CN104224730A - Preparation method of silicon dioxide/octacalcium phosphate particles capable of releasing methylthionine chloride monomers - Google Patents
Preparation method of silicon dioxide/octacalcium phosphate particles capable of releasing methylthionine chloride monomers Download PDFInfo
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- CN104224730A CN104224730A CN201410450289.7A CN201410450289A CN104224730A CN 104224730 A CN104224730 A CN 104224730A CN 201410450289 A CN201410450289 A CN 201410450289A CN 104224730 A CN104224730 A CN 104224730A
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Abstract
The invention provides a preparation method of silicon dioxide/octacalcium phosphate particles capable of releasing methylthionine chloride monomers. The preparation method of silicon dioxide/octacalcium phosphate particles capable of releasing the methylthionine chloride monomers comprises the following steps: sequentially adding ammonium hydroxide, methylthionine chloride, tetraethoxysilane and a silane coupling agent into a solution containing water and ethyl alcohol, then stirring for 4 hours, centrifuging and washing the solution, then preparing the solution into a silicon dioxide colloidal solution containing methylthionine chloride by ethyl alcohol; then adding citric acid, calcium nitrate and diammonium hydrogen phosphate into the solution containing water and ethyl alcohol, adjusting pH value of the solution to 9 by ammonia water, subsequently adding polyethylene glycol and stirring for one hour, pouring the silicon dioxide colloidal solution containing methylthionine chloride into the solution, stirring for 3 hours, centrifuging, washing and drying the solution to obtain the silicon dioxide/octacalcium phosphate particles capable of releasing the methylthionine chloride monomers. The method is simple in process and low in costs of raw materials; the industrial production is easy to be implemented; the particles prepared by the method have good compatibility and are easy to be degraded; the methylthionine chloride is released from the particles in the form of monomer molecules into the solution; meanwhile, the releasing behavior is convenient to control.
Description
Technical field
The invention provides a kind of preparation method discharging the silica/phosphoric acid eight calcium granule of methylene blue monomer, belong to technical field of chemical raw material production.
Background technology
Methylene blue can treat the disease such as malaria and urinary tract infection, is widely used in fields such as photochemical therapies, to suppressing the gathering of Tau albumen also to have positive effect in treatment alzheimer's disease, therefore enjoys researcher extensive concern.Methylene blue molecule exists with monomer and dimeric mode in the solution, and the aggregated forms of molecule has appreciable impact to performances such as photochemo-therapeutic effect, redox property and cell membrane span abilities.Compared to methylene blue dimer, methylene blue monomer transits to excited state under photo-excitation conditions, in the process that de excitation is sent out, excess energy is absorbed by oxygen molecule, oxygen molecule is become and has the singlet oxygen molecular of murdering effect to bacterial cell, realize therapeutic effect with photochemically reactive mechanism of action; The ability that methylene blue monomer is reduced is also very strong, and reduction-state enters cell interior after can crossing over cell membrane.And the probability that methylene blue dimer produces singlet oxygen molecular by photochemical reaction is almost nil, can not be reduced, also cannot crosses over cell membrane.
Under solution condition, methylene blue molecule is difficult to be existed with monomeric fashion, and when especially can realize the higher concentration dosage of therapeutic effect, monomer is often gathered into dimer molecule, and therapeutic effect can decline greatly.The ability that is reduced of methylene blue monomers in vivo is very strong in addition, and be very easily excreted, circulation time in vivo is short, arrives the negligible amounts of the methylene blue monomer of pathological tissues.For solving the problem, research worker (S. Zhang, Z. Chu, C. Yin, C. Zhang, G. Lin, Q. Li, J. Am. Chem. Soc. 2013,135,5709-5716) adopt the mode of wrapping up methylene blue molecule in pharmaceutical carrier, the sustained release of methylene blue molecule can be ensured, extend methylene blue action time in vivo, but the correlational study that methylene blue mainly exists with monomeric form in the solution has no report.
