CN108888765B - Preparation method of methylene blue aggregate-releasing silicon dioxide/shellac composite particle containing methylene blue - Google Patents
Preparation method of methylene blue aggregate-releasing silicon dioxide/shellac composite particle containing methylene blue Download PDFInfo
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- CN108888765B CN108888765B CN201810778140.XA CN201810778140A CN108888765B CN 108888765 B CN108888765 B CN 108888765B CN 201810778140 A CN201810778140 A CN 201810778140A CN 108888765 B CN108888765 B CN 108888765B
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- A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
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- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
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- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
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Abstract
The invention provides a preparation method of a methylene blue aggregate-containing silicon dioxide/shellac composite particle, belonging to the technical field of chemical raw material production. Adding ammonia water, methylene blue and ethyl orthosilicate into a mixed solution of water and ethanol, stirring for 4 hours, centrifuging, washing, drying at 70 ℃, dispersing the prepared silicon dioxide particles containing the methylene blue into a shellac solution, dropwise adding a phosphate buffer solution, stirring for 1 hour, centrifuging, washing, drying at room temperature, and carrying out heat treatment on the prepared silicon dioxide/shellac composite particles containing the methylene blue at 90-180 ℃ for 24 hours to obtain the silicon dioxide/shellac composite particles containing the methylene blue, wherein the silicon dioxide/shellac composite particles containing the methylene blue aggregate are released. The method has simple process, low raw material price and easy industrial production, and the obtained particles have good biocompatibility and are easy to degrade. Methylene blue is released from the interior of the particle into solution mainly in the form of dimers and trimers.
Description
Technical Field
A preparation method of a methylene blue aggregate-containing silicon dioxide/shellac composite particle belongs to the field of chemical raw material preparation methods.
Background
The photochemical kinetic therapy is a novel treatment mode which utilizes active substances generated by photochemical reaction of photosensitive molecules to destroy pathological cells so as to achieve a treatment effect, namely, the photosensitive molecules are converted into an excited state from a ground state under the excitation of light, and in the molecular excitation process, redundant energy is transferred to surrounding oxygen molecules so that the oxygen molecules are converted into active singlet oxygen molecules to achieve a sterilization effect, and the photochemical kinetic therapy is a type II photochemical reaction route; under the condition of no oxygen or low oxygen, the photosensitive molecules generate active free radicals through charge transfer in the photosensitive molecule aggregate molecules, and further generate active oxygen Reactants (ROS) including highly reactive peroxy molecules, so as to achieve the effects of sterilization and disease treatment, which is a type I photochemical reaction route.
In normal tissue cells, oxygen is supplied from the blood to meet the normal needs of human tissue, and the oxygen concentration in the blood is maintained within a reasonable distribution, such as a heart blood oxygen concentration of about 17mmHg at rest and a spleen oxygen concentration of about 65 mmHg. However, in the diseased cells, the diseased cells are always in a hypoxic or anoxic state due to the imbalance between oxygen supply and oxygen consumption. For example, in solid tumor tissue, neoplastic cells and stromal cells consume more oxygen than they supply, primarily because: the limited oxygen supply due to abnormalities in tumor microvascular structure and function, the limited oxygen supply due to the pattern of oxygen diffusion in the surrounding tissues, and the reduced oxygen supply due to anemic factors.
Therefore, when the photosensitive molecules, such as methylene blue, are administered to a hypoxic or anaerobic state, the photochemical reaction effect of the type ii provided by the methylene blue monomer is very limited, because the oxygen concentration is too low to generate enough singlet oxygen molecules, so that the therapeutic effect is greatly reduced, and the photochemical reaction of the type i involved by the methylene blue molecules in a dimer form is not affected by the oxygen concentration, so that higher photochemical reaction efficiency can be achieved in lesion tissues such as tumors, and the efficiency of the photochemical kinetic therapy can be further improved.
The methylene blue dimer can be obtained by increasing the concentration of methylene blue, and the methylene blue can also be wrapped in a drug carrier to obtain a slow release carrier of the methylene blue dimer, such as the technical scheme provided by ZL201410436007.8, but the release behaviors of the drug carrier mentioned in the technical scheme are not very different in different solution environments, and the pH sensitive effect of the dimer release behavior cannot be realized, because the pH value in normal human tissues is 7.2-7.4, and the pH value in diseased cells is about 4.3. Therefore, the research for exploring the drug carrier with the release behavior of the methylene blue aggregate sensitive to the pH value is extremely important, and related reports are very few.
