CN108888765A - A kind of silica containing methylene blue/shellac composite particles preparation method discharging methylene blue aggregation - Google Patents
A kind of silica containing methylene blue/shellac composite particles preparation method discharging methylene blue aggregation Download PDFInfo
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- CN108888765A CN108888765A CN201810778140.XA CN201810778140A CN108888765A CN 108888765 A CN108888765 A CN 108888765A CN 201810778140 A CN201810778140 A CN 201810778140A CN 108888765 A CN108888765 A CN 108888765A
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- methylene blue
- shellac
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
- A61K41/0057—Photodynamic therapy with a photosensitizer, i.e. agent able to produce reactive oxygen species upon exposure to light or radiation, e.g. UV or visible light; photocleavage of nucleic acids with an agent
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- 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
- A61K47/02—Inorganic compounds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5015—Organic compounds, e.g. fats, sugars
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Abstract
The present invention provides a kind of silica containing methylene blue/shellac composite particles preparation method for discharging methylene blue aggregation, belongs to technical field of chemical raw material production.It is stirred 4 hours after ammonium hydroxide, methylene blue and ethyl orthosilicate is added in the mixed solution of water and ethyl alcohol, through centrifugation, washs and dried under 70 °C, the silica dioxide granule containing methylene blue being prepared is dispersed in shellac solution, phosphate buffer is added dropwise again, it is centrifuged, washs and through drying at room temperature after stirring 1 hour, the silica containing the methylene blue/shellac composite particles being prepared are heat-treated 24 hours under 90 ~ 180 °C to get the silica containing the methylene blue/shellac composite particles for arriving release methylene blue aggregation.This method simple process, cost of material are low and easy to industrialized production, and granular biological compatibility obtained is good, degradable.Methylene blue is mainly discharged from inside particle into solution in the form of dimer and tripolymer.
Description
Technical field
A kind of silica containing methylene blue/shellac composite particles preparation method discharging methylene blue aggregation,
Belong to industrial chemicals preparation method field.
Background technique
Photochemistry motivation therapy is the active material generated using the photochemical reaction of photosensitive molecular, destroys sick cell,
In a manner of the novel therapeutic for reaching therapeutic effect, i.e., photosensitive molecular is changed into excitation state by ground state under light excitation, and in molecule
In excitation process, by extra energy transmission to the oxygen molecule of surrounding, oxygen molecule is made to become active singlet oxygen molecular, realized
Bactericidal effect, this is the IIth class photochemical reaction route；And under anaerobic or hypoxia condition, photosensitive molecular is then by photosensitive point
Sub- aggregation intramolecule electric charge transfer generates living radical, and then generates reactive oxygen species object（ROS）, including high response
Cross oxygen molecule, with achieve the effect that sterilization and treatment disease, this is the Ith class photochemical reaction route.
In normal histocyte, the normal demand of tissue, and blood can satisfy by the oxygen that blood provides
In oxygen concentration be maintained in a reasonable distribution, if the concentration of oxygen in heart blood during the break is about 17mmHg,
It is about the oxygen concentration of 65mmHg in spleen.But in sick cell, due to supplying oxygen the imbalance with oxygen consumption, so that sick cell
Always the state in hypoxemia or anaerobic.For example, neoplastic cell and stroma cell disappear to oxygen in solid tumor tissues
Consumption is greater than the keeping of oxygen, and main cause has：The caused oxygen level of supply of the exception of tumor-microvessel structure and function is limited, all
Enclosing oxygen level of supply caused by Oxygen supplied level caused by tissue oxygen diffusion way is limited and anaemia factor reduces.
It can be seen that when being administered photosensitive molecular, such as methylene blue to hypoxemia or anaerobic state, methylene blue monomer institute
The IIth class photochemical reaction effect provided is very limited, because oxygen concentration is too low to be not enough to generate enough singlet oxygens
Its therapeutic effect is greatly lowered in son, and the Ith class photochemical reaction that the methylene blue molecule of dimerization volume morphing is participated in is then
It is not influenced by oxygen concentration, higher photochemical reaction efficiency can be realized in the pathological tissues such as tumour, and then improve photochemical
Learn the efficiency of photodynamic therapy.
