CN108159430B

CN108159430B - Preparation method of mequindox taste-masking nano prodrug

Info

Publication number: CN108159430B
Application number: CN201810034215.3A
Authority: CN
Inventors: 鲍光明; 袁厚群; 胡国良; 何后军; 刘宝生; 王小莺; 刘婵娟; 王立琦; 罗军荣; 陈书鹏
Original assignee: Jiangxi Agricultural University
Current assignee: Jiangxi Agricultural University
Priority date: 2018-01-12
Filing date: 2018-01-12
Publication date: 2020-11-03
Anticipated expiration: 2038-01-12
Also published as: CN108159430A

Abstract

The invention provides a preparation method of mequindox taste-masking nano prodrug, which is amino-functionalized MCM-41 type mesoporous nano material MSN-NH₂As a carrier, the mequindox is fixed in the pore canal of the mesoporous nano material through an acid-sensitive Schiff base covalent bond to prepare the mequindox nano prodrug MEQ @ MSN-NH₂To achieve the purpose of taste masking. Mequindox was successfully loaded into the pores of the mesoporous silica and formed into dispersed spherical particles with an average diameter of about 100 nm. In vitro release experiment results show that the release rate of the nano-drug in simulated saliva within 5 minutes is only 8.7 percent, so that the nano-drug has good taste masking performance; the drug can be rapidly released in the artificial gastric juice, 67 percent of the total drug loading can be released within 30min, and the release is basically finished within 24 hours, which shows excellent drug delivery and sustained release performance.

Description

Preparation method of mequindox taste-masking nano prodrug

Technical Field

The invention relates to a preparation method of a mequindox taste-masking nano prodrug.

Background

Mequindox (Mequindox, MEQ) is an antibacterial and growth-promoting drug developed successfully in China, has good curative effects on yellow scour, white scour of piglets, calf diarrhea, paratyphoid, pullorum disease, avian colibacillosis and the like, has a wide antibacterial spectrum, is not easy to generate drug resistance, and is low in price, so that the Mequindox and MEQ are taken as the first-choice drugs for treating intestinal infection of livestock and poultry. However, mequindox has limited its use due to poor water solubility, bitter taste, and rapid metabolism. Therefore, the development of mequindox taste-masking nano prodrug by a simple and effective method for overcoming the problems of mequindox bitter taste, rapid metabolism and the like is an urgent need of veterinary clinical.

MCM-41 type Mesoporous Silica Nanoparticles (MSN) have the characteristics of uniform mesoporous pore channels, stable framework structures, good biocompatibility and the like, and are considered as ideal drug carriers; moreover, the huge specific surface area and specific pore volume of MSN can load various drugs in the mesoporous pore channel, and can play a role in slowly releasing the drugs and improve the durability of the drug effect. Therefore, in recent years, studies on the pharmaceutical sustained-release agent of MCM-41 type MSN have been increasingly conducted. However, as an open mesoporous material, a drug can freely enter and exit a pore channel of the mesoporous material, and in order to endow the controlled release performance of the mesoporous material, the mesoporous material generally needs to be subjected to complicated functional modification, which undoubtedly causes the problems of complicated production process, high price and the like in the future. Therefore, it is one of the focuses of the current research to develop a controlled release preparation with simple process and using mesoporous material as a carrier, especially a veterinary drug preparation.

Disclosure of Invention

In order to overcome the problems of mequindox such as bitter taste and rapid metabolism, the invention provides a preparation method of a mequindox taste-masking nano prodrug. Amino-functionalized MCM-41 type mesoporous nano material (MSN-NH)₂) As a drug carrier, the mequindox is fixed through Schiff base covalent bondIs fixed on the mesoporous nano material to realize the simple and effective delivery of mequindox through the mesoporous material.

