CN104998305B - A kind of composite inorganic membranes suppository and preparation method thereof - Google Patents
A kind of composite inorganic membranes suppository and preparation method thereof Download PDFInfo
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- CN104998305B CN104998305B CN201510466917.5A CN201510466917A CN104998305B CN 104998305 B CN104998305 B CN 104998305B CN 201510466917 A CN201510466917 A CN 201510466917A CN 104998305 B CN104998305 B CN 104998305B
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Abstract
The invention discloses a kind of composite inorganic membranes suppository and preparation method thereof, polyglutamic acid sodium solution and carboxymethyl chitosan solution are prepared respectively, and two kinds of described solution are mixed, are stirred at room temperature well mixed.Mixed solution is added in a certain amount of atoleine, after emulsion dispersion, reactant is cooled to 10 DEG C, 10Wt.% glutaraldehyde water solution and 4Wt.% hydrochloric acid solution is slowly added dropwise successively again, 25 DEG C slowly are warming up to after stirring crosslinking 2h, continues stirring reaction 4h, is finally warming up to 45 DEG C, reactor evaporation aqueous phase is opened wide, makes complex microsphere completion of cure.Polyglutamic acid and carboxymethyl chitosan composite inorganic membranes are finally obtained, the product has application prospect in terms of vascular occlusive agent is prepared.
Description
Technical field
The invention discloses a kind of preparation method of composite inorganic membranes suppository, belong to medical material preparing technical field.
Background technology
Arterial embolization is a kind of mediatory type treatment technology, has been widely used in the preoperative bolt of various solid tumors at present
Plug treatment.Japanese scholars proposed TACE (Transcaheter cloure) in 1977, by arterial embolism and arterial chemotherapy medicine
Thing perfusion is combined, and treatment liver cancer is applied to earliest, the catheter perfusion chemotherapeutics of target artery is inserted under radioscopy, is used
Suppository is subject to embolism, can either block tumour blood supply so that tumour lacks necessary nutrition supply, and medicine is enhanced again to swollen
The lethality of knurl and the system toxicity for reducing medicine, embolotherapy turn into one of most important technology of tumor intervention therapeutic,
Had a clear superiority compared with traditional chemotherapy technology.
Embolism microball prepares that material source is more, prepares the host material selected by embolism microball and is generally divided into two major classes：
Non-degradable type high polymer material and degradable high polymer material are such as white including natural degradable type high polymer material
Albumen, gelatin, starch, cyclodextrin, chitin and chitosan etc., and synthesized degradable type polymeric material, such as PLA, poly- alkane
Base alpha-cyanoacrylate fat etc..Biodegradable macromolecule drug bearing microsphere has good biocompatibility, biological degradability, reason
Change and biological stability, extremely low toxicity, and the higher load property of medicine, therefore it is micro- about biodegradable macromolecule load medicine in recent years
The research of ball is more and more.
Polyglutamic acid is a kind of amino acid polymer, according to different polymerization methodses, can be divided into α-polyglutamic acid and γ-poly-
Glutamic acid.α-polyglutamic acid is mainly made by chemical synthesis, but synthesis technique is complicated and accessory substance is more, low yield.
The synthetic method of gamma-polyglutamic acid has a lot, wherein Production by Microorganism Fermentation polyglutamic acid, and cost is low and production process environment
Pollution is small, so current research direction emphasis concentrates on gamma-polyglutamic acid (γ-PGA).
There is more side chain carboxyl group (- COOH), in the basic conditions in negative electrical charge on the strand of polyglutamic acid, it is easy to
The stable compound of generation is combined with the high polymer or small-molecule drug of some oppositely chargeds, is that one kind biological can preferably drop
The pharmaceutical high polymer material of solution.
Doxorubicin hydrochloride is a kind of broad-spectrum anti-cancer drug, has killing action to kinds of tumor cells, is adapted to mammary gland
The chemotherapeutic treatment of cancer, lung cancer, soft tissue neoplasm, osteosarcoma, carcinoma of urinary bladder etc..Doxorubicin hydrochloride is positively charged, can be with negative electrical charge base
Compound action occurs for group.Embolism microball is prepared as raw material from polyglutamic acid, except with biocompatibility and degradability
The advantages of outside, it is also possible to by electrostatic interaction load positive charge medicine so that prepare load stype suppository.