Wherein, methylene blue dimer can be obtained by improving the concentration of methylene blue, can also be by methylene blue
Package obtains the slow-released carrier of methylene blue dimer, the technology as provided by ZL201410436007.8 into pharmaceutical carrier
Scheme, but the release behavior of pharmaceutical carrier mentioned by technical solution difference in different solutions environment is little, is not able to achieve
The pH sensitive effect of dimer release behavior, because pH value is 7.2 ~ 7.4 in normal human tissue, and in sick cell
PH value is about 4.3.Therefore exploring has the research of the pharmaceutical carrier of methylene blue aggregation release behavior of pH sensitive abnormal
It is important, and relevant report is considerably less.
Summary of the invention
The object of the present invention is to provide a kind of silica/shellac containing methylene blue for discharging methylene blue aggregation is multiple
The preparation method of particle is closed, it is characterized in that：
（1）Ammonium hydroxide and methylene blue are sequentially added in aqueous and ethyl alcohol solution, ethyl orthosilicate is added after 15 minutes in stirring,
Wherein the volume ratio of water, ethyl alcohol, ammonium hydroxide and ethyl orthosilicate is 5:26.74: 0.72:1, the concentration of methylene blue is 2.32 millis
After mole every liter, stirring 4 hours, centrifuge separation obtains sediment, successively uses the acetate of ethyl alcohol and pH=3.6 to delay sediment
Fliud flushing washing, wherein the ethyl alcohol of washing and the volume of acetate buffer solution and the volume ratio of ethyl orthosilicate are respectively 34.88：1
With 5.81：1, then the sediment for being centrifuged acquisition is dried 24 hours under 70 °C to get the dioxy containing methylene blue is arrived
Silicon carbide particle；
（2）Shellac is dissolved in ethyl alcohol, shellac solution is prepared, wherein the concentration of shellac is 10 gram per liters, will be through step
（1）The silica dioxide granule containing methylene blue being prepared is put into shellac solution, makes the silica containing methylene blue
Grain concentration be 10 gram per liters, ultrasonic treatment after five minutes, by pH value be 7.2~7.4 phosphate buffer with 0.5 ml/min
The speed of clock is added in the shellac solution containing the silica dioxide granule containing methylene blue, wherein the volume of phosphate buffer
Volume ratio with the shellac solution of the silica dioxide granule containing methylenum careuleum is 3：1, stirring was centrifugally separating to obtain sedimentation after 1 hour
Object is washed with deionized after sediment and dries 12 hours at room temperature, that is, silica/worm containing methylene blue is prepared
Glue composite particles；
（3）It will be through step（2）The silica containing the methylene blue/shellac composite particles being prepared are under 90~180 °C
The silica containing methylene blue/shellac composite particles of release methylene blue aggregation are prepared in reason 24 hours.
Wherein, it is continuously added in the phosphate buffer for being 7.2~7.4 by pH value containing the titanium dioxide containing methylene blue
During the shellac solution of silicon particle, shellac molecule in ethanol solution is dissolved in gradually from ethyl alcohol and phosphate buffer
It is precipitated out, and is deposited to the silica particles containing methylene blue in mixed solution, obtain the dioxy containing methylene blue
SiClx/shellac composite particles.It is small that 24 are handled under 90~180 °C in the silica that will contain methylene blue/shellac composite particles
When during, melting, densification occur for the shellac on composite particles surface, and composite particles Methylene Blue molecular aggregates are anti-
It answers, is changed into aggregation, wherein optimal treatment temperature is 120 °C, release methylene blue aggregation is prepared contains methylene
Silica/shellac composite particles of base indigo plant.
The beneficial effects of the present invention are：
（1）This method simple process, cost of material are low and easy to industrialized production；
（2）The silica containing methylene blue/shellac composite particles surface of preparation-obtained release methylene blue aggregation
For natural shellac, good biocompatibility is degradable, can use safely；
（3）The solution of different pH value, such as pH value be 7.2 ~ 7.4 phosphate buffer and pH value be 1.2 simulation hydrochloric acid it is slow
Fliud flushing Methylene Blue is from the silica containing methylene blue/shellac composite particles of release methylene blue aggregation with poly-
The form of collective's molecule is discharged into solution, and the mode of release shows as slow release, and release behavior is to soaking solution
PH sensitive；
（4）Silica containing methylene blue/shellac composite particles are handled 24 hours under 90~180 °C, adjustable worm
The consistency of glue clad, and then methylene blue aggregation molecule can be regulated and controled from release methylene blue aggregation containing methylene
The speed discharged in blue silica/shellac composite particles.
Detailed description of the invention
Fig. 1 be the embodiment of the present invention 1 be prepared release methylene blue aggregation the silica containing methylene blue/
The X-ray diffraction spectrogram of shellac composite particles.