The technical scheme adopted by the invention is as follows:

a preparation method of mequindox taste-masking nano prodrug comprises the following steps:

(1) synthesis of mesoporous nano material MSN

Sequentially adding 2.0g (5.48mmol) of CTAB and 7.0mL of 2mol/L NaOH solution into 960mL of distilled water, stirring at 900r/min, heating to raise the temperature of the solution to 80 ℃, dropwise adding 10mL (44.8mmol) of TEOS into the reaction mixed solution, changing the reaction mixture from colorless to blue and quickly into white emulsion in the dropwise adding process, continuing stirring at 900r/min for 2h after dropwise adding is finished, cooling to room temperature, carrying out reduced pressure filtration to collect white precipitate, fully washing the precipitate with secondary distilled water and methanol sequentially, and drying at room temperature under reduced pressure to obtain 3.7g of MCM-41 type mesoporous nanomaterial CTAB @ MSN containing a template; in order to remove CTAB template in the pore channel of the mesoporous material, 2.0g of prepared CTAB @ MSN containing the template material is weighed and dispersed in 50mL of methanol, 1.0mL of concentrated hydrochloric acid is added, the reaction mixed solution is stirred and refluxed for 12 hours in a water bath kettle at 80 ℃, the centrifugally collected solid sample is dispersed in 50mL of methanol again, 1.0mL of concentrated hydrochloric acid is added, the reaction mixed solution is refluxed for 12 hours again, the centrifugally collected solid is fully washed and centrifuged by methanol, and the 1.26g of MCM-41 type white powdery mesoporous nano material MSN is obtained after normal temperature reduced pressure drying.

(2) Aminated mesoporous silicon nano material MSN-NH₂Synthesis of (2)

Dispersing 1.0g of mesoporous nano material MSN in 2mL of n-hexane, then adding 1.0mL of 3-Aminopropyltrimethoxysilane (APTES) into the suspension, stirring at normal temperature for 48h, fully washing a solid sample collected after centrifugation by using methanol, and centrifuging to obtain 1.08g of MCM-41 type white powdery aminated mesoporous silicon nano material MSN-NH₂。

(3) Synthesis of MEQ @ MSN-NH2

Respectively weighing 200mg of amino functionalized nano material MSN-NH₂And 300mg mequindox in a round bottom containing 30mL of methanolHeating and refluxing the mixture in a flask for 5 hours, concentrating the mixture under reduced pressure, fully washing a solid product by using methanol to remove excessive mequindox, centrifugally collecting a solid sample, and drying the solid sample under reduced pressure at normal temperature to obtain 211mg of pale yellow solid powder MEQ @ MSN-NH₂。

The Schiff base connected between the mesoporous silica nano-carrier and the mequindox has acid sensitivity, so that the Schiff base can stably exist in a neutral cavity environment, and a drug is firmly bound in the nano-carrier to achieve the effect of taste masking; on the other hand, when the drug reaches the acid gastric juice, the Schiff base responding to the pH value is broken, and the mequindox can be released, so that the purpose of drug delivery is achieved. In vitro release experiments show that the mequindox nano-drug has good taste masking performance and drug transport performance.

The invention has the advantages that:

coupling mequindox to an amino-functionalized mesoporous nano material through an acid-sensitive Schiff base to prepare the pH-responsive mequindox taste-masking nano prodrug. The preparation method of the mequindox taste-masking agent is simple, easy to operate and cheap and easily available in materials. The release rate of the nano-drug in simulated saliva within 5 minutes is only 8.7 percent of the total drug loading rate, so that the nano-drug has good taste masking performance; the drug can be rapidly released in the artificial gastric juice, 67 percent of the drug-loading rate can be released within 30min, and the release is basically finished within 24 hours, which shows the excellent drug delivery function. The taste of mequindox is masked through pH-response control, the problems of food refusal and the like of cultured animals stimulated by the contact of mequindox and taste buds in the oral cavity can be avoided, the defect of difficult water solubility of mequindox can be overcome, the absorption effect of the drug is ensured, the action time of mequindox can be prolonged, and the defect of rapid metabolism is improved through slow release.

Drawings

FIG. 1 shows MSN-NH₂(a) And MEQ @ MSN-NH₂(b) Scanning electron micrograph (c).

FIG. 2 shows MSN-NH₂(a) And MEQ @ MSN-NH₂(b) Transmission electron micrograph (D).

FIG. 3 shows a diagram of nanoparticle MSN-NH₂And MEQ @ MSN-NH₂Nitrogen adsorption-desorption isotherm ofA wire.

