CN109549928A - A kind of compound microballoon of Chitosan-Thiolated Polymers/calcium carbonate and preparation method thereof - Google Patents
A kind of compound microballoon of Chitosan-Thiolated Polymers/calcium carbonate and preparation method thereof Download PDFInfo
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- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
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Abstract
The present invention relates to a kind of compound microballoons of Chitosan-Thiolated Polymers/calcium carbonate and preparation method thereof, specifically disclose a kind of compound microballoon of Chitosan-Thiolated Polymers/calcium carbonate, the skeleton with Chitosan-Thiolated Polymers and the porous structure calcium carbonate being adsorbed on skeleton.Preparation method includes the following steps: i, prepares Chitosan-Thiolated Polymers；Ii, porous structure calcium carbonate is prepared；Iii, the combination compound microballoon of Chitosan-Thiolated Polymers/calcium carbonate.The invention has the advantages that comparing unmodified chitosan, Chitosan-Thiolated Polymers have many advantages, such as good water-soluble, rush permeability, adhesiveness；Compared to ordinary calcium carbonate microballoon, the calcium carbonate microspheres of porous structure, there is the specific surface area more arrived, drug carrying ability is excellent.The advantage of the present invention comprehensive Chitosan-Thiolated Polymers and porous calcium carbonate, prepares the compound microballoon of Chitosan-Thiolated Polymers/calcium carbonate.
Description
Technical field
This patent is related to a kind of compound microballoon of Chitosan-Thiolated Polymers/calcium carbonate and preparation method thereof, belongs to medical bio material
Material field.
Background technique
Chitosan is Natural polycations polysaccharide, has good biocompatibility, degradability, has been widely used in
Bone tissue engineer field, typical case include newtype drug Transmission system and tissue engineering bracket.The positive charge of chitosan can be with
Enhance the absorption to mucous membrane, therefore extend and release the time and enhance osmosis, embodies good adhesiveness, while having good
Biological degradability well, antibiotic property.On the other hand, the amino on chitosan changes frequently as active site for the various of chitosan
Property provide may.The modification of chitosan can assign chitosan with new performance, and the chitosan of sulfhydrylation not only inherits chitosan
Above-mentioned advantage, solubility promotees permeability, adhesiveness and biological safety etc. and is all substantially better than unmodified chitosan.
Calcium carbonate is from a wealth of sources, Nantural non-toxic and biocompatibility is good, degradable in vivo and sensitive to pH,
The triggering drug release under weakly acidic condition may be implemented, the specific surface area of porous structure is very suitable to load some drugs, is one
The good pharmaceutical carrier of kind.For the hydroxyapatite being usually used in bone tissue engineer, calcium carbonate has preferably drop
Xie Xing, and the calcium carbonate of porous structure can load and some be conducive to Osteoblast Differentiation growth factor.
Summary of the invention
One aspect of the invention provides a kind of compound microballoon of Chitosan-Thiolated Polymers/calcium carbonate, poly- with sulfhydrylation shell
The skeleton of sugar and the porous structure calcium carbonate granule being adsorbed on skeleton.
In the inventive solutions, the molecular weight of Chitosan-Thiolated Polymers skeleton is 50000-100000.
In the inventive solutions, the partial size of the compound microballoon of Chitosan-Thiolated Polymers/calcium carbonate is 500-600 μm.
Another aspect of the invention provides a kind of use of the compound microballoon of Chitosan-Thiolated Polymers/calcium carbonate as pharmaceutical carrier
On the way.
Another aspect of the invention provides a kind of load medicine Chitosan-Thiolated Polymers/compound microballoon of calcium carbonate, on the microballoon
It is also loaded active ingredient.
In the inventive solutions, the active constituent is that term active constituent refers to have for human or animal's energy
Enough play the role of the artificial synthesized or natural materials for the treatment of or prevention.
In the inventive solutions, Chitosan-Thiolated Polymers the preparation method comprises the following steps:
I-1) chitosan is dissolved in acidic aqueous solution, obtains chitosan acid solution；Preferably, chitosan and acidity are water-soluble
The mass volume ratio concentration of liquid is 1-2mg/mL, and the acidic aqueous solution is aqueous acetic acid；
I-2) in the chitosan acid solution for obtaining 2- iminothiolane hydrochloride addition step i-1)；Adjusting pH is 4-6,
It reacts to complete；
I-3 the liquid dialysis for) obtaining step i-2) removes unreacted 2- iminothiolane hydrochloride, it is preferable that institute
State dialysis select to shut off molecular weight for 8000-14000 bag filter；
I-4) the dialysis product for obtaining step i-3) is lyophilized, and obtains Chitosan-Thiolated Polymers.