Polymer plug microballoon needs crosslinking in forming process, but is directly produced by the carboxyl of polyglutamic acid side chain
The severe reaction conditions of covalent cross-linking, expensive catalyst, reaction condition is difficult to control.In order to prepare the polymer containing polyglutamic acid
Microballoon, this patent takes ion complex technique to prepare mixed with polymers solution first, then scattered and chemical by anti-phase suspension
Crosslinking is successfully prepared embolism microball.Some technical strategies taken are described below.
Present invention：
From gamma-polyglutamic acid as base stock, gamma-polyglutamic acid sodium solution is prepared first.Due to pure polyglutamic acid
In side chain carboxyl group it is non-protonated, solubility in deionized water is very low, thus the present invention polyglutamic acid is added to first
3Wt.% suspension (mass percent) is formed in ionized water, 5Wt.% sodium carbonate liquor, which is then added dropwise, to be made in polyglutamic acid
Carboxyl deprotonation be transformed into carboxyl anion, until formed homogeneous transparent polyglutamic acid sodium solution；Again by carboxymethyl chitosan
It is added to the carboxymethyl chitosan solution that 4Wt.% is formed in deionized water.
Further polyglutamic acid sodium solution is mixed with carboxymethyl chitosan solution, is stirred at room temperature and is formed uniformly two kinds of polymerizations
Amino formation compound in carboxyl and carboxymethyl chitosan in the mixed solution of thing, gamma-polyglutamic acid sodium.
A certain amount of atoleine is taken to be placed in three mouthfuls of reaction flasks, department Pan 80 that 0.2Wt.% is added thereto is (relative
In atoleine weight) stirring 30 minutes, then measure the mixed solution of above-mentioned polyglutamic acid sodium and carboxymethyl chitosan in proportion,
It is added in atoleine and continues to stir, after the completion of emulsification, reactant is cooled to 10 DEG C, then glutaraldehyde water is slowly added dropwise successively
Solution and hydrochloric acid solution, carboxymethyl chitosan is crosslinked by the reaction of glutaraldehyde and amino, and polyglutamic acid sodium passes through electrostatic
Compound action and inierpeneirating network structure are merged with carboxymethyl chitosan, are slowly warming up to 25 DEG C after stirring 2h, are persistently stirred
Reaction 4h is mixed, 45 DEG C are finally warming up to, reactor evaporation aqueous phase is opened wide, makes complex microsphere completion of cure.In glutaraldehyde water solution
Middle addition hydrochloric acid solution, makes the sodium carbonate in solution produce carbon dioxide bubble in acid condition, microballoon is in cross-linking process
Duct is formed, is easy to improve drug loading rate and carries medicine speed.
It is 1 according to volume ratio by changing polyglutamic acid sodium solution with carboxymethyl chitosan solution:1、1:2、1:3、1:4 systems
Standby mixed solution, so as to understand the different influences to microballoon of component.
In the preparation method of composite inorganic membranes suppository, the volume of atoleine is polyglutamic acid sodium and carboxymethyl chitosan
4 times to 8 times of sugared mixed liquor volume.
In the preparation method of composite inorganic membranes suppository, the method gradually heated up is taken, it is to avoid microsphere surface reacted
It hurry up.Reaction system is cooled to 10 DEG C by glutaraldehyde solution before adding, and is slowly heated up again after stirring 2h after glutaraldehyde solution addition
To 25 DEG C.Reaction is finished, and system temperature is raised, and vapors away moisture, microballoon gradually completion of cure.
Beneficial effects of the present invention：
(1) selection polyglutamic acid sodium is combined with carboxymethyl chitosan, makes two kinds of polymer effective by electrostatic interaction
It is merged, by carboxymethyl chitosan glutaraldehyde cross-linking, obtains three-dimensional network polymer structure, makes microballoon stable.Poly- paddy
Propylhomoserin sodium is merged with carboxymethyl chitosan by electrostatic compound action and formation inierpeneirating network structure, two polymers compositions
It is evenly distributed.
