CN108066316A - The method that insoluble drug solubility is improved using silicon nano-carrier - Google Patents
The method that insoluble drug solubility is improved using silicon nano-carrier Download PDFInfo
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Abstract
The invention discloses the method that insoluble drug solubility is improved using silicon nano-carrier, technical points are:Silane-water solution is as water phase, Qula leads to X 100, alkane, alcohols and pore-foaming agent mixed solvent for oil phase, water is added to formation water-in-oil inverse microemulsion in oil phase under agitation, ethyl orthosilicate (TEOS) and ammonium hydroxide are added in after microemulsion stabilization, silicon nanoparticle is formed in emulsion interface triggering polymerisation, it adds in acetone and terminates reaction, silicon nanoparticle is added in acetic acid solution after cleaning and dissolves pore-foaming agent to get nanometer grain.The nanometer grain of preparation has hollow structure, and grain size is 20 100nm, and a diameter of 5 20nm of center cavity, mesopore diameter is 1 10nm.The hollow meso-porous nano grain can encapsulate insoluble drug, improve the solubility and bioavilability of drug, new platform is provided for insoluble medicine solubilising.
Description
Technical field
This technology is related to field of biological pharmacy, particularly a kind of silicon nano-carrier that can improve insoluble drug solubility
Preparation method improves insoluble medicine solubility and bioavilability.
Background technology
One of an important factor for drug solubility is influence drug bioavailability, insoluble drug is because of dissolving in water
Degree is smaller, it is difficult to be absorbed by organisms, cause bioavilability relatively low, clinical drug effect is poor.According to statistics, the development phase is entered at present
The accounting of insoluble drug be increased to 70% from 40%, these drugs cause preparation prescription and technique due to poorly water-soluble
Complexity, bioavilability there are it is more the problem of.Therefore, the solubility and bioavilability of insoluble drug how are improved, is made
Insoluble drug realize dosage form variation be Pharmaceutical study hot and difficult issue and new drug development during important choose
War.At present there are many insoluble medicine solubilization method, such as using mixed solvent or solubilizer, cosolvent classical way are added,
The emerging medicament solubilization technology such as cyclodextrin encapsulated, microencapsulation, liposome, mixed micelle, solid dispersion technology, these solubilization techniques
The solubility property of insoluble medicine can preferably be improved, had a good application prospect.But these solubilization techniques also have should
It may be to the absorption of some drugs, physiological activity, toxicity, irritation, stabilization with limitation, such as addition of solubilizer, cosolvent
Property has an impact;Solid dispersions need pyroprocess when preparing, and do not apply to the medicament solubilization of stability difference;Liposome stability
Difference etc..Inorganic mesoporous silicon materials are widely used in field of drug delivery in recent years, the material have larger specific surface area, can
The surface duct of control can be adsorbed and load substantial amounts of drug molecule, and it is slow so as to play to slow down the rate of release of drug
Effect is released, while good biocompatibility makes it have good distribution and discharge capacity in vivo.Due to nano junction
The duct of structure, drug molecule loading are wherein difficult to conclude to form crystal again, so as to maintain amorphous state, therefore it is very suitable
It attaches together and carries insoluble drug to improve its dissolubility and stability.The form of mesoporous silicon material pharmaceutical carrier is mainly micron at present
Grade carrier or grain size are more than the nanoparticle of 200nm, and mesoporous to improve drug load with 2-50nm in carrier.By
It is larger (being more than 200nm) in the grain size of carrier, therefore there are problems that being not easy by cellular uptake.The grain size of drug delivery system is straight
The circulation time and cellular uptake mechanism for influencing it in blood are connect, grain size is more than the sub-micron of 500nm after intravenous injection administration
Particle is absorbed or by capillary network by intrapulmonary capillary mechanical retention rapidly, and grain size is more than the particle of 100nm easily by liver
With the reticuloendothelial system phagocytic of spleen and remove, grain size can enter hepatic parenchymal cells in the particle of 50-100nm, and grain size
Particle less than 50nm can then penetrate by lymphatic system and reticuloendothelial system in tumor blood vessels to enter tumour cell.
Therefore, if wanting, silicon Nano medication delivery system is made to enter after human body not to be removed quickly by body, and safe and reliable entrance cell,
Then need silicon Nano medication delivery system that there is smaller grain size.
