CN104225614A - Chitosan grafted polylactic acid composite microsphere simultaneously carried with hydrophilic and hydrophobic biological molecules and preparation method of chitosan grafted polylactic acid composite microsphere - Google Patents
Chitosan grafted polylactic acid composite microsphere simultaneously carried with hydrophilic and hydrophobic biological molecules and preparation method of chitosan grafted polylactic acid composite microsphere Download PDFInfo
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Abstract
The invention discloses a chitosan grafted polylactic acid composite microsphere simultaneously carried with hydrophilic and hydrophobic biological molecules and a preparation method of the chitosan grafted polylactic acid composite microsphere, and belongs to the technical field of biological medical materials, functional macromolecular microspheres and medicament control release. The composite microsphere consists of chitosan grafted polylactic acid, hydrophilic biological molecules and hydrophobic biological molecules. The preparation method of the composite microsphere comprises the steps of dissolving the hydrophobic biological molecules into a chitosan grafted polylactic acid solution to obtain a core-shell type micellar solution, then adding the hydrophilic biological molecules, dropping the micellar solution into an oil phase under the action of a surface active agent to obtain water-covering oil type mixed emulsion, adding a crosslinking agent to further crosslink the micellar solution to obtain a sphere, and forming the chitosan grafted polylactic acid composite microsphere simultaneously carried with hydrophilic and hydrophobic biological molecules. The preparation method disclosed by the invention obtains the novel composite microsphere, so that partitioning distribution of the hydrophilic and hydrophobic biological molecules is realized, and the chitosan grafted polylactic acid composite microsphere can be expected to be widely applied in the field of medicament control release and tissue defect repairing.
Description
Technical field
The invention belongs to bio-medical material, functionalized macromolecular microsphere and drug controlled release technical field, be specifically related to chitosan grafted polylactic acid complex microsphere carrying hydrophobe biomolecule and preparation method thereof.
Background technology
The growth promoter of tissue and organ is subject to the synergism of various biomolecules.In order to utilize the strategy of organizational project to repair disease damage tissue, usually need various biomolecules to be jointly delivered to defect.Along with continuing to bring out of new material structures method for designing, people developed the common Delivery vehicles (Zhou Ping of a series of biomolecule, Wang Changchun, clock tinkling of pieces of jades etc. with the targeting composite Nano pharmaceutical preparation of carrying hydrophilic and dewatering medicament and preparation method thereof .CN 102397256A, 2012), its size is so small to have only several nanometer from some tens of pm.Compared with delivering with traditional single biomolecule, these novel common Delivery vehicles have better therapeutic effect undoubtedly, thus show good application prospect in field of tissue engineering technology.
Chitosan and poly-lactic acid material, due to the two superior biology performance and good biological degradability, are thus widely used in the Co ntrolled release carrier of biomolecule.Traditionally, this bi-material is mainly used as the Co ntrolled release of single creature molecule.Specifically, chitosan belongs to hydrophilic extra-cellular matrix glycan, is especially suitable for use as the Co ntrolled release of hydrophilic biomolecule.Polylactic acid belongs to hydrophobic aliphatic polyester, is especially suitable for use as the Co ntrolled release of hydrophobic biomolecules.In order to realize the common delivery of hydrophobe biomolecule, the composite of exploitation chitosan and polylactic acid is attempted in much research.
Sum up, the major way preparing chitosan and lactic acid composite material at present has two kinds, and one is physical blending, and another kind is chemical modification.Physical blending adopts the method for solution casting or emulsion self assembly that the two is carried out compound (Niu Xufeng, Fan Yubo, Li Xiaoming etc. hydrophilic extra-cellular matrix glycan/hydrophobic aliphatic polyester composite and preparation method thereof .CN 101829355B, 2013).But, polylactic acid is oil-soluble macromolecule, be dissolved in some organic solvents, and chitosan is highly hydrophilic, be insoluble to organic solvent, be only dissolved in the dilute acid soln of minority, up to the present, also do not find the solvent that simultaneously can dissolve chitosan and polylactic acid, the potential problems that therefore physical blending exists are that mixing is uneven, and existence is separated.Chitosan and low molecular weight or its precursor (comprising lactide and lactic acid) are normally carried out graft copolymerization (Niu Xufeng by chemical modification, Fan Yubo, Li Xiaoming etc. the preparation method .CN 102898656A of chitosan/aliphatic polyester amphipathic graft copolymer, 2013).But, employing chemical modification prepares chitosan and polylactic acid graft copolymer is by no means easy, its reason comprises: first, the glass transition temperature of chitosan is higher, and will decompose before starting fusing, this just makes to adopt traditional melt polymerization process itself and polylactic acid copolymerization to be become quite difficulty; The second, as previously mentioned, because the hydrophobe different from those of chitosan and polylactic acid is too large, and do not have the solvent that simultaneously can dissolve this two classes material, this just makes to adopt the technique of polymerisation in solution that the two is carried out copolymerization and usually counts out due to inhomogeneous reaction.Therefore, although chitosan and lactic acid composite material show performance more better than homogenous material, it is not still suitable for the common delivery of hydrophobe biomolecule.