(2) due to containing substantial amounts of carboxyl in polyglutamic acid sodium and carboxymethyl chitosan glycan molecule, therefore it can improve to medicine
The load of adriamycin.
(3) embolism microball preparation process of the invention is simple, nontoxic, environment-friendly.
(4) prepare that composite inorganic membranes regular appearance, particle diameter distribution be suitable, bio-compatible with method of the present invention
Property it is good, by 121 DEG C of high-temperature sterilizations, sealing is placed to be remained to keep outward appearance constant for 24 months, and performance is stable, and microballoon preparation condition holds
It is easy to control, there is application prospect in terms of antitumor suppository is prepared.
Brief description of the drawings
The form of Fig. 1 complex microspheres, polyglutamic acid sodium (PGA) compares 1 with carboxymethyl chitosan (CMC) by liquor capacity：4 shapes
Into compound.
The grain for the complex microsphere that Fig. 2 polyglutamic acids sodium solution and carboxymethyl chitosan solution are mixed with by different volumes ratio
Footpath distribution map
The infrared spectrum of each materials of Fig. 3, (a) polyglutamic acid sodium；(b) polyglutamic acid sodium and carboxymethyl chitosan saccharide complex
(1：1)；(c) carboxymethyl chitosan
Fig. 4 PGA/CMC complex microspheres represent microsphere sample PGA/CMC- respectively in the carrying drug ratio at each time point, B, C, D, E
4, PGA/CMC-3, PGA/CMC-2 and PGA/CMC-1.
Embodiment：
Embodiment 1：The synthesis of complex microsphere
Prepare polyglutamic acid sodium solution：3 grams of polyglutamic acids are added to the polyglutamic that 3Wt.% is formed in 97 grams of deionized waters
Sour suspension (mass percent), is added dropwise 5Wt.% sodium carbonate liquor, observation until formation homogeneous transparent polyglutamic acid sodium is molten
Liquid；
Prepare carboxymethyl chitosan solution：4 grams of carboxymethyl chitosans are added in 96 grams of deionized waters and form 4Wt.%
Carboxymethyl chitosan solution；
Measure 5 milliliters of polyglutamic acid sodium solutions and the mixing of 5 milliliters of carboxymethyl chitosan solutions, be stirred at room temperature be formed uniformly it is mixed
Solution is closed, until bubble-free in solution；Take 40 milliliters of liquid paraffin to be placed in 100mL three-necked flask, and add 0.8 thereto
Ke Sipan 80 (relative to atoleine) is stirred 30 minutes, then measures above-mentioned polyglutamic acid sodium and carboxymethyl chitosan in proportion
Mixed solution, is added in atoleine and continues to stir, and it is 350rmp to control mixing speed, emulsifies after 6h, reactant is cooled down
To 10 DEG C, 10Wt.% 0.2 milliliter of glutaraldehyde water solution is first slowly added dropwise, then 4Wt.% hydrochloric acid solution is added dropwise until pH is
25 DEG C slowly are warming up to after 5, stirring 2h, continues stirring reaction 4h, is finally warming up to 45 DEG C, reactor evaporation aqueous phase is opened wide, makes
Complex microsphere completion of cure, dries by filtering, with after ethanol and deionized water cyclic washing, obtains microballoon product, be labeled as
PGA/CMC-1。
Embodiment 2：The synthesis of complex microsphere
3.3 milliliters of polyglutamic acid sodium solutions and 6.7 milliliters of carboxymethyl chitosan solution mixing are measured, 40 milliliters of liquid are added to
In body paraffin oil, other such as embodiments 1 obtain microballoon Product Labeling for PGA/CMC-2.
Embodiment 3：The synthesis of complex microsphere
2.5 milliliters of polyglutamic acid sodium solutions and 7.5 milliliters of carboxymethyl chitosan solution mixing are measured, 40 milliliters of liquid are added to
In body paraffin oil, other such as embodiments 1 obtain microballoon Product Labeling for PGA/CMC-3.
Embodiment 4：The synthesis of complex microsphere
2.0 milliliters of polyglutamic acid sodium solutions and 8.0 milliliters of carboxymethyl chitosan solution mixing are measured, 40 milliliters of liquid are added to
In body paraffin oil, other such as embodiments 1 obtain microballoon Product Labeling for PGA/CMC-4.
