CN110063939A - Shock wave mediates the hollow hydroxyapatite of release to carry medicine particle and preparation method thereof - Google Patents
Shock wave mediates the hollow hydroxyapatite of release to carry medicine particle and preparation method thereof Download PDFInfo
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Abstract
The invention discloses a kind of shock waves, and the hollow hydroxyapatite of release to be mediated to carry medicine particle, the load medicine 150~220nm of grain diameter, 5~10nm of wall thickness.The load medicine preparation method of granules is also disclosed, including prepares Tris aqueous slkali, PEG and drug are added thereto, dissolves and Tween80 and Triton-100 solution is added dropwise in sequence again, stir 20~60min, form non-ionic surface active vesicle solution；Reaction solution is squeezed using sieve film, is ultrasonically formed hydroxyapatite hollow template solution；The solution is placed in nitrogen environment again, slowly alternately adds CaCl2And Na2HPO4Solution, centrifugation, washing precipitating are dried in vacuo to get required nano particle.Load medicine particle homogeneity produced by the present invention is good, and sphere wall is thin and good rigidity, is easy to occur under the adaptation energy effect with biological effect that shell is broken, and realization is released effectively drug, improves bone local drug concentration.
Description
Technical field
The present invention relates to hydroxyapatite nanoparticle technical fields, and the sky of release is mediated more particularly to a kind of shock wave
Heart hydroxyapatite carries medicine particle and preparation method thereof.
Background technique
With the universal aging of population, osteoporosis is the emerging public health problem an of global concern.For
The local treatment strategy in the specific bone region easily fractured potentially contributes to reduce the incidence of osteoporotic fracture.It is minimally invasive
The development that (IO) is injected in CT Guided Percutaneous is so that the Local delivery on specific objective bone can be used for preventing or treating sclerotin
Osteoporotic fractures, so IO approach is widely studied as the alternative solution of intravenous route.
The chemical component and crystal structure of hydroxyapatite and human body hard tissue are very much like, have unique bioactivity
And biocompatibility, and hollow hydroxyapatite has the advantages that greatly improve drugloading rate, is widely used in organizational project, bone
Reparation and substitution and dental material etc. in.[Xianyan Yang, the et al.Intra-bone marrow such as Yang
injection of trace elements co-doped calcium phosphate microparticles for the
treatment of osteoporotic rat.[J].J Biomed Mater Res A.2017 105(5):1422-
1432.] hydroxyapatite local delivery to the pulp cavity for adulterating microelement is achieved the purpose that treat osteoporosis.But
It after hydroxyapatite enters pulp cavity as pharmaceutical carrier, is influenced by organismic internal environment, the drug locally discharged becomes
Property or release be subject to certain restrictions, to reduce local drug concentration, expected effect is not achieved.
Foreign scholar has found that ultrasonic wave can mediate the targeted drug release rate of nano-carrier to improve, to make malignant tumour office
Portion reaches satisfied blood concentration.External knock wave (extracorporeal shock wave, ESW) is also that one kind can be transmitted
The sound wave of energy, and there are more characteristics compared with ultrasonic wave, machine is acted on by its mechanical effect, cavitation effect and fuel factor
Body achieves good curative effect in treatment caput femoris necrosis, bone nonunion, osteoporosis diseases.But applicant's early period is dynamic
Object is outer it was found that, when using extracorporeal shock wave energy to mediate the hollow hydroxyl phosphorus being prepared according to existing preparation method
Lime stone nano particle (preparation method as disclosed in existing patent application 200710067822.1) is when bone locally discharges, to bone
Suitable energy with biological effect can not be such that hollow hydroxyapatite nanoparticle ruptures, and discharge the zoledronic acid medicine of package
Object cannot then reach satisfied treatment and preventive effect.
It can be seen that hollow hydroxyapatite nanoparticle of above-mentioned existing load medicine and preparation method thereof is in structure, method
On using, it is clear that there are still there is inconvenient and defect, and need to be further improved.How a kind of new shock wave is founded
It mediates the hollow hydroxyapatite of release to carry medicine particle and preparation method thereof, can realize bone group under shock wave mediates in vitro
The release for knitting interior drug meets local drug concentration demand, obtains promising result, real to belong to one of current important research and development project.
