CN108159430A - A kind of preparation method of mequindox taste masking nano-prodrug - Google Patents
A kind of preparation method of mequindox taste masking nano-prodrug Download PDFInfo
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Abstract
The present invention provides a kind of preparation method of mequindox taste masking nano-prodrug, with the 41 type meso-porous nano material MSN NH of MCM of amino functional2For carrier, mequindox is fixed in the duct of meso-porous nano material by the schiff bases covalent bond of acid-sensitive, mequindox nano-prodrug MEQ@MSN NH are made2, to realize the purpose of taste masking.Mequindox is successfully loaded in the hole of mesoporous silicon oxide, and forms the dispersion spherical particle that average diameter is about 100nm.Extracorporeal releasing experiment the result shows that, release rate of the Nano medication in saliva is simulated in 5 minutes is only 8.7%, it is seen that its taste masking is functional；It is discharged rapidly in simulated gastric fluid, the 67% of releasable total drugloading rate in 30min in 24 hours discharges and finish, shows its excellent drug carrier and sustained release performance substantially.
Description
Technical field
The present invention relates to the preparation methods of mequindox taste masking nano-prodrug.
Background technology
Mequindox also known as trichomonas net (Mequindox, MEQ) are the antibacterial and growth promotion medicine succeeded in developing by China, right
Piglet yellow scour, dysentery characterized by white mucous stool, calf diarrhea, paratyphoid, the white scour of chicken, avian colibacillosis etc. have the effect of fine, and antimicrobial spectrum
Extensively, be not likely to produce drug resistance, it is cheap and as the drug of first choice for the treatment of animal and bird intestines infection.But mequindox is because water-soluble
Property poor, bitter, metabolism is fast and limits its application.Therefore, before developing mequindox taste masking nanometer by simple effective method
Medicine for overcome mequindox bitter, metabolism it is fast the problems such as veterinary clinic there is an urgent need to.
MCM-41 types mesoporous silicon dioxide nano particle (mesoporous silica nanoparticles, MSN) has
The features such as uniform mesopore orbit, the skeleton structure of stabilization and good biocompatibility and be considered as that ideal drug carries
Body；Moreover, specific surface area huge MSN and specific pore volume can load a variety of drugs, and can be to medicine in its mesopore orbit
Object plays slow releasing function, improves the persistence of drug effect.Therefore, MCM-41 types MSN grinding in terms of drug delays controlling agent in recent years
Study carefully increasingly extensive.However, as opening mesoporous material, drug can its freely in or out duct, in order to assign its controlled capability
It can, it usually needs cumbersome ground functional modification is carried out to mesoporous material, this can undoubtedly be caused in the future, and production technology complexity, price are held high
Your the problems such as.Therefore, sustained-release preparation of the development technology simply using mesoporous material as carrier is one of focus of current research,
Especially veterinary drug preparation is even more so.
Invention content
In order to overcome mequindox bitter, be metabolized the problems such as fast, before a kind of mequindox taste masking nanometer
The preparation method of medicine.With the MCM-41 type meso-porous nano materials (MSN-NH of amino functional2) it is pharmaceutical carrier, pass through schiff bases
Mequindox is fixed on meso-porous nano material by covalent bond, and simply and effectively acetyl first is being delivered by mesoporous material to realize
Quinoline.