In the present invention, the porous structure calcium carbonate granule the preparation method comprises the following steps:
Ii-1 the mixed aqueous solution for) preparing carboxymethyl chitosan and calcium chloride, is denoted as solution A, prepare chondroitin sulfate and
The mixed aqueous solution of carbonic acid ammonia, is denoted as solution B；
Ii-2) solution B is slowly dropped in solution A, the reaction was continued after completion of dropwise addition to complete；
Ii-3) the mixed liquor high speed centrifugation for obtaining step ii-2), gained precipitating are washed with deionized for several times, drying,
Obtain the calcium carbonate granule of porous structure；
Optional, further include step ii-4) calcium carbonate granule and active ingredient solution are mixed, it is made and carries medicine carbonic acid
Calcium particle.
Another aspect of the invention provides a kind of preparation method of compound microballoon of Chitosan-Thiolated Polymers/calcium carbonate, packet
Include following steps:
I, Chitosan-Thiolated Polymers are prepared；
Ii, porous structure calcium carbonate granule particle is prepared；
Iii, the compound microballoon of Chitosan-Thiolated Polymers/calcium carbonate is prepared.
In the inventive solutions, the compound microballoon of Chitosan-Thiolated Polymers/calcium carbonate the preparation method comprises the following steps:
Chitosan-Thiolated Polymers the preparation method comprises the following steps:
I, Chitosan-Thiolated Polymers are prepared；
I-1) chitosan is dissolved in acidic aqueous solution, obtains chitosan acid solution；Preferably, chitosan and acidity are water-soluble
The mass volume ratio concentration of liquid is 1-2mg/mL, and the acidic aqueous solution is aqueous acetic acid；
I-2) in the chitosan acid solution for obtaining 2- iminothiolane hydrochloride addition step i-1)；Adjusting pH is 4-6,
It reacts to complete；
I-3 the liquid dialysis for) obtaining step i-2) removes unreacted 2- iminothiolane hydrochloride, it is preferable that institute
State dialysis select to shut off molecular weight for 8000-14000 bag filter,；
I-4) the dialysis product for obtaining step i-3) is lyophilized, and obtains Chitosan-Thiolated Polymers.
Ii, porous structure calcium carbonate is prepared；
Ii-1 the mixed aqueous solution for) preparing carboxymethyl chitosan and calcium chloride, is denoted as solution A, prepare chondroitin sulfate and
The mixed aqueous solution of carbonic acid ammonia, is denoted as solution B；
Ii-2) solution B is slowly dropped in solution A, the partial size of rate of addition control calcium carbonate is adjusted, after completion of dropwise addition
The reaction was continued to complete；
Ii-3) the mixed liquor high speed centrifugation for obtaining step ii-2), gained precipitating are washed with deionized for several times, drying,
Obtain the calcium carbonate of porous structure；
Optionally, further include step ii-4) calcium carbonate of porous structure is mixed with active ingredient solution, make active constituent
It is supported on the calcium carbonate of porous structure, obtains carrying medicine calcium carbonate；
Iii, the compound microballoon of Chitosan-Thiolated Polymers/calcium carbonate is prepared；
Iii-1 Chitosan-Thiolated Polymers aqueous solution) is prepared, disperses calcium carbonate or load medicine calcium carbonate in above-mentioned aqueous solution；
Iii-2) the obtained mixed solution of step iii-1) is added drop-wise in the sodium tripolyphosphate solution of certain volume, trimerization
The mixed solution that sodium radio-phosphate,P-32 solution is obtained with step iii-1), volume ratio are 100:1~10:1, are slowly stirred 36-40 hours；
Iii-3 dry after) standing, obtain the compound microballoon of Chitosan-Thiolated Polymers/calcium carbonate.
Wherein, the mass ratio of Chitosan-Thiolated Polymers and porous structure calcium carbonate is 10:1~5:1.
