheres containing ion exchange functional groups |
| CN104338185A (en) * | 2014-11-06 | 2015-02-11 | 石家庄亿生堂医用品有限公司 | Carboxymethyl chitosan microsphere embolization agent and preparation method thereof |
| CN104548123A (en) * | 2014-12-11 | 2015-04-29 | 江南大学 | Preparation of acylated and modified gelatin embolization microsphere |
| CN105273209A (en) * | 2014-06-09 | 2016-01-27 | 江南大学 | Preparation for modified chitosan poly(2-acrylamide-2-methylpropanesulfonic acid) composite microballoon |
| CN107321326A (en) * | 2017-07-03 | 2017-11-07 | 重庆大学 | Anionic polymer grafting chitosan magnetic composite microsphere and preparation method and application |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101125225A (en) * | 2007-08-10 | 2008-02-20 | 苏州迦俐生生物医药科技有限公司 | Microsphere type embolic agent and preparation technology thereof |
| CN101775386A (en) * | 2010-01-26 | 2010-07-14 | 武汉工业学院 | Method for immobilizing trypsinase by chitosan microspheres |
| CN102784112B (en) * | 2011-05-19 | 2014-08-06 | 东华理工大学 | Preparation method for porous slow-release microsphere of chitosan graft copolymer |
| CN103965403A (en) * | 2013-01-24 | 2014-08-06 | 孙亮 | Novel method for grafting chitosan onto 2-acrylamido-2-methylpropanesulfonic acid (AMPS) |
| CN104208756A (en) * | 2014-08-29 | 2014-12-17 | 石家庄亿生堂医用品有限公司 | Preparation method of carboxymethyl chitosan microspheres |
| CN104474575B (en) * | 2014-12-03 | 2017-06-30 | 广州肽莱医药科技有限公司 | Shitosan hemostatic material that covalent cross-linking is formed and preparation method thereof |
-
2016
- 2016-08-08 CN CN201610650166.7A patent/CN106110334B/en active Active
- 2016-11-04 KR KR1020187007546A patent/KR102083023B1/en active IP Right Grant
- 2016-11-04 WO PCT/CN2016/104511 patent/WO2018028058A1/en active Application Filing
Patent Citations (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102462664A (en) * | 2010-11-18 | 2012-05-23 | 华侨大学 | Sulfonyl sulfhydryl chitosan interventional chemoembolization slow-release microsphere and preparation method thereof |
| CN103304417A (en) * | 2012-03-15 | 2013-09-18 | 江南大学 | Preparation method and application of amphiphatic copolymer modified chitosan compound |
| CN103977458A (en) * | 2014-05-28 | 2014-08-13 | 南京弗来明医疗器械有限公司 | Polyhydroxyl polymer embolized microsphere and preparation process thereof |
| CN105273209A (en) * | 2014-06-09 | 2016-01-27 | 江南大学 | Preparation for modified chitosan poly(2-acrylamide-2-methylpropanesulfonic acid) composite microballoon |
| CN104258474A (en) * | 2014-10-15 | 2015-01-07 | 江南大学 | Embolic microspheres containing ion exchange functional groups |
| CN104258474B (en) * | 2014-10-15 | 2015-09-23 | 江南大学 | A kind of embolism microball containing ion exchanging function group and preparation method thereof |
| CN104338185A (en) * | 2014-11-06 | 2015-02-11 | 石家庄亿生堂医用品有限公司 | Carboxymethyl chitosan microsphere embolization agent and preparation method thereof |
| CN104548123A (en) * | 2014-12-11 | 2015-04-29 | 江南大学 | Preparation of acylated and modified gelatin embolization microsphere |
| CN107321326A (en) * | 2017-07-03 | 2017-11-07 | 重庆大学 | Anionic polymer grafting chitosan magnetic composite microsphere and preparation method and application |
Non-Patent Citations (6)
| Title |
|---|
| 于广利等编著: "《糖药物学》", 31 October 2012, 中国海洋大学出版社 * |
| 侯志勇等: ""动脉栓塞微球的研究进展"", 《中国医药科学》 * |
| 张猛: ""载药栓塞微球的制备及控释性能研究"", 《中国优秀硕士学位论文全文数据库工程科技Ⅰ辑》 * |
| 徐忠编: "《功能性变性淀粉》", 30 April 2010, 中国轻工业出版社 * |
| 曹元龙等: ""表面改性羧甲基壳聚糖栓塞微球的制备及性能研究"", 《化工新型材料》 * |
| 王国全主编: "《聚合物改性第3版》", 31 May 2016, 中国轻工业出版社 * |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108264612A (en) * | 2018-02-25 | 2018-07-10 | 温岭汉德高分子科技有限公司 | A kind of preparation method of chitosan-poly- 2- acrylamide-2-methylpro panesulfonic acid sodium copolymers for monocrystalline silicon making herbs into wool |
| CN108264612B (en) * | 2018-02-25 | 2020-10-09 | 温岭汉德高分子科技有限公司 | Preparation method of chitosan-poly (2-acrylamide-2-methylpropanesulfonic acid) sodium sulfonate copolymer for monocrystalline silicon texturing |
| CN109464702A (en) * | 2019-01-14 | 2019-03-15 | 浙江瑞谷生物科技有限公司 | Alveolar bone repairing material and its preparation method and application containing BMP-2 |
| 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 |
| CN112168787A (en) * | 2020-09-24 | 2021-01-05 | 山东瑞安泰医疗技术有限公司 | Functional degradable drug eluting microsphere and preparation method thereof |