The technical solution adopted by the present invention is：
A kind of preparation method of mequindox taste masking nano-prodrug, includes the following steps：
(1) synthesis of meso-porous nano material MSN
The NaOH solution 7.0mL of 2.0g (5.48mmol) CTAB and 2mol/L is added in the distilled water of 960mL successively,
It is stirred with the speed of 900r/min, and after heating solution temperature being made to be raised to 80 DEG C, 10mL is added dropwise into reaction mixture
The TEOS of (44.8mmol), reaction mixture is blue from no discoloration during dropwise addition and quickly becomes white emulsion, is added dropwise
After the completion, continue to stir 2h with the speed of 900r/min, be cooled to room temperature, be filtered under diminished pressure collection white depositions, the sediment
It is fully washed with redistilled water and methanol successively, reduced pressure at room temperature obtains MCM-41 type meso-porous nano materials of the 3.7g containing masterplate
CTAB@MSN；In order to remove the CTAB masterplates in mesoporous material duct, 2.0g CTAB containing the masterplate material@of above-mentioned preparation are weighed
MSN is scattered in 50mL methanol, and adds in the concentrated hydrochloric acid of 1.0mL, and reaction mixture is stirred at reflux 12 in 80 DEG C of water-bath
After hour, the solid sample being collected by centrifugation is scattered in again in 50mL methanol, and adds in the concentrated hydrochloric acid of 1.0mL, and reaction is mixed
After conjunction liquid flows back 12 hours again, the solid being collected by centrifugation fully is washed with methanol, centrifuged, and room temperature is dried under reduced pressure to obtain 1.26g
MCM-41 type white powder meso-porous nano materials MSN.
(2) amination nanometer material MSN-NH2Synthesis
1.0g meso-porous nano materials MSN is scattered in 2mL n-hexanes, states add in 1.0mL's in suspension then up
3- aminopropyl trimethoxysilanes (APTES), stirring at normal temperature 48h, the solid sample being collected after centrifugation fully washs with methanol, from
The heart collects to obtain 1.08g MCM-41 type white powder amination nanometer materials MSN-NH2。
(3) synthesis of MEQ@MSN-NH2
The nano material MSN-NH of 200mg amino functionals is weighed respectively2With 300mg mequindoxes in filling 30mL methanol
Round-bottomed flask in, be heated to reflux 5h, after reduced pressure, solid product is fully washed to remove excessive acetyl first with methanol
Quinoline, is collected by centrifugation solid sample, and room temperature obtains 211mg faint yellow solid powder MEQ@MSN-NH after being dried under reduced pressure2。
Since the schiff bases between connection mesoporous silicon dioxide nano carrier and mequindox has sensitivity to acid, in neutrality
In cavity environment, which can be stabilized, and drug is firmly bound by nano-carrier, and plays the effect of taste masking；
On the other hand, when drug is reached in acidic gastric juice, the schiff bases fracture of pH value response, mequindox can be released, be reached
The purpose of drug carrier.Extracorporeal releasing experiment shows that the mequindox Nano medication has good taste masking performance and medicament transport
Performance.
The advantage of the invention is that：
Mequindox is coupled on the meso-porous nano material of amino functional obtained one by the schiff bases of acid-sensitive
Kind has pH response type mequindox taste masking nano-prodrugs.The preparation method of the mequindox odor mask is simple, easily operated, material
Expect cheap and easy to get.Release rate of the Nano medication in saliva is simulated in 5 minutes is only the 8.7% of its total drugloading rate, it is seen that its
Taste masking is functional；It is discharged rapidly in simulated gastric fluid, 30min can release the 67% of drugloading rate, be released substantially in 24 hours
It discharges complete, shows its excellent drug carrier function.The taste masking of mequindox is realized by pH- response controls, it not only can be with
The problems such as mequindox is avoided to contact stimulated cultivated animals food refusal with taste bud in oral cavity, and mequindox can be overcome
The shortcomings that slightly water-soluble, ensure that the assimilation effect of drug, additionally it is possible to extend the action time of mequindox, be improved by being sustained
It is metabolized the shortcomings that fast.
Description of the drawings
Fig. 1 is MSN-NH2(a) and MEQ@MSN-NH2(b) scanning electron microscope (SEM) photograph.
Fig. 2 is MSN-NH2(a) and MEQ@MSN-NH2(b) transmission electron microscope picture.
Fig. 3 is nano particle MSN-NH2And MEQ@MSN-NH2Nitrogen adsorption-desorption isotherm.
Fig. 4 is nano particle MSN-NH2And MEQ@MSN-NH2BJH methods obtain pore size distribution curve.
Fig. 5 is MSN (a), MSN-NH2(b)、MEQ@MSN-NH2(c) and the FTIR spectrum figure of MEQ (d).
Fig. 6 is MSN, MSN-NH of nano particle2And MEQ@MSN-NH2Thermogravimetric curve.