Disclosure of Invention
The invention aims to provide a preparation method of a methylene blue aggregate-containing silicon dioxide/shellac composite particle, which is characterized by comprising the following steps:
(1) adding ammonia water and methylene blue into a solution containing water and ethanol in sequence, stirring for 15 minutes, adding tetraethoxysilane, wherein the volume ratio of the water to the ethanol to the ammonia water to the tetraethoxysilane is 5:26.74: 0.72:1, the concentration of the methylene blue is 2.32 millimoles per liter, stirring for 4 hours, performing centrifugal separation to obtain a sediment, washing the sediment with ethanol and an acetate buffer solution with the pH =3.6 in sequence, wherein the volume ratio of the ethanol and the acetate buffer solution used for washing to the tetraethoxysilane is 34.88: 1 and 5.81: 1, drying the sediment obtained by centrifugal separation at 70 ℃ for 24 hours to obtain silicon dioxide particles containing methylene blue;
(2) dissolving shellac in ethanol to prepare a shellac solution, wherein the concentration of shellac is 10 g/l, putting the silica particles containing methylene blue prepared in step (1) into the shellac solution to make the concentration of the silica particles containing methylene blue 10 g/l, performing ultrasonic treatment for 5 minutes, and then adding a phosphate buffer solution with a pH value of 7.2-7.4 to the shellac solution containing the silica particles containing methylene blue at a speed of 0.5 ml/min, wherein the volume ratio of the phosphate buffer solution to the shellac solution containing the silica particles containing methylene blue is 3: 1, stirring for 1 hour, performing centrifugal separation to obtain a sediment, washing the sediment with deionized water, and drying at room temperature for 12 hours to obtain the silica/shellac composite particle containing methylene blue;
(3) and (3) treating the silica/shellac composite particle containing methylene blue prepared in the step (2) at 90-180 ℃ for 24 hours to prepare the silica/shellac composite particle containing methylene blue releasing methylene blue aggregates.
In the process of continuously adding a phosphate buffer solution with the pH value of 7.2-7.4 into a shellac solution containing silica particles containing methylene blue, shellac molecules dissolved in an ethanol solution are gradually precipitated from a mixed solution of ethanol and the phosphate buffer solution and are deposited on the surfaces of the silica particles containing methylene blue, so as to obtain the silica/shellac composite particles containing methylene blue. In the process of treating the silicon dioxide/shellac composite particles containing methylene blue at 90-180 ℃ for 24 hours, the shellac on the surfaces of the composite particles is melted and densified, methylene blue molecules in the composite particles are subjected to aggregation reaction and are converted into aggregates, wherein the optimal treatment temperature is 120 ℃, and the silicon dioxide/shellac composite particles containing methylene blue and releasing methylene blue aggregates are prepared.
The invention has the beneficial effects that:
(1) the method has simple process, low raw material price and easy industrial production;
(2) the prepared silicon dioxide/shellac composite particle containing methylene blue releasing methylene blue aggregates has natural shellac on the surface, good biocompatibility, easy degradation and safe use;
(3) in solutions with different pH values, such as phosphate buffer solution with the pH value of 7.2-7.4 and simulated gastric acid buffer solution with the pH value of 1.2, methylene blue self-releasing methylene blue aggregates in the silicon dioxide/shellac composite particles containing methylene blue are released into the solution in the form of aggregate molecules, the release mode is shown as slow release, and the release behavior is sensitive to the pH value of the soaking solution;
(4) the silica/shellac composite particle containing methylene blue is treated at 90-180 ℃ for 24 hours, so that the density of the shellac coating layer can be adjusted, and the release speed of methylene blue aggregate molecules in the silica/shellac composite particle containing methylene blue aggregates released by the methylene blue aggregate molecules can be further adjusted and controlled.
Drawings
FIG. 1 is an X-ray diffraction pattern of methylene blue aggregate-releasing silica/shellac composite particle prepared in example 1 of the present invention.