Summary of the invention
The technical problem to be solved in the present invention is to provide a kind of shock waves, and the hollow hydroxyapatite of release to be mediated to carry medicine
Grain can mediate the lower release for realizing drug in bone tissue by shock wave in vitro, meet local drug concentration demand, obtain full
Meaning effect, to overcome the shortcomings of the hollow hydroxyapatite nanoparticle of existing load medicine.
In order to solve the above technical problems, the hollow hydroxyapatite that the present invention provides a kind of shock wave mediation release carries medicine
Grain, the spherical partial size that the hollow hydroxyapatite carries medicine particle is 150~220nm, the spherical shell body wall of the nano particle
Thickness is 5~10nm.
As an improvement of the present invention, the hollow hydroxyapatite carry the spherical partial size of medicine particle be 170~
200nm, the spherical shell wall thickness of the nano particle are 6~9nm.
The present invention also provides a kind of shock waves, and the hollow hydroxyapatite of release to be mediated to carry the preparation method of medicine particle, described
Preparation method includes the following steps:
(1) Tris solution is prepared, adjusting pH is 11~12, forms A liquid.
(2) polyethylene glycol and water soluble drug are added in Xiang Suoshu A liquid, stirring is to being completely dissolved, and while agitating
Tween80 and Triton-100 solution is slowly added dropwise in sequence, and 20~60min of magnetic agitation forms B liquid, that is, contains packaging medicine
Non-ionic surface active vesica solution；The effect of Triton-100 solution is to keep the non-ionic surface to be formed living in the step
Property vesica rigidity increase, the hydroxyapatite being conveniently subsequently formed the vesicle surface precipitate.
(3) the B liquid is squeezed using the sieve film that sieve diameter is 200nm, is allowed to form the capsule of uniform size
Bubble collects the liquid for squeezing film, and places it in 5~15min of ultrasound in Ultrasound Instrument, forms C liquid, that is, contains certain partial size
Hydroxyapatite hollow template solution.
(4) the C liquid is transferred in neck round bottom flask, under the conditions of magnetic agitation, is continued from side flask neck mouth
It is passed through nitrogen, so that flask interior is formed nitrogen environment, is then slowly alternately added CaCl2Solution and Na2HPO4Solution, and make
The molar ratio of Ca/P is 1~1.67, forms D liquid.
(5) it takes the D liquid to be centrifuged, washs precipitating with deionized water and dehydrated alcohol, then be dried in vacuo to obtained precipitating,
It collects and carries medicine particle up to the hollow hydroxyapatite.
It is further improved, the concentration of Tris solution is 0.1~0.5M in the step (1), and pH value, which is adjusted, to be used
0.1NNaOH solution.
It is further improved, the step (2) specifically: the polyethylene glycol of 0.15~0.2g is added into A liquid described in 5ml
4000 and water soluble drug, it stirs in lesser trochanter and is completely dissolved down toward the Macrogol 4000, and sequence while agitating
The 1%Triton-100 solution of 1.5~2gTween80 and 2ml is slowly added dropwise, 20~60min of magnetic agitation forms B liquid.
It is further improved, the ultrasound condition of Ultrasound Instrument is 40KHz, 100W in the step (3)；The sieve film is poly- carbon
Acid esters film.
It is further improved, the step (4) specifically: the C liquid is transferred to the double-necked round bottom containing A liquid described in 50ml
In flask, under the conditions of magnetic agitation, from side, flask neck mouth is continually fed into nitrogen, so that flask interior is formed nitrogen environment, so
It is slowly added to the CaCl of 1ml0.1~0.5M afterwards2Solution continues after stirring 10min, is slowly added to 1ml0.1~0.8M's
Na2HPO4Solution continues after stirring 10min, is slowly added to CaCl described in 1ml again2Solution continues after stirring 8min, slowly
Na described in 1ml is added2HPO4Solution continues after stirring 8min, repeatedly, after repeating the mixing time between the solution of addition
2min, the CaCl to be added are once once reduced earlier above2Solution and Na2HPO4When solution total amount respectively reaches 5ml, stop
It is added dropwise, continues 2~12h of stirring, form D liquid.The step can guarantee that the hydroxyapatite being deposited on vesicle surface is uniform, finally
Form the spherical shell of very thin thickness.
It is further improved, the condition of magnetic agitation is 100rpm in the step (4), wherein being slowly added to the CaCl2
Solution and Na2HPO4The speed of solution is 1 drop/sec.
It is further improved, D liquid deionized water described in the step (5) and dehydrated alcohol wash precipitating 3 times, then 35
It is dried overnight, collects in~40 DEG C of vacuum ovens, be stored at room temperature the hollow hydroxyapatite and carry medicine particle.