| CN112316199A (en) * | 2020-11-16 | 2021-02-05 | 江南大学 | Modified carboxymethyl chitosan microsphere and preparation method and application thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2018028058A1 (en) | 2018-02-15 |
| KR102083023B1 (en) | 2020-02-28 |
| KR20180057622A (en) | 2018-05-30 |
| CN106110334B (en) | 2019-11-15 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN106110334A (en) | A kind of preparation method of surface-functionalized medicine-carried eluting microsphere | |
| CN105968373B (en) | One kind is containing zwitterionic multiple antitumor carrier micelle of acid-sensitive and its preparation method and application | |
| CN105816920A (en) | Preparation method of modified sodium alginate embolization microspheres | |
| Mu et al. | Unsaturated nitrogen-rich polymer poly (l-histidine) gated reversibly switchable mesoporous silica nanoparticles using “graft to” strategy for drug controlled release | |
| CN106693040A (en) | Preparation method of drug-loadable polyvinyl alcohol eluted microspheres | |
| KR102237234B1 (en) | Integrated nanosystem for co-transporting genes/drugs with liver targeting and method for manufacturing the same | |
| WO2015179997A1 (en) | Polyhydroxyl polymer embolic microsphere and preparation process therefor | |
| CN107496358A (en) | A kind of enhanced hydrogel of liposome and its application | |
| US11359044B2 (en) | Preparation and application of novel multifunctional nanocomposite material with new photosensitizer | |
| CN107617108A (en) | A kind of core crosslinking nano grain of double targetings and pH/ redox sensitives and its preparation method and application | |
| CN106750376A (en) | A kind of preparation method of the sensitive reversible crosslink nano-micelle of the turnover reduction of electric charge | |
| CN105859990B (en) | The polymer of side chain sulfur-bearing caprylyl, its preparation method and polymer vesicle prepared therefrom and its application | |
| Yi et al. | Synthesis, characterization, and formulation of poly-puerarin as a biodegradable and biosafe drug delivery platform for anti-cancer therapy | |
| CN108659232A (en) | Semisolid acid-sensitive amphipathic segmented copolymer and preparation method and its usage | |
| Chen et al. | A biomimicking and electrostatic self-assembly strategy for the preparation of glycopolymer decorated photoactive nanoparticles | |
| CN111603568A (en) | Charge reversal type polypeptide composite nano-drug and preparation method and application thereof | |
| Khan et al. | Chondroitin sulfate-based redox-responsive nanoparticles for melanoma-targeted drug delivery | |
| CN111632154A (en) | Phase-transition nanobubble, preparation method and application thereof | |
| Kou et al. | Preparation and application of a polymer with pH/temperature-responsive targeting | |
| Zhang et al. | Zwitterionic choline phosphate conjugated folate-poly (ethylene glycol): a general decoration of erythrocyte membrane-coated nanoparticles for enhanced tumor-targeting drug delivery | |
| CN108186571A (en) | Reversible crosslink asymmetry vesica is preparing the application in treating acute leukemia drug | |
| CN104784153A (en) | Folic acid modified sulfobetaine-chitosan nano-granule as well as preparation method and application thereof | |
| CN111202719A (en) | Active natural product nano drug delivery system and preparation method and application thereof | |
| CN106279678B (en) | A kind of preparation for the reduction-sensitive nano-micelle that can covalently carry medicine | |
| Wang et al. | Self-assembled iRGD-R7-LAHP-M nanoparticle induced sufficient singlet oxygen and enhanced tumor penetration immunological therapy |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20230329 Address after: Room 403, Building 2, Laojie Library, Dianbu Town, Feidong County, Hefei City, Anhui Province, 231699 Patentee after: Hefei guiqian Information Technology Co.,Ltd. Address before: No. 1800 road 214122 Jiangsu Lihu Binhu District City of Wuxi Province Patentee before: Jiangnan University Effective date of registration: 20230329 Address after: Room 801, 8th Floor, Building A-3, Jinrui Lugu Science Park, No. 28, Lutian Road, Changsha High tech Development Zone, Changsha City, Hunan Province, 410221 Patentee after: Changsha Jingyi Pharmaceutical Technology Co.,Ltd. Address before: Room 403, Building 2, Laojie Library, Dianbu Town, Feidong County, Hefei City, Anhui Province, 231699 Patentee before: Hefei guiqian Information Technology Co.,Ltd. |
|
| TR01 | Transfer of patent right |