FIG. 4 shows a diagram of nanoparticle MSN-NH₂And MEQ @ MSN-NH₂Pore size distribution curve obtained by BJH method (1).

FIG. 5 shows MSN (a), MSN-NH₂(b)、MEQ@MSN-NH₂(c) And Fourier infrared spectra of MEQ (d).

FIG. 6 shows the MSN, MSN-NH of nanoparticles₂And MEQ @ MSN-NH₂Thermogravimetric curve of (c).

FIG. 7 shows MEQ @ MSN-NH of nano-drugs in simulated saliva and simulated gastric fluid₂The cumulative drug release profile of (1).

Detailed Description

The invention is further illustrated by the following specific examples, in combination with corresponding experiments to further illustrate the beneficial effects of the invention. The present disclosure is not limited thereto and should not be construed as limiting the scope of the present disclosure.

Example 1:

1 materials and methods

1.1 time and place of experiment

The invention is completed in veterinary drug research institute of animal science and technology college of Jiangxi agricultural university from 10 months in 2013 to 4 months in 2014.

1.2 test materials and instruments

1.2.1 Experimental reagents cetyl trimethyl ammonium bromide (CTAB, chemical purity), 3-aminopropyl triethoxy silane (APTES, chemical purity), tetraethoxysilane (TEOS, chemical purity) used in the experiment were purchased from Shanghai chemical reagent company, China pharmaceutical group; mequindox, Huanggang division, agricultural and pharmaceutical Co., Ltd, Beijing; conventional reagents such as concentrated hydrochloric acid (analytically pure), sodium hydroxide (analytically pure), absolute ethyl alcohol (analytically pure) and the like are purchased from chemical reagent factories of Fochen, Tianjin and are made by secondary distilled water (self-made).

1.2.2 Experimental instruments field emission Scanning Electron Microscope (SEM) model S4800, Hitachi, Japan; transmission Electron Microscope (TEM) model FEI Tecnai G20, FEI Corp; n is a radical of₂The adsorption-desorption experiment adopts a full-automatic specific surface and pore analyzer TriStar II 3020 model of American Michk company and a BELSORP-max model of Japanese Bayer company, and the sample is shown in-1Experiments are carried out at 95.9 ℃, and the data adopts a BET-BJH method to calculate the specific surface area and the pore diameter; the ultraviolet test used was a G54 ultraviolet-visible spectrophotometer manufactured by Shanghai prism technology Co., Ltd.

1.3 Experimental procedures

1.3.1 Synthesis of mesoporous nanomaterial MSN 2.0g (5.48mmol) CTAB and 7.0mL of 2mol/L NaOH solution are sequentially added into 960mL of distilled water, stirred at 900r/min, heated to raise the temperature of the solution to 80 ℃, 10mL (44.8mmol) of TEOS is added dropwise into the reaction mixture, the reaction mixture turns from colorless to blue and quickly turns into white emulsion in the dropwise adding process, stirring at 900r/min for 2h continuously, cooling to room temperature, filtering under reduced pressure to collect white precipitate, the precipitate is fully washed with secondary distilled water and methanol in turn, and dried under reduced pressure at room temperature to obtain 3.7g MCM template-containing type mesoporous nanomaterial CTAB @ MSN of MCM-41 type. In order to remove CTAB template in the pore channel of the mesoporous material, 2.0g of prepared CTAB @ MSN containing the template material is weighed and dispersed in 50mL of methanol, 1.0mL of concentrated hydrochloric acid is added, the reaction mixed solution is stirred and refluxed for 12 hours in a water bath kettle at 80 ℃, the centrifugally collected solid sample is dispersed in 50mL of methanol again, 1.0mL of concentrated hydrochloric acid is added, the reaction mixed solution is refluxed for 12 hours again, the centrifugally collected solid is fully washed and centrifuged by methanol, and the 1.26g of MCM-41 type white powdery mesoporous nano material MSN is obtained after normal temperature reduced pressure drying.