Summary of the invention
The object of the invention is to overcome the deficiencies in the prior art, provide with chitosan grafted polylactic acid complex microsphere carrying hydrophobe biomolecule and preparation method thereof.
In the present invention, described complex microsphere is made up of jointly chitosan grafted polylactic acid material and hydrophilic biomolecule, hydrophobic biomolecules.
In the present invention, described chitosan grafted polylactic acid material be according to patent " Niu Xufeng, Fan Yubo, Li Xiaoming etc. the preparation method .CN 102898656A of chitosan/aliphatic polyester amphipathic graft copolymer, 2013 " be prepared from.
In the present invention, described hydrophilic biomolecule refers to water-soluble protein, polypeptide, hormone or antibiotics.
In the present invention, described hydrophobic biomolecules refers to the protein, polypeptide, hormone or the antibiotics that dissolve in dimethyl sulfoxide.
In the present invention, the preparation method of described complex microsphere comprises following each step:
(1) be dissolved in dimethyl sulfoxide by chitosan grafted polylactic acid material, add hydrophobic biomolecules in proportion, consumption is 0.1 ~ 10% of chitosan grafted polylactic acid quality;
(2) solution that the above-mentioned first step obtains being transferred to molecular cut off is in the bag filter of 6 ~ 8 kilodaltons, dialyses 12 ~ 24 hours under room temperature, obtains the chitosan grafted polylactic acid core-shell type micellar solution of wrapping up hydrophobic biomolecules;
(3) micellar solution that above-mentioned second step obtains being concentrated to concentration is 1 ~ 5% (mass volume ratio), and add hydrophilic biomolecule in proportion, consumption is 0.1 ~ 10% of chitosan grafted polylactic acid quality, obtains aqueous phase;
(4) under churned mechanically effect, be added drop-wise in the oil phase containing surfactant by the aqueous phase that above-mentioned 3rd step obtains, the consumption of surfactant is 0.5 ~ 5% of oil phase volume, obtains water-in-oil type mixed emulsion;
(5) under churned mechanically effect, in the mixed emulsion of above-mentioned 4th step, drip cross-linking agent, continue reaction 1 ~ 4 hour, make the crosslinked balling-up further of the micellar solution of chitosan grafted polylactic acid;
(6) reacting complete, centrifugal breakdown of emulsion, replace washing precipitation with excessive oil ether and isopropyl alcohol, in triplicate, finally pellet frozen is dried to constant weight, obtaining the chitosan grafted polylactic acid complex microsphere with carrying hydrophobe biomolecule.
Surfactant described in said method refers to class 60 of department, class 80 of department, class 65 of department or class 85 of department.
Oil phase described in said method refers to mineral oil or liquid paraffin.
Cross-linking agent described in said method comprises ion crosslinking agent and chemical cross-linking agent, and ion crosslinking agent refers to sodium sulfate, sodium citrate or sodium tripolyphosphate, and chemical cross-linking agent refers to formaldehyde or glutaraldehyde.
Compared with prior art, its major advantage is in the present invention:
(1) utilize chitosan grafted polylactic acid material as the Co ntrolled release carrier of biomolecule, achieve the subregion of hydrophobe medicine in complex microsphere and exist.Hydrophobic drug is mainly distributed in the core portion of chitosan grafted polylactic acid core-shell type micelle, in the shell portion that hydrophilic medicament is then mainly distributed in chitosan grafted polylactic acid core-shell type micelle and gap between micelle and micelle.
(2) complex microsphere of a kind of novelty that what the present invention obtained is, wherein hydrophilic and parcel amount that is hydrophobic biomolecules can be regulated and controled respectively by the method for the invention, the release behavior of two kinds of medicines can be regulated and controled by the crosslinking degree of the molecular weight and complex microsphere that change chitosan grafted polylactic acid material, thus makes complex microsphere get a good chance of being used widely at drug controlled release and Repair of tissue defect field.
