CN103690959A - Injectable hollow hydroxyapatite microsphere/chitosan composite drug carrier material and preparation method thereof - Google Patents
Injectable hollow hydroxyapatite microsphere/chitosan composite drug carrier material and preparation method thereof Download PDFInfo
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- CN103690959A CN103690959A CN201310627494.1A CN201310627494A CN103690959A CN 103690959 A CN103690959 A CN 103690959A CN 201310627494 A CN201310627494 A CN 201310627494A CN 103690959 A CN103690959 A CN 103690959A
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Abstract
The invention discloses an injectable hollow hydroxyapatite microsphere/chitosan composite drug carrier material. The material comprises the following components in percentage by weight: 0.5-2wt% of hollow hydroxyapatite, 2wt% of chitosan, 5.6wt% of beta-sodium glycerophosphate and 90.4-91.9 wt% of water. The preparation method comprises the following steps: first, loading drug in the hollow sodium hydroxyapatite microsphere; then, preparing chitosan thermo-sensitive hydrogel; finally, mixing the drug-loaded hollow hydroxyapatite microsphere and the chitosan thermo-sensitive hydrogel in a solid-liquid ratio of (0.05-0.2)g/10ml, and stirring to obtain the injectable hollow hydroxyapatite microsphere/chitosan composite drug carrier material. The material can realize slow and controlled release of drug, gives the material injectable molding property, and realizse minimally invasive therapy to bone defect or fracture.
Description
Technical field
The invention belongs to bio-medical material technical field, relate in particular to hollow hydroxyapatite micro-sphere/chitosan combination drug carrier material of a kind of injection moldable and preparation method thereof.
Background technology
Syringeability hydrogel is to be flowing liquid before pointed injection, and method that can be by injection, and can gelatinizing-in-situ in subcutaneous injection enters body, forms and has the support of three-dimensional porous structure, and bring into play the effect of bone conduction.Chitosan (chitosan, be called for short CS), it is the alkaline polysaccharide of the unique a large amount of existence of nature, can through zymolysis, be hydrolyzed in vivo, product is nontoxic to human body, there is good histocompatibility, biodegradability and adhesiveness, and wide material sources, low price, be convenient to large-scale production.In addition, chitosan also has antithrombotic, promotes wound healing and the biological activitys such as reconstruction soft, sclerous tissues, thereby obtained deep research and application widely in medical science, field of biology.The temperature sensitive aquagel of Chinese patent CN101148520A research shows that sodium β-glycerophosphate can induce chitosan at the lower sol-gel transition that occurs of physiological temp (37 ℃), gives its injection moldable.Compare to traditional hydrogel, injection aquagel class medical embedded material has adapted to the requirement of Minimally Invasive Surgical Technology development, has Wicresoft and hinders the advantages such as repair tissue is damaged or lopsided, tissue injury is little, do not destroy the blood confession of reparation district, operation is simple.
Medicament slow release technology refers to the slow non-equilibrium release to medicine, particularly short to the half-life or need the medicine of frequent drug administration, can make blood drug level steady, and peak valley fluctuation is little, is conducive to the curative effect that keeps medicine constant.In CS, contain a large amount of free amine groups, with positive charge, there is stronger adsorption, can combined acid molecule, utilize this specific character of chitosan, carrier that can be using it as somatomedin, controls the rate of release of somatomedin.Chinese patent CN101574512A is combined aquagel with multiple promotion angiogenesis factor, show that chitosan temperature-sensitive hydrogel can realize the slow release of the multiple factors such as bFGF, PDGF-BB, VEGF.Yet research also shows separately, by medicine and chitosan-based Material cladding, to have the short defect of burst drug release, deenergized period at treatment initial stage.