Fig. 7 is MEQ@MSN-NH of the Nano medication in simulation saliva and simulated gastric fluid2Cumulative release curve.
Specific embodiment
Below by way of specific embodiment, the invention will be further described, and combines corresponding experiment and further illustrate the present invention
Advantageous effect.But present disclosure is not limited thereto, it is impossible to therefore and it is interpreted as limitation of the scope of the invention.
Embodiment 1：
1 materials and methods
1.1 test periods, place
The present invention is in October, 2013 in April, 2014 in veterinary drug research institute of animal science and technology institute of Agricultural University Of Jiangxi
Interior completion.
1.2 test materials and instrument
1.2.1 the used cetyl trimethylammonium bromide of experiment reagent experiment (CTAB, chemistry are pure), 3- aminopropyls three
Ethoxysilane (APTES, chemistry are pure), ethyl orthosilicate (TEOS, chemistry are pure) are purchased from Chinese Medicine group Solution on Chemical Reagents in Shanghai
Company；Mequindox, Beijing middle peasant send out Huang gang branch company of pharmaceutcal corporation, Ltd；Concentrated hydrochloric acid (analysis is pure), sodium hydroxide (analysis
It is pure), the conventional reagents such as absolute ethyl alcohol (analysis pure) be purchased from Tianjin good fortune morning chemical reagent factory, redistilled water (self-control).
1.2.2 laboratory apparatus field emission scanning electron microscope (SEM) is Hitachi, Japan S4800 types；Transmitted electron
Microscope (TEM) is FEI Co. of U.S. FEI Tecnai G20 types；N2Adsorption-desorption experiment is using the complete of Merck ＆ Co., Inc of the U.S.
Automatic specific surface and 3020 types of pore analysis instrument TriStar II and the BELSORP-max types of Japanese Beyer Co., Ltd, sample-
It is tested at 195.9 DEG C, data calculate specific surface area and aperture using BET-BJH methods；Ultraviolet test uses Shanghai rib light
The G54 ultraviolet-uisible spectrophotometers of Technology Co., Ltd.'s production.
1.3 experimentation
1.3.1 the synthesis of meso-porous nano material MSN is successively by the NaOH solution of 2.0g (5.48mmol) CTAB and 2mol/L
7.0mL is added to the distilled water of 960mL, is stirred with the speed of 900r/min, after heating makes the temperature of solution be raised to 80 DEG C, to anti-
The TEOS that 10mL (44.8mmol) is added dropwise in mixed liquor is answered, reaction mixture is blue and fast by no discoloration during dropwise addition
Speed becomes white emulsion, continues to stir 2h with the speed of 900r/min, is cooled to room temperature, is filtered under diminished pressure collection white precipitate
Object, the sediment are fully washed successively with redistilled water and methanol, and reduced pressure at room temperature obtains MCM-41 types of the 3.7g containing masterplate
Meso-porous nano material C TAB@MSN.In order to remove the CTAB masterplates in mesoporous material duct, the 2.0g for weighing above-mentioned preparation contains mould
Plate material CTAB@MSN are scattered in 50mL methanol, and add in the concentrated hydrochloric acid of 1.0mL, and reaction mixture is in 80 DEG C of water-bath
After being stirred at reflux 12 hours, the solid sample being collected by centrifugation is scattered in again in 50mL methanol, and adds in the dense salt of 1.0mL
Acid, after reaction mixture flows back 12 hours again, the solid being collected by centrifugation fully is washed with methanol, centrifuged, and room temperature decompression is dry
It is dry to obtain 1.26g MCM-41 type white powder meso-porous nano materials MSN.