Therefore, the present invention develops a kind of preparation side for the small particle silicon administration nano-drug administration system that can encapsulate insoluble drug
Method improves the solubility and bioavilability of insoluble drug, new platform is provided for insoluble drug solubilising.
The content of the invention
For the problem that current mesoporous silicon pharmaceutical carrier grain size is larger (being more than 200nm), it is not easy by cellular uptake, the present invention
Provide a kind of small particle silicon nanoparticle preparation method that can encapsulate insoluble drug, improve insoluble drug solubility and
Bioavilability.
To achieve the above object, technical scheme is as follows:Small particle silicon nanoparticle is prepared using reverse microemulsion method,
And encapsulate insoluble drug by pharmaceutical carrier of the nanoparticle, it is characterised in that comprise the following steps that:
1) silane is dissolved in water formation microemulsion water phase, and triton x-100, alkane, alcohols and pore-foaming agent are mixed to form micro emulsion
Liquid oil phase;
(2) oil phase is added in reactor and is stirred, and it is anti-that water then is added to formation water-in-oil type in oil phase
Phase microemulsion system continues to stir microemulsion;
(3) ethyl orthosilicate (TEOS) and ammonium hydroxide triggering polymerisation are added in after microemulsion is stablized, reaction is happened at micro emulsion
Liquid interface ultimately forms silicon nanoparticle, adds in acetone after reaction and terminates reaction;
(4) silicon nanoparticle is collected by centrifugation, and is cleaned 2-5 times with absolute ethyl alcohol and deionized water successively, removal is unreacted
Monomer and solvent;
(5) the silicon nanoparticle cleaned up is added in acetic acid solution, and the pore-foaming agent in nanoparticle is dissolved under stirring condition,
It is formed on silicon nanoparticle shell mesoporous, 2-5 times is cleaned to get nanometer grain with deionized water;
(6) silicon nanoparticle using solvent infusion method load insoluble drug, insoluble drug be dissolved in organic solvent be made into it is molten
Then liquid adds in silicon nanoparticle and is incubated with;Nanoparticle is collected by centrifugation to be cleaned 4-10 times with PBS buffer solutions, washes away unloaded
Drug to get carry medicine silicon nanoparticle.
Silicon nanoparticle prepared by above-mentioned technique is hollow, grain size 20-100nm, center cavity a diameter of 5-20nm, mesoporous
A diameter of 1-10nm, porosity 20-40%;
Silane in above-mentioned steps (1) includes but not limited to aminopropyl triethoxysilane (APS), 3- (glycidyl)
Propyl trimethoxy silicane (GPTMS), 3- (methacryloxy) propyl trimethoxy silicane (MEMO), dichloro-dimethyl silicon
Alkane (DMCS), trim,ethylchlorosilane (TMCS), hexamethyldisilazane (HMDS) etc.;Alkane includes but not limited to n-hexane, first
Alkane, propane, butane, hexane, heptane, octane etc.;Alcohols includes but not limited to methanol, ethyl alcohol, propyl alcohol, isopropanol, n-butanol, different
Butanol, n-amyl alcohol, n-hexyl alcohol, n-octyl alcohol, n-heptanol etc.;Pore-foaming agent includes but not limited to cetyl trimethylammonium bromide
(CTAB), dodecyl benzyl dimethyl ammonium chloride (DDBAC), didecyl Dimethy ammonium chloride (DDAC), tetrabutyl phosphonium bromide
Ammonium (TBAB), succimide, urea, CaCO3、MgCO3Deng.
The concentration of silane is 0.1-1% (w/v, g/ml) in water phase in the step (1);Distribution ratio is grouped in oil phase is:
Pore-foaming agent 0.001-0.1% (w/v, g/ml), alkane 59.999-79.999% (w/v, g/ml), Triton X-100 10-
20% (w/v, g/ml), alcohols 10-20% (w/v, g/ml).
Water phase and the ratio of oil phase are 1 in above-mentioned steps (2):5-40, mixing speed 200-1000rpm;Stirring is stablized
Time is 20-120min.
The final concentration of 0.1-1% of addition (w/v, g/ml) of ethyl orthosilicate (TEOS) in the upper step (3), adds in
Mass concentration (w/v, g/ml) is 28% ammonium hydroxide, and the final concentration of 0.1-1% of addition (w/v, g/ml) for adjusting ammonium hydroxide;During reaction
Between for 12-48h, reaction temperature is 20-40 DEG C;Acetone addition is the 20-50% of reaction system total volume..