FIG. 2 is an SEM scanning electron microscope photograph of methylene blue aggregate-releasing silica/shellac composite particles prepared in example 1 of the present invention.
FIG. 3 shows the release of methylene blue from the methylene blue aggregate-releasing silica/shellac composite particle containing methylene blue prepared in example 1 of the present invention over time in a phosphate buffer solution having a pH of 7.2 to 7.4.
Fig. 4 is a graph of methylene blue release over time from methylene blue aggregate-releasing silica/shellac composite particles containing methylene blue prepared in example 1 of the present invention in a simulated gastric acid buffer at pH 1.2.
Fig. 5 shows the release of methylene blue from the silica/shellac composite particle containing methylene blue prepared in step (2) of example 1 of the present invention over time in a phosphoric acid buffer solution having a pH value of 7.2 to 7.4.
Fig. 6 is a graph showing the release of methylene blue over time from silica/shellac composite particles containing methylene blue prepared in step (2) of example 1 of the present invention in a simulated gastric acid buffer at pH 1.2.
Detailed Description
The present invention is further illustrated by the following examples.
Example 1
(1) Sequentially adding ammonia water and methylene blue into a solution containing water and ethanol, stirring for 15 minutes, and then adding tetraethoxysilane, wherein the dosage of the water, the ethanol, the ammonia water and the tetraethoxysilane is respectively 17.2: 92: 2.48: 3.44 ml, the concentration of methylene blue is 2.32 mmol/l, after stirring for 4 hours, centrifuging to obtain a precipitate, washing the precipitate with ethanol and acetate buffer with pH =3.6 in sequence, wherein the amounts of the ethanol and the acetate buffer used for washing are 120 ml and 20 ml respectively, and drying the precipitate obtained by centrifuging at 70 ℃ for 24 hours to obtain silica particles containing methylene blue;
(2) dissolving shellac in ethanol to prepare a shellac solution, wherein the concentration of shellac is 10 g/l, putting the silica particles containing methylene blue prepared in step (1) into the shellac solution to make the concentration of the silica particles containing methylene blue 10 g/l, performing ultrasonic dispersion treatment for 5 minutes, adding a phosphate buffer solution with the pH value of 7.2-7.4 into the shellac solution containing the silica particles containing methylene blue at the speed of 0.5 ml/min, wherein the use amount of the phosphate buffer solution and the use amount of the shellac solution containing the silica particles containing methylene blue are respectively 30 ml and 10 ml, stirring for 1 hour, performing centrifugal separation to obtain a precipitate, washing the precipitate with deionized water, and drying at room temperature for 12 hours to prepare the silica/shellac composite particles containing methylene blue;
(3) and (3) treating the silica/shellac composite particle containing methylene blue prepared in the step (2) at 120 ℃ for 24 hours to prepare the silica/shellac composite particle containing methylene blue releasing methylene blue aggregates.
The phase of the particles was analyzed by X-ray diffraction (see fig. 1).
The morphology of the particles was examined by SEM scanning electron microscopy (see figure 2).
The behavior of methylene blue self-releasing methylene blue aggregates in the silica/shellac composite particle containing methylene blue in a phosphate buffer solution with a pH value of 7.2 to 7.4 and a simulated gastric acid buffer solution with a pH value of 1.2, which are released by methylene blue self-releasing methylene blue aggregates, is measured by a visible light spectrophotometry (see fig. 3 and fig. 4, respectively). The absorption peak at 610 nm is mainly due to the released methylene blue dimer molecules, and the absorption peak at 560 nm is mainly due to the released methylene blue trimer molecules. It can be seen that in the solution, methylene blue is released from the methylene blue aggregate-containing silica/shellac composite particle in the form of aggregates, with almost no monomer content, mainly dimers and trimers.
For comparison, the behavior of methylene blue released from the interior of the silica/shellac composite particle containing methylene blue prepared by the step (2) of example 1 in a phosphate buffer solution having a pH value of 7.2 to 7.4 and a simulated gastric acid buffer solution having a pH value of 1.2 was measured by a visible light spectrophotometry (see fig. 5 and 6, respectively). The absorption peak at 664 nm is due primarily to the released methylene blue monomer molecules, and the absorbance at 610 nm is due primarily to the released methylene blue dimer molecules. It can be seen that methylene blue is released from the methylene blue-containing silica/shellac composite particle prepared in step (2) of example 1 in the form of monomer and dimer in the solution.