It is further improved, the water soluble drug is Zoledronic Acid, Alendronate sodium, etidronate, Risedronic Acid
Sodium or ibandronate.
By adopting such a design, the present invention has at least the following advantages:
1, preparation method of the present invention by into Tris aqueous slkali be added polyethylene glycol and nonionic surface active agent it is molten
Liquid is initially formed the non-ionic surface active vesicle solution containing packaging medicine, then by sieving pressing steps, makes to be formed uniform big
Small vesica, then by a nitrogen environment, being slowly alternately added CaCl2Solution and Na2HPO4Solution guarantees hydroxyl phosphorus
Lime stone is uniformly deposited on vesicle surface, and the shock wave for ultimately forming very thin thickness mediates the hollow hydroxyapatite of release to carry medicine
Particle meets the effect that drug is released effectively under external knock wave mediates.
2, by using Triton-100 solution in preparation method of the present invention, make the non-ionic surface active vesica to be formed
Rigidity increases, and the hydroxyapatite being conveniently subsequently formed is precipitated in the vesicle surface.
3, spherical hollow hydroxyapatite made from preparation method of the present invention carry medicine particle diameter 150~200nm it
Between, uniformity is good, and the spherical shell wall good rigidity of nano particle, and wall thickness is 5~10nm, is allowed to suitable with biological effect
It is easy to happen the broken of shell under suitable shock wave energy effect, bone local drug concentration is improved, meets the mesh for preventing and treating disease
's.
Detailed description of the invention
The above is merely an overview of the technical solutions of the present invention, in order to better understand the technical means of the present invention, below
In conjunction with attached drawing, the present invention is described in further detail with specific embodiment.
Fig. 1 is the grain size distribution that the hollow hydroxyapatite that the present invention is prepared carries medicine particle.
Fig. 2 is the high power scanning electron microscope (SEM) photograph that the hollow hydroxyapatite that the present invention is prepared carries medicine particle, and wherein 2a is
120 times of scanning electron microscope (SEM) photographs, 2b are 300 times of scanning electron microscope (SEM) photographs.
Fig. 3 is the high power transmission electron microscope picture that the hollow hydroxyapatite that the present invention is prepared carries medicine particle.
Fig. 4 is that the high power under the hollow hydroxyapatite that is prepared of the present invention carries medicine particle shock wave mediates in vitro is swept
Electron microscope is retouched, it is electron microscope under 0bar mediated conditions that wherein 4a, which is external knock wave, and 4b is that external knock wave is that 2bar mediates item
Electron microscope under part, 4c are that external knock wave is electron microscope under 3bar mediated conditions.
Fig. 5 is the obtained hollow ball-shape hydroxyapatite nanoparticle of prior art preparation under shock wave mediates in vitro
High power scanning electron microscope (SEM) photograph, it is electron microscope under 0bar mediated conditions that wherein 5a, which is external knock wave, and 5b is that external knock wave is 2bar
Electron microscope under mediated conditions, 5c are that external knock wave is electron microscope under 3bar mediated conditions.
Specific embodiment
Embodiment 1
0.1MTris solution is prepared, pH is adjusted between 11~12 using 0.1NNaOH solution, forms A liquid.
0.15gPEG4000,0.5M Zoledronic Acid are dissolved in the A liquid of 5ml, are put into lesser trochanter in the stirring of 200rpm
Under, until PEG4000 is completely dissolved, then sequence instills the 1%Triton-100 solution of 1.5gTween80 solution and 2ml,
20min is stirred under 100rpm magnetic agitation, forms B liquid.
B liquid is squeezed using 200nm polycarbonate membrane, collects the liquid squeezed out, places it in Ultrasound Instrument (ultrasound
Condition are as follows: 40KHz, 100W) in ultrasound 5min, synthesize the hydroxyapatite hollow template of certain partial size and uniform particle diameter, form C
Liquid.