Acetic acid concentration is 10%-100% (w/v) in above-mentioned steps (5), and additive amount is the 50-200% of nanoparticle volume;
Mixing speed is 200-1000rpm, reaction time 1-8h;Reaction temperature is 20-40 DEG C;
The drug loaded in above-mentioned steps (6) includes but not limited to curcumin, brufen, phenobarbital, chloramphenicol, red mould
Element, vincaleukoblastinum, nitrofurazone, amphotericin B, resveratrol, lycopene, flavones, saponin(e, resistance to general acid, sulindac, Radix Salviae Miltiorrhizae
Ketone, vitamin A acid etc.;
Solvent for use includes but not limited to the vegetable oil such as castor oil, soya-bean oil, peanut oil, olive oil, vinegar in above-mentioned steps (6)
The esters such as acetoacetic ester, ethyl oleate and atoleine, carbon tetrachloride, chloroform equal solvent;
Hollow nanometer grain incubation time in drug solution is 4-24h in above-mentioned steps (6).
The invention has the advantages that
(1) hollow nanometer grain is prepared using reverse microemulsion method in the present invention, its preparation method is simple, is wrapped by oil
One step of water reverse microemulsion system is i.e. available, and be easy to purify, without chemical modification, do not introduce other organic solvents etc..
(2) compared with other mesoporous silicon carriers, hollow nanometer grain grain size is smaller, and has hollow structure, greatly
Specific surface area is added greatly, makes it have higher drug delivered payload capability.
(3) hollow nanometer grain grain size is smaller, is easy to obtain preferable drug effect by cellular uptake.
Description of the drawings
Fig. 1 is the TEM image and particle diameter distribution for the hollow nanometer grain for encapsulating curcumin.
Fig. 2 is adriamycin and carries adriamycin silicon nanoparticle in positioning intracellular Hela, bar=30 μm.
Fig. 3 is the TEM image and particle diameter distribution for the hollow nanometer grain for encapsulating curcumin.
Fig. 4 is the TEM image and particle diameter distribution for the hollow nanometer grain for encapsulating curcumin.
Specific embodiment
The present invention is described in detail with reference to specific embodiment.Following embodiment will be helpful to the technology of this field
Personnel further understand the present invention, but do not form any limitation of the invention.Anyone is within the scope of the invention as claimed
Any type of modification made, still within the claims in the present invention protection domain.Embodiment 1
(1) aminopropyl triethoxysilane (APS) aqueous solution of 0.50% ((w/v)) is prepared as microemulsion water phase, is prepared
Cetyl trimethylammonium bromide (CTAB), hexamethylene, Triton X-100 and n-octyl alcohol mixed solution are microemulsion oil phase, respectively
Component proportion is cetyl trimethylammonium bromide (CTAB) 0.15% (w/v), hexamethylene 65.5% (w/v), Triton X-
100 18.15% (w/v), n-octyl alcohol 16.2% (w/v);
(2) oil phase is added in reactor and is stirred, and water is mutually slowly added into oil phase by speed of agitator 400rpm
The ratio of middle formation water-in-oil inverse microemulsion system, water phase and oil phase is 1:20, continue stirring 30min and form stable micro emulsion
Liquid;
(3) addition ethyl orthosilicate (TEOS) and ammonium hydroxide triggering polymerisation, ethyl orthosilicate (TEOS) and ammonium hydroxide add
Dosage is 0.45% (w/v) and 0.40% (w/v) of microemulsion system total volume, and 25 DEG C of reactions form silicon nanoparticle, reaction for 24 hours
After add in acetone terminate reaction, acetone addition be total volume 20.00%, formed silicon nanoparticle;
(4) silicon nanoparticle is cleaned three times successively with absolute ethyl alcohol and deionized water, removes unreacted monomer and solvent;
(5) nanoparticle cleaned up is added in 50% isometric (w/v) acetic acid solution, in the item of 400rpm rotating speeds
Under part react 1h removal nanoparticle in pore-foaming agent formed it is mesoporous, deionized water clean three times to get nanometer grain;
(6) silicon nanoparticle loads insoluble drug using solvent infusion method, and curcumin, which is dissolved in ethanol solution, is made into concentration
For 50mg/ml solution, measure 5ml curcumins solution and add in 50mg silicon nanoparticles, 25 DEG C are incubated for 24 hours;Nanoparticle use is collected by centrifugation
The PBS solution of pH 7.4 is cleaned five times, washes away the curcumin of unloaded to get the silicon nanoparticle of curcumin is loaded.