Another aspect of the invention provides a kind of load medicine Chitosan-Thiolated Polymers/calcium carbonate compound microballoon preparation method,
It includes the following steps:
I, Chitosan-Thiolated Polymers are prepared；
Ii, preparation carry medicine porous structure calcium carbonate granule；
Iii, preparation carry medicine Chitosan-Thiolated Polymers/compound microballoon of calcium carbonate.
In the inventive solutions, carry medicine Chitosan-Thiolated Polymers/compound microballoon of calcium carbonate the preparation method comprises the following steps:
Chitosan-Thiolated Polymers the preparation method comprises the following steps:
I, Chitosan-Thiolated Polymers are prepared；
I-1) chitosan is dissolved in acidic aqueous solution, obtains chitosan acid solution；Preferably, chitosan and acidity are water-soluble
The mass volume ratio concentration of liquid is 1-2mg/mL, and the acidic aqueous solution is aqueous acetic acid；
I-2) in the chitosan acid solution for obtaining 2- iminothiolane hydrochloride addition step i-1)；Adjusting pH is 4-6,
It reacts to complete；
I-3 the liquid dialysis for) obtaining step i-2) removes unreacted 2- iminothiolane hydrochloride, it is preferable that institute
State dialysis select to shut off molecular weight for 8000-14000 bag filter,；
I-4) the dialysis product for obtaining step i-3) is lyophilized, and obtains Chitosan-Thiolated Polymers.
Ii, porous structure calcium carbonate is prepared；
Ii-1 the mixed aqueous solution for) preparing carboxymethyl chitosan and calcium chloride, is denoted as solution A, prepare chondroitin sulfate and
The mixed aqueous solution of carbonic acid ammonia, is denoted as solution B；
Ii-2) solution B is slowly dropped in solution A, the partial size of rate of addition control calcium carbonate is adjusted, after completion of dropwise addition
The reaction was continued to complete；
Ii-3) the mixed liquor high speed centrifugation for obtaining step ii-2), gained precipitating are washed with deionized for several times, drying,
Obtain the calcium carbonate of porous structure；
Ii-4 the calcium carbonate of porous structure is mixed with active ingredient solution), active constituent is made to be supported on porous structure
On calcium carbonate, obtain carrying medicine calcium carbonate granule；
Iii, the compound microballoon of Chitosan-Thiolated Polymers/calcium carbonate is prepared；
Iii-1 Chitosan-Thiolated Polymers aqueous solution) is prepared, medicine calcium carbonate granule will be carried and be scattered in above-mentioned aqueous solution；
Iii-2) the obtained mixed solution of step iii-1) is added drop-wise in the sodium tripolyphosphate solution of certain volume, trimerization
The mixed solution that sodium radio-phosphate,P-32 solution is obtained with step iii-1), volume ratio are 100:1~10:1, are slowly stirred 36-40 hours；
Iii-3 dry after) standing, obtain the compound microballoon of Chitosan-Thiolated Polymers/calcium carbonate.
Wherein, the mass ratio of Chitosan-Thiolated Polymers and load medicine porous structure calcium carbonate granule is 10:1~5:1.
The invention proposes a kind of preparation methods of compound microballoon of Chitosan-Thiolated Polymers/calcium carbonate.The compound microballoon can be with
It is used as pharmaceutical carrier slow-release.
The invention proposes a kind of preparation method of compound microballoon of Chitosan-Thiolated Polymers/calcium carbonate, preparation process is divided into three
Part, comprising the following steps:
1. the preparation of Chitosan-Thiolated Polymers
(1) chitosan (molecular weight 5~100,000) is dissolved in the aqueous acetic acid that volumetric concentration is 1%, chitosan and vinegar
The mass volume ratio concentration of aqueous acid is 1-2mg/mL, obtains the acetum of chitosan；
(2) in the chitosan-acetic acid solution for obtaining 2- iminothiolane hydrochloride addition step (1)；With NaOH solution tune
Section pH is 4-6, is protected from light, continuously stirs 24-30 hours；
(3) mixed liquor that step (2) obtains is placed in the bag filter that molecular cut off is 8000-14000, dialyse 4-6
It, removes unreacted 2- iminothiolane hydrochloride；
(5) it will be freezed in -20 DEG C of refrigerators of dialysis product that step (3) obtains, until liquid freezes completely.In vacuum freeze-drying
Machine freeze-drying, obtains Chitosan-Thiolated Polymers；
2. the preparation of porous structure calcium carbonate
1) mixed aqueous solution for preparing carboxymethyl chitosan and calcium chloride, is denoted as solution A, prepares chondroitin sulfate and carbonic acid
The mixed aqueous solution of ammonia, is denoted as solution B；
2) solution B for obtaining step 1) is slowly dropped in solution A, adjusts the grain of rate of addition control calcium carbonate microspheres
Diameter, the reaction was continued after completion of dropwise addition 0.5-1 hours；
3) the mixed liquor high speed centrifugation for obtaining step 2), gained precipitating are washed with deionized for several times, and drying obtains more
The calcium carbonate microspheres of pore structure.
