CN103735535A - Preparation method of polyamino acid-based hydrogel microcapsule - Google Patents
Preparation method of polyamino acid-based hydrogel microcapsule Download PDFInfo
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- CN103735535A CN103735535A CN201410000687.9A CN201410000687A CN103735535A CN 103735535 A CN103735535 A CN 103735535A CN 201410000687 A CN201410000687 A CN 201410000687A CN 103735535 A CN103735535 A CN 103735535A
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Abstract
The invention relates to a preparation method of a polyamino acid-based hydrogel microcapsule, and belongs to the technical field of a controlled release material of a biological medicine. The preparation method is characterized by comprising the steps of initiating ring opening polymerization of amino acid-N-carboxylic acid anhydride by taking inorganic particle processed by surface amination as an initiator, removing a protecting group, cross-linking a graft polymer through polyelectrolyte with an amino group on side chain, and acid-etching an inorganic particle template, thus obtaining the microcapsule which is uniform in particle size and has a hollow or porous structure, wherein particle size range of the microcapsule is about 150-1400nm. The submicron polyamino acid-based hydrogel microcapsule prepared by the method is biodegradable, controllable in size, stable and uniform. The polyelectrolyte microcapsule has sensitive pH and ion responsiveness, therefore, the microcapsule can realize embedding and release of a core material. In addition, the microcapsule, through active amino and carboxyl terminals in a capsule wall material, can bond with a medicine, a targeted group and the like through a covalent bond, and the microcapsule has wide application prospect in the field of medicine controlled release.
Description
Technical field
The present invention relates to a kind of preparation method of polyamino acid based aquagel microcapsule, belong to bio-pharmaceutical controlled-release material technical field.
Background technology
Hydrogel microcapsule has cancellated pharmaceutical carrier as a class, due to it, to have stability higher, and specific surface area is large, and chemistry and 3D physical arrangement are adjustable, in water, swelling ratio height and environment sting the plurality of advantages such as answering property (as pH, temperature, reducing agent, enzyme etc.), be subject to increasing concern (J. K. Oh, R. Drumright, D. J. Siegwart and K. Matyjaszewski, Prog. Polym. Sci., 2008,33,448 ~ 477).The preparation method of hydrogel microcapsule has a variety of, and wherein more conventional have interfacial polymerization and a phase detachment technique.Yet, the microcapsule that these technology prepare due to exist some common problems such as shell is coated inhomogeneous, reunion, residual organic solvent etc. have limited its application in medicine controlled releasing field.（Y.?F.?Fan,?Y.?N.?Wang,?Y.?G.?Fan,?J.?B.?Ma?Int.?J.?Pharm.?2006,324,?158~167）。
Here, we proposed first a kind of on inorganic particulate the polyamino acid of grafting band carboxyl, recycling is cross-linked it with amino polyelectrolyte, last etching inorganic particulate template is prepared the method for microcapsule.The method is by selecting the good inorganic particulate template of monodispersity, control surface of inorganic particles percent grafting, crosslinked condition etc., can obtain uniform particle diameter, cyst wall has the hydrogel microcapsule of cross-linked network structure, and can on nanoscale, realize the control to hydrogel microcapsule structure, composition, form, wall thickness.The polyamino acid material adopting can discharge natural micromolecule aminoacid in degradation process, so material has good biocompatibility, easily by body, is absorbed and metabolism.The cyst material of two kinds of polyelectrolyte formations has been given again the sensitive good pH of microcapsule, ion responsitivity.In addition, the active amino containing in cyst material and c-terminus, can, by combinations such as covalent bond and medicine and targeting groups, have broad application prospects in medicine controlled releasing field.
Summary of the invention
One of object of the present invention is to provide a kind of polyamino acid based aquagel microcapsule.
Two of object of the present invention is to provide the preparation method of this hydrogel microcapsule.
