CN107158473A - A kind of calcium phosphate bone cement for embedding load medicine silica nodule and its preparation method and application - Google Patents
A kind of calcium phosphate bone cement for embedding load medicine silica nodule and its preparation method and application Download PDFInfo
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Abstract
A kind of calcium phosphate bone cement for embedding load medicine silica nodule and its preparation method and application.Self-curing component and the nano material heated are mixed the present invention relates to a kind of life, modified bone cement solid phase powder is obtained, wherein alpha tricalcium phosphates material parcel delivery effect, taxol@silica nodules play a part of anticancer；Based on sodium phosphate, using phosphonized chitosan, hydroxypropyl methyl cellulose, gelatin as modifying agent, neutral bone cement solidify liquid is prepared, formula syringeability is improved；Bone cement solid phase powder is mixed with solidify liquid, cured product main component hydroxyapatite is added, taxol@silica nodules have good degradation capability in vivo.Method is easy, raw materials used simple, suitable for a large amount of productions.Newly formula improves the biocompatibility of green bone cement to the load medicine developed, and by adding the taxol@silica nodules with heat-therapeutic action, the silica nodule calcium phosphate bone cement syringeability that embedding carries medicine increases.
Description
Technical field
The present invention relates to a kind of method of biology medical material technical field, more particularly to a kind of embedding carries medicine silica nodule
Calcium phosphate bone cement and its preparation method and application.
Technical background
Bone tumour (bone tumor) is the tumour for betiding bone or its affiliated group's (blood vessel, nerve, marrow etc.), is
Common disease.With as the other tissues of body, its definite etiology unknown.Tumour is divided into benign tumour and malignant tumour.Benign tumour
Easily remove totally, do not shift typically, do not recur, to organ, tissue only extruding, blocking action；Malignant tumour destruction tissue,
The 26S Proteasome Structure and Function of organ, downright bad bleeding and infects, seriously threatens human life together.Bone tumour or tumor-like lesion are scraped with performing the operation
Based on removing or cutting off.Tumor operation makes every effort to thorough, in case recurrence or cause after canceration, surgery excision is repaiied with filling artificial synthesis bone
Multiple material is filled and treated.Although operation can quickly cut off primary lesion, but if excision is not clean, cancer cell can also
Continue to spread, but chemotherapeutics such as taxol, doxorubicin hydrochloride, daunorubicin, vincristine etc. are in healing patient or substantially
Extend useful effect in terms of patient vitals, but also have sizable toxic side effect to human normal cell.By anti-cancer drug preparation
Change reduction toxic side effect to become as research emphasis.
Silica nodule drug carrier material, that is, pass through sol/gel method and a kind of new delivery material of self assembling process formation
Si content is less than the silica network structure that one layer of atomic thickness is formed in 4%, lipid layer in material, silica nodule, adds stabilization
Property, solve the problem of stability is poor.As liposome, silica nodule has bilayer lipid membrane imitated vesicle structure, biocompatibility
It is good, and can be biodegradable, it will not remain in vivo.It can not only embed hydrophily, lipophilic medicament, or even also
Can amphipathic medicine.By the use of silica nodule as pharmaceutical carrier can convey small molecule anticancer drug, pharmaceutical grade protein, gene and
The material of the various difference in functionalitys such as magnetic-particle, so as to realize the joint of multi-medicament or multiple therapy methods, makes and examines
Disconnected cancer and the powerful for killing cancer cell.It is controllable to contain medicine by regulating and controlling silica nodule surface Si-O-Si condensation degree
Rate of release.Research has shown that, with the increase of Si-O-Si condensation degrees, drug release rate reduction.
The present invention combines medicine silica nodule embedding techniques and syringeability inorganic calcium phosphate bone cement material and is combined, can be
Formed with artificial bone, silica nodule medicine is fixed on inside artificial bone after alpha- Hydration of Tricalcium Phosphate, medicine after internal injection
Slowly it can be discharged and be degraded with the progressively degraded of shell again, and then be safely metabolized out external.
The content of the invention
To overcome the deficiencies in the prior art, the present invention provides a kind of preparation side for embedding and carrying medicine silica nodule calcium phosphate bone cement
Method.