1.3.2 1.0g meso-porous nano materials MSN is scattered in 2mL by the synthesis of amination nanometer material MSN-NH2
In n-hexane, the 3- aminopropyl trimethoxysilanes (APTES) that 1.0mL is added in suspension, stirring at normal temperature are stated then up
48h, the solid sample being collected after centrifugation fully are washed with methanol, 1.08g MCM-41 type white powder amino are collected by centrifugation to obtain
Change nanometer material MSN-NH2。
1.3.3 the synthesis of MEQ@MSN-NH2 weighs the nano material MSN-NH of 200mg amino functionals respectively2With
300mg mequindoxes are heated to reflux 5h in filling in the round-bottomed flask of methanol of 30mL.After reduced pressure, solid product first
Alcohol is fully washed to remove excessive mequindox and solid sample to be collected by centrifugation, and it is yellowish that room temperature obtains 211mg after being dried under reduced pressure
Color solid powder MEQ@MSN-NH2。
1.3.4 the preparation of simulation saliva (pH=6.6) and simulated gastric fluid (pH=1.0)
Simulated gastric fluid：Concentrated hydrochloric acid 16.4mL is taken, adds water about 800mL and pepsin 10g, after shaking up, is diluted with water into
1000mL adjust up to (《Republic of China Veterinary Pharmacopoeia》The preparation method of 2015 editions two annex 90).
Simulate saliva：Weigh sodium chloride 400mg, potassium chloride 400mg, CALCIUM CHLORIDE DIHYDRATE 795mg, two hypophosphite monohydrate dihydros
Sodium 690mg, potassium rhodanate 300mg, nine hydrated sodium sulfide 5mg and urea 1000mg first with after the distillation water dissolution of 800mL, determine
Hold to 1000ml, with dilute hydrochloric acid tune pH=6.6 to obtain the final product.
1.3.5 extracorporeal releasing experiment research weighs the nanoparticle MEQ MSN-NH after certain loading gage medicine2It is dissolved in artificial stomach
It in liquid, is stirred under the conditions of 37 DEG C for 24 hours, drug is made to discharge completely, centrifuged, collect supernatant；Precipitation sequentially adds the artificial of equivalent
Gastric juice is stirred for 24 hours under the conditions of 37 DEG C, centrifuge washing, and is repeated 2 times.Supernatant is merged, with UV-Vis spectrophotometric determinations
Drugloading rate is calculated according to standard curve in light absorption value.
Drugloading rate (%)=(gross mass of quality/drug-carrying nanometer particle of mequindox in drug-carrying nanometer particle) × 100%；
Envelop rate (%)=(mequindox amount in the Nano medication being collected into/the mequindox amount actually put into) ×
100%.
1.3.6 extracorporeal releasing experiment research accurately weighs a certain amount of medicament-carried nano material MEQ@MSN-NH2It is dispersed in 1mL
It discharges in solvent, is fitted into the bag filter that molecular cut off is 14000, is respectively put into the buffer solution of 19mL and dialyses.Setting
The condition of buffer solution is respectively to simulate saliva (pH=6.6), T=37 DEG C and T=37 DEG C of simulated gastric fluid (pH=1.0), every
A period of time takes out a certain amount of buffer solution and surveys its absorbance, and the buffer solution tested, which is poured into original solution, to be discharged,
The medicine realeasing rate of different time can be calculated by the ultraviolet spectra for measuring mequindox in taken buffer solution.
2 results and analysis
2.1 MEQ@MSN-NH2Carry the front and rear characterization of medicine
Fig. 1 a, Fig. 1 b are respectively MSN-NH2With MEQ@MSN-NH2Scanning electron microscope (Scanning Electron
Microscope, SEM) photo, as seen from the figure, carry the MSN-NH before and after medicine2With MEQ@MSN-NH2It is all spherical for uniform nanometer
Particle, but the two is having no apparent difference in person, illustrates that drug is loaded into inside mesopore orbit.
By sample MSN-NH2With MEQ@MSN-NH2Transmission electron microscope (Transmission Electron
Microscopy, TEM) picture (such as Fig. 2) understands that their grain size may each be about 100nm, and all arranges the hole of clear rule
Road structure.The shape appearance of meso-porous nano material before and after load medicine also without marked difference, further prompts drug to be loaded into
To the mesoporous inside of material.