Yao Aihua etc. prepare the hydroxyapatite micro-sphere of a kind of porous surface, inner hollow by borate glass converted in-situ method, studies have shown that this material is as the recombinate carrier of bone morphogenetic protein (rhBMP-2) of people, the growth factor-loaded external slow release cycle reaches more than 30 days, and the uninfluenced (Yao Aihua etc. of the activity of somatomedin, hollow hydroxyapatite micro-sphere is as the research of rhBMP-2 slow-released carrier, Journal of Inorganic Materials, 2011,26 (9): 974-978).But to first need to make its molding and there is certain mechanical property by hollow hydroxyapatite micro-sphere for clinical treatment, in order to realize minimally-invasive treatment damaged to bone or fracture, require material to there is injection moldable simultaneously.Therefore,, using hollow hydroxyapatite micro-sphere as decentralized photo, be undoubtedly a kind of desirable selection with the compound combination drug carrier that is prepared into of chitosan-based hydrogel.
Summary of the invention
Defect for prior art, hollow hydroxyapatite micro-sphere/chitosan combination drug the carrier material that the object of this invention is to provide a kind of injection moldable, in composite, hollow hydroxyapatite micro-sphere is decentralized photo, temperature-sensitive hydrogel prepared by chitosan and sodium β-glycerophosphate is continuous phase, the medicines such as skeletal growth factor are loaded in hollow hydroxyapatite micro-sphere, and hydrogel prepared by itself and chitosan and sodium β-glycerophosphate is compound, can realize the slow of medicine, controllable release, give material injection moldable simultaneously, realization to bone damaged or fracture minimally-invasive treatment.
Another object of the present invention is to provide a kind of preparation method of hollow hydroxyapatite micro-sphere/chitosan combination drug carrier material of above-mentioned injection moldable.
To achieve these goals, technical scheme of the present invention is as follows:
The invention provides a kind of injectable hollow hydroxyapatite micro-sphere/chitosan combination drug carrier material, comprise the component of following quality percentage composition:
Described hollow hydroxyapatite micro-sphere is of a size of 2～5 μ m.
The deacetylation of described chitosan is 80～95%.
Described medicine is the antibiotics such as the protein such as the somatomedin such as rhBMP-2, lysozyme, vancomycin.
The present invention also provides a kind of preparation method of above-mentioned injectable hollow hydroxyapatite micro-sphere/chitosan combination drug carrier material, comprise the following steps: first, medicine is loaded in hollow hydroxyapatite micro-sphere, then prepare chitosan temperature-sensitive hydrogel, finally, the hollow hydroxyapatite micro-sphere that is loaded with medicine be take to solid-to-liquid ratio as (0.05～0.2) g/10ml mixes with chitosan temperature-sensitive hydrogel, stir and obtain injectable hollow hydroxyapatite micro-sphere/chitosan combination drug carrier material.
The preparation method of described hollow hydroxyapatite micro-sphere comprises the following steps:
Take 7.4gLi
2cO
3, 10gCaCO
3with 97.6g H
3bO
3powder fully mixes in mortar; The powder of mixing is placed in to platinum crucible, in the siliconit high temperature furnace of 1100 ℃, heating and melting 30min; Vitreous humour shrend chilling by fusing, makes borate glass, wherein Li
2o, CaO, B
2o
3mol ratio be respectively 10%, 10% and 80%; By after glass blocks fragmentation, obtaining mean diameter is the glass particle of 2～5 μ m; The glass particle that sieves is out sprayed in the tube furnace of 700 ℃, make spherical borate glass microsphere; Take the glass microsphere after 1g nodularization, joining 100ml concentration is 0.25mol/L, the K that pH is 9.0
2hPO
4in solution, be statically placed in 25 ℃ of calorstats, soak and take out afterwards for 10 days; Remove soak, with after washed with de-ionized water three times, then clean once with dehydrated alcohol, be placed in the dry 24h of 80 ℃ of baking ovens, make hollow hydroxyapatite micro-sphere.
The useful load of described medicine in hollow hydroxyapatite micro-sphere is >10 μ g/g.