The inventive method is with previously prepared surface amination inorganic particulate, to cause aminoacid, on its surface, ring-opening polymerisation occurs, thus in surface of inorganic particles grafting polyamino acid; Then adopt Iodotrimethylsilane, trim,ethylchlorosilane or bromotrimethylsilane etc. to there is the benzyl in the deprotection agent deaminate acid of similar structures, obtain the compound particle of surface of inorganic particles grafting polyamino acid; By compound particle being cross-linked with amino polyelectrolyte on side chain; Finally above-mentioned compound particle is immersed in to etching inorganic particulate in acid solution, obtains the polyamino acid based aquagel microcapsule of inner hollow or porous;
According to above-mentioned reaction mechanism, the present invention adopts following technical scheme:
The present invention is a kind of prepares above-mentioned polyamino acid based aquagel microcapsule, it is characterized in that the concrete steps of the method are:
A. under inert atmosphere, the amino inorganic particulate of the band preparing in advance, aminoacid-N-carboxylic acid anhydrides are scattered in dioxane to ultrasonic dispersion 0.5 ~ 1 hour with the mass ratio of 1:1 ~ 1:4; At 15 ~ 25 ℃ of temperature, stirring reaction is 72 hours, the system thickness that becomes; Reactant liquor is slowly poured in dehydrated alcohol, and adularescent material is separated out; Filter, with absolute ethanol washing, be dried, obtain the inorganic compounding particle of polyamino acid ester on surface grafting; Described inorganic particulate is any in silicon dioxide, zinc oxide, hydroxyapatite, tricalcium phosphate; Its structure is porous or solid, and size is 50 ~ 1000nm; Described aminoacid is any in glutamic acid and aspartic acid;
B. the polyamino acid ester inorganic compounding particle of step a gained band blocking group is dissolved in dichloromethane, with every 0.5 ~ 1.0 g compound particle, add the ratio of 0.3 ~ 0.5mL deprotection agent to add deprotection agent again, 35 ~ 40 ℃ of anhydrous and oxygen-free lucifuge reactions 12 ~ 20 hours, reactant liquor is poured in water saturated petroleum ether and precipitated, sucking filtration, and with absolute ether and deionized water rinsing, be dried and can obtain white powder, be polyamino acid compound particle, described deprotection agent is: any of Iodotrimethylsilane, trim,ethylchlorosilane, bromotrimethylsilane;
C. step b gained polyamino acid compound particle is dissolved in weak caustic solution, by every 30mg compound particle, add 40 ~ 70mg N-hydroxy succinic acid acid anhydride, its pH value is adjusted to after 4 ~ 6, then adds 90 ~ 120mg EDC, reaction 6 ~ 12h;
D. will be with amino polyelectrolyte to be dissolved in weak acid solution in addition, filter, obtain clear liquid, and its pH value is adjusted to 3 ~ 5; Standby;
E. the weak caustic solution of step c gained polyamino acid compound particle is dropwise joined in the amino polyelectrolyte solution of band of above-mentioned steps d gained, in this process, keep higher stir speed (S.S.); By centrifugal, washing, obtains white powder; In product, polyamino acid is 1:0.1 ~ 1:1 with the mass ratio with amino polyelectrolyte; The amino polyelectrolyte of described band is: any one of chitosan, polylysine, polyacrylamide;
F. 3-5ml acid solution is joined in above-mentioned steps e gained white powder, with etching inorganic particulate; Ultrasonic 15 ~ 60mins, by centrifugal, washing, obtains white powder; Described acid solution is any of dichloroacetic acid, trifluoroacetic acid, Fluohydric acid., dilute hydrochloric acid, spirit of vinegar.
Compared with the existing technology, the present invention has advantages of following outstanding: the present invention is at previously prepared surface of inorganic particles grafting polyamino acid, the polyelectrolyte of employing side chain band amino is as cross-linking agent and etch away inorganic particulate, the microcapsule obtaining has extraordinary monodispersity, and size is controlled, inner hollow, useful as drug slow-released carrier.Cyst material is polyamino acid, therefore has good biocompatibility, can be degraded into voluntarily amino acid monomer in vivo, and catabolite can be absorbed by body, can not produce toxic and side effects; By regulating the ratio of monomer and initiator, control the ratio of cyst wall and core; Adopt polyelectrolyte as capsule material, there is sensitive pH, ion responsitivity, can realize targeted drug and discharge, have broad application prospects.
The specific embodiment
below in conjunction with embodiment, describe the present invention.
embodiment mono-
1. the preparation of silicon dioxide grafted polyglutamic acid benzyl ester compound particle:
In dry 100mL eggplant-shape bottle, add average diameter at the amination silicon dioxide granule 1g of 200nm left and right, γ-benzyl-Pidolidone-N-carboxylic acid anhydrides 3g, the new dioxane 60mL steaming; The logical nitrogen circulation of evacuation 3 ~ 5 times, maintenance reaction bulb is nitrogen atmosphere, ultrasonic dispersion 0.5 ~ 1h; 15 ~ 25 ℃ of stirring reaction 2 ~ 3d, reactant liquor becomes viscous solution.Reactant liquor is slowly poured in dehydrated alcohol and precipitated, and now adularescent material is separated out; Filter, with absolute ethanol washing, vacuum drying, obtains silicon dioxide/poly benzyl glutamate compound particle.