Accompanying drawing explanation
Accompanying drawing is the schematic diagram with the chitosan grafted polylactic acid complex microsphere carrying hydrophobe biomolecule.
Detailed description of the invention
The present invention is further illustrated below in conjunction with specific embodiments, but these embodiments do not limit the scope of the invention.
Embodiment 1: the chitosan grafted polylactic acid complex microsphere carrying hydrophobic biomolecules
Take 1.0 grams of chitosan grafted polylactic acids to be dissolved in 10 milliliters of dimethyl sulfoxide, add 10 milligrams of steroid hormone fluocinolone acetonide.Until completely dissolved, the solution obtained being transferred to molecular cut off is in the bag filter of 6 ~ 8 kilodaltons, dialyse 24 hours under room temperature, changed a deionized water every 6 hours, obtain the chitosan grafted polylactic acid core-shell type micellar solution of wrapping up fluocinolone acetonide.Micellar solution being concentrated to concentration is 3% (mass volume ratio), under churned mechanically effect, is added dropwise to 100 milliliters containing in the mineral oil of 2% (mass volume ratio) class of department 80, forms water-in-oil type mixed emulsion.In mixed emulsion, add the sodium tripolyphosphate solution that 2.5 grams of concentration are 10% (mass volume ratio), continue stirring reaction 4 hours, make micellar solution crosslinked balling-up further.React complete, centrifugal breakdown of emulsion, replace washing precipitation with excessive oil ether and isopropyl alcohol, in triplicate, finally pellet frozen is dried to constant weight, obtain the chitosan grafted polylactic acid complex microsphere carrying hydrophobicity steroid hormone fluocinolone acetonide.
Embodiment 2: the chitosan grafted polylactic acid complex microsphere carrying hydrophobic biomolecules
Take 1.0 grams of chitosan grafted polylactic acids to be dissolved in 10 milliliters of dimethyl sulfoxide, add 10 milligrams of anticarcinogen paclitaxels.Until completely dissolved, the solution obtained being transferred to molecular cut off is in the bag filter of 6 ~ 8 kilodaltons, dialyse 24 hours under room temperature, changed a deionized water every 6 hours, obtain the chitosan grafted polylactic acid core-shell type micellar solution of wrapping up paclitaxel.Micellar solution being concentrated to concentration is 3% (mass volume ratio), under churned mechanically effect, is added dropwise to 100 milliliters containing in the mineral oil of 2% (mass volume ratio) class of department 80, forms water-in-oil type mixed emulsion.In mixed emulsion, add the sodium tripolyphosphate solution that 2.5 grams of concentration are 10% (mass volume ratio), continue stirring reaction 4 hours, make micellar solution crosslinked balling-up further.React complete, centrifugal breakdown of emulsion, replace washing precipitation with excessive oil ether and isopropyl alcohol, in triplicate, finally pellet frozen is dried to constant weight, obtain the chitosan grafted polylactic acid complex microsphere carrying hydrophobic anticancer medicine paclitaxel.
Embodiment 3: the chitosan grafted polylactic acid complex microsphere carrying hydrophilic biomolecule
Take 1.0 grams of chitosan grafted polylactic acids, be dissolved in 10 milliliters of dimethyl sulfoxide.Until completely dissolved, the solution obtained being transferred to molecular cut off is in the bag filter of 6 ~ 8 kilodaltons, dialyses 24 hours under room temperature, changes a deionized water, obtain the core-shell type micellar solution of chitosan grafted polylactic acid every 6 hours.Micellar solution being concentrated to concentration is 3% (mass volume ratio), add 10 milligrams of somatomedin bone morphogenetic protein 2s, under churned mechanically effect, be added dropwise to 100 milliliters containing in the mineral oil of 2% (mass volume ratio) class of department 80, form water-in-oil type mixed emulsion.In mixed emulsion, add the sodium tripolyphosphate solution that 2.5 grams of concentration are 10% (mass volume ratio), continue stirring reaction 4 hours, make micellar solution crosslinked balling-up further.React complete, centrifugal breakdown of emulsion, replace washing precipitation with excessive oil ether and isopropyl alcohol, in triplicate, finally pellet frozen is dried to constant weight, obtain the chitosan grafted polylactic acid complex microsphere carrying Hydrophilic growth factor bone morphogenetic protein 2.
