CN106236734A - The preparation of mesoporous silicon oxide/insulin nanoparticles that phenylboric acid is modified and application - Google Patents
The preparation of mesoporous silicon oxide/insulin nanoparticles that phenylboric acid is modified and application Download PDFInfo
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Abstract
The present invention relates to preparation and the application of mesoporous silicon oxide/insulin nanoparticles that phenylboric acid is modified, the problem that can effectively solve conventional medicament carrier unidirectional release medicine, technical scheme is, first synthesizing mesoporous silicon dioxide nanoparticle, amino is modified, then by physical absorption, at meso-hole structure internal load drug insulin on its surface, further modify phenylboric acid and polysaccharide, obtain mesoporous silicon oxide/insulin nanoparticles that phenylboric acid is modified；Synthesis technique of the present invention is simple, and the nanoparticle of preparation has good biocompatibility, it is possible to the release valve of switch medicine repeatedly, release for medicine has slow-releasing and controlled-releasing action, in vivo can long circulating, reduce administration number of times, be the innovation on Remedies for diabetes.
Description
Technical field
The present invention relates to medicine, particularly phenylboric acid modify mesoporous silicon oxide/insulin nanoparticles preparation and should
With.
Background technology
Diabetes (Diabetes Mellitus, DM) be current etiology and pathogenesis recognize the most completely common
Incretion metabolism disease.Due to hypoinsulinism or effect defect caused by based on chronic hyperglycemia, merge fat
The syndrome being characterized with protein metabolism disorder.Insulin for treating diabetes starts from nineteen twenty-two, the most still for treatment 1 type glycosuria
Sick choice drug has irreplaceable effect.The route of administration of insulin is subcutaneous injection, and every day, insulin injection maintained
Blood sugar level, this reflects the control situation of diabetes to a certain extent, but under this and normal physiological conditions, pancreas is to blood glucose water
Flat regulation and maintenance also fall far short, it is possible to can cause cardiovascular disease, nephropathy, cataract etc..Although developing in recent years
And have developed the route of administration of multiple insulin, but the blood glucose fluctuation body harm to patient can't be overcome at all.Therefore send out
The change uelralante system according to internal concentration of glucose of bright one " self-regulation " " controllable type " " on-off " is compeled at eyebrow
Eyelash.
Mesoporous silicon dioxide nano particle (mesoporous silica nanoparticles, MSN) have 2～
The homogeneous mesoporous pore size of continuously adjustable in the range of 50nm, the duct of rule, stable framing structure, be prone to modify inside and outside
The feature such as surface and physiological-toxicity-free, is highly suitable as the carrier of drug molecule.Meanwhile, MSN has huge specific surface area
(＞ 900m2/g) and specific pore volume (＞ 0.9cm3/g), can load various medicine in duct, and medicine can play slow release work
With, improve the persistency of drug effect.Therefore, MSN is paid attention to day by day in the application of controlled drug transmission system aspects in recent years,
Chiyoung Park etc. utilizes 3-aminopropyltriethoxywerene werene first mesoporous silicon dioxide nano particle to be carried out surface to change
Property so that it is surface is with amino, and then recycling contains the polymer of end carboxyl and amido modified meso-porous titanium dioxide pasc reaction, is being situated between
Hole silica surface modifies one layer of pH responsive polymer, the drug molecule in controllable release mesoporous silicon oxide duct.Though
So mesoporous silicon oxide is the most much studied as pharmaceutical carrier, but fresh as reversible " on-off " formula medicament carrier system
Appear in the newspapers.
Phenylboric acid group (phenylboronic acid, PBA) can with containing vicinal diamines compound (as glucose,
Polyvinyl alcohol) Reversible binding five yuan or hexatomic ring reversible ester become study hotspot in recent years, and therefore, PBA is drawn by Kitano etc.