Described medicine is loaded in hollow hydroxyapatite micro-sphere and comprises the following steps: medicine is dissolved in PBS phosphate buffer, makes the aqueous phase solution that concentration is 0.01～50g/L; In the environment of 0～4 ℃, 1g hollow hydroxyapatite micro-sphere sample is soaked in the aqueous phase solution of 50mL medicine, put it in vacuum drying oven, keep vacuum 0.05MPa, make drug solution diffuse under pressure hollow hydroxyapatite micro-sphere inner, after 10～30min, take out, with PBS phosphate buffer, rinse hollow hydroxyapatite micro-sphere, through lyophilization, obtain being loaded with the hollow hydroxyapatite micro-sphere of medicine.
The preparation method of described chitosan temperature-sensitive hydrogel comprises the following steps: take in the HCl solution that 0.2g chitosan is dissolved in 9ml0.1M magnetic agitation 12 hours; 500mg sodium β-glycerophosphate is dissolved in after 1ml deionized water, is then added drop-wise to slowly in chitosan solution, and the mass ratio of chitosan, sodium β-glycerophosphate, deionized water is 0.2:0.5:10; Vacuum filtration obtains the chitosan temperature-sensitive hydrogel that concentration homogeneous is 2wt%, and pH is 7.16.
Hollow hydroxyapatite micro-sphere/chitosan combination drug carrier material tool of the injection moldable that compared with prior art, prepared by the present invention has the following advantages:
1, hollow hydroxyapatite micro-sphere/chitosan combination drug carrier material of the prepared injection moldable of the present invention has good sustained drug release effect; Chitosan is a kind of extracellular matrix polysaccharide, has good mechanical property and controlled degradation rate, and itself is drug carrier material; Hollow hydroxyapatite micro-sphere also has good slow releasing function to medicine because of its hollow structure and porous surface; The sustained release performance of both compound rear further raising composites, without the prominent phenomenon of releasing.
2, the present invention utilizes Thermo-sensitive and the plasticity of aquagel, give composite injection moldable, under room temperature, material has mobility, is expelled to after body internal skeleton defect, under body temperature effect, realize material gel, thereby meet the requirement of less invasive techniques.
3, there is gelation in the prepared material of the present invention under physiological temp, and it is controlled to realize setting time; With existing medicine carrying material, compare, this material injection moldable, can be used for the minimally-invasive treatment that bone is damaged and fracture; Under room temperature, can keep for a long time liquid, and after being elevated to physiological temp (37 ℃), there is gelation in temperature.
Accompanying drawing explanation
Fig. 1 is for carrying the external elution profiles schematic diagram of hollow hydroxyapatite micro-sphere/chitosan combination drug carrier material of rhBMP-2.
Fig. 2 is the schematic diagram that the hydroxyapatite micro-sphere/chitosan of hollow shown in Fig. 1 combination drug carrier material gel time is measured.
Fig. 3 is the stereoscan photograph of the hydroxyapatite micro-sphere/chitosan of hollow shown in Fig. 1 combination drug carrier material.
The specific embodiment
Below in conjunction with the drawings and specific embodiments, the present invention is described in detail.
In hollow hydroxyapatite micro-sphere/chitosan combination drug carrier material: decentralized photo is a hollow hydroxyapatite micro-sphere, continuous phase is hydrogel prepared by chitosan and sodium β-glycerophosphate.The preparation process of this combination drug carrier is as follows:
(1) preparation of hollow hydroxyapatite micro-sphere: take 7.4gLi
2cO
3, 10gCaCO
3with 97.6g H
3bO
3powder fully mixes in mortar.The powder of mixing is placed in to platinum crucible, in the siliconit high temperature furnace of 1100 ℃, heating and melting 30min.Vitreous humour shrend chilling by fusing, makes borate glass, wherein Li
2o, CaO, B
2o
3mol ratio be respectively 10%, 10% and 80%.By after glass blocks fragmentation, obtaining mean diameter is the glass particle of 2-5 μ m.The glass particle that sieves is out sprayed in the tube furnace of 700 ℃, make spherical borate glass microsphere.Take the glass microsphere after 1g nodularization, joining 100ml concentration is 0.25mol/L, the K that pH is 9.0
2hPO
4in solution, be statically placed in 25 ℃ of calorstats, soak and take out afterwards for 10 days.Remove soak, with after washed with de-ionized water three times, then clean once with dehydrated alcohol, be placed in the dry 24h of 80 ℃ of baking ovens, make hollow hydroxyapatite micro-sphere.