2. adopt Iodotrimethylsilane deprotection to prepare silicon dioxide grafted polyglutamic acid compound particle: in dry 100mL ampere bottle, to add silicon dioxide/poly benzyl glutamate compound particle 1g, be dissolved in the new dichloromethane steaming of 25mL; The logical nitrogen circulation of evacuation 3 ~ 5 times, maintenance reaction bulb is nitrogen atmosphere, adds 0.3mL Iodotrimethylsilane under lucifuge condition; 40 ℃ of lucifuge reaction 20h; Reactant liquor is poured in water saturated petroleum ether and is precipitated, sucking filtration, and with absolute ether and a large amount of deionized water rinsing numbers all over after, dryly can obtain white powder, be silicon dioxide/polyglutamic acid compound particle, percent grafting is 50.9%.
3. adopt chitosan crosslinked silicon dioxide/polyglutamic acid compound particle:
25mg silicon dioxide/polyglutamic acid compound particle is dissolved in 5ml dimethyl sulfoxide or weak caustic solution, by every 30mg compound particle, add 40 ~ 70mg N-hydroxy succinic acid acid anhydride, its pH value is adjusted to after 4 ~ 6, add again 90 ~ 120mg EDC, reaction 6 ~ 12h; 25mg chitosan is dissolved in 5ml weak acid solution, filters, obtain clear liquid, and its pH value is adjusted to 3 ~ 5; Under stirring condition, the weak caustic solution of silicon dioxide/polyglutamic acid compound particle is dropwise joined in chitosan solution centrifugal, washing, obtain white powder; 3 ~ 5ml hydrofluoric acid solution is joined in white powder, to etch away inorganic particulate; Ultrasonic 15 ~ 60min, centrifugal, washing, the hollow microcapsule obtaining, its particle diameter is 330 ~ 350nm.
embodiment bis-
The present embodiment and embodiment mono-are basic identical, and difference is: in step 1, the quality that adds monomer γ-benzyl-Pidolidone-N-carboxylic acid anhydrides is 2g; In step 2, the volume that adds Iodotrimethylsilane is 0.18mL.Other reagent dosages and operating condition are constant.The particle diameter of the chitosan/polyglutamic acid hydrogel microcapsule finally obtaining is 270 ~ 310nm.
embodiment tri-
The present embodiment and embodiment mono-are basic identical, and difference is: in step 2, deprotection agent used is trim,ethylchlorosilane (0.3mL); In step 3, the amino polyelectrolyte of band used is lysine.Other reagent dosages and operating condition are constant.The particle diameter of last gained polylysine/polyglutamic acid hydrogel microcapsule is 320 ~ 370nm.
embodiment tetra-
The present embodiment and embodiment mono-are basic identical, and difference is: in step 3, the amino polyelectrolyte of band used is polyacrylamide.Other reagent dosages and operating condition are constant.The particle diameter of last gained polyacrylamide/polyglutamic acid hydrogel microcapsule is 260 ~ 300nm.
embodiment five
The present embodiment and embodiment mono-are basic identical, and difference is: in step 1, silicon dioxide particle diameter used is 100nm; In step 2, the monomer adding is β-benzyl-L-Aspartic acid-N-carboxylic acid anhydrides.Other reagent dosages and operating condition are constant.The particle diameter of last gained chitosan/poly-aspartate hydrogel microcapsule is 200 ~ 240nm.
embodiment six
The present embodiment and embodiment mono-are basic identical, and difference is: in step 1, inorganic particulate used is the tricalcium phosphate of diameter 100nm; In step 3, the acid solution adding is 0.1M dilute hydrochloric acid.Other reagent dosages and operating condition are constant.The particle diameter of last gained chitosan/polyglutamic acid hydrogel microcapsule is 215 ~ 250nm.
embodiment seven
The present embodiment and embodiment mono-are basic identical, and difference is: in step 1, inorganic particulate used is the zinc oxide of diameter 300nm; In step 3, the acid solution adding is 0.1M spirit of vinegar.Other reagent dosages and operating condition are constant.The particle diameter of last gained chitosan/polyglutamic acid hydrogel microcapsule is 450 ~ 550nm.
embodiment eight
The present embodiment and embodiment mono-are basic identical, and difference is: in step 1, inorganic particulate used is the hydroxyapatite of diameter 150nm; In step 3, the acid solution adding is dichloroacetic acid.Other reagent dosages and operating condition are constant.The particle diameter of last gained chitosan/polyglutamic acid hydrogel microcapsule is 220 ~ 340nm.