Enter in poly-(NVP) and form poly-(NVP-co-PBA) as glucose-sensitive molecule.PVA is due to containing two
Hydroxyl and form complex with poly-(NVP-co-PBA), insulin is added in this system, the formation of complex and dissociate can
To cause the change of viscosity, complex is gel state when being formed, and competes boric acid base group, along with Portugal with PVA after adding glucose
The increase of grape sugar concentration, gel cross-linkage density reduces, becomes dissolved colloidal state, and the release of insulin increases, thus available in response to
The release of concentration of glucose change.But medicine can only once be loaded and discharge by such carrier system, it is impossible to circulation is carried out,
Therefore this invention address that a kind of reversible load insulin system of exploitation.
Summary of the invention
For above-mentioned situation, for overcoming the defect of prior art, the purpose of the present invention is just to provide Jie that phenylboric acid is modified
The preparation of hole silicon dioxide/insulin nanoparticles and application, the problem that can effectively solve conventional medicament carrier unidirectional release medicine.
The technical scheme that the present invention solves is, first synthesizing mesoporous silicon dioxide nanoparticle, modifies amino on its surface, so
Afterwards by physical absorption, at meso-hole structure internal load drug insulin, further modify phenylboric acid and polysaccharide, must be based on benzene
Mesoporous silicon oxide/the insulin nanoparticles of boric acid modified；
Comprise the following steps:
(1) prepare mesoporous silicon dioxide nano particle: by sodium hydroxide solution 3.0-4.0mL that molar concentration is 2mol/L with
400-500mL distilled water mixes, and under the conditions of 75-85 DEG C, stirring adds 1.0-1.2g cetyl trimethylammonium bromide, then
Dropping 5.0-5.8mL tetraethyl orthosilicate, stirs 1.5-2.5h, filters, vacuum drying, 500-600 DEG C of calcining 3.5-4.5h,
Obtain mesoporous silicon dioxide nano particle；
(2) ammonification of mesoporous silicon dioxide nano particle: 400-600mg mesoporous silicon dioxide nano particle is scattered in 40-60mL
In dry toluene, stirring under room temperature, drip 1.0-2.0mL 3-aminopropyl dimethylamino silane, stir 25-35min, heating rises
Temperature is to 100-120 DEG C, and reflux 24h, and sucking filtration obtains amination mesoporous silicon dioxide nano particle；
(3) 40-60mg amination mesoporous silicon dioxide nano particle and 20-30mg insulin are dissolved in 40-60mL hydrochloric acid molten
In liquid, 8-12 DEG C of lucifuge stirring 24h, obtain mesoporous silicon oxide/insulin nanoparticles；
(4) mesoporous silicon oxide/insulin nanoparticles 20-40mg of step (3) gained is dissolved into 20-40mL organic solvent
In solution A, by 6.0-8.0mg phenylboric acid and 10-14mg 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride
Being dissolved in 5-10mL organic solvent, stirring 30min obtains solution B, solution B is joined in solution A, 24h is stirred at room temperature,
Mesoporous silicon oxide/the insulin nanoparticles modified based on phenylboric acid；
Described organic solvent is the one in ethanol, dimethyl sulfoxide, dimethylformamide or dichloromethane.
The particle diameter of mesoporous silicon oxide/insulin nanoparticles that prepared phenylboric acid is modified is 150-170nm.
Described phenylboric acid has glucose responding, and polysaccharide has vicinal diamines structure, good biocompatibility.
The drug loading of described insulin is 23%-27%.Phenylboric acid is 1:3-5 with the mass ratio of silicon dioxide.
Mesoporous silicon oxide/insulin nanoparticles that prepared phenylboric acid is modified is in preparing Remedies for diabetes
Application.
Mesoporous silicon oxide/insulin nanoparticles that phenylboric acid prepared by the inventive method is modified can be used for diabetes medicament
Preparation, it is possible to automatic sensing in the patient concentration of glucose change, it is possible to reversible opening with close insulin release
Valve, whether the release of regulating medicine, maintains the stable blood sugar level of patient, it is to avoid blood glucose fluctuation induction complication.
Synthesis technique of the present invention is simple, and the nanoparticle of preparation has good biocompatibility, it is possible to switch medicine repeatedly
Release valve, the release for medicine has slow-releasing and controlled-releasing action, in vivo can long circulating, reduce administration number of times, be glycosuria
Innovation on sick medicine.