C liquid is all transferred in the neck round bottom flask containing 50mlA liquid, under the conditions of 100rpm magnetic agitation, from
Side flask neck mouth is continually fed into nitrogen, and flask interior is made to form nitrogen environment.Then (1 drop/sec) is slowly added dropwise
1ml0.1MCaCl21ml0.1MNa is slowly added dropwise after 100rpm stirs 10min in solution2HPO4Solution, 100rpm continue to stir
After 10min, 1ml0.1MCaCl is slowly added dropwise again21ml0.1MNa is slowly added dropwise after stirring 8min in solution2HPO4Solution, such as
This is repeatedly.Addition repeats primary reduction 2min primary earlier above after the mixing time between solution, CaCl in reaction system to be added2
Solution and Na2HPO4When solution total amount respectively reaches 5ml, stop being added dropwise, and 100rpm continues to stir 2h.Later to reaction solution from
The heart washs precipitating 3 times with deionized water and dehydrated alcohol, is dried overnight in 35 DEG C of vacuum ovens, collection obtains hollow hydroxyl
Base apatite carries medicine particle 1, is stored at room temperature.
Embodiment 2
0.5MTris solution is prepared, pH is adjusted between 11~12 using 0.1NNaOH solution, forms A liquid.
0.2gPEG4000,0.5M Alendronate sodium are dissolved in the A liquid of 5ml, are put into lesser trochanter in the stirring of 200rpm
Under, until PEG4000 is completely dissolved, then sequence instills the 1%Triton-100 solution of 2gTween80 solution and 2ml,
60min is stirred under 100rpm magnetic agitation, forms B liquid.
B liquid is squeezed using 200nm polycarbonate membrane, collects the liquid squeezed out, places it in Ultrasound Instrument (ultrasound
Condition are as follows: 40KHz, 100W) in ultrasound 15min, synthesize the hydroxyapatite hollow template of certain partial size and uniform particle diameter, formed
C liquid.
C liquid is all transferred in the neck round bottom flask containing 50mlA liquid, under the conditions of 100rpm magnetic agitation, from
Side flask neck mouth is continually fed into nitrogen, and flask interior is made to form nitrogen environment.Then (1 drop/sec) is slowly added dropwise
1ml0.5MCaCl21ml0.5MNa is slowly added dropwise after 100rpm stirs 10min in solution2HPO4Solution, 100rpm continue to stir
After 10min, 1ml0.5MCaCl is slowly added dropwise again21ml0.5MNa is slowly added dropwise after stirring 8min in solution2HPO4Solution, such as
This is repeatedly.Addition repeats primary reduction 2min primary earlier above after the mixing time between solution, CaCl in reaction system to be added2
Solution and Na2HPO4When solution total amount respectively reaches 5ml, stop being added dropwise, and 100rpm continues to stir 12h.Later to reaction solution
Centrifugation is washed precipitating 3 times with deionized water and dehydrated alcohol, is dried overnight in 40 DEG C of vacuum ovens, collection obtains hollow
Hydroxyapatite carries medicine particle 2, is stored at room temperature.
Embodiment 3
0.3MTris solution is prepared, pH is adjusted between 11~12 using 0.1NNaOH solution, forms A liquid.
0.2gPEG4000,0.5M etidronate are dissolved in the A liquid of 5ml, are put into lesser trochanter in the stirring of 200rpm
Under, until PEG4000 is completely dissolved, then sequence instills the 1%Triton-100 solution of 1.5gTween80 solution and 2ml,
50min is stirred under 100rpm magnetic agitation, forms B liquid.
B liquid is squeezed using 200nm polycarbonate membrane, collects the liquid squeezed out, places it in Ultrasound Instrument (ultrasound
Condition are as follows: 40KHz, 100W) in ultrasound 10min, synthesize the hydroxyapatite hollow template of certain partial size and uniform particle diameter, formed
C liquid.
C liquid is all transferred in the neck round bottom flask containing 50mlA liquid, under the conditions of 100rpm magnetic agitation, from
Side flask neck mouth is continually fed into nitrogen, and flask interior is made to form nitrogen environment.Then (1 drop/sec) is slowly added dropwise
1ml0.4MCaCl21ml0.25MNa is slowly added dropwise after 100rpm stirs 10min in solution2HPO4Solution, 100rpm continue to stir
After 10min, 1ml0.4MCaCl is slowly added dropwise again21ml0.25MNa is slowly added dropwise after stirring 8min in solution2HPO4Solution,
Repeatedly.Addition repeat it is primary after the mixing time between solution once reduce 2min earlier above, in reaction system to be added
CaCl2Solution and Na2HPO4When solution total amount respectively reaches 5ml, stop being added dropwise, and 100rpm continues to stir 10h.Later to anti-
It answers liquid to be centrifuged, washs precipitating 3 times with deionized water and dehydrated alcohol, be dried overnight in 35 DEG C of vacuum ovens, collection obtains
Hollow hydroxyapatite carries medicine particle 3, is stored at room temperature.