Summary of the invention
The object of this invention is to provide a kind of preparation method discharging the silica/phosphoric acid eight calcium granule of methylene blue monomer, for achieving the above object, the technical solution adopted in the present invention step is as follows:
(1) in the mixed solution of moisture and ethanol, to add successively after ammonia, methylene blue and ethyl orthosilicate 15 minutes, add silane coupler, then stirring reaction is after 4 hours, centrifugal and be mixed with the silica colloid solution containing methylene blue with ethanol again with after washing with alcohol precipitum;
(2) in the mixed solution of moisture and ethanol, regulate the pH value to 9 of solution with ammonia after adding citric acid, lime nitrate and diammonium phosphate successively, add Polyethylene Glycol subsequently, what step (1) prepared after 1 hour by stirring reaction pours into containing the silica colloid solution of methylene blue, then stirring reaction 3 hours;
(3) reaction solution step (2) obtained is centrifugal, and with after washing with alcohol precipitum under 60oC dry 12 hours, namely obtains discharging methylene blue monomer for main silica/phosphoric acid eight calcium granule.
Wherein, in step (1), the volume ratio of water, ethanol, ammonia and ethyl orthosilicate is 26.74:5:0.72:1, and the concentration of methylene blue is 2.32 mMs often liter.Silane coupler is vinyltrimethoxy silane, and the volume ratio of addition and ethyl orthosilicate is 0.1:1 ~ 0.3:1, and best addition is 30% of ethyl orthosilicate addition.
In step (2), the volume ratio of water and ethanol is 3:1, and the concentration of citric acid is 0.058 ~ 0.174 mM often liter, and best is 0.116 mM often liter.In solution, the concentration of lime nitrate and diammonium phosphate is respectively 0.0567 mM often liter and 0.0349 mM often liter, and the mol ratio of the ethyl orthosilicate addition in lime nitrate addition and step (1) is 0.68:1.The molecular weight of Polyethylene Glycol is 400 ~ 6000, and concentration is that 0.83 ~ 10 micromole often rises, and the molecular weight of best Polyethylene Glycol is 2000, and best concentration is that 2.5 micromoles often rise.When regulating the pH value to 9 of reaction solution, calcium ion in solution and phosphate anion can generate OCP, under the synergism of citric acid and Polyethylene Glycol, be deposited into the silica particles containing methylene blue, and then prepare the silica/phosphoric acid eight calcium granule of release methylene blue monomer.
Beneficial effect of the present invention is:
(1) this method technique is simple, cost of material is low and be easy to suitability for industrialized production;
(2) silane coupler add the silica dioxide granule dispersibility in the solution that can improve containing methylene blue, be conducive to the deposition of OCP layer, increase substantially the operating performance of preparation technology;
(3) the silica/phosphoric acid eight calcium particle surface of preparation-obtained release methylene blue monomer is Polyethylene Glycol, citric acid and OCP layer, good biocompatibility, easily degrade in human body fluid environment, degraded ion is friendly ion in body, can use safely;
(4) in the solution of different pH value, as phosphorus buffer (pH=7.2 ~ 7.4) and simulation lysosome buffer (pH=4.7) Methylene Blue are released in solution from all main form with monomer molecule of silica/phosphoric acid calcium granule interior of release methylene blue monomer, and the behavior of release can conveniently regulating and controlling;
(5) due to the special construction of the silica/phosphoric acid eight calcium granule of release methylene blue monomer, the time that methylene blue molecule discharges from granule interior extends greatly, extend the methylene blue molecule time of staying in vivo by being conducive to, and then its absorbed efficiency in vivo can be increased substantially.
Accompanying drawing explanation
Fig. 1 is X-ray diffraction spectrogram (b) that JCPDS card is numbered the silica/phosphoric acid eight calcium granule of the release methylene blue monomer that standard X-ray diffraction spectrogram (a) of the OCP of 26-1056 and the embodiment of the present invention 1 prepare.
Fig. 2 is the SEM electron scanning micrograph of the silica/phosphoric acid eight calcium granule of the release methylene blue monomer that the embodiment of the present invention 1 prepares.
Fig. 3 is the behavior discharged in the silica/phosphoric acid eight calcium granule of the release methylene blue monomer prepared from the embodiment of the present invention 1 at different solutions Methylene Blue.A () is in phosphorus buffer; B () is in the lysosomal buffer of simulation.