Detailed description of the invention
Below in conjunction with embodiment, the detailed description of the invention of the present invention is described in further detail.
Embodiment 1
The present invention, in being embodied as, can be realized by following steps:
(1) mesoporous silicon dioxide nano particle is prepared: by sodium hydroxide solution 3.0mL and 400mL that molar concentration is 2mol/L
Distilled water mixes, and under the conditions of 75 DEG C, stirring adds 1.0g cetyl trimethylammonium bromide, then drips the positive silicic acid of 5.0mL four
Ethyl ester, stirs 1.5h, filters, vacuum drying, 500 DEG C of calcining 3.5h, obtains mesoporous silicon dioxide nano particle；
(2) ammonification of mesoporous silicon dioxide nano particle: 400mg mesoporous silicon dioxide nano particle is scattered in 40mL dry toluene
In, stir under room temperature, drip 1.0mL 3-aminopropyl dimethylamino silane, stir 25min, be heated to 100 DEG C, backflow
24h, sucking filtration, obtain amination mesoporous silicon dioxide nano particle；
(3) 40mg amination mesoporous silicon dioxide nano particle and 20mg insulin are dissolved in 40mL hydrochloric acid solution, 8 DEG C
Lucifuge stirring 24h, obtains mesoporous silicon oxide/insulin nanoparticles；
(4) mesoporous silicon oxide/insulin nanoparticles 20mg of step (3) gained is dissolved in 20mL ethanol to obtain solution A,
6.0mg phenylboric acid and 10mg 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride are dissolved in 5mL ethanol,
Stirring 30min obtains solution B, solution B is joined in solution A, 24h is stirred at room temperature, the mesoporous dioxy must modified based on phenylboric acid
SiClx/insulin nanoparticles.
Embodiment 2
The present invention, in being embodied as, can be realized by following steps:
(1) mesoporous silicon dioxide nano particle is prepared: by sodium hydroxide solution 4.0mL and 500mL that molar concentration is 2mol/L
Distilled water mixes, and under the conditions of 85 DEG C, stirring adds 1.2g cetyl trimethylammonium bromide, then drips the positive silicic acid of 5.8mL four
Ethyl ester, stirs 2.5h, filters, vacuum drying, 600 DEG C of calcining 4.5h, obtains mesoporous silicon dioxide nano particle；
(2) ammonification of mesoporous silicon dioxide nano particle: 600mg mesoporous silicon dioxide nano particle is scattered in 60mL dry toluene
In, stir under room temperature, drip 2.0mL 3-aminopropyl dimethylamino silane, stir 35min, be heated to 120 DEG C, backflow
24h, sucking filtration, obtain amination mesoporous silicon dioxide nano particle；
(3) 60mg amination mesoporous silicon dioxide nano particle and 30mg insulin are dissolved in 60mL hydrochloric acid solution, 12 DEG C
Lucifuge stirring 24h, obtains mesoporous silicon oxide/insulin nanoparticles；
(4) mesoporous silicon oxide/insulin nanoparticles 40mg of step (3) gained is dissolved in 40mL dimethyl sulfoxide
Solution A, is dissolved into 10mL by 8.0mg phenylboric acid and 14mg 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride
In dimethyl sulfoxide, stirring 30min obtains solution B, solution B is joined in solution A, 24h is stirred at room temperature, must repair based on phenylboric acid
Mesoporous silicon oxide/the insulin nanoparticles of decorations.