(2) loading of rhBMP2 (rhBMP-2) in hollow hydroxyapatite micro-sphere: in order to verify the medicament slow release performance of composite, rhBMP-2 is loaded in hollow hydroxyapatite micro-sphere.Concrete grammar is: rhBMP-2 is dissolved in PBS phosphate buffer, makes the aqueous phase solution that concentration is 0.01g/L; In the environment of 0～4 ℃, 1g hollow hydroxyapatite micro-sphere sample is soaked in the aqueous phase solution of 50mL rhBMP-2, put it in vacuum drying oven, keep vacuum 0.05MPa, make rhBMP-2 solution diffuse under pressure hollow hydroxyapatite micro-sphere inner, after 30min, take out, with PBS phosphate buffer, rinse microsphere, after lyophilization, save backup, the useful load of rhBMP-2 in hollow hydroxyapatite micro-sphere is about >10 μ g/g.
(3) configuration of chitosan temperature-sensitive hydrogel: take in the HCl solution that 0.2g chitosan is dissolved in 9ml0.1M magnetic agitation 12 hours; 500mg sodium β-glycerophosphate is dissolved in after 1ml deionized water, is then added drop-wise to slowly in chitosan solution, and the mass ratio of chitosan, sodium β-glycerophosphate, deionized water is 0.2:0.5:10.Vacuum filtration obtains the chitosan temperature-sensitive hydrogel that the concentration of homogeneous is 2wt%, and pH is in 7.16 left and right.
(4) preparation of the hollow hydroxyapatite/chitosan composite of injection moldable: the hollow hydroxyapatite that is loaded with rhBMP-2 is mixed and magnetic agitation 1h with solid-to-liquid ratio (0.05～0.2) g/10ml with above-mentioned chitosan temperature-sensitive hydrogel, obtain uniform milky composite aquogel, for carrying rhBMP-2 hollow hydroxyapatite/chitosan composite.
The external slow release cycle of rhBMP-2 hollow hydroxyapatite micro-sphere/chitosan combination drug carrier material is carried in test, and as shown in Figure 1, as shown in Figure 1, under this condition, the slow-release time of rhBMP-2 can reach 30 days to result, and without obviously dashing forward and release phenomenon.This is mainly because chitosan itself is exactly a kind of slow-release material, so rhBMP-2 hollow hydroxyapatite micro-sphere/chitosan combination drug carrier material that is loaded with of preparing as carrier with chitosan has better slow release effect.Fig. 2 shows that hollow hydroxyapatite micro-sphere/chitosan combination drug carrier material prepared by the present embodiment keeps good mobility at normal temperatures, and gelation occurs after bringing up to 37 ℃ temperature, and the presetting period can be controlled in 3～20min.As shown in Figure 3, as shown in Figure 3, the hollow hydroxyapatite micro-sphere that is loaded with rhBMP-2 is evenly distributed the scanning electron microscope result of gained hollow hydroxyapatite micro-sphere/chitosan combination drug carrier material in chitosan solution.
The preparation process that combination drug carrier carries lysozyme is as follows:
(1) preparation of hollow hydroxyapatite micro-sphere: take 7.4gLi
2cO
3, 10gCaCO
3with 97.6g H
3bO
3powder fully mixes in mortar.The powder of mixing is placed in to platinum crucible, in the siliconit high temperature furnace of 1100 ℃, heating and melting 30min.Vitreous humour shrend chilling by fusing, makes borate glass, wherein Li
2o, CaO, B
2o
3mol ratio be respectively 10%, 10% and 80%.By after glass blocks fragmentation, obtaining mean diameter is the glass particle of 2-5 μ m.The glass particle that sieves is out sprayed in the tube furnace of 700 ℃, make spherical borate glass microsphere.Take the glass microsphere after 1g nodularization, joining 100ml concentration is 0.25mol/L, the K that pH is 9.0
2hPO
4in solution, be statically placed in 25 ℃ of calorstats, soak and take out afterwards for 10 days.Remove soak, with after washed with de-ionized water three times, then clean once with dehydrated alcohol, be placed in the dry 24h of 80 ℃ of baking ovens, make hollow hydroxyapatite micro-sphere.