Optional further includes mixing active constituent with calcium carbonate microspheres, and preparation carries medicine calcium carbonate.
3. the preparation of the compound microballoon of Chitosan-Thiolated Polymers/calcium carbonate
(1) a certain concentration Chitosan-Thiolated Polymers aqueous solution is prepared, disperses above-mentioned aqueous solution for calcium carbonate or drug bearing microsphere
In；
(2) mixed solution that step (1) obtains is added drop-wise in isometric sodium tripolyphosphate solution, is slowly stirred 36-
40 hours；
(3) it after step (2) operation, stands, gained precipitating is washed with deionized for several times, and naturally dry obtains mercapto
Base chitosan/compound the microballoon of calcium carbonate.
The advantage of the present invention comprehensive Chitosan-Thiolated Polymers and porous calcium carbonate, it is compound to prepare Chitosan-Thiolated Polymers/calcium carbonate
Microballoon.Chitosan-Thiolated Polymers can improve the dissolubility and mucosa-adherent of chitosan.Calcium carbonate is compared to being usually used in bone tissue work
For hydroxyapatite in journey, have better degradability, meanwhile, with porous structure calcium carbonate be suitble to supported active at
Point.
Detailed description of the invention
Fig. 1 is compound microballoon scanning electron microscope (SEM) photo of Chitosan-Thiolated Polymers/calcium carbonate.Wherein, a is compound
The whole pattern of microballoon；B is the surface topography of compound microballoon；C and d is the cross-section morphology of compound microballoon, and white particle is in figure
Calcium carbonate microspheres.
Fig. 2 is the release profiles of drug model rhodamine B in the compound microballoon of Chitosan-Thiolated Polymers/calcium carbonate.
Specific embodiment
Embodiment 1: the preparation of the compound microballoon of molecular weight 5~100,000 Chitosan-Thiolated Polymers/calcium carbonate
1. the preparation of Chitosan-Thiolated Polymers
(1) it weighs and is dissolved in chitosan 400mg (molecular weight 5~100,000) in the aqueous acetic acid that volumetric concentration is 1%, make
It is continuously stirred 6 hours with blender, until chitosan is completely dissolved, solution is in clear state；
(2) it weighs 40mg 2- iminothiolane hydrochloride and is added in chitosan-acetic acid solution；Prepare the NaOH of 5mol/L
NaOH solution is added dropwise in solution in the above solution, until pH=6.Using tinfoil encapsulation reaction beaker, and use blender
It continuously stirs 24 hours；
(3) mixed liquor that step (2) obtains is placed in the bag filter that molecular cut off is 8000-14000, successively successively
Use 5mmol/L HCl solution, 5mmol/L HCl solution (NaCl that mass fraction is 1% is added), 5mmol/L HCl solution
(NaCl that mass fraction is 1% is added), 5mmol/L HCl solution and the dialysis of 1mmol/L HCl solution, dialysis 24 is small every time
When；
(4) it will be freezed in -20 DEG C of refrigerators of dialysis product that step (3) obtains, until liquid freezes completely.In vacuum freeze-drying
Machine freeze-drying, obtains molecular weight 5~100,000 Chitosan-Thiolated Polymers；
2. prepared by porous structure calcium carbonate
(1) the mixed aqueous solution 10ml for preparing carboxymethyl chitosan (10mg/ml) and calcium chloride (0.4mol/L), is denoted as molten
Liquid A prepares the mixed aqueous solution 10ml of chondroitin sulfate (20mg/ml) and carbonic acid ammonia (0.8mol/l), is denoted as solution B；
(2) solution B that step (1) obtains is slowly dropped in solution A, rate of addition 60ml/h, completion of dropwise addition is subsequent
Continuous reaction 0.5 hour；
(3) the mixing 10000rap/min for obtaining step (2) is centrifuged 5 minutes, and gained precipitating is washed with deionized 4
Secondary, drying obtains the calcium carbonate microspheres of 2 μm of average diameter or so of porous structure.