Embodiment 3
The present invention, in being embodied as, can be realized by following steps:
(1) mesoporous silicon dioxide nano particle is prepared: by sodium hydroxide solution 3.5mL and 450mL that molar concentration is 2mol/L
Distilled water mixes, and under the conditions of 80 DEG C, stirring adds 1.1g cetyl trimethylammonium bromide, then drips the positive silicic acid of 5.2mL four
Ethyl ester, stirs 2h, filters, vacuum drying, 550 DEG C of calcining 4h, obtains mesoporous silicon dioxide nano particle；
(2) ammonification of mesoporous silicon dioxide nano particle: 500mg mesoporous silicon dioxide nano particle is scattered in 45mL dry toluene
In, stir under room temperature, drip 1.2mL 3-aminopropyl dimethylamino silane, stir 30min, be heated to 110 DEG C, backflow
24h, sucking filtration, obtain amination mesoporous silicon dioxide nano particle；
(3) 50mg amination mesoporous silicon dioxide nano particle and 25mg insulin are dissolved in 45mL hydrochloric acid solution, 10 DEG C
Lucifuge stirring 24h, obtains mesoporous silicon oxide/insulin nanoparticles；
(4) mesoporous silicon oxide/insulin nanoparticles 30mg of step (3) gained is dissolved in 30mL dimethylformamide
Obtain solution A, 6.5mg phenylboric acid and 12mg 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride are dissolved into 7mL
In dimethylformamide, stirring 30min obtains solution B, solution B is joined in solution A, 24h is stirred at room temperature, must be based on phenylboric acid
Mesoporous silicon oxide/the insulin nanoparticles modified.
Embodiment 4
The present invention, in being embodied as, can be realized by following steps:
(1) mesoporous silicon dioxide nano particle is prepared: by sodium hydroxide solution 3.2mL and 470mL that molar concentration is 2mol/L
Distilled water mixes, and under the conditions of 80 DEG C, stirring adds 1.1g cetyl trimethylammonium bromide, then drips the positive silicic acid of 5.5mL four
Ethyl ester, stirs 2h, filters, vacuum drying, 550 DEG C of calcining 4h, obtains mesoporous silicon dioxide nano particle；
(2) ammonification of mesoporous silicon dioxide nano particle: 450mg mesoporous silicon dioxide nano particle is scattered in 50mL dry toluene
In, stir under room temperature, drip 1.5mL 3-aminopropyl dimethylamino silane, stir 30min, be heated to 110 DEG C, backflow
24h, sucking filtration, obtain amination mesoporous silicon dioxide nano particle；
(3) 50mg amination mesoporous silicon dioxide nano particle and 25mg insulin are dissolved in 50mL hydrochloric acid solution, 10 DEG C
Lucifuge stirring 24h, obtains mesoporous silicon oxide/insulin nanoparticles；
(4) mesoporous silicon oxide/insulin nanoparticles 35mg of step (3) gained is dissolved in 35mL dichloromethane molten
Liquid A, is dissolved into 8mL bis-by 7.0mg phenylboric acid and 11mg 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride
In chloromethanes, stirring 30min obtains solution B, solution B is joined in solution A, 24h is stirred at room temperature, and must modify based on phenylboric acid
Mesoporous silicon oxide/insulin nanoparticles.
The present invention modifies phenylboric acid and the polysaccharide containing vicinal diamines on mesoporous silicon dioxide nano particle surface, utilizes phenylboric acid
Glucose-sensitive and the binding site of vicinal diamines base and glucose competition phenylboric acid of polysaccharide, set up glucose-sensitive
Reversible insulin releasing system, not only against can the drawback of conventional medicament transmission system unidirectional release medicine, and this system
There is the characteristic of slow controlled release, in vivo can long circulating, reduce administration number of times, material therefor is respectively provided with good bio-compatible
Property, it is to avoid the secondary of body is answered by series of chemical.Related experiment data is as follows:
One, the mesoporous silicon oxide/insulin nanoparticles modified based on phenylboric acid sweeps analysis of spectrum:
Based on mesoporous silicon oxide/insulin nanoparticles that phenylboric acid is modified, the present invention is carried out Fourier's infared spectrum analysis can
Know: when after phenylboric acid with mesoporous silicon dioxide nano particle coupling, at 1645cm-1, occur in that the stretching vibration peak of amido link,
The peak of boron-oxygen key is occurred in that, it was demonstrated that phenylboric acid is effectively connected on mesoporous silicon dioxide nano particle at 1325cm-1.