(2) loading of lysozyme in hollow hydroxyapatite micro-sphere: lysozyme is dissolved in PBS phosphate buffer, makes the aqueous phase solution that concentration is 20g/L; In the environment of 0～4 ℃, 1g hollow hydroxyapatite micro-sphere sample is soaked in the aqueous phase solution of 50mL lysozyme, put it in vacuum drying oven, keep vacuum 0.05MPa, make lysozyme soln diffuse under pressure hollow hydroxyapatite micro-sphere inner, after 10min, take out, with PBS phosphate buffer, rinse microsphere, after lyophilization, save backup, the useful load of lysozyme in hollow hydroxyapatite micro-sphere is about >40mg/g.
(3) configuration of chitosan temperature-sensitive hydrogel: take in the HCl solution that 0.2g chitosan is dissolved in 9ml0.1M magnetic agitation 12 hours; 500mg sodium β-glycerophosphate is dissolved in after 1ml deionized water, is then added drop-wise to slowly in chitosan solution, and the mass ratio of chitosan, sodium β-glycerophosphate, deionized water is 0.2:0.5:10.Vacuum filtration obtains the chitosan temperature-sensitive hydrogel that the concentration of homogeneous is 2wt%, and pH is in 7.16 left and right.
(4) preparation of the hollow hydroxyapatite/chitosan composite of injection moldable: the hollow hydroxyapatite that is loaded with lysozyme is mixed and magnetic agitation 1h with solid-to-liquid ratio (0.05～0.2) g/10ml with above-mentioned chitosan temperature-sensitive hydrogel, obtain uniform milky composite aquogel, for carrying lysozyme hollow hydroxyapatite/chitosan composite.
Embodiment 3
The preparation process that combination drug carrier carries vancomycin is as follows:
(1) preparation of hollow hydroxyapatite micro-sphere: take 7.4gLi
2cO
3, 10gCaCO
3with 97.6g H
3bO
3powder fully mixes in mortar.The powder of mixing is placed in to platinum crucible, in the siliconit high temperature furnace of 1100 ℃, heating and melting 30min.Vitreous humour shrend chilling by fusing, makes borate glass, wherein Li
2o, CaO, B
2o
3mol ratio be respectively 10%, 10% and 80%.By after glass blocks fragmentation, obtaining mean diameter is the glass particle of 2-5 μ m.The glass particle that sieves is out sprayed in the tube furnace of 700 ℃, make spherical borate glass microsphere.Take the glass microsphere after 1g nodularization, joining 100ml concentration is 0.25mol/L, the K that pH is 9.0
2hPO
4in solution, be statically placed in 25 ℃ of calorstats, soak and take out afterwards for 10 days.Remove soak, with after washed with de-ionized water three times, then clean once with dehydrated alcohol, be placed in the dry 24h of 80 ℃ of baking ovens, make hollow hydroxyapatite micro-sphere.
(2) loading of vancomycin in hollow hydroxyapatite micro-sphere: vancomycin is dissolved in PBS phosphate buffer, makes the aqueous phase solution that concentration is 50g/L; In the environment of 0～4 ℃, 1g hollow hydroxyapatite micro-sphere sample is soaked in the aqueous phase solution of 50mL vancomycin, put it in vacuum drying oven, keep vacuum 0.05MPa, make vancomycin solution diffuse under pressure hollow hydroxyapatite micro-sphere inner, after 10min, take out, with PBS phosphate buffer, rinse microsphere, after lyophilization, save backup, the useful load of vancomycin in hollow hydroxyapatite micro-sphere is about >10mg/g.