Fig. 2 be the embodiment of the present invention 1 be prepared release methylene blue aggregation the silica containing methylene blue/
The SEM electron scanning micrograph of shellac composite particles.
Fig. 3 is that the phosphate buffer Methylene Blue for being 7.2 ~ 7.4 in pH value is prepared from the embodiment of the present invention 1
Discharge the case where discharging at any time in the silica containing methylene blue/shellac composite particles of methylene blue aggregation.
Fig. 4 is that the simulation hydrochloric acid buffer Methylene Blue for being 1.2 in pH value is released from what the embodiment of the present invention 1 was prepared
Put the case where discharging at any time in the silica containing methylene blue/shellac composite particles of methylene blue aggregation.
Fig. 5 be pH value be 7.2 ~ 7.4 phosphate buffer solution Methylene Blue from through 1 step of the embodiment of the present invention（2）
The case where being discharged at any time in the silica containing the methylene blue/shellac composite particles being prepared.
Fig. 6 be pH value be 1.2 simulation hydrochloric acid buffer Methylene Blue from through 1 step of the embodiment of the present invention（2）System
The case where being discharged at any time in the standby obtained silica containing methylene blue/shellac composite particles.
Specific embodiment
The present invention is further illustrated with reference to embodiments.
Embodiment 1
（1）Ammonium hydroxide and methylene blue are sequentially added in aqueous and ethyl alcohol solution, ethyl orthosilicate is added after 15 minutes in stirring,
Wherein the dosage of water, ethyl alcohol, ammonium hydroxide and ethyl orthosilicate is respectively 17.2：92：2.48：3.44 milliliters, the concentration of methylene blue
It is 2.32 mMs every liter, after stirring 4 hours, centrifuge separation obtains sediment, and sediment is successively used to ethyl alcohol and pH=3.6
Acetate buffer washing, wherein the ethyl alcohol of washing and the dosage of acetate buffer solution are respectively 120 milliliters and 20 milliliters, then are incited somebody to action
The sediment for being centrifuged acquisition dries 24 hours under 70 °C to get the silica dioxide granule containing methylene blue is arrived；
（2）Shellac is dissolved in ethyl alcohol, shellac solution is prepared, wherein the concentration of shellac is 10 gram per liters, will be through step
（1）The silica dioxide granule containing methylene blue being prepared is put into shellac solution, makes the silica containing methylene blue
Grain concentration be 10 gram per liters, ultrasonic disperse handle 5 minutes, by pH value be 7.2~7.4 phosphate buffer with 0.5 milliliter/
The speed of minute is added in the shellac solution containing the silica dioxide granule containing methylene blue, wherein the use of phosphate buffer
The dosage of amount and the shellac solution of the silica dioxide granule containing methylenum careuleum is respectively 30 milliliters and 10 milliliters, after stirring 1 hour from
The isolated sediment of the heart is washed with deionized after sediment and dries 12 hours at room temperature, that is, is prepared containing methylene
Blue silica/shellac composite particles；
（3）It will be through step（2）The silica containing the methylene blue/shellac composite particles being prepared handle 24 under 120 °C
Hour, that is, the silica containing methylene blue/shellac composite particles of release methylene blue aggregation are prepared.
The object phase of X-ray diffraction method analysis particle（See Fig. 1）.
The pattern of SEM scanning electron microscope detection particle（See Fig. 2）.
Visible spectrophotometry measurement pH value be 7.2~7.4 phosphate buffer and pH value be 1.2 simulation stomach
Acid buffer Methylene Blue is from inside the silica containing methylene blue/shellac composite particles of release methylene blue aggregation
The behavior of release（Fig. 3 and Fig. 4 are seen respectively）.Released methylene blue two is stemmed primarily from the absorption peak of 610 nanometers
Polymer molecular stems primarily from released methylene blue trimeric molecules in the absorption peak of 560 nanometers.It can be seen that
In the solution, methylene blue is in the form of aggregation from the silica/worm containing methylene blue for discharging methylene blue aggregation
It is released in glue composite particles, content of monomer is almost without mainly dimer and tripolymer.