Two, the sign of the mesoporous silicon oxide/insulin nanoparticles modified based on phenylboric acid:
1, the mensuration of insulin content in mesoporous silicon oxide/insulin nanoparticles based on phenylboric acid modification
Use ultraviolet spectrophotometer, at 276nm wavelength, measure the content of insulin, calculate the drug loading of sample with formula (1),
Drug loading reaches about 25%:
The medication amount of drug loading (%)=loading/(medication amount of loading+carrier amount) × 100 formulas (1)
2, the mesoporous silicon oxide/insulin nanoparticles particle diameter modified based on phenylboric acid and the mensuration of current potential
Take the mesoporous silicon oxide/insulin nanoparticles modified based on phenylboric acid in right amount to be dispersed in water, swash by Nano-ZS90 type
Light nano-particle size analysis instrument records its particle diameter and current potential is respectively 150 ~ 170nm and 18.2 ± 2.5mV.
Three, the drug release experiment of the mesoporous silicon oxide/insulin nanoparticles modified based on phenylboric acid
Polysaccharide/PBA-MSN/INS the solution taking 1mL known drug content is placed in bag filter (MWCO=25000), immerses respectively
In the PBS solution of the pH7.4 of the 50mL glucose solution (0,3,5,10mg/mL) containing variable concentrations, shake in constant-temperature table
Swinging, fixing constant-temperature table temperature 37.0 ± 0.5 DEG C, rotating speed is 100r/min.In 0,5,1,2,4,8,12,24,36,48h take
Sample, every sub-sampling supplements the release medium of same volume simultaneously, uses HPLC method to measure INS content, calculates cumulative release amount, calculates
Cumulative release percentage rate.Release data are fitted, inquire into its release Mechanisms under different concentration of glucose.Data result
Showing, when 36h, insulin is 0, and the preparation in the glucose solution of 3,5,10mg/mL is 10%, and 50%, 65%,
92%, show that said preparation has obvious concentration of glucose according to lazyness.
Four, the cell growth inhibition assay of the mesoporous silicon oxide/insulin nanoparticles modified based on phenylboric acid
Using srb assay, select the HeLa cell of exponential phase, adjusting cell number is that 1 × 104/mL is inoculated in 96 holes cultivations
Plate, every hole 100 μ L (edge hole is filled with aseptic PBS), add different sample solutions, respectively after cell attachment growth 24h
For: blank group, polysaccharide/PBA-MSN group, polysaccharide/PBA-MSN/INS group.Sample solution and cell add after cultivating 24h, every hole
Add the fixing cell of 50% trichloroacetic acid (TCA) of 50 4 DEG C of pre-coolings of μ L, move into 4 DEG C of refrigerators after fixing 10min and fix 1h,
Taking-up discards fixative, is washed with deionized water 5 times, dries, natural drying at room temperature.After room temperature is dried, every hole adds SRB dye liquor 50
μ L, room temperature lucifuge is placed 15～30min dyeing, is abandoned dye liquor, wash 5 times with the glacial acetic acid of 1%, drying at room temperature.Afterwards, with 150 μ L
The dyestuff that non-buffered Tris alkali liquor (10mM, pH=10.5) dissolving is combined with cell protein, shaking table micro oscillation (37 DEG C, 100rpm,
At microplate reader 515nm wavelength, 10min) survey the OD value of each aperture, calculate inhibitory rate of cell growth (%)=(1-experimental group
OD value/matched group OD value) × 100%, it being calculated polysaccharide/PBA-MSN group, the cell growth of polysaccharide/PBA-MSN/INS group presses down
Rate processed is respectively 3.8%, and 4.5%.Result shows, carrier polysaccharide/PBA-MSN and preparation polysaccharide/PBA-MSN/INS is at test dose
Under to cell without overt toxicity.