The purpose of the present invention is achieved through the following technical solutions,：
It is a kind of to embed the preparation method for carrying medicine silica nodule calcium phosphate bone cement, it is characterised in that to comprise the steps of：
（1）Self-curing component and the nano material heated are mixed, modified bone cement solid phase powder, wherein alpha- phosphorus is obtained
Sour three calcium materials parcel delivery effect, taxol silica nodule plays a part of anticancer；
（2）Based on sodium phosphate, using phosphonized chitosan, hydroxypropyl methyl cellulose, gelatin as modifying agent, neutral bone is prepared
Cement solidification liquid, improves formula syringeability；
（3）Bone cement solid phase powder is mixed with solidify liquid, cured product main component hydroxyapatite, taxol@is added
Silica nodule has good degradation capability in vivo.
Step（2）The mass fraction of sodium phosphate is 10-20%, the quality point of phosphonized chitosan in described phosphoric acid solution
Number is 0.01-1%, and the mass fraction of hydroxypropyl methyl cellulose is 0.01-1%, and the mass fraction of gelatin is 0.01-1%；Prepare
Mode is room-temperature dissolution or less than 60 DEG C heating hydrotropies, can also be aided with mechanical agitation or magnetic agitation.
Step（1）Described taxol@silica nodules mass fraction is 0.1-1%.
Alpha- tricalcium phosphates particle diameter is 15-100nm, and taxol@silica nodules are 100-200nm；Hybrid mode is to use
Powder is fully ground by agate mortar in dry environment.
Comprise the following steps that：
（1）The preparation of silica nodule raw material：
Cetylamine and alcohol solvent are added in three-necked bottle, the bromohexadecane of 1/2 mole is fully added after dissolving, addition is urged
Stop reaction after agent natrium carbonicum calcinatum, backflow 120h, double cetylamines are refining to obtain repeatedly；By double cetylamines and butanedioic acid
Acid anhydride is added in dry tetrahydrofuran, fully reacts 24h, is concentrated, successively with 10% citric acid and saturation chlorination after being dissolved with chloroform
Sodium point liquid washing, crude product is obtained after solvent evaporation, then refined with recrystallized from acetonitrile；Product after refined is in 1- (3- diformazan ammonia
Base propyl group) -3- ethyl-carbodiimide hydrochlorides（EDC）Under catalysis, react, prepare siliceous with aminopropyl triethoxysilane
Body coarse raw materials, column chromatography is refining to obtain the smart raw material of silica nodule；
（2）Carry the preparation of paclitaxel silicon plastid：
By step（1）In obtained component dissolved with chloroform, rotary evaporation removes solvent, adds water solution into lipid film, ultrasound
Disperse and in 60 DEG C of rotation concussions of water-bath, obtain suspension；The carbonic acid adipose membrane of 50nm pore sizes was extruded, particle size is obtained equal
Even silica nodule；When carrying medicine, each component chloroform is dissolved, rotary evaporation removes solvent, adds the medicines such as taxol, adds water
Solution is into lipid film, and ultrasonic disperse simultaneously shakes in 60 DEG C of rotations of water-bath, obtains suspension, extruded the carbonic acid of 50nm pore sizes
Adipose membrane, obtains carrying the uniform targeting silica nodule of Types of Medicine particle size, and obtain solid state powder using freeze-drying；
（3）The preparation of drug carrier silica nodule bone cement：
Prepare mass fraction be 10% sodium dihydrogen phosphate, manner of formulation can be room-temperature dissolution or ultrasonic dissolution assisting, can be with auxiliary
With mechanical agitation or magnetic agitation；
Phosphonized chitosan is added into the solution according to solidification formula of liquid, the phosphorylation that mass fraction is 0.01-1% is configured to
Chitosan solution；
Hydroxypropyl methyl cellulose, gelatin are added into sodium phosphate-phosphoric acid chitosan solution according to solidification formula of liquid, is obtained most
Whole mass fraction is 0.01-1% hydroxypropyl methyl cellulose and 0.01-1% gelatin modified solidify liquid；
By calcium sulfate bone cement and step（2）Obtained load paclitaxel silicon plastid is with mass ratio 1000:1、 500:1、 200：1
Or 100:1 mixing, hybrid mode is to be fully ground in dry environment powder using agate mortar；
Bone cement powder is reconciled with solidify liquid by required solid-to-liquid ratio, you can obtain that hardening time is suitable, syringeability compared with
Good embedding carries medicine silica nodule calcium phosphate bone cement.
If solidify liquid is long-term without being stored in 4 DEG C of environment, being pre-dissolved before use.It is described be pre-dissolved mode be 37 DEG C with
Lower heating makes solidify liquid turn into runny liquid
One kind embedding carries medicine silica nodule calcium phosphate bone cement, it is characterised in that prepared according to any of the above-described methods described.