The present invention passes through N2Adsorption-desorption analytic approach is to MSN-NH2Carry specific surface area, Kong Rong and the aperture progress before and after medicine
Research.It is shown by Fig. 3, carries the MSN-NH before medicine2Nitrogen adsorption-desorption isotherm be typical IV type adsorption isotherm,
Show its orderly meso-hole structure.The pharmaceutical carrier MSN-NH that BET method obtains2Specific surface area is 864.503m2/ g, Kong Rongwei
0.894cm3/g；The pore size distribution curve (Fig. 4) that BJH methods obtain shows MSN-NH2Have narrow pore-size distribution, be averaged
Aperture is 1.7566nm.MSN-NH2Good meso-hole structure ensure that its unique load efficacy of a drug.Since drug occupies mesoporous material
Duct space and MSN-NH2It compares, carries the sample MEQ@MSN-NH after medicine2Specific surface area, Kong Rong and aperture will decline,
This and MEQ@MSN-NH2Nitrogen adsorption-detachment assays data (table 1) be identical, show that mequindox has loaded really
Mesopore orbit to carrier suffers.
The structural parameters of 1 nano particle MSN-NH2 and MEQ@MSN-NH2 of table
Sample MSN, MSN-NH2With MEQ@MSN-NH2Infrared spectrogram (see Fig. 5) display, positioned at 1093cm-1、799cm-1、470cm-1The absorption at place is the suction that asymmetric stretching vibration, symmetrical stretching vibration and the bending vibration of Si-O-Si is given birth to respectively
Peak is received, positioned at 1632cm-1The absorption peak at place is attributed to the hydrone characteristic peak of MCM-41 types ordered mesoporous silicon absorption, is located at
3436cm-1The characteristic absorption at place is the flexural vibrations peak of silicone hydroxyl Si-OH and hydrone.The presence of the above absorption peak is into one
Step has proved the structure of MCM-41 type ordered mesoporous silicons MSN；Sample MSN-NH2With MEQ@MSN-NH2Also there is phase in more than position
The absorption peak answered implys that covalent drug incorporation to the amino functional of sample MSN and below does not all cause load medicinal material
The skeleton variation of material.In addition to this, compared to MSN, sample MSN-NH2In 1534cm-1The new feature peak that place occurs can be attributed to primary
The asymmetric curvature shock absorption of the N-H keys of amine shows mesoporous material by success amination.And with carry medicine before MSN-NH2Phase
Than sample MEQ@MSN-NH2Absorption peak by 1534cm-1It is displaced to 1552cm-1Place, this variation can be attributed to nano-carrier
(absorption peak is located at 1696cm to the amino on surface with the carbonyl in mequindox molecule-1) form schiff bases covalent bond the reason of institute
It causes.
The thermal stability of sample can be evaluated by thermogravimetry.Mesoporous material MSN is removed abjection duct in 100 DEG C
The desorption of the low boiling points volatile matter such as water and methanol of middle absorption is weightless outer, and property stablizes (Fig. 6) at high temperature, and small weightlessness is main
It is attributed to the degradation of micro pore-foaming agent CATB remaining in mesopore orbit；And sample MSN-NH2With MEQ@MSN-NH2In high temperature
Area suffers from apparent weightlessness, and similar thermogravimetric curve shape implies drug molecule in a manner of covalent bond and load
Drug material forms prodrugs for sample MSN-NH2Occur at 300~550 DEG C lasting weightless feature key factor in
The degradation of remaining micro pore-foaming agent CATB in third amino and duct, 550 DEG C or more of weightless then Master Home is mesoporous material
On the deep decomposition of the methylene that is modified and micro pore-foaming agent CATB.For sample MEQ@MSN-NH2It is small from 150 DEG C of appearance
Weightless key factor just have begun slowly to decompose in the mequindox being coupled on mesoporous material, 300~550 DEG C notable
Skeletal disintegration of the weightless then Master Home for the mequindox of imino group connection, 550 DEG C or more of weightlessness is then mainly by acetyl first
The depth degradation of quinoline skeleton from figure in addition it can have found, with the material MSN-NH before load medicine2It compares, unit mass
MEQ@MSN-NH2The quality 5% more lost, this matches with total drugloading rate of drug.