Five, the internal response formula behavior evaluation of the mesoporous silicon oxide/insulin nanoparticles modified based on phenylboric acid
Employing normal rat is animal model, respectively at setting time point (such as 0,3,5,10,12,24,36,48h) intravenous injection
Glucose solution (0.3g/kg), and in 0 moment intravenous injection INS solution (0.5IU/kg), polysaccharide/PBA-MSN/INS(INS
0.5IU/kg) with PBA-MSN/INS(INS 0.5IU/kg), INS solution component is not administered twice in 0 and 1h；In certain time
Interval blood sampling, measures blood sugar level by blood glucose meter.Gained blood glucose value being fitted the time, the self-regulation evaluating preparation is released
Exoergic power.Result shows, contrasts with INS solution group and PBA-MSN/INS group, polysaccharide/PBA-MSN/INS group can longer time
Between maintain glucose level relatively low in blood, illustrate that this nanoparticle has sensitivity to concentration of glucose in vivo, it is possible to
Effective uelralante.
Shown by above experiment: the present invention has an Advantageous Effects highlighted below:
(1) present invention is by the binding site of polysaccharide with internal glucose competitive binding phenylboric acid, it is possible to according to internal Portugal
The release valve opening and closing insulin that grape sugar concentration is reversible, it is achieved the drug delivery system that intelligence is controlled, in vivo can
Enough long circulating, reduce administration number of times, maintain stable blood sugar level, significantly avoid the complication caused due to blood glucose fluctuation.
(2) MSN particle diameter is little, and surface is easily modified so that this system can stablize lasting being present in physiological environment, huge
Specific surface area (＞ 900m2/g) and specific pore volume (＞ 0.9cm3/g), various medicine can be loaded in duct, and can be to medicine
Play slow releasing function, improve the persistency of drug effect.
(3) material therefor of the present invention is respectively provided with good biocompatibility, system is simple, safety, it is to avoid a series ofization
Learn the problem that reaction brings, and the preparation method of mesoporous silicon oxide/insulin nanoparticles based on phenylboric acid modification be simple,
With low cost, it is easy to prepare on a large scale, economic and social benefit is huge, is the innovation on Remedies for diabetes.
Claims (7)
1. the preparation method of mesoporous silicon oxide/insulin nanoparticles that phenylboric acid is modified, it is characterised in that the most synthesising mesoporous
Silica dioxide nano particle, modifies amino, then by physical absorption, at meso-hole structure internal load medicine islets of langerhans on its surface
Element, further modifies phenylboric acid and polysaccharide, obtains mesoporous silicon oxide/insulin nanoparticles that phenylboric acid is modified；
Specifically include following steps:
(1) prepare mesoporous silicon dioxide nano particle: by sodium hydroxide solution 3.0-4.0mL that molar concentration is 2mol/L with
400-500mL distilled water mixes, and under the conditions of 75-85 DEG C, stirring adds 1.0-1.2g cetyl trimethylammonium bromide, then
Dropping 5.0-5.8mL tetraethyl orthosilicate, stirs 1.5-2.5h, filters, vacuum drying, 500-600 DEG C of calcining 3.5-4.5h,
Obtain mesoporous silicon dioxide nano particle；
(2) ammonification of mesoporous silicon dioxide nano particle: 400-600mg mesoporous silicon dioxide nano particle is scattered in 40-60mL
In dry toluene, stirring under room temperature, drip 1.0-2.0mL 3-aminopropyl dimethylamino silane, stir 25-35min, heating rises
Temperature is to 100-120 DEG C, and reflux 24h, and sucking filtration obtains amination mesoporous silicon dioxide nano particle；
(3) 40-60mg amination mesoporous silicon dioxide nano particle and 20-30mg insulin are dissolved in 40-60mL hydrochloric acid molten
In liquid, 8-12 DEG C of lucifuge stirring 24h, obtain mesoporous silicon oxide/insulin nanoparticles；
(4) mesoporous silicon oxide/insulin nanoparticles 20-40mg of step (3) gained is dissolved into 20-40mL organic solvent
In solution A, by 6.0-8.0mg phenylboric acid and 10-14mg 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride
Being dissolved in 5-10mL organic solvent, stirring 30min obtains solution B, solution B is joined in solution A, 24h is stirred at room temperature,
Mesoporous silicon oxide/the insulin nanoparticles modified based on phenylboric acid；
Described organic solvent is the one in ethanol, dimethyl sulfoxide, dimethylformamide or dichloromethane.