(3) configuration of chitosan temperature-sensitive hydrogel: take in the HCl solution that 0.2g chitosan is dissolved in 9ml0.1M magnetic agitation 12 hours; 500mg sodium β-glycerophosphate is dissolved in after 1ml deionized water, is then added drop-wise to slowly in chitosan solution, and the mass ratio of chitosan, sodium β-glycerophosphate, deionized water is 0.2:0.5:10.Vacuum filtration obtains the chitosan temperature-sensitive hydrogel that the concentration of homogeneous is 2wt%, and pH is in 7.16 left and right.
(4) preparation of the hollow hydroxyapatite/chitosan composite of injection moldable: the hollow hydroxyapatite that is loaded with vancomycin is mixed and magnetic agitation 1h with solid-to-liquid ratio (0.05～0.2) g/10ml with above-mentioned chitosan temperature-sensitive hydrogel, obtain uniform milky composite aquogel, for carrying vancomycin hollow hydroxyapatite/chitosan composite.
The above-mentioned description to embodiment is can understand and apply the invention for ease of those skilled in the art.Person skilled in the art obviously can easily make various modifications to these embodiment, and General Principle described herein is applied in other embodiment and needn't passes through performing creative labour.Therefore, the invention is not restricted to the embodiment here, those skilled in the art are according to announcement of the present invention, and not departing from the improvement that category of the present invention makes and revise all should be within protection scope of the present invention.
Claims (9)
1. injectable hollow hydroxyapatite micro-sphere/chitosan combination drug carrier material, is characterized in that: the component that comprises following quality percentage composition:
2. injectable hollow hydroxyapatite micro-sphere/chitosan combination drug carrier material according to claim 1, is characterized in that: described hollow hydroxyapatite micro-sphere is of a size of 2～5 μ m.
3. injectable hollow hydroxyapatite micro-sphere/chitosan combination drug carrier material according to claim 1, is characterized in that: the deacetylation of described chitosan is 80～95%.
4. injectable hollow hydroxyapatite micro-sphere/chitosan combination drug carrier material according to claim 1, is characterized in that: described medicine is rhBMP-2, lysozyme or vancomycin.
5. the preparation method of the arbitrary described injectable hollow hydroxyapatite micro-sphere/chitosan combination drug carrier material of a claim 1 to 4, it is characterized in that: comprise the following steps: first, medicine is loaded in hollow hydroxyapatite micro-sphere, then prepare chitosan temperature-sensitive hydrogel, finally, the hollow hydroxyapatite micro-sphere that is loaded with medicine be take to solid-to-liquid ratio as (0.05～0.2) g/10ml mixes with chitosan temperature-sensitive hydrogel, stir and obtain injectable hollow hydroxyapatite micro-sphere/chitosan combination drug carrier material.
6. the preparation method of injectable hollow hydroxyapatite micro-sphere/chitosan combination drug carrier material according to claim 5, is characterized in that: the preparation method of described hollow hydroxyapatite micro-sphere comprises the following steps:
Take 7.4gLi
2cO
3, 10gCaCO
3with 97.6g H
3bO
3powder fully mixes in mortar; The powder of mixing is placed in to platinum crucible, in the siliconit high temperature furnace of 1100 ℃, heating and melting 30min; Vitreous humour shrend chilling by fusing, makes borate glass, wherein Li
2o, CaO, B
2o
3mol ratio be respectively 10%, 10% and 80%; By after glass blocks fragmentation, obtaining mean diameter is the glass particle of 2～5 μ m; The glass particle that sieves is out sprayed in the tube furnace of 700 ℃, make spherical borate glass microsphere; Take the glass microsphere after 1g nodularization, joining 100ml concentration is 0.25mol/L, the K that pH is 9.0
2hPO
4in solution, be statically placed in 25 ℃ of calorstats, soak and take out afterwards for 10 days; Remove soak, with after washed with de-ionized water three times, then clean once with dehydrated alcohol, be placed in the dry 24h of 80 ℃ of baking ovens, make hollow hydroxyapatite micro-sphere.