It is a kind of to embed the application for carrying medicine silica nodule calcium phosphate bone cement.
The advantage of the invention is that：
1. preparation method is easy, raw materials used simple, suitable for a large amount of productions.
2. newly formula improves the biocompatibility of green bone cement to the load medicine developed, there is heat-therapeutic action by adding
Taxol@silica nodules, embedding carry medicine silica nodule calcium phosphate bone cement syringeability increase.
Brief description of the drawings
1st, Fig. 1 is the silica nodule carrier and the SEM photograph of taxol@silica nodules of demand in embodiment 1,2,3,4.
2nd, Fig. 2 is that embodiment 1 prepares the SEM photograph obtained after the bone cement solidification containing silica nodule.
3rd, Fig. 3 is the force diagram for the bone cement bone piece that embodiment 1,2,3,4 solidifies.
4th, Fig. 4 is the correlation curve of heating type bone cement and common bone cement suppression tumour cell in embodiment 4.
Embodiment
Following examples are implemented premised on inventive technique scheme, give detailed embodiment and specific behaviour
Make process, but protection scope of the present invention is not limited to following embodiments.
Embodiment 1
Alpha- tricalcium phosphates are dispersed in absolute ethyl alcohol and are configured to 40g/L solution, liquid phase grinding is carried out with 400rpm mixing
4h, then adds 1000 in the solution:1 taxol@silica nodules, add 0.5% gelatin, continue in ball mill ball
15min is ground, powder will be obtained after resulting solution rotary evaporation.Wherein alpha- tricalcium phosphates：Taxol@silica nodule=1000:1
0.1g phosphonized chitosans, 0.15g gelatin, 0.1g hydroxypropyl methyl celluloses are weighed, 19.65g dibastic sodium phosphates are dissolved in
In solution, 20% dibastic sodium phosphate, 1% phosphonized chitosan, 1.5% gelatin, the bone cement of 1% hydroxypropyl methyl cellulose are prepared
Solidify liquid.
Bone cement powder is reconciled with solidify liquid by 2-2.5g/mL solid-to-liquid ratio, reference standard ASTM C191 are determined
Presetting period is 11 min.
Embodiment 2
Alpha- tricalcium phosphates are dispersed in absolute ethyl alcohol and are configured to 40g/L solution, liquid phase grinding is carried out with 400rpm mixing
4h, then adds 500 in the solution:1 taxol@silica nodules, add 0.5% gelatin, continue in ball mill ball milling
15min, will obtain powder after resulting solution rotary evaporation.Wherein alpha- tricalcium phosphates：Taxol@silica nodule=500:1
0.1g phosphonized chitosans, 0.15g gelatin, 0.1g hydroxypropyl methyl celluloses are weighed, 19.65g dibastic sodium phosphates are dissolved in
In solution, 20% dibastic sodium phosphate, 1% phosphonized chitosan, 1.5% gelatin, the bone cement of 1% hydroxypropyl methyl cellulose are prepared
Solidify liquid.
Bone cement powder is reconciled with solidify liquid by 2-2.5g/mL solid-to-liquid ratio, reference standard ASTM C191 are determined
Presetting period is 15min.
Embodiment 3
Alpha- tricalcium phosphates are dispersed in absolute ethyl alcohol and are configured to 40g/L solution, liquid phase grinding is carried out with 400rpm mixing
4h, then adds 200 in the solution:1 taxol@silica nodules, add 0.5% gelatin, continue in ball mill ball milling
15min, will obtain powder after resulting solution rotary evaporation.Wherein alpha- tricalcium phosphates：Taxol@silica nodule=200:1
0.1g phosphonized chitosans, 0.15g gelatin, 0.1g hydroxypropyl methyl celluloses are weighed, 19.65g dibastic sodium phosphates are dissolved in
In solution, 20% dibastic sodium phosphate, 1% phosphonized chitosan, 1.5% gelatin, the bone cement of 1% hydroxypropyl methyl cellulose are prepared
Solidify liquid.
Bone cement powder is reconciled with solidify liquid by 2-2.5g/mL solid-to-liquid ratio, reference standard ASTM C191 are determined
Presetting period is 16 min.