For control for the sake of, it is seen that light spectrophotometry measurement pH value be 7.2~7.4 phosphate buffer and pH value be
The step of 1.2 simulation hydrochloric acid buffer Methylene Blue is from through embodiment 1（2）The titanium dioxide containing methylene blue being prepared
The behavior discharged inside silicon/shellac composite particles（Fig. 5 and Fig. 6 are seen respectively）.It is to be mostly derived from institute in the absorption peak of 664 nanometers
The methylene blue monomer molecule released is to be mostly derived from released methylene blue dimerization in the absorbance of 610 nanometers
Body molecule.It can be seen that in the solution, methylene blue in the form of monomer and dimer from through embodiment 1 the step of（2）Preparation
It is released in the obtained silica containing methylene blue/shellac composite particles.
Claims (1)
1. a kind of silica containing methylene blue/shellac composite particles preparation method for discharging methylene blue aggregation,
It is characterized in including the following steps：
Step 1. sequentially adds ammonium hydroxide and methylene blue in aqueous and ethyl alcohol solution, and positive silicic acid is added after 15 minutes in stirring
Ethyl ester, wherein the volume ratio of water, ethyl alcohol, ammonium hydroxide and ethyl orthosilicate is 5:26.74: 0.72:1, the concentration of methylene blue is
After 2.32 mMs every liter, stirring 4 hours, centrifuge separation obtains sediment, and sediment is successively used to the vinegar of ethyl alcohol and pH=3.6
Phthalate buffer washing, wherein the ethyl alcohol of washing and the volume of acetate buffer solution and the volume ratio of ethyl orthosilicate are respectively
34.88：1 and 5.81：1, then the sediment for being centrifuged acquisition is dried 24 hours under 70 °C to get to containing methylene blue
Silica dioxide granule；
Shellac is dissolved in ethyl alcohol and shellac solution is prepared by step 2., and wherein the concentration of shellac is 10 gram per liters, will be through step
Rapid 1 silica dioxide granule containing methylene blue being prepared is put into shellac solution, makes the silica containing methylene blue
Grain concentration be 10 gram per liters, ultrasonic treatment after five minutes, by pH value be 7.2~7.4 phosphate buffer with 0.5 ml/min
The speed of clock is added in the shellac solution containing the silica dioxide granule containing methylene blue, wherein the volume of phosphate buffer
Volume ratio with the shellac solution of the silica dioxide granule containing methylenum careuleum is 3：1, stirring was centrifugally separating to obtain sedimentation after 1 hour
Object is washed with deionized after sediment and dries 12 hours at room temperature, that is, silica/worm containing methylene blue is prepared
Glue composite particles；
Step 3. is by the silica containing the methylene blue/shellac composite particles being prepared through step 2 under 90~180 °C
The silica containing methylene blue/shellac composite particles of release methylene blue aggregation are prepared in processing 24 hours.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810778140.XA CN108888765B (en) | 2018-07-16 | 2018-07-16 | Preparation method of methylene blue aggregate-releasing silicon dioxide/shellac composite particle containing methylene blue |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810778140.XA CN108888765B (en) | 2018-07-16 | 2018-07-16 | Preparation method of methylene blue aggregate-releasing silicon dioxide/shellac composite particle containing methylene blue |
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| Publication Number | Publication Date |
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| CN108888765A true CN108888765A (en) | 2018-11-27 |
| CN108888765B CN108888765B (en) | 2021-02-26 |
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| CN201810778140.XA Expired - Fee Related CN108888765B (en) | 2018-07-16 | 2018-07-16 | Preparation method of methylene blue aggregate-releasing silicon dioxide/shellac composite particle containing methylene blue |
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
-
2018
- 2018-07-16 CN CN201810778140.XA patent/CN108888765B/en not_active Expired - Fee Related
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 (5)
| Title |
|---|
| CHENGFENG LI ET AL: ""Release behavior of methylene blue dimers from silica-methylene blue@octacalcium phosphate powders in phosphate-buffered saline and lysosome-like buffer"", 《J SOL-GEL SCI TECHNOL》 * |
| STEFAN HENNING ET AL: ""Sealing liquid-filled pectinate capsules with a shellac coating"", 《JOURNAL OF MICROENCAPSULATION》 * |
| WEI ZHANG ET AL: ""Modulation of release mechanisms of methylene blue (MB) monomers and dimers from silica-MB@shellac synthesized by antisolvent crystallization"", 《MATERIALS SCIENCE & ENGINEERING C》 * |
| WENHAO WANG ET AL: ""Improved photodynamic efficiency for methylene blue from silica-methylene blue@tannic acid-Fe(III) ions complexes in aqueous solutions"", 《ADVANCED POWDER TECHNOLOGY》 * |
| 南京林产工业学院 主编: "《林产化学工业手册下册》", 31 August 1981, 中国林业出版社出版 * |
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