Embodiment 5：The synthesis of complex microsphere
3 grams of polyglutamic acids are added to the polyglutamic acid suspension that 3Wt.% is formed in 97 grams of deionized waters, 5Wt.% is added dropwise
Sodium carbonate liquor, formed homogeneous transparent polyglutamic acid sodium solution；4 grams of carboxymethyl chitosans are added in 96 grams of deionized waters
Form 4Wt.% carboxymethyl chitosan solution.
Take 50 milliliters of liquid paraffin to be placed in 250mL three-necked flask, and add 1 gram of department Pan 80 thereto and stir 30 points
Clock, measures 5 milliliters of polyglutamic acid sodium solutions and the mixing of 5 milliliters of carboxymethyl chitosan solutions, is stirred at room temperature that to be formed uniformly mixing molten
Liquid, is added in atoleine and continues to stir, and it is 350rmp to control mixing speed, emulsifies after 6h, reactant is cooled into 10 DEG C,
5.0Wt.%~the 10Wt.% for accounting for two kinds of polymer weight by glutaraldehyde again is calculated, and the glutaraldehyde that 10Wt.% is slowly added dropwise is water-soluble
Liquid, the follow-up hydrochloric acid solution for adding 4Wt.% to pH is 5, is slowly warming up to 25 DEG C after stirring 2h, continues stirring reaction 4h, finally
Be warming up to 45 DEG C, open wide reactor evaporation aqueous phase, make complex microsphere completion of cure, by filtering, it is anti-with ethanol and deionized water
After backwashing is dried after washing, and microballoon product is obtained, labeled as PGA/CMC-5.
Embodiment 6：The synthesis of complex microsphere
Be the same as Example 5, but the consumption of atoleine is 60 milliliters, 1.2 grams of department Pan 80, remaining formula is constant, is answered
Microballoon is closed, labeled as PGA/CMC-6.
Embodiment 7：The synthesis of complex microsphere
Be the same as Example 5, but the consumption of atoleine is 70 milliliters, 1.4 grams of department Pan 80, remaining formula is constant, is answered
Microballoon is closed, labeled as PGA/CMC-7.
Embodiment 8：The synthesis of complex microsphere
Be the same as Example 5, but the consumption of atoleine is 80 milliliters, 1.6 grams of department Pan 80, remaining formula is constant, is answered
Microballoon is closed, labeled as PGA/CMC-8.
Embodiment 9：Complex microsphere performance test and sign
Take the complex microsphere that different mixing proportion is synthesized on slide, pass through ordinary optical microscope observable microballoon
Pattern, the sphericity of microballoon, adhesion situation and the size for tentatively inferring its particle diameter, observe its distribution situation etc., example is shown in accompanying drawing
1。
Respectively to particle size interval after sieving below 100 μm, 100~300 μm, 300~500 μm of microballoon is weighed,
The percentage that microballoon gross mass is accounted for per class interval microballoon is calculated, accompanying drawing 2 is as a result seen.
Using the total reflection types of Fourier infrared spectrograph Nicolet 6700, respectively to polyglutamic acid sodium, polyglutamic acid sodium
With carboxymethyl chitosan saccharide complex (1：1), the structure of carboxymethyl chitosan is measured, and as a result sees accompanying drawing 3.(a) with (c) respectively
It is PGA and CMC infrared absorption spectroscopy, (b) is the infrared absorption spectroscopy of PGA/CMC complex microspheres, it can be seen that
3415cm-1It is-OH and-NH2Stretching vibration peak, 1415cm-1And 1612cm-1Place's absworption peak is COO-Symmetrical and asymmetric stretch
Contracting vibration peak, 1650cm-1And 1538cm-1Place is then the absworption peak of amide groups, mainly by carbonylic stretching vibration, C-N stretching vibrations
Or N-H flexural vibrations cause to there occurs that crosslinked action generates amide groups this demonstrate the aldehyde radical in the amino and glutaraldehyde in CMC
Group, it is known that obtained microballoon should be polyglutamic acid/carboxymethyl chitosan saccharide complex.