Embodiment 4
Alpha- tricalcium phosphates are dispersed in absolute ethyl alcohol and are configured to 40g/L solution, liquid phase grinding is carried out with 400rpm mixing
4h, then adds 100 in the solution:1 taxol@silica nodule particles, add 0.5% gelatin, continue in ball mill
Ball milling 15min, will obtain powder after resulting solution rotary evaporation.Wherein alpha- tricalcium phosphates：Taxol@silica nodules particle=
100:1
0.1g phosphonized chitosans, 0.15g gelatin, 0.1g hydroxypropyl methyl celluloses are weighed, 19.65g dibastic sodium phosphates are dissolved in
In solution, 20% dibastic sodium phosphate, 1% phosphonized chitosan, 1.5% gelatin, the bone cement of 1% hydroxypropyl methyl cellulose are prepared
Solidify liquid.
Bone cement powder is reconciled with solidify liquid by 2-2.5g/mL solid-to-liquid ratio, reference standard ASTM C191 are determined
Presetting period is 18min.
Material is as shown in Fig. 2 after preparation-obtained bone cement solidification, after bone cement solidification, alpha- tricalcium phosphates hair
Hydration reaction is given birth to, particle grows up to needle-like in hydration process, and needle construction is interleaved with each other, siliceous with certain mechanical strength
Body is particles cured in the material, and the pattern and performance of bone cement are had no effect on the whole.
Bone piece after the bone cement for the taxol@silica nodules that adulterated in embodiment 1-4 is solidified, as shown in Figure 3.Embodiment 1
In, when silica nodule is in extremely low content（Mass fraction one thousandth）.Until in embodiment 4, silica nodule brings up to matter in content
Measure fraction percent for the moment, compared with blank group, the mechanical property after it solidifies is not reduced.
Bone cement skeleton after solidification in embodiment 4 is put into the culture dish containing MG osteosarcoma cells, contrast 24
The cells survival rate of hour, as a result as shown in Figure 4.Blank group is the bone cement of filling silica nodule, and observed result illustrates not bright
To fill the bone cement solidification group of taxol@silica nodules in aobvious cytotoxicity, embodiment 1- embodiments 4, find in embodiment 1
Cells survival rate is 92.7%, and cells survival rate is that cells survival rate is 72.3% in 84.4%, embodiment 3 in embodiment 2, is implemented
Cells survival rate is 59.3% in example 4.As a result the block bone cement of explanation embedding taxol has good cancer cell killing effect
Energy.
Claims (8)
1. a kind of embed the preparation method for carrying medicine silica nodule calcium phosphate bone cement, it is characterised in that comprises the steps of：
（1）Self-curing component and the nano material heated are mixed, modified bone cement solid phase powder, wherein alpha- phosphorus is obtained
Sour three calcium materials parcel delivery effect, taxol silica nodule plays a part of anticancer；
（2）Based on sodium phosphate, using phosphonized chitosan, hydroxypropyl methyl cellulose, gelatin as modifying agent, prepare neutral
Bone cement solidify liquid, improves formula syringeability；
（3）Bone cement solid phase powder is mixed with solidify liquid, cured product main component hydroxyapatite, taxol@is added
Silica nodule has good degradation capability in vivo.
2. embedding according to claim 1 carries the preparation method of medicine silica nodule calcium phosphate bone cement, it is characterised in that step
Suddenly（2）The mass fraction of sodium phosphate is 10-20% in described phosphoric acid solution, the mass fraction of phosphonized chitosan for 0.01-
1%, the mass fraction of hydroxypropyl methyl cellulose is 0.01-1%, and the mass fraction of gelatin is 0.01-1%；Manner of formulation is room
Temperature dissolving or less than 60 DEG C heating hydrotropies, can also be aided with mechanical agitation or magnetic agitation.
3. embedding according to claim 1 carries the preparation method of medicine silica nodule calcium phosphate bone cement, it is characterised in that step
Suddenly（1）Described taxol@silica nodules mass fraction is 0.1-1%.
4. embedding according to claim 3 carries the preparation method of medicine silica nodule calcium phosphate bone cement, it is characterised in that
Alpha- tricalcium phosphates particle diameter is 15-100nm, and taxol@silica nodules are 100-200nm；Hybrid mode is to use agate mortar
Powder is fully ground in dry environment.