Fig. 4 is that after being released into solution in the silica/phosphoric acid eight calcium granule of the release methylene blue monomer prepared from the embodiment of the present invention 1 at different solutions Methylene Blue, methylene blue monomer is ratio (A664/A610) situation over time between the absorbance (A610) of 610 nanometers at 664 nanometers absorbances (A664) and dimer.A () is in phosphorus buffer; B () is in simulation lysosome buffer.
Fig. 5 be different solutions Methylene Blue hang oneself the step (1) of the embodiment of the present invention 1 preparation-obtained containing the silica dioxide granule of methylene blue in the behavior that discharges.A () is in phosphorus buffer; B () is in the lysosomal buffer of simulation.
Fig. 6 be different solutions Methylene Blue hang oneself the step (1) of the embodiment of the present invention 1 preparation-obtained containing the silica dioxide granule of methylene blue in be released into solution after, methylene blue monomer is in the absorbance (A664) of 664 nanometers and ratio (A664/A610) the over time situation of dimer between the absorbance (A610) of 610 nanometers.A () is in phosphorus buffer; B () is in the lysosomal buffer of simulation.
Detailed description of the invention
The present invention is further illustrated below in conjunction with embodiment.
Embodiment 1:
(1) in the solution containing 92 milliliters of ethanol and 17.2 ml waters, add after 2.48 milliliters of ammonia stir and add methylene blue again, stir after 10 minutes, add 3.44 milliliters of ethyl orthosilicates again, the concentration of methylene blue is made to be 2.32 mMs often liter, add vinyltrimethoxy silane solution 1.03 milliliters after 15 minutes, stirring reaction is centrifugal and with after washing with alcohol precipitum, be mixed with the silica colloid solution containing methylene blue with ethanol after 4 hours;
(2) in the solution containing 138.3 ml waters and 46.1 milliliters of ethanol, add citric acid, lime nitrate and diammonium phosphate successively, its concentration is made to be respectively 0.116 mM often liter, 0.0567 mM often liter and 0.0349 mM often liter, the pH value to 9 of solution is regulated until completely dissolved with ammonia, add the Polyethylene Glycol that molecular weight is 2000 again, its concentration is made to be that 2.5 micromoles often rise, the silica colloid solution containing methylene blue that step (1) prepared after 1 hour by stirring reaction is poured into, stirring reaction 3 hours;
(3) reaction solution step (2) obtained is centrifugal, and with namely obtaining the silica/phosphoric acid eight calcium granule discharging methylene blue monomer after washing with alcohol under 70oC after dry 12 hours.
The thing phase (see figure 1) of X-ray diffraction method analysing particulates.Wherein, the broadening diffraction maximum of amorphous silicon di-oxide appears at the position of in Fig. 1 (a) about 25 degree, and finds the diffraction maximum also having OCP in Fig. 1 (a) after contrasting with Fig. 1 (b).
SEM scanning electron microscope detects the pattern (see figure 2) of granule.
For the purpose of contrast, the silica colloid solution containing methylene blue prepared by the step (1) through embodiment 1 obtains precipitum through centrifugal, obtains the silica dioxide granule containing methylene blue under 60oC after dry 12 hours.Visible spectrophotometry is determined at the behavior (seeing Fig. 3 and Fig. 5 respectively) of phosphorus buffer and the silica/phosphoric acid eight calcium granule of the lysosomal buffer Methylene Blue of simulation from release methylene blue monomer and the silica dioxide granule inside release containing methylene blue, and the methylene blue monomer discharged is in the absorbance (A664) of 664 nanometers and the ratio (A664/A610) of dimer between the absorbance (A610) of 610 nanometers situation (seeing Fig. 4 and Fig. 6 respectively) over time.
Find after tested, the parcel amount containing the silicon dioxide Methylene Blue of methylene blue is 32.97 mg/g, and the parcel amount discharging the silica/phosphoric acid eight calcium granule Methylene Blue of methylene blue monomer is 34.61 mg/g.In the solution of different pH value, the silica/phosphoric acid eight calcium granule interior slow releasing of methylene blue self-contained release methylene blue monomer, and also the behavior of release is to the pH sensitive of solution, and can conveniently regulating and controlling (see figure 3).