Silicon nanoparticle prepared by above-mentioned technique is hollow nanoparticle, and average grain diameter is 29.85 ± 2.95, nanoparticle centre bore
A diameter of 12.36 ± 3.70nm (Fig. 1), shell wall surface mesopore diameter be 8.62 ± 1.34nm, porosity 28.74%, turmeric
White, quiet clothes carrying capacity be 0.43g/g silicon nanoparticles, envelop rate 93.15%.Carrying curcumin silicon nanoparticle, there is spontaneous targeting to gather
The ability (Fig. 2) of mitochondria, process are:The cell density for adjusting human cervical carcinoma cell Hela suspensions is 5 × 104/ mL, takes
1mL cell suspension inoculations are into laser co-focusing capsule.Supernatant discarding after incubation is paved with ware bottom to cell, adds in containing isoconcentration
Doxorubicin hydrochloride (DOX), the culture medium for carrying medicine silicon nanoparticle (Si-DOX), 4h is incubated with cell altogether.Culture medium is discarded, is added in
The Mitotracker Deep Red probe solutions of 1mL 100nM are incubated 30min.Supernatant discarding, cell PBS cleaning 3 times
Afterwards, the positioning scenarios of the observation of laser confocal microscope system DOX, Si-DOX in the cell.Wherein, DOX and Mitotracker
Deep Red are excited respectively with 488nm and 633nm, and corresponding transmitted wave is 520-600nm and 650-700nm.The results show pair
In free adriamycin, mainly gather in nucleus, the Pearson's coefficient (Pearson ' s Coefficient) of the two is
0.126±0.032.And adriamycin does not enter nucleus, but be uniformly dispersed in cytoplasm, with Mitotracker points
Scattered region is identical, and the Pearson's coefficient of the two is 0.762 ± 0.065, shows that adriamycin is largely assembled in cell mitochondrial.
Embodiment 2
(1) aminopropyl triethoxysilane (APS) aqueous solution of 1.00% (w/v) is prepared as microemulsion water phase, prepares ten
Six alkyl trimethyl ammonium bromides (CTAB), hexamethylene, Triton X-100 and n-octyl alcohol mixed solution be microemulsion oil phase, each group
Distribution ratio is cetyl trimethylammonium bromide (CTAB) 0.3% (w/v), hexamethylene 60.00% (w/v), Triton X-100
21.00% (w/v), n-octyl alcohol 18.70% (w/v);
(2) oil phase is added in reactor and is stirred, and water is mutually slowly added into oil phase by speed of agitator 300rpm
The ratio of middle formation water-in-oil inverse microemulsion system, water phase and oil phase is 1:15, continue stirring 60min and form stable micro emulsion
Liquid;
(3) addition ethyl orthosilicate (TEOS) and ammonium hydroxide triggering polymerisation, ethyl orthosilicate (TEOS) and ammonium hydroxide add
Dosage is 0.80% (w/v) and 0.70% (w/v) of microemulsion system total volume, and 30 DEG C of reaction 12h form silicon nanoparticle, reaction
After add in acetone terminate reaction, acetone addition be total volume 25.00%;
(4) silicon nanoparticle is cleaned three times successively with absolute ethyl alcohol and deionized water, removes unreacted monomer and solvent;
(5) nanoparticle cleaned up is added in 30% isometric (w/v) acetic acid solution, in the item of 400rpm rotating speeds
Under part react 2h removal nanoparticle in pore-foaming agent formed it is mesoporous, deionized water clean three times to get nanometer grain;
(6) silicon nanoparticle loads insoluble drug using solvent infusion method, and curcumin, which is dissolved in ethanol solution, is made into concentration
For 50mg/ml solution, measure 5ml curcumins solution and add in 50mg silicon nanoparticles, 25 DEG C are incubated for 24 hours;Nanoparticle use is collected by centrifugation
The PBS solution of pH 7.4 is cleaned five times, washes away the curcumin of unloaded to get the silicon nanoparticle of curcumin is loaded.
Silicon nanoparticle prepared by above-mentioned technique is hollow nanoparticle, and average grain diameter is 29.85 ± 2.95nm, nanoparticle center
Bore dia is 16.62 ± 1.65nm (Fig. 3), and shell wall surface mesopore diameter is that 7.07 ± 2.54nm curcumins useful load is 0.37g/
G silicon nanoparticles, envelop rate 92.16%, porosity 25.83%.