Embodiment 4: the chitosan grafted polylactic acid complex microsphere carrying hydrophilic biomolecule
Take 1.0 grams of chitosan grafted polylactic acids, be dissolved in 10 milliliters of dimethyl sulfoxide.Until completely dissolved, the solution obtained being transferred to molecular cut off is in the bag filter of 6 ~ 8 kilodaltons, dialyses 24 hours under room temperature, changes a deionized water, obtain the core-shell type micellar solution of chitosan grafted polylactic acid every 6 hours.Micellar solution being concentrated to concentration is 3% (mass volume ratio), add 10 milligrams of antibiotic doxorubicin, under churned mechanically effect, be added dropwise to 100 milliliters containing in the mineral oil of 2% (mass volume ratio) class of department 80, form water-in-oil type mixed emulsion.In mixed emulsion, add the sodium tripolyphosphate solution that 2.5 grams of concentration are 10% (mass volume ratio), continue stirring reaction 4 hours, make micellar solution crosslinked balling-up further.React complete, centrifugal breakdown of emulsion, replace washing precipitation with excessive oil ether and isopropyl alcohol, in triplicate, finally pellet frozen is dried to constant weight, obtain the chitosan grafted polylactic acid complex microsphere carrying hydrophilic antibiotics amycin.
Embodiment 5: with the chitosan grafted polylactic acid complex microsphere carrying hydrophobe biomolecule
Take 1.0 grams of chitosan grafted polylactic acids to be dissolved in 10 milliliters of dimethyl sulfoxide, add 10 milligrams of steroid hormone fluocinolone acetonide.Until completely dissolved, the solution obtained being transferred to molecular cut off is in the bag filter of 6 ~ 8 kilodaltons, dialyse 24 hours under room temperature, changed a deionized water every 6 hours, obtain the chitosan grafted polylactic acid core-shell type micellar solution of wrapping up fluocinolone acetonide.Micellar solution being concentrated to concentration is 3% (mass volume ratio), add 10 milligrams of somatomedin bone morphogenetic protein 2s, under churned mechanically effect, be added dropwise to 100 milliliters containing in the mineral oil of 2% (mass volume ratio) class of department 80, form water-in-oil type mixed emulsion.In mixed emulsion, add the sodium tripolyphosphate solution that 2.5 grams of concentration are 10% (mass volume ratio), continue stirring reaction 4 hours, make micellar solution crosslinked balling-up further.React complete, centrifugal breakdown of emulsion, replaces washing precipitation with excessive oil ether and isopropyl alcohol, in triplicate, finally pellet frozen being dried to constant weight, obtaining the chitosan grafted polylactic acid complex microsphere with carrying hydrophobicity steroid hormone fluocinolone acetonide and Hydrophilic growth factor bone morphogenetic protein 2.
Embodiment 6: with the chitosan grafted polylactic acid complex microsphere carrying hydrophobe biomolecule
Take 1.0 grams of chitosan grafted polylactic acids to be dissolved in 10 milliliters of dimethyl sulfoxide, add 10 milligrams of anticarcinogen paclitaxels.Until completely dissolved, the solution obtained being transferred to molecular cut off is in the bag filter of 6 ~ 8 kilodaltons, dialyse 24 hours under room temperature, changed a deionized water every 6 hours, obtain the chitosan grafted polylactic acid core-shell type micellar solution of wrapping up paclitaxel.Micellar solution being concentrated to concentration is 3% (mass volume ratio), add 10 milligrams of antibiotic doxorubicin, under churned mechanically effect, be added dropwise to 100 milliliters containing in the mineral oil of 2% (mass volume ratio) class of department 80, form water-in-oil type mixed emulsion.In mixed emulsion, add the sodium tripolyphosphate solution that 2.5 grams of concentration are 10% (mass volume ratio), continue stirring reaction 4 hours, make micellar solution crosslinked balling-up further.Reacting complete, centrifugal breakdown of emulsion, replace washing precipitation with excessive oil ether and isopropyl alcohol, in triplicate, finally pellet frozen is dried to constant weight, obtaining the chitosan grafted polylactic acid complex microsphere with carrying hydrophobic anticancer medicine paclitaxel and hydrophilic antibiotics amycin.
Claims (8)
1., with the chitosan grafted polylactic acid complex microsphere carrying hydrophobe biomolecule, it is characterized in that, described complex microsphere is made up of jointly chitosan grafted polylactic acid material and hydrophilic biomolecule, hydrophobic biomolecules.
2., according to claim 1 with the chitosan grafted polylactic acid complex microsphere carrying hydrophobe biomolecule, it is characterized in that, described hydrophilic biomolecule refers to water-soluble protein, polypeptide, hormone or antibiotics.