Acetonideexample
Medicine particle 1,2,3 is carried to the hollow hydroxyapatite that above three embodiments obtain and carries out granularity Detection, as a result such as
Shown in attached drawing 1, the hollow hydroxyapatite which obtains carries medicine grain diameter and concentrates within the scope of 150~220nm, compared with
Excellent is 170~200nm, and size is close, and homogeneity is good, as shown in Fig. 2.
Medicine particle 1,2,3 is carried by the hollow hydroxyapatite obtained to above three embodiments again and carries out high power transmission electricity
Mirror analysis, it can be seen that the hollow hydroxyapatite carries spherical shell wall thickness about 5~10nm of medicine particle, and more excellent is 6~9nm.
Comparative example
The hollow hydroxyapatite that above three embodiments are obtained carries medicine particle 1,2,3, and uses existing preparation method
The hollow hydroxyapatite nanoparticle (preparation method as disclosed in existing patent application 200710067822.1) being prepared
The morphological analysis of nano particle after progress external knock wave intervention mediation, referring to attached Figure 4 and 5.Fig. 4 is that the present invention is prepared
Hollow hydroxyapatite carry medicine particle shock wave mediate in vitro under high power scanning electron microscope (SEM) photograph, Fig. 5 is that prior art preparation obtains
High power scanning electron microscope (SEM) photograph of the hollow ball-shape hydroxyapatite nanoparticle arrived under shock wave mediates in vitro, a is body in figure
Combined use of ESWL is electron microscope under 0bar mediated conditions, and b is that external knock wave is electron microscope under 2bar mediated conditions, and c is body
Combined use of ESWL is electron microscope under 3bar mediated conditions.
Can be seen that from attached Figure 4 and 5, shock wave is under 2bar, 3bar mediated conditions in vitro, two kinds of nano particles it is broken
Degree completes difference, and the hollow hydroxyapatite that the present invention is prepared carries medicine particle and mediates release suitable for external knock wave
Drug, is able to achieve good broken, realizes and is released effectively to spherical contained drug.
To sum up, the hollow hydroxyapatite of release is mediated to carry medicine for shock wave using what the application preparation method obtained
Sphericity is good for grain, homogeneity is good, and sphere wall is thin and good rigidity, is easy to issue in the adaptation energy effect with biological effect
Raw shell is broken, and realization is released effectively drug, improves the purpose of bone local drug concentration.
The above described is only a preferred embodiment of the present invention, be not intended to limit the present invention in any form, this
Field technical staff makes a little simple modification, equivalent variations or modification using the technology contents of the disclosure above, all falls within this hair
In bright protection scope.
Claims (10)
1. a kind of shock wave mediates the hollow hydroxyapatite of release to carry medicine particle, which is characterized in that the hollow hydroxy-apatite
The spherical partial size that stone carries medicine particle is 150~220nm, and the spherical shell wall thickness of the nano particle is 5~10nm.
2. hollow hydroxyapatite according to claim 1 carries medicine particle, which is characterized in that the hollow hydroxyapatite
The spherical partial size for carrying medicine particle is 170~200nm, and the spherical shell wall thickness of the nano particle is 6~9nm.
3. the preparation method that a kind of shock wave mediates the hollow hydroxyapatite load medicine particle of release, which is characterized in that the system
Preparation Method includes the following steps:
(1) Tris solution is prepared, adjusting pH is 11~12, forms A liquid；
(2) polyethylene glycol and water soluble drug are added in Xiang Suoshu A liquid, stirring is to being completely dissolved, and sequence while agitating
Tween80 and Triton-100 solution is slowly added dropwise, 20~60min of magnetic agitation forms B liquid, i.e., containing the non-of packaging medicine
The solution of ion surface active vesica；
(3) the B liquid is squeezed using the sieve film that sieve diameter is 200nm, collects and squeezed the liquid of film, and by its
It is placed in 5~15min of ultrasound in Ultrasound Instrument, forms C liquid, the i.e. solution of the hydroxyapatite hollow template containing certain partial size；
(4) the C liquid is transferred in neck round bottom flask, under the conditions of magnetic agitation, from side, flask neck mouth is continually fed into
Nitrogen makes flask interior form nitrogen environment, is then slowly alternately added CaCl2Solution and Na2HPO4Solution, and make Ca/P's
Molar ratio is 1~1.67, forms D liquid；
(5) it takes the D liquid to be centrifuged, washs precipitating with deionized water and dehydrated alcohol, then be dried in vacuo to obtained precipitating, collect
Medicine particle is carried up to the hollow hydroxyapatite.