Especially, in phosphorus buffer and the lysosomal buffer of simulation, A664/A610 value (see figure 4) when discharging in the silica/phosphoric acid eight calcium granule of the release methylene blue monomer containing methylene blue that methylene blue prepares from embodiment 1 will far above A664/A610 value (see figure 6) when discharging in the silica dioxide granule of self-contained methylene blue.Visible, methylene blue is mainly released in solution with the form of monomer in the silica/phosphoric acid eight calcium granule of release methylene blue monomer.
Claims (8)
1. discharge a preparation method for the silica/phosphoric acid eight calcium granule of methylene blue monomer, it is characterized in that comprising the following steps:
Step 1. is in the solution containing second alcohol and water, to add successively after ammonia, methylene blue and ethyl orthosilicate 15 minutes, add silane coupler again, stirring reaction 4 hours, centrifugal and be mixed with the silica colloid solution containing methylene blue with ethanol again with after washing with alcohol precipitum;
Step 2. is in the solution of moisture and ethanol, regulate the pH value to 9 of solution with ammonia after adding citric acid, lime nitrate and diammonium phosphate successively, add Polyethylene Glycol subsequently, what step 1 prepared after 1 hour by stirring reaction pours into containing the silica colloid solution of methylene blue, then stirring reaction 3 hours;
The reaction solution that step 2 obtains by step 3. is centrifugal, and with after washing with alcohol precipitum under 70oC dry 12 hours, namely obtains the silica/phosphoric acid eight calcium granule discharging methylene blue monomer.
2. a kind of preparation method discharging the silica/phosphoric acid eight calcium granule of methylene blue monomer according to claim 1, it is characterized in that: in step 1, the volume ratio of water, ethanol, ammonia and ethyl orthosilicate is 26.74:5:0.72:1, the concentration of methylene blue is 2.32 mMs often liter.
3. a kind of preparation method discharging the silica/phosphoric acid eight calcium granule of methylene blue monomer according to claim 1, it is characterized in that: in step 1, silane coupler is vinyltrimethoxy silane, the volume ratio of addition and ethyl orthosilicate is 0.1:1 ~ 0.3:1.
4. a kind of preparation method discharging the silica/phosphoric acid eight calcium granule of methylene blue monomer according to claim 1, it is characterized in that: in step 2, the volume ratio of water and ethanol is 3:1, the concentration of lime nitrate and diammonium phosphate is respectively 0.0567 mM often liter and 0.0349 mM often liter.
5. a kind of preparation method discharging the silica/phosphoric acid eight calcium granule of methylene blue monomer according to claim 1, is characterized in that: in step 2, the concentration of citric acid is 0.058 ~ 0.174 mM often liter.
6. a kind of preparation method discharging the silica/phosphoric acid eight calcium granule of methylene blue monomer according to claim 1, is characterized in that: the mol ratio of the ethyl orthosilicate addition in step 2 in lime nitrate addition and step 1 is 0.68:1.
7. a kind of preparation method discharging the silica/phosphoric acid eight calcium granule of methylene blue monomer according to claim 1, is characterized in that: in step 2, the concentration of Polyethylene Glycol is that 0.83 ~ 10 micromole often rises.
8. a kind of preparation method discharging the silica/phosphoric acid eight calcium granule of methylene blue monomer according to claim 1, is characterized in that: in step 2, the molecular weight of Polyethylene Glycol is 400 ~ 6000 grams every mole.
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| CN109233806A (en) * | 2018-09-25 | 2019-01-18 | 山东理工大学 | A method of there is the silica dioxide granule containing methylene blue of high fluorescent using heat treatment auxiliary preparation |
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Cited By (2)
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| CN109233806A (en) * | 2018-09-25 | 2019-01-18 | 山东理工大学 | A method of there is the silica dioxide granule containing methylene blue of high fluorescent using heat treatment auxiliary preparation |
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