3. the preparation of the compound microballoon of Chitosan-Thiolated Polymers/calcium carbonate
(1) the tripolyphosphate sodium water solution that 400mL mass fraction is 10% is prepared.Preparing 10mL mass fraction is 2%
40mg calcium carbonate microspheres are added in Chitosan-Thiolated Polymers solution, are uniformly mixed solution using ultrasonic cell disruptor；
(2) 400mL sodium tripolyphosphate solution is at the uniform velocity stirred using magnetic stirring apparatus, Chitosan-Thiolated Polymers and carbon is added dropwise
The mixed solution of sour calcium microballoon persistently stirs 36 hours later, and control mixing speed guarantees that microballoon does not rupture；
(3) it after step (2) operation, stands, gained precipitating is washed with deionized 4 times, and naturally dry is averaged
500-600 μm of diameter of the compound microballoon of Chitosan-Thiolated Polymers/calcium carbonate.
Embodiment 2 carries the preparation of medicine Chitosan-Thiolated Polymers/calcium carbonate compound microballoon
(1) 0.01M rhodamine B 40ml (containing rhodamine B 191.6mg) solution is prepared, 400mg porous calcium carbonate is added,
It is protected from light, is slowly stirred 12h, measure drugloading rate.
(2) the tripolyphosphate sodium water solution that 1600mL mass fraction is 10% is prepared.Preparing 40mL mass fraction is 2%
Chitosan-Thiolated Polymers (molecular weight 5~100,000) solution is added 400mg calcium carbonate microspheres, is made using ultrasonic cell disruptor molten
Liquid is uniformly mixed.
(3) at the uniform velocity stir 1600mL sodium tripolyphosphate solution using magnetic stirring apparatus, be added dropwise Chitosan-Thiolated Polymers with
The mixed solution of calcium carbonate microspheres persistently stirs 36 hours later, and control mixing speed guarantees that microballoon does not rupture.
(4) it stands and pours out sodium tripolyphosphate solution after waiting microballoon precipitating, and it is micro- to use deionized water to wash gained repeatedly
Compound microballoon is placed in naturally dry in surface plate by ball.
Embodiment 3 carries the compound microballoon release test of medicine Chitosan-Thiolated Polymers/calcium carbonate
(1) load medicine Chitosan-Thiolated Polymers/compound microballoon of calcium carbonate obtained in 100mg embodiment 2 is weighed, 5mL phosphorus is added
In phthalate buffer, and it is added in bag filter.
(2) 95mL phosphorus will be placed in containing load medicine Chitosan-Thiolated Polymers/calcium carbonate compound microballoon bag filter in step (1)
In phthalate buffer, it is stirred continuously.
(3) in specific time, draw 5mL from the phosphate buffer in step (2), detection wherein rhodamine B it is dense
Degree, and calculate release rate.
Although the present invention has been described and illustrated herein with reference to the preferred embodiments thereof, for those skilled in the art
For member, the invention may be variously modified and varied.Various changes, variation and equivalent of the invention is by appended right
The content of claim covers.
Claims (10)
1. a kind of compound microballoon of Chitosan-Thiolated Polymers/calcium carbonate, skeleton with Chitosan-Thiolated Polymers and it is adsorbed on skeleton
Porous structure calcium carbonate granule.
2. compound microballoon according to claim 1, wherein the molecular weight of Chitosan-Thiolated Polymers skeleton is 50000-
100000；Preferably, the mass ratio of Chitosan-Thiolated Polymers and porous structure calcium carbonate granule is 10:1~5:1.
3. compound microballoon according to claim 1 or 2, the partial size of the compound microballoon of Chitosan-Thiolated Polymers/calcium carbonate is 500-
600μm。
4. a kind of purposes of compound microballoon of Chitosan-Thiolated Polymers/calcium carbonate as pharmaceutical carrier.
5. a kind of load medicine Chitosan-Thiolated Polymers/compound microballoon of calcium carbonate, it is also loaded on the complex microsphere described in claim 1-3
Active ingredient.