Embodiment 10：The drug carrying ability of complex microsphere
Weigh each 20mg of PGA/CMC complex microspheres, be respectively placed in 10mL concentration be 1mg/mL Doxorubicin solution in (containing Ah
Mycin 10mg), certain time is slowly stirred, the absorbance of adriamycin is determined by ultra-violet absorption spectrum, is obtained according to standard curve
To the concentration of adriamycin, carrying drug ratio is calculated.
Claims (5)
1. a kind of preparation method of composite inorganic membranes suppository, following steps are experienced it is characterized in that preparing：
(1) polyglutamic acid sodium solution is prepared：Polyglutamic acid is added to the suspension that 3Wt% is formed in deionized water, 5Wt% is added dropwise
Sodium carbonate liquor until formed homogeneous transparent polyglutamic acid sodium solution；
(2) carboxymethyl chitosan solution is prepared：Carboxymethyl chitosan is added to the carboxymethyl shell that 4Wt% is formed in deionized water
Glycan solution；
(3) the polyglutamic acid sodium solution described in above-mentioned (1), (2) is mixed with carboxymethyl chitosan solution, be stirred at room temperature uniform
Mixed solution is formed, until bubble-free in solution；
(4) take a certain amount of atoleine to be placed in 100mL three-necked flask, and add thereto relative to atoleine
0.2Wt% department Pan 80, stirs 30 minutes, then measure above-mentioned polyglutamic acid sodium in proportion and the mixing of carboxymethyl chitosan is molten
Liquid, is added in atoleine and continues to stir, and it is 350rmp to control mixing speed, emulsifies after 6h, reactant is cooled into 10 DEG C,
25 DEG C slowly are warming up to after 10Wt% glutaraldehyde water solution and 4Wt% hydrochloric acid solution, stirring 2h is slowly added dropwise successively again, is held
Continuous stirring reaction 4h, is finally warming up to 45 DEG C, opens wide reactor evaporation aqueous phase, makes complex microsphere completion of cure, gained polyglutamic
The diameter of sour sodium and carboxymethyl chitosan complex microsphere is between 100 microns to 500 microns, microballoon regular appearance.
2. a kind of preparation method of composite inorganic membranes suppository as claimed in claim 1, wherein polyglutamic acid sodium solution and carboxylic
Methyl chitosan solution is respectively 1 according to volume ratio:1、1:2、1:3、1:4 prepare mixed solution.
3. a kind of preparation method of composite inorganic membranes suppository as claimed in claim 1, the volume of wherein atoleine is poly-
4 times to 8 times of sodium glutamate and carboxymethyl chitosan mixed liquor volume.
4. a kind of preparation method of composite inorganic membranes suppository as claimed in claim 1, before wherein glutaraldehyde solution is added
Reaction system is cooled to 10 DEG C, 2h is stirred after glutaraldehyde solution is added, then be slowly warming up to 25 DEG C, it is to avoid microsphere surface is anti-
Should be too fast.
5. a kind of preparation method of composite inorganic membranes suppository as claimed in claim 1, wherein in claim 1 step (4)
In, 5.0Wt%~10Wt% that the addition of 10Wt% glutaraldehyde water solution accounts for two kinds of polymer weight by glutaraldehyde is calculated；
4Wt% hydrochloric acid solution addition is by untill reaching that pH is determined as 5.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103536970A (en) * | 2013-10-25 | 2014-01-29 | 北京大学 | Embolic material, and preparation method and use 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 |
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| US9504761B2 (en) * | 2011-04-20 | 2016-11-29 | University Of Central Florida Research Foundation, Inc. | Stabilized chitosan-based nanoparticles and methods for making the same |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103536970A (en) * | 2013-10-25 | 2014-01-29 | 北京大学 | Embolic material, and preparation method and use 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 |
Non-Patent Citations (2)
| Title |
|---|
| Poly(L-glutamic acid)/chitosan polyelectrolyte complex porous microspheres as cell microcarriers for cartilage regeneration;Jianjun Fang et al;《Acta Biomaterialia》;20130908;第10卷(第1期);276-288 * |
| 介入栓塞用微球制剂的应用和研究进展;于开涛 等;《介入放射学杂志》;20020430;第11卷(第2期);132-134 * |
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