3., according to claim 1 with the chitosan grafted polylactic acid complex microsphere carrying hydrophobe biomolecule, it is characterized in that, described hydrophobic biomolecules refers to the protein, polypeptide, hormone or the antibiotics that dissolve in dimethyl sulfoxide.
4., with a preparation method for the chitosan grafted polylactic acid complex microsphere of year hydrophobe biomolecule, it is characterized in that comprising following each step:
(1) be dissolved in dimethyl sulfoxide by chitosan grafted polylactic acid material, add hydrophobic biomolecules in proportion, consumption is 0.1 ~ 10% of chitosan grafted polylactic acid quality;
(2) solution that the above-mentioned first step obtains being transferred to molecular cut off is in the bag filter of 6 ~ 8 kilodaltons, dialyses 12 ~ 24 hours under room temperature, obtains the chitosan grafted polylactic acid core-shell type micellar solution of wrapping up hydrophobic biomolecules;
(3) micellar solution that above-mentioned second step obtains being concentrated to concentration is 1 ~ 5% (mass volume ratio), and add hydrophilic biomolecule in proportion, consumption is 0.1 ~ 10% of chitosan grafted polylactic acid quality, obtains aqueous phase;
(4) under churned mechanically effect, be added drop-wise in the oil phase containing surfactant by the aqueous phase that above-mentioned 3rd step obtains, the consumption of surfactant is 0.5 ~ 5% of oil phase volume, obtains water-in-oil type mixed emulsion;
(5) under churned mechanically effect, in the mixed emulsion of above-mentioned 4th step, drip cross-linking agent, continue reaction 1 ~ 4 hour, make the crosslinked balling-up further of the micellar solution of chitosan grafted polylactic acid;
(6) reacting complete, centrifugal breakdown of emulsion, replace washing precipitation with excessive oil ether and isopropyl alcohol, in triplicate, finally pellet frozen is dried to constant weight, obtaining the chitosan grafted polylactic acid complex microsphere with carrying hydrophobe biomolecule.
5. according to claim 4 with the preparation method of the chitosan grafted polylactic acid complex microsphere of year hydrophobe biomolecule, it is characterized in that, described surfactant refers to class 60 of department, class 80 of department, class 65 of department or class 85 of department.
6., according to claim 4 with the preparation method of the chitosan grafted polylactic acid complex microsphere of year hydrophobe biomolecule, it is characterized in that, described oil phase refers to mineral oil or liquid paraffin.
7. according to claim 4 with the preparation method of the chitosan grafted polylactic acid complex microsphere of year hydrophobe biomolecule, it is characterized in that, described cross-linking agent comprises ion crosslinking agent and chemical cross-linking agent, ion crosslinking agent refers to sodium sulfate, sodium citrate or sodium tripolyphosphate, and chemical cross-linking agent refers to formaldehyde or glutaraldehyde.
8. the chitosan grafted polylactic acid complex microsphere of the same year hydrophobe biomolecule prepared according to the arbitrary preparation method of claim 2 ~ 7.
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| CN112844340A (en) * | 2021-02-24 | 2021-05-28 | 毛星星 | Nano magnetic adsorbent with core-shell structure and preparation method thereof |
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| CN109172874A (en) * | 2018-09-18 | 2019-01-11 | 福建师范大学 | A method of preparing the polylactic acid microsphere of gelatin surface graft modification |
| CN109568601A (en) * | 2019-01-29 | 2019-04-05 | 吉林津升制药有限公司 | A kind of protein and peptide drugs dual-microsphere and preparation method thereof and insulin dual-microsphere |
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| CN112516367A (en) * | 2020-10-27 | 2021-03-19 | 明基材料（芜湖）有限公司 | Composition for promoting wound healing and preparation method thereof |
| CN112493317A (en) * | 2020-11-26 | 2021-03-16 | 拉格比(广东)健康科技有限公司 | Composition containing lactoferrin and preparation method thereof |
| CN112493317B (en) * | 2020-11-26 | 2021-11-30 | 拉格比(广东)健康科技有限公司 | Composition containing lactoferrin and preparation method thereof |
| CN112844340A (en) * | 2021-02-24 | 2021-05-28 | 毛星星 | Nano magnetic adsorbent with core-shell structure and preparation method thereof |
| CN114569781A (en) * | 2022-03-02 | 2022-06-03 | 上海交通大学 | Polysaccharide conjugate hemostatic material, preparation method and application thereof |
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