7. the preparation method of injectable hollow hydroxyapatite micro-sphere/chitosan combination drug carrier material according to claim 5, is characterized in that: the useful load of described medicine in hollow hydroxyapatite micro-sphere is >10 μ g/g.
8. the preparation method of injectable hollow hydroxyapatite micro-sphere/chitosan combination drug carrier material according to claim 5, it is characterized in that: described medicine is loaded in hollow hydroxyapatite micro-sphere and comprises the following steps: medicine is dissolved in PBS phosphate buffer, makes the aqueous phase solution that concentration is 0.01～50g/L; In the environment of 0～4 ℃, 1g hollow hydroxyapatite micro-sphere sample is soaked in the aqueous phase solution of 50mL medicine, put it in vacuum drying oven, keep vacuum 0.05MPa, make drug solution diffuse under pressure hollow hydroxyapatite micro-sphere inner, after 10～30min, take out, with PBS phosphate buffer, rinse hollow hydroxyapatite micro-sphere, through lyophilization, obtain being loaded with the hollow hydroxyapatite micro-sphere of medicine.
9. the preparation method of injectable hollow hydroxyapatite micro-sphere/chitosan combination drug carrier material according to claim 5, it is characterized in that: the preparation method of described chitosan temperature-sensitive hydrogel comprises the following steps: take in the HCl solution that 0.2g chitosan is dissolved in 9ml0.1M magnetic agitation 12 hours; 500mg sodium β-glycerophosphate is dissolved in after 1ml deionized water, is then added drop-wise to slowly in chitosan solution, and the mass ratio of chitosan, sodium β-glycerophosphate, deionized water is 0.2:0.5:10; Vacuum filtration obtains the chitosan temperature-sensitive hydrogel that concentration homogeneous is 2wt%, and pH is 7.16.
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| CN104689375A (en) * | 2015-03-26 | 2015-06-10 | 福州大学 | Multi-gradient drug-loading microsphere having magnetic response and prepared through dual in-situ hybridization |
| CN104689374A (en) * | 2015-03-26 | 2015-06-10 | 福州大学 | Organic/inorganic biphase hybridization target magnetic traditional Chinese medicine carrying composite microsphere |
| CN104940897A (en) * | 2015-06-11 | 2015-09-30 | 同济大学 | PH sensitive type compound drug carrier material and preparation method thereof |
| CN105342989A (en) * | 2015-12-14 | 2016-02-24 | 天津医科大学口腔医院 | Aspirin-encapsulated nano-microsphere composite temperature-sensitive gel slow-release inhibitor |
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| CN110433331A (en) * | 2019-08-26 | 2019-11-12 | 四川大学 | A kind of bioactive bracket and preparation method thereof |
| CN111317709A (en) * | 2020-03-20 | 2020-06-23 | 西安理工大学 | Injectable dual-drug-loaded composite chitosan hydrogel and preparation method thereof |
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| CN103920192A (en) * | 2014-04-04 | 2014-07-16 | 北京大学口腔医院 | Preparation method and application of bioactive factor loaded temperature-sensitive composite gel carrier |
| CN104056304A (en) * | 2014-07-02 | 2014-09-24 | 昆明医科大学第一附属医院 | Growth-factor-chitosan-microsphere loaded DBM support joint cartilage repairing material |
| CN104689375A (en) * | 2015-03-26 | 2015-06-10 | 福州大学 | Multi-gradient drug-loading microsphere having magnetic response and prepared through dual in-situ hybridization |
| CN104689374A (en) * | 2015-03-26 | 2015-06-10 | 福州大学 | Organic/inorganic biphase hybridization target magnetic traditional Chinese medicine carrying composite microsphere |
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| CN116212118A (en) * | 2023-04-01 | 2023-06-06 | 中国海洋大学 | Composite bone repair material with controllable degradation rate and preparation method thereof |
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