5. embedding according to claim 1 carries the preparation method of medicine silica nodule calcium phosphate bone cement, it is characterised in that tool
Body step is as follows：
（1）The preparation of silica nodule raw material：
Cetylamine and alcohol solvent are added in three-necked bottle, the bromohexadecane of 1/2 mole is fully added after dissolving, addition is urged
Stop reaction after agent natrium carbonicum calcinatum, backflow 120h, double cetylamines are refining to obtain repeatedly；By double cetylamines and amber
Acid anhydrides is added in dry tetrahydrofuran, fully reacts 24h, is concentrated, successively with 10% citric acid and saturation after being dissolved with chloroform
Sodium chloride point liquid washing, crude product is obtained after solvent evaporation, then refined with recrystallized from acetonitrile；Product after refined is in 1- (3- bis-
Methylaminopropyl) -3- ethyl-carbodiimide hydrochlorides（EDC）Under catalysis, react, be prepared into aminopropyl triethoxysilane
To silica nodule coarse raw materials, column chromatography is refining to obtain the smart raw material of silica nodule；
（2）Carry the preparation of paclitaxel silicon plastid：
By step（1）In obtained component dissolved with chloroform, rotary evaporation removes solvent, adds water solution into lipid film, ultrasound
Disperse and in 60 DEG C of rotation concussions of water-bath, obtain suspension；The carbonic acid adipose membrane of 50nm pore sizes was extruded, particle size is obtained
Uniform silica nodule；When carrying medicine, each component chloroform is dissolved, rotary evaporation removes solvent, adds the medicines such as taxol,
Solution add water into lipid film, ultrasonic disperse simultaneously shakes in 60 DEG C of rotations of water-bath, obtains suspension, extruded 50nm pore sizes
Carbonic acid adipose membrane, obtain carrying the uniform targeting silica nodule of Types of Medicine particle size, and obtain solid state powder using freeze-drying；
（3）The preparation of drug carrier silica nodule bone cement：
Prepare mass fraction be 10% sodium dihydrogen phosphate, manner of formulation can be room-temperature dissolution or ultrasonic dissolution assisting, can be with auxiliary
With mechanical agitation or magnetic agitation；
Phosphonized chitosan is added into the solution according to solidification formula of liquid, the phosphorylation that mass fraction is 0.01-1% is configured to
Chitosan solution；
Hydroxypropyl methyl cellulose, gelatin are added into sodium phosphate-phosphoric acid chitosan solution according to solidification formula of liquid, is obtained most
Whole mass fraction is 0.01-1% hydroxypropyl methyl cellulose and 0.01-1% gelatin modified solidify liquid；
By calcium sulfate bone cement and step（2）Obtained load paclitaxel silicon plastid is with mass ratio 1000:1、 500:1、 200：1
Or 100:1 mixing, hybrid mode is to be fully ground in dry environment powder using agate mortar；
Bone cement powder is reconciled with solidify liquid by required solid-to-liquid ratio, you can obtain that hardening time is suitable, syringeability compared with
Good embedding carries medicine silica nodule calcium phosphate bone cement.
6. embedding according to claim 5 carries the preparation method of medicine silica nodule calcium phosphate bone cement, it is characterised in that if
Solidify liquid is long-term without being stored in 4 DEG C of environment, being pre-dissolved before use.
7. described in be pre-dissolved mode be that heating makes solidify liquid as runny liquid less than 37 DEG C
One kind embedding carries medicine silica nodule calcium phosphate bone cement, it is characterised in that according to any methods described systems of claim 1-6
It is standby to obtain.
8. embedding carries the application of medicine silica nodule calcium phosphate bone cement according to claim 7.
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| CN201710316651.5A CN107158473B (en) | 2017-05-08 | 2017-05-08 | Calcium phosphate bone cement embedded with drug-loaded silica plastid and preparation method and application thereof |
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Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101362066A (en) * | 2008-09-27 | 2009-02-11 | 同济大学 | Preparation method of liposome embedded quantum dots silicon dioxide microspheres and products thereof |
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| CN101362066A (en) * | 2008-09-27 | 2009-02-11 | 同济大学 | Preparation method of liposome embedded quantum dots silicon dioxide microspheres and products thereof |
| CN101485904A (en) * | 2009-02-13 | 2009-07-22 | 天津大学 | Injectable calcium sulphate-based sustained-release implantation component containing medicine-carrying particle and application |
| CN102895216A (en) * | 2012-10-24 | 2013-01-30 | 中山大学 | Anti-cancer medicament silicon plastid microcapsule and preparation method thereof |
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| CN106146544A (en) * | 2015-04-28 | 2016-11-23 | 东北林业大学 | A kind of preparation method of silica nodule precursor organosilan |
| CN105251058A (en) * | 2015-11-05 | 2016-01-20 | 上海纳米技术及应用国家工程研究中心有限公司 | Method for preparing drug-loaded injection type calcium sulfate bone cement for promoting bone growth |
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