The preparation method of mesoporous silicon oxide/insulin nanoparticles that phenylboric acid the most according to claim 1 is modified, it is special
Levy and be, comprise the following steps:
(1) mesoporous silicon dioxide nano particle is prepared: by sodium hydroxide solution 3.0mL and 400mL that molar concentration is 2mol/L
Distilled water mixes, and under the conditions of 75 DEG C, stirring adds 1.0g cetyl trimethylammonium bromide, then drips the positive silicic acid of 5.0mL four
Ethyl ester, stirs 1.5h, filters, vacuum drying, 500 DEG C of calcining 3.5h, obtains mesoporous silicon dioxide nano particle；
(2) ammonification of mesoporous silicon dioxide nano particle: 400mg mesoporous silicon dioxide nano particle is scattered in 40mL dry toluene
In, stir under room temperature, drip 1.0mL 3-aminopropyl dimethylamino silane, stir 25min, be heated to 100 DEG C, backflow
24h, sucking filtration, obtain amination mesoporous silicon dioxide nano particle；
(3) 40mg amination mesoporous silicon dioxide nano particle and 20mg insulin are dissolved in 40mL hydrochloric acid solution, 8 DEG C
Lucifuge stirring 24h, obtains mesoporous silicon oxide/insulin nanoparticles；
(4) mesoporous silicon oxide/insulin nanoparticles 20mg of step (3) gained is dissolved in 20mL ethanol to obtain solution A,
6.0mg phenylboric acid and 10mg 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride are dissolved in 5mL ethanol,
Stirring 30min obtains solution B, solution B is joined in solution A, 24h is stirred at room temperature, the mesoporous dioxy must modified based on phenylboric acid
SiClx/insulin nanoparticles.
The preparation method of mesoporous silicon oxide/insulin nanoparticles that phenylboric acid the most according to claim 1 is modified, it is special
Levy and be, comprise the following steps:
(1) mesoporous silicon dioxide nano particle is prepared: by sodium hydroxide solution 4.0mL and 500mL that molar concentration is 2mol/L
Distilled water mixes, and under the conditions of 85 DEG C, stirring adds 1.2g cetyl trimethylammonium bromide, then drips the positive silicic acid of 5.8mL four
Ethyl ester, stirs 2.5h, filters, vacuum drying, 600 DEG C of calcining 4.5h, obtains mesoporous silicon dioxide nano particle；
(2) ammonification of mesoporous silicon dioxide nano particle: 600mg mesoporous silicon dioxide nano particle is scattered in 60mL dry toluene
In, stir under room temperature, drip 2.0mL 3-aminopropyl dimethylamino silane, stir 35min, be heated to 120 DEG C, backflow
24h, sucking filtration, obtain amination mesoporous silicon dioxide nano particle；
(3) 60mg amination mesoporous silicon dioxide nano particle and 30mg insulin are dissolved in 60mL hydrochloric acid solution, 12 DEG C
Lucifuge stirring 24h, obtains mesoporous silicon oxide/insulin nanoparticles；
(4) mesoporous silicon oxide/insulin nanoparticles 40mg of step (3) gained is dissolved in 40mL dimethyl sulfoxide
Solution A, is dissolved into 10mL by 8.0mg phenylboric acid and 14mg 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride
In dimethyl sulfoxide, stirring 30min obtains solution B, solution B is joined in solution A, 24h is stirred at room temperature, must repair based on phenylboric acid
Mesoporous silicon oxide/the insulin nanoparticles of decorations.