Claims (1)
1. a preparation method for polyamino acid based aquagel microcapsule, is characterized in that having following preparation process and step:
A. under inert atmosphere, the amino inorganic particulate of the band preparing in advance, aminoacid-N-carboxylic acid anhydrides are scattered in dioxane to ultrasonic dispersion 0.5 ~ 1 hour with the mass ratio of 1:1 ~ 1:4; At 15 ~ 25 ℃ of temperature, stirring reaction is 72 hours, the system thickness that becomes; Reactant liquor is slowly poured in dehydrated alcohol, and adularescent material is separated out; Filter, with absolute ethanol washing, be dried, obtain the inorganic compounding particle of polyamino acid ester on surface grafting; Described inorganic particulate is any in silicon dioxide, zinc oxide, hydroxyapatite, tricalcium phosphate; Its structure is porous or solid, and size is 50 ~ 1000nm; Described aminoacid is any in glutamic acid and aspartic acid;
B. the polyamino acid ester inorganic compounding particle of step a gained band blocking group is dissolved in dichloromethane, with every 0.5 ~ 1.0 g compound particle, add the ratio of 0.3 ~ 0.5mL deprotection agent to add deprotection agent again, 35 ~ 40 ℃ of anhydrous and oxygen-free lucifuge reactions 12 ~ 20 hours, reactant liquor is poured in water saturated petroleum ether and precipitated, sucking filtration, and with absolute ether and deionized water rinsing, be dried and can obtain white powder, be polyamino acid compound particle, described deprotection agent is: any of Iodotrimethylsilane, trim,ethylchlorosilane, bromotrimethylsilane;
C. step b gained polyamino acid compound particle is dissolved in weak caustic solution, by every 30mg compound particle, add 40 ~ 70mg N-hydroxy succinic acid acid anhydride, its pH value is adjusted to after 4 ~ 6, then adds 90 ~ 120mg EDC, reaction 6 ~ 12h;
D. will be with amino polyelectrolyte to be dissolved in weak acid solution in addition, filter, obtain clear liquid, and its pH value is adjusted to 3 ~ 5; Standby;
E. the weak caustic solution of step c gained polyamino acid compound particle is dropwise joined in the amino polyelectrolyte solution of band of above-mentioned steps d gained, in this process, keep higher stir speed (S.S.); By centrifugal, washing, obtains white powder; In product, polyamino acid is 1:0.1 ~ 1:1 with the mass ratio with amino polyelectrolyte; The amino polyelectrolyte of described band is: any one of chitosan, polylysine, polyacrylamide;
F. 3-5ml acid solution is joined in above-mentioned steps e gained white powder, with etching inorganic particulate; Ultrasonic 15 ~ 60mins, by centrifugal, washing, obtains white powder; Described acid solution is any of dichloroacetic acid, trifluoroacetic acid, Fluohydric acid., dilute hydrochloric acid, spirit of vinegar.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104151562A (en) * | 2014-05-19 | 2014-11-19 | 上海大学 | Nano ferroferric oxide/polyamino acid magnetic composite particle and preparation method thereof |
| CN104826161A (en) * | 2015-04-28 | 2015-08-12 | 上海大学 | Poly(amino acid) based porous microgel material for tissue engineering and preparation method thereof |
| CN105597640A (en) * | 2016-01-14 | 2016-05-25 | 安徽大学 | Method of using SMA as template to prepare chitosan nano microcapsules |
| WO2022194759A1 (en) * | 2021-03-18 | 2022-09-22 | Agfa-Gevaert Nv | Poly(amino acid) based capsules |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101744789A (en) * | 2010-01-21 | 2010-06-23 | 上海大学 | Biological medicine carrying microcapsule which can degrade nanometer porous polymer L- glutamic acid/ chitosan and preparing method thereof |
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101744789A (en) * | 2010-01-21 | 2010-06-23 | 上海大学 | Biological medicine carrying microcapsule which can degrade nanometer porous polymer L- glutamic acid/ chitosan and preparing method thereof |
Non-Patent Citations (2)
| Title |
|---|
| ZHIQIANG FENG等: "Polyphosphazene Microcapsules Fabricated through Covalent Assembly", 《MACROMOLECULAR RAPID COMMUNICATIONS》, no. 30, 31 December 2009 (2009-12-31), pages 448 - 452 * |
| 范国强等: "交联壳聚糖水凝胶填充层状微胶囊的制备与性能", 《高等学校化学学报》, vol. 29, no. 10, 31 October 2008 (2008-10-31), pages 2086 - 2090 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104151562A (en) * | 2014-05-19 | 2014-11-19 | 上海大学 | Nano ferroferric oxide/polyamino acid magnetic composite particle and preparation method thereof |
| CN104826161A (en) * | 2015-04-28 | 2015-08-12 | 上海大学 | Poly(amino acid) based porous microgel material for tissue engineering and preparation method thereof |
| CN105597640A (en) * | 2016-01-14 | 2016-05-25 | 安徽大学 | Method of using SMA as template to prepare chitosan nano microcapsules |
| WO2022194759A1 (en) * | 2021-03-18 | 2022-09-22 | Agfa-Gevaert Nv | Poly(amino acid) based capsules |
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