1.3.2 Synthesis of aminated mesoporous silicon nanomaterial MSN-NH2 mesoporous silicon nanomaterial MSN 1.0g is dispersed in n-hexane 2mL, then 3-Aminopropyltrimethoxysilane (APTES) 1.0mL is added into the suspension, stirring is carried out at normal temperature for 48h, the solid sample collected after centrifugation is fully washed by methanol, and 1.08g MCM-41 type white powdery aminated mesoporous silicon nanomaterial MSN-NH is obtained after centrifugation₂。

1.3.3 Synthesis of MEQ @ MSN-NH2 separately weighed 200mg of amino-functionalized nanomaterial MSN-NH₂And 300mg of mequindox in a round bottom flask containing 30mL of methanol, heated at reflux for 5 h. After concentration under reduced pressure, the solid product was washed thoroughly with methanol to remove excess mequindox and centrifuged to collect a solid sample, which was dried under reduced pressure at room temperature to obtain 211mg of a pale yellow solidPowder MEQ @ MSN-NH₂。

1.3.4 formulation of simulated saliva (pH 6.6) and simulated gastric fluid (pH 1.0)

Artificial gastric juice: taking 16.4mL of concentrated hydrochloric acid, adding about 800mL of water and 10g of pepsin, shaking up, adding water to dilute into 1000mL, and adjusting to obtain the composition (preparation method of appendix 90 in the second part of pharmacopoeia of the people's republic of China 2015).

Simulated saliva: weighing 400mg of sodium chloride, 400mg of potassium chloride, 795mg of calcium chloride dihydrate, 690mg of sodium dihydrogen phosphate dihydrate, 300mg of potassium thiocyanate, 5mg of sodium sulfide nonahydrate and 1000mg of urea, dissolving with 800mL of distilled water, fixing the volume to 1000mL, and adjusting the pH value to 6.6 by using dilute hydrochloric acid to obtain the sodium chloride.

1.3.5 in vitro Release Experimental study weighing a certain amount of drug-loaded nanoparticles MEQ @ MSN-NH₂Dissolving in artificial gastric juice, stirring at 37 deg.C for 24 hr to completely release the medicine, centrifuging, and collecting supernatant; adding equal amount of artificial gastric juice into the precipitate, stirring at 37 deg.C for 24 hr, centrifuging, washing, and repeating for 2 times. And combining the supernatants, measuring a light absorption value by using a UV-Vis spectrophotometer, and calculating according to a standard curve to obtain the drug loading rate.

The drug loading capacity (%) - (the mass of mequindox in the drug-loaded nanoparticles/the total mass of the drug-loaded nanoparticles) is multiplied by 100%;

the encapsulation ratio (%) × (amount of mequindox in the collected nano-drug/amount of mequindox actually put) × 100%.

1.3.6 in vitro Release Experimental study accurately weighing a certain amount of drug-loaded nanomaterial MEQ @ MSN-NH₂Dispersing in 1mL release solvent, loading into dialysis bag with molecular weight cutoff of 14000, and dialyzing in 19mL buffer solution respectively. The conditions of the buffer solution are respectively set as simulated saliva (pH 6.6), T37 ℃ and artificial gastric juice (pH 1.0), T37 ℃, a certain amount of buffer solution is taken out at intervals to measure the absorbance, the tested buffer solution is poured into the original solution for release, and the release rate at different time can be calculated by measuring the ultraviolet spectrum of the mequindox in the taken buffer solution.

2 results and analysis

2.1 MEQ@MSN-NH₂Characterization before and after drug loading

FIG. 1a and FIG. 1b are MSN-NH, respectively₂And MEQ @ MSN-NH₂The Scanning Electron Microscope (SEM) photograph of (1) shows MSN-NH before and after drug loading₂And MEQ @ MSN-NH₂The two are uniform nano spherical particles, but the two have no obvious difference in appearance, which indicates that the medicine is loaded in the mesoporous pore canal.

From sample MSN-NH₂And MEQ @ MSN-NH₂The Transmission Electron Microscope (TEM) pictures (as shown in FIG. 2) show that the particles have a diameter of about 100nm and are well-ordered. The appearance of the mesoporous nano material before and after drug loading has no obvious