2.2MEQ@MSN-NH2 drugloading rates and envelop rate
Prepare a series of odor mask MEQ@MSN-NH of concentration2Simulated gastric fluid solution, use ultraviolet-visible spectrophotometer
Its absorbance is measured, standard curve is made according to the correspondence of concentration-absorbance.Nano-carrier and second are destroyed by simulated gastric fluid
Schiff bases connecting key between acyl first quinoline causes drug release, measures the absorbance of mequindox in simulated gastric fluid, according to standard song
Line computation goes out the concentration of mequindox, further in accordance with the formula of the amount of containing and envelop rate calculate the two is respectively 8.6% He
6.1%.
2.3 odor mask MEQ@MSN-NH2Release in vitro research
Fig. 7 is that the dynamics that mequindox discharges under simulation saliva and simulated gastric fluid stimulation from mesoporous material respectively is bent
Line, by cumulative release curve it is found that drug discharges rapidly in simulated gastric fluid (pH value 1.0), the burst size in 30min is more than total
Drugloading rate denies 67%；And in simulation saliva (pH value 6.6), drug release amount only only has the drug release in 11%, 5min in 30min
Amount is even more arrived less less than 9%.Usually during the administration, residence time will be shorter in the oral cavity for drug, and drug release amount will more
It is few, so as to refuse to take medicine by cultivated animals because of the bitter taste of mequindox.
3 discuss
The preparation of 3.1pH responsive type mequindox nanometer odor masks and its taste masking mechanism
This experiment has synthesized MCM-41 type mesoporous silicon oxides with cetyl trimethylammonium bromide (CTAB) for template
Nanoparticle.Although mesoporous material is it is verified that have good drug carrying ability, the unmodified mesoporous material of MCM-41 types
The duct of material remains open state, and drug can enter porous space, equally can also be freely from drug storage chamber
In release.In order to realize that mequindox selectivity in acidic gastric juice discharges, the present invention is with three ethoxy of 3- aminopropyls
Base silane has carried out amino functional to the duct of MCM-41 meso-porous nanos and MSN-NH is made2, so that it is in a manner of schiff bases
Fixed mequindox (MEQ@MSN-NH2) and achieve the purpose that taste masking.
Schiff bases refers to a kind of compound containing methylene amido C=N, also known as imines.Although two of carbon atom connection
Substituent group is all that the imines of aliphatic alkyl is unstable, still, if in two substituent groups there are one the imines for aryl if it is relatively steady
It is fixed and easily prepared.Since the carbonyl in mequindox molecule and aromatic rings are conjugated, the present invention flows back in methanol solution
Mequindox can be made to be coupled in the form of schiff bases covalent bond on meso-porous nano material and form MEQ@MSN-NH2Before nanometer
Medicine.In neutral oral environment, the schiff bases covalent systems of the stabilization can hinder the release of drug, play the effect of taste masking；
However the schiff bases of acid-sensitive reaches stomach, that is, hydrolyzable and releases drug.
3.2 odor mask MEQ@MSN-NH2External performance study
The taste bud for experiencing bitter taste is mainly distributed on tongue root, and the taste bud in drug and oral cavity is separated and plays taste masking and makees
With being one of many merits that drug packet covers technology.The evaluation of taste is equally the important link of taste masking technology development.In order to gram
Different animals are taken to the sensibility that bitter taste of drug senses and the subjectivity for tasting evaluation method, the present invention is by simulating drug
The taste masking function and effect studied to evaluate mequindox nano-prodrug of release performance in saliva and simulated gastric fluid, to ensure to tie
The reliability and reproducibility of opinion.
Although the pH value of digestive juice is affected by many factors, the pH value of normal saliva and gastric juice is respectively in 6.6~7.1 Hes
Between 0.9~1.5, therefore the pH value of simulation saliva of the present invention and simulated gastric fluid is respectively 6.6 and 1.0, to ensure
The reliability of evaluation.