The preparation method of mesoporous silicon oxide/insulin nanoparticles that phenylboric acid the most according to claim 1 is modified, it is special
Levy and be, comprise the following steps:
(1) mesoporous silicon dioxide nano particle is prepared: by sodium hydroxide solution 3.5mL and 450mL that molar concentration is 2mol/L
Distilled water mixes, and under the conditions of 80 DEG C, stirring adds 1.1g cetyl trimethylammonium bromide, then drips the positive silicic acid of 5.2mL four
Ethyl ester, stirs 2h, filters, vacuum drying, 550 DEG C of calcining 4h, obtains mesoporous silicon dioxide nano particle；
(2) ammonification of mesoporous silicon dioxide nano particle: 500mg mesoporous silicon dioxide nano particle is scattered in 45mL dry toluene
In, stir under room temperature, drip 1.2mL 3-aminopropyl dimethylamino silane, stir 30min, be heated to 110 DEG C, backflow
24h, sucking filtration, obtain amination mesoporous silicon dioxide nano particle；
(3) 50mg amination mesoporous silicon dioxide nano particle and 25mg insulin are dissolved in 45mL hydrochloric acid solution, 10 DEG C
Lucifuge stirring 24h, obtains mesoporous silicon oxide/insulin nanoparticles；
(4) mesoporous silicon oxide/insulin nanoparticles 30mg of step (3) gained is dissolved in 30mL dimethylformamide
Obtain solution A, 6.5mg phenylboric acid and 12mg 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride are dissolved into 7mL
In dimethylformamide, stirring 30min obtains solution B, solution B is joined in solution A, 24h is stirred at room temperature, must be based on phenylboric acid
Mesoporous silicon oxide/the insulin nanoparticles modified.
The preparation method of mesoporous silicon oxide/insulin nanoparticles that phenylboric acid the most according to claim 1 is modified, it is special
Levy and be, comprise the following steps:
(1) mesoporous silicon dioxide nano particle is prepared: by sodium hydroxide solution 3.2mL and 470mL that molar concentration is 2mol/L
Distilled water mixes, and under the conditions of 80 DEG C, stirring adds 1.1g cetyl trimethylammonium bromide, then drips the positive silicic acid of 5.5mL four
Ethyl ester, stirs 2h, filters, vacuum drying, 550 DEG C of calcining 4h, obtains mesoporous silicon dioxide nano particle；
(2) ammonification of mesoporous silicon dioxide nano particle: 450mg mesoporous silicon dioxide nano particle is scattered in 50mL dry toluene
In, stir under room temperature, drip 1.5mL 3-aminopropyl dimethylamino silane, stir 30min, be heated to 110 DEG C, backflow
24h, sucking filtration, obtain amination mesoporous silicon dioxide nano particle；
(3) 50mg amination mesoporous silicon dioxide nano particle and 25mg insulin are dissolved in 50mL hydrochloric acid solution, 10 DEG C
Lucifuge stirring 24h, obtains mesoporous silicon oxide/insulin nanoparticles；
(4) mesoporous silicon oxide/insulin nanoparticles 35mg of step (3) gained is dissolved in 35mL dichloromethane molten
Liquid A, is dissolved into 8mL bis-by 7.0mg phenylboric acid and 11mg 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride
In chloromethanes, stirring 30min obtains solution B, solution B is joined in solution A, 24h is stirred at room temperature, and must modify based on phenylboric acid
Mesoporous silicon oxide/insulin nanoparticles.
6. the system of the mesoporous silicon oxide/insulin nanoparticles modified according to the phenylboric acid described in any one of claim 1 or 2-5
Preparation Method, it is characterised in that the particle diameter of mesoporous silicon oxide/insulin nanoparticles that prepared phenylboric acid is modified is 150-
170nm。
7. mesoporous silicon oxide/insulin nanoparticles that the phenylboric acid that prepared by method described in any one of claim 1 or 2-5 is modified
Application in preparing Remedies for diabetes.
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| CN108421049A (en) * | 2017-12-29 | 2018-08-21 | 广东药科大学 | Mesoporous carbon particle of insulin and preparation method thereof, oral preparation and application |
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| CN110302381A (en) * | 2019-07-24 | 2019-10-08 | 南京工业大学 | Mesoporous silica nanosphere with carborane modified on surface and preparation method thereof |
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