Embodiment 3
(1) preparing 3- (methacryloxy) propyl trimethoxy silicane (MEMO) of 0.40% (w/v), (aqueous solution is
Microemulsion water phase, preparing cetyl trimethylammonium bromide (CTAB), butane, Triton X-100 and n-heptanol mixed solution is
Microemulsion oil phase, each group distribution ratio is dodecyl benzyl dimethyl ammonium chloride (DDBAC) 0.2% (w/v), butane 55.45%
(w/v), Triton X-100 19.20% (w/v), n-heptanol 25.15% (w/v);
(2) oil phase is added in reactor and is stirred, and water is mutually slowly added into oil phase by speed of agitator 300rpm
The ratio of middle formation water-in-oil inverse microemulsion system, water phase and oil phase is 1:20, continue stirring 60min and form stable micro emulsion
Liquid;
(3) addition ethyl orthosilicate (TEOS) and ammonium hydroxide triggering polymerisation, ethyl orthosilicate (TEOS) and ammonium hydroxide add
Dosage is 0.40% (w/v) and 0.30% (w/v) of microemulsion system total volume, and 30 DEG C of reaction 12h form silicon nanoparticle, reaction
After add in acetone terminate reaction, acetone addition be total volume 40.00%;
(4) silicon nanoparticle is cleaned three times successively with absolute ethyl alcohol and deionized water, removes unreacted monomer and solvent;
(5) nanoparticle cleaned up is added in 50% isometric (w/v) acetic acid solution, in the item of 400rpm rotating speeds
Under part react 1h removal nanoparticle in pore-foaming agent formed it is mesoporous, deionized water clean three times to get nanometer grain;
(6) silicon nanoparticle loads insoluble drug using solvent infusion method, and curcumin, which is dissolved in ethanol solution, is made into concentration
For 50mg/ml solution, measure 5ml curcumins solution and add in 50mg silicon nanoparticles, 25 DEG C are incubated for 24 hours;Nanoparticle use is collected by centrifugation
The PBS solution of pH 7.4 is cleaned five times, washes away the curcumin of unloaded to get the silicon nanoparticle of curcumin is loaded.
Silicon nanoparticle prepared by above-mentioned technique is hollow nanoparticle, and average grain diameter is 38.03 ± 3.77nm, nanoparticle center
Bore dia be 17.01 ± 1.40 (Fig. 4), shell wall surface mesopore diameter be 9.32 ± 1.36nm, porosity 29.68%, turmeric
White, quiet clothes carrying capacity be 0.14g/g silicon nanoparticles, envelop rate 89.31%.
Claims (9)
1. the method for insoluble drug solubility is improved using silicon nano-carrier, which is characterized in that comprise the following steps that:
(1) silane is dissolved in water formation microemulsion water phase, and triton x-100, alkane, alcohols and pore-foaming agent are mixed to form microemulsion oil
Phase;
(2) oil phase is added in reactor and is stirred, and it is micro- that water then is added to formation water-in-oil type reverse phase in oil phase
Newborn system continues to stir microemulsion;
(3) ethyl orthosilicate (TEOS) and ammonium hydroxide triggering polymerisation are added in after microemulsion is stablized, reaction is happened at microemulsion circle
At face, silicon nanoparticle is ultimately formed, acetone is added in after reaction and terminates reaction;
(4) silicon nanoparticle is collected by centrifugation, and is cleaned 2-5 times with absolute ethyl alcohol and deionized water successively, removes unreacted monomer
And solvent;
(5) the silicon nanoparticle cleaned up is added in acetic acid solution, the pore-foaming agent in nanoparticle is dissolved under stirring condition, in silicon
It is formed mesoporous on nanoparticle shell, 2-5 times is cleaned to get nanometer grain with deionized water;
(6) silicon nanoparticle loads insoluble drug using solvent infusion method, and insoluble drug is dissolved in organic solvent wiring solution-forming, so
Silicon nanoparticle is added in afterwards to be incubated with;Nanoparticle is collected by centrifugation to be cleaned 4-10 times with PBS buffer solutions, washes away the medicine of unloaded
Object is to get load medicine silicon nanoparticle.