Claims (1)
1. A preparation method of a methylene blue aggregate-containing silicon dioxide/shellac composite particle is characterized by comprising the following steps:
step 1, sequentially adding ammonia water and methylene blue into a solution containing water and ethanol, stirring for 15 minutes, then adding tetraethoxysilane, wherein the volume ratio of the water to the ethanol to the ammonia water to the tetraethoxysilane is 5:26.74: 0.72:1, the concentration of the methylene blue is 2.32 millimoles per liter, stirring for 4 hours, then carrying out centrifugal separation to obtain a sediment, sequentially washing the sediment with ethanol and an acetate buffer solution with the pH =3.6, wherein the volume ratio of the ethanol and the acetate buffer solution used for washing to the tetraethoxysilane is 34.88: 1 and 5.81: 1, drying the sediment obtained by centrifugal separation at 70 ℃ for 24 hours to obtain silicon dioxide particles containing methylene blue;
step 2, dissolving shellac in ethanol to prepare a shellac solution, wherein the concentration of shellac is 10 grams per liter, putting the silica particles containing methylene blue prepared in step 1 into the shellac solution to make the concentration of the silica particles containing methylene blue 10 grams per liter, after 5 minutes of ultrasonic treatment, adding a phosphate buffer solution with a pH value of 7.2-7.4 to the shellac solution containing the silica particles containing methylene blue at a speed of 0.5 ml/minute, wherein the volume ratio of the phosphate buffer solution to the shellac solution containing the silica particles containing methylene blue is 3: 1, stirring for 1 hour, performing centrifugal separation to obtain a sediment, washing the sediment with deionized water, and drying at room temperature for 12 hours to obtain the silica/shellac composite particle containing methylene blue;
and 3, treating the silica/shellac composite particle containing methylene blue prepared in the step 2 at 120 ℃ for 24 hours to prepare the silica/shellac composite particle containing methylene blue releasing methylene blue aggregates.
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Citations (4)
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| JPS55158848A (en) * | 1979-05-31 | 1980-12-10 | Hitachi Metals Ltd | Bentonite |
| WO2011107945A1 (en) * | 2010-03-04 | 2011-09-09 | Cosmo Technologies Ltd. | Solid composition for the oral administration of dyes and diagnostic use thereof |
| CN104255744A (en) * | 2014-08-30 | 2015-01-07 | 山东理工大学 | Method for preparing silicon dioxide/octacalcium phosphate granules for releasing methylene blue dimer |
| CN104888217A (en) * | 2009-06-12 | 2015-09-09 | 鹿特丹伊拉斯谟大学医疗中心 | Targeted nano-photo drug for photodynamic therapy of cancer |
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Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS55158848A (en) * | 1979-05-31 | 1980-12-10 | Hitachi Metals Ltd | Bentonite |
| CN104888217A (en) * | 2009-06-12 | 2015-09-09 | 鹿特丹伊拉斯谟大学医疗中心 | Targeted nano-photo drug for photodynamic therapy of cancer |
| WO2011107945A1 (en) * | 2010-03-04 | 2011-09-09 | Cosmo Technologies Ltd. | Solid composition for the oral administration of dyes and diagnostic use thereof |
| CN102811747A (en) * | 2010-03-04 | 2012-12-05 | 科斯莫科技有限公司 | Solid composition for the oral administration of dyes and diagnostic use thereof |
| CN104255744A (en) * | 2014-08-30 | 2015-01-07 | 山东理工大学 | Method for preparing silicon dioxide/octacalcium phosphate granules for releasing methylene blue dimer |
Non-Patent Citations (4)
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| "Modulation of release mechanisms of methylene blue (MB) monomers and dimers from silica-MB@shellac synthesized by antisolvent crystallization";Wei Zhang et al;《Materials Science & Engineering C》;20191024;第107卷;1-13 * |
| "Release behavior of methylene blue dimers from silica-methylene blue@octacalcium phosphate powders in phosphate-buffered saline and lysosome-like buffer";Chengfeng Li et al;《J Sol-Gel Sci Technol》;20150422;第75卷;397-406 * |
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