6. the preparation method of the described in any item compound microballoons of Chitosan-Thiolated Polymers/calcium carbonate of claim 1-3 and 5, packet
Include following steps:
I, Chitosan-Thiolated Polymers are prepared；
Ii, it prepares porous structure calcium carbonate granule or carries medicine calcium carbonate granule；
Iii, the combination compound microballoon of Chitosan-Thiolated Polymers/calcium carbonate.
7. preparation method according to claim 6, Chitosan-Thiolated Polymers the preparation method comprises the following steps:
I-1) chitosan is dissolved in acidic aqueous solution, obtains chitosan acid solution；Preferably, chitosan and acidic aqueous solution
Mass volume ratio concentration is 1-2mg/mL, and the acidic aqueous solution is aqueous acetic acid；
I-2) in the chitosan acid solution for obtaining 2- iminothiolane hydrochloride addition step i-1)；Adjusting pH is 4-6, reaction
To complete；
I-3 the liquid dialysis for) obtaining step i-2) removes unreacted 2- iminothiolane hydrochloride, it is preferable that described
Analysis select to shut off molecular weight for 8000-14000 bag filter；
I-4) the dialysis product for obtaining step i-3) is lyophilized, and obtains Chitosan-Thiolated Polymers.
8. preparation method according to claim 6, the step of preparing porous structure calcium carbonate granule are as follows:
Ii-1 the mixed aqueous solution for) preparing carboxymethyl chitosan and calcium chloride, is denoted as solution A, prepares chondroitin sulfate and carbonic acid
The mixed aqueous solution of ammonia, is denoted as solution B；
Ii-2) solution B is slowly dropped in solution A, the reaction was continued after completion of dropwise addition to complete；
Ii-3) the mixed liquor high speed centrifugation for obtaining step ii-2), gained precipitating are washed with deionized for several times, and drying obtains
The calcium carbonate granule of porous structure；
Optionally, further include step ii-4) calcium carbonate granule of porous structure is mixed with active ingredient solution, it is made and carries
Medicine calcium carbonate granule.
9. preparation method according to claim 6, the method for combining the compound microballoon of Chitosan-Thiolated Polymers/calcium carbonate are as follows:
Iii-1 Chitosan-Thiolated Polymers aqueous solution) is prepared, disperses calcium carbonate granule or load medicine calcium carbonate granule in sulfhydrylation shell and gather
In sugar aqueous solution；
Iii-2) the obtained mixed solution of step iii-1) is added drop-wise in the sodium tripolyphosphate solution of certain volume, tripolyphosphate
Sodium solution is 100:1~10:1 with the obtained mixed liquor volume ratio of step iii-1), is slowly stirred 36-40 hours；
Iii-3 dry after) standing, obtain the compound microballoon of Chitosan-Thiolated Polymers/calcium carbonate.
10. according to the described in any item preparation methods of claim 6-9, wherein Chitosan-Thiolated Polymers and porous structure calcium carbonate
Particle or the mass ratio for carrying medicine calcium carbonate granule are 10:1~5:1.
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Cited By (4)
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| CN109970040A (en) * | 2019-05-08 | 2019-07-05 | 贵州大学 | A method of mesoporous carbon is prepared by carbon nitrogen source double-driving force of chitosan |
| CN112007619A (en) * | 2020-08-28 | 2020-12-01 | 玉林师范学院 | Chitosan calcium carbonate composite adsorbent for adsorption and preparation method thereof |
| CN113274547A (en) * | 2021-04-16 | 2021-08-20 | 西安理工大学 | Preparation method of pH response type organic-inorganic composite bone cement |
| CN114432503A (en) * | 2022-04-12 | 2022-05-06 | 北京大学口腔医学院 | Drug-loaded bone repair material and preparation method and application thereof |
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| CN112007619B (en) * | 2020-08-28 | 2023-03-31 | 玉林师范学院 | Chitosan calcium carbonate composite adsorbent for adsorption and preparation method thereof |
| CN113274547A (en) * | 2021-04-16 | 2021-08-20 | 西安理工大学 | Preparation method of pH response type organic-inorganic composite bone cement |
| CN114432503A (en) * | 2022-04-12 | 2022-05-06 | 北京大学口腔医学院 | Drug-loaded bone repair material and preparation method and application thereof |
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