2. according to the method described in claim 1, it is characterized in that, the silane in the step (1) includes but not limited to aminopropyl
Triethoxysilane (APS), 3- (glycidyl) propyl trimethoxy silicane (GPTMS), 3- (methacryloxy) third
Base trimethoxy silane (MEMO), dichlorodimethylsilane (DMCS), trim,ethylchlorosilane (TMCS), hexamethyldisilazane
(HMDS) one or two or more kinds in such as;Alkane includes but not limited to n-hexane, methane, propane, butane, hexane, heptane, pungent
One or two or more kinds in alkane etc.;Alcohols includes but not limited to methanol, ethyl alcohol, propyl alcohol, isopropanol, n-butanol, isobutanol, just
One or two or more kinds in amylalcohol, n-hexyl alcohol, n-octyl alcohol, n-heptanol etc.;Pore-foaming agent includes but not limited to cetyl front three
Base ammonium bromide (CTAB), dodecyl benzyl dimethyl ammonium chloride (DDBAC), didecyl Dimethy ammonium chloride (DDAC), four
Butylammonium bromide (TBAB), succimide, urea, CaCO3、MgCO3One or two or more kinds in;
The concentration of silane is 0.1-1% (w/v, g/ml) in water phase in the step (1);Distribution ratio is grouped in oil phase is:Pore
Agent 0.001-0.1% (w/v, g/ml), alkane 59.999-79.999% (w/v, g/ml), Triton X-100 10-20% (w/
V, g/ml), alcohols 10-20% (w/v, g/ml).
3. according to the method described in claim 1, it is characterized in that, in the step (2) volume ratio of water phase and oil phase be 1:
5-40, mixing speed 200-2000rpm;Mixing time is 20-120min;
It is dense to add in quality by the final concentration of 0.1-1% of addition (w/v, g/ml) of ethyl orthosilicate (TEOS) in the step (3)
It spends for the ammonium hydroxide of 28% (w/v, g/ml), and the final concentration of 0.1-1% of addition (w/v, g/ml) (w/v, g/ml) for adjusting ammonium hydroxide;
Reaction time is 12-48h, and reaction temperature is 20-40 DEG C;Acetone addition is the 20-50% of reaction system total volume.
4. according to the method described in claim 1, it is characterized in that, in the step (5) acetic acid concentration for 10%-100% (w/v,
G/ml), the additive amount in the acetic acid late into the night is the 50-200% of nanoparticle volume;Mixing speed is 200-1000rpm, and the reaction time is
1-8h;Reaction temperature is 20-40 DEG C.
5. according to the method described in claim 1, it is characterized in that, prepared silicon nanoparticle have hollow structure, grain size 20-
100nm, a diameter of 5-20nm of center cavity, mesopore diameter is 1-10nm, porosity 20-40% on wall surface.
6. according to the method described in claim 1, it is characterized in that, silicon nanoparticle have the function of it is Mitochondrially targeted, can be with spontaneous poly-
Collect in human or animal's cell mitochondrial.
7. according to the method described in claim 1, it is characterized in that, the drug loaded in the step (6) is the medicine for being insoluble in water
Object includes but not limited to curcumin, brufen, phenobarbital, chloramphenicol, erythromycin, vincaleukoblastinum, nitrofurazone, anphotericin
B, resveratrol, lycopene, flavones, saponin(e, how one kind in general acid, sulindac, tanshinone, vitamin A acid etc. or two kinds with
On.
8. it is characterized in that in the step (6) solvent for use include but not limited to castor oil, soya-bean oil, peanut oil, olive oil according to
Method described in claim 1, ethyl acetate, ethyl oleate, atoleine, carbon tetrachloride, one kind in chloroform or two kinds with
On.
9. according to the method described in claim 1, it is characterized in that, hollow nanometer grain is molten in drug in the step (6)
Incubation time is 4-24h in liquid.
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CN110898006A (en) * | 2019-11-07 | 2020-03-24 | 莆田学院 | Drug-loaded micron mesoporous silicon, transdermal preparation thereof, preparation method and application |
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CN109221178B (en) * | 2018-10-08 | 2021-01-26 | 江苏省农业科学院 | Dissolving method and application of zinc thiazole raw medicine |
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CN110898006B (en) * | 2019-11-07 | 2021-11-05 | 莆田学院 | Drug-loaded micron mesoporous silicon, transdermal preparation thereof, preparation method and application |
CN110623943A (en) * | 2019-11-14 | 2019-12-31 | 吉林大学第一医院 | Medicine carrying application of flexible hollow mesoporous organic silicon oxide |
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