Since the schiff bases of the ketone carbonyl formation on the amino and mequindox of nano carrier material channel surfaces is by therewith
The static stabilization of aromatic rings on the drug molecule of conjugation so that the imido key can firmly fetter in neutral saliva
Mequindox in mesopore orbit without the chance sensed by taste bud, so as to achieve the purpose that taste masking.On the other hand, with medicine
When object is transported to acid stomach from oral cavity, the schiff bases as pH value acid-sensitive will be hydrolyzed by hydrochloric acid in gastric juice, and drug can be from
Support material internal releases the purpose to realize medicament transport.
4 conclusions
Mequindox by the schiff bases of acid-sensitive is coupled on the meso-porous nano material of amino functional and made by the present invention
The one kind obtained has pH response type mequindox taste masking nano-prodrugs.The preparation method of the mequindox odor mask is simple, is easy to
Operation, material are cheap and easy to get.Its release in vitro result of study shows：Release of the Nano medication in saliva is simulated in 5 minutes
Rate is only the 8.7% of its total drugloading rate, it is seen that its taste masking is functional；It is discharged rapidly in simulated gastric fluid, 30min, that is, releasable
Go out the 67% of drugloading rate, release finishes substantially in 24 hours, shows its excellent drug carrier function.Pass through pH- response controls
The taste masking of mequindox is realized, not only caused cultivated animals food refusal can be contacted with taste bud in oral cavity to avoid mequindox
The problems such as, and the water solubility of mequindox can be overcome, it ensure that the assimilation effect of drug, additionally it is possible to extend mequindox
Action time improves the shortcomings that metabolism is fast by being sustained.Therefore, we have reason to believe that this is based on pH- response mequindoxes and receives
The taste masking system of rice prodrug will have a good application prospect.
Claims (1)
1. a kind of preparation method of mequindox taste masking nano-prodrug, it is characterised in that：Include the following steps：
(1) synthesis of meso-porous nano material MSN
The NaOH solution 7.0mL of 2.0g (5.48mmol) CTAB and 2mol/L is added in the distilled water of 960mL successively, with
The speed of 900r/min, and heat solution temperature is made to be raised to 80 DEG C after, 10mL is added dropwise into reaction mixture
The TEOS of (44.8mmol), reaction mixture is blue from no discoloration during dropwise addition and quickly becomes white emulsion, is added dropwise
Continue to stir 2h with the speed of 900r/min after the completion, be cooled to room temperature, be filtered under diminished pressure collection white depositions, the sediment according to
Secondary fully to be washed with redistilled water and methanol, reduced pressure at room temperature obtains MCM-41 type meso-porous nano materials of the 3.7g containing masterplate
CTAB@MSN；In order to remove the CTAB masterplates in mesoporous material duct, 2.0g CTAB containing the masterplate material@of above-mentioned preparation are weighed
MSN is scattered in 50mL methanol, and adds in the concentrated hydrochloric acid of 1.0mL, and reaction mixture is stirred at reflux 12h in 80 DEG C of water-bath
Afterwards, the solid sample being collected by centrifugation is scattered in again in 50mL methanol, and adds in the concentrated hydrochloric acid of 1.0mL, reaction mixture
It flows back again after 12h, the solid being collected by centrifugation fully is washed with methanol, centrifuged, and room temperature is dried under reduced pressure to obtain 1.26g MCM-41
Type white powder meso-porous nano material MSN；
(2) synthesis of amination nanometer material MSN-NH2
1.0g meso-porous nano materials MSN is scattered in 2mL n-hexanes, states the 3- ammonia that 1.0mL is added in suspension then up
Propyl trimethoxy silicane (APTES), stirring at normal temperature 48h, the solid sample being collected after centrifugation fully are washed with methanol, centrifuge receipts
Collect to obtain 1.08g MCM-41 type white powder amination nanometer materials MSN-NH2；
(3) synthesis of MEQ@MSN-NH2
The nano material MSN-NH of 200mg amino functionals is weighed respectively2With 300mg mequindoxes in the circle for filling 30mL methanol
In the flask of bottom, 5h is heated to reflux, after reduced pressure, solid product is fully washed with methanol to remove excessive mequindox,
Solid sample is collected by centrifugation, room temperature obtains 211mg faint yellow solid powder MEQ@MSN-NH after being dried under reduced pressure2。
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