4. the preparation method that hollow hydroxyapatite according to claim 3 carries medicine particle, which is characterized in that the step
(1) concentration of Tris solution is 0.1~0.5M in, and pH value adjusts the NaOH solution for using 0.1N.
5. the preparation method that hollow hydroxyapatite according to claim 4 carries medicine particle, which is characterized in that the step
(2) specifically: the Macrogol 4000 and water soluble drug of 0.15~0.2g are added into A liquid described in 5ml, is stirred in lesser trochanter
It is completely dissolved down toward the Macrogol 4000, and is sequentially slowly added dropwise 1.5~2gTween80's and 2ml while agitating
1%Triton-100 solution, 20~60min of magnetic agitation form B liquid.
6. the preparation method that hollow hydroxyapatite according to claim 5 carries medicine particle, which is characterized in that the step
(3) ultrasound condition of Ultrasound Instrument is 40KHz, 100W in；The sieve film is polycarbonate membrane.
7. the preparation method that hollow hydroxyapatite according to claim 5 carries medicine particle, which is characterized in that the step
(4) specifically: the C liquid is transferred to containing in the neck round bottom flask of A liquid described in 50ml, under the conditions of magnetic agitation, from
Side flask neck mouth is continually fed into nitrogen, so that flask interior is formed nitrogen environment, is then slowly added into 1ml0.1~0.5M's
CaCl2Solution continues after stirring 10min, is slowly added to the Na of 1ml0.1~0.8M2HPO4Solution continues after stirring 10min, then
It is secondary to be slowly added to CaCl described in 1ml2Solution continues after stirring 8min, is slowly added to Na described in 1ml2HPO4Solution continues to stir
After 8min, repeatedly, repeat once once to reduce 2min earlier above after adding the mixing time between solution, to be added is described
CaCl2Solution and Na2HPO4When solution total amount respectively reaches 5ml, stops being added dropwise, continue 2~12h of stirring, form D liquid.
8. the preparation method that hollow hydroxyapatite according to claim 7 carries medicine particle, which is characterized in that the step
(4) condition of magnetic agitation is 100rpm in, wherein being slowly added to the CaCl2Solution and Na2HPO4The speed of solution be 1 drop/
Second.
9. the preparation method that hollow hydroxyapatite according to claim 7 carries medicine particle, which is characterized in that the step
(5) deionized water of D liquid described in and dehydrated alcohol wash precipitating 3 times, then are dried overnight in 35~40 DEG C of vacuum ovens,
It collects, is stored at room temperature the hollow hydroxyapatite and carries medicine particle.
10. the preparation method that hollow hydroxyapatite according to claim 3 carries medicine particle, which is characterized in that the water
Soluble drug is Zoledronic Acid, Alendronate sodium, etidronate, risedronate sodium or ibandronate.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111870616A (en) * | 2020-05-15 | 2020-11-03 | 吴宏伟 | Composite nano particle for targeted inhibition of bone tumor and preparation method thereof |
| CN112675130A (en) * | 2020-12-29 | 2021-04-20 | 中国人民解放军总医院第三医学中心 | Application of hollow nano-particles in preparation of osteoporosis treatment drug |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN111870616A (en) * | 2020-05-15 | 2020-11-03 | 吴宏伟 | Composite nano particle for targeted inhibition of bone tumor and preparation method thereof |
| CN112675130A (en) * | 2020-12-29 | 2021-04-20 | 中国人民解放军总医院第三医学中心 | Application of hollow nano-particles in preparation of osteoporosis treatment drug |
| CN112675130B (en) * | 2020-12-29 | 2023-04-25 | 中国人民解放军总医院第三医学中心 | Application of hollow nano particles in preparation of osteoporosis treatment medicine |
| CN114642772A (en) * | 2022-04-13 | 2022-06-21 | 湖南师范大学 | Tragacanth/chitosan/hybrid nano apatite ternary composite porous material and preparation method thereof |
| CN114642772B (en) * | 2022-04-13 | 2023-01-06 | 湖南师范大学 | Tragacanth/chitosan/hybrid nano apatite ternary composite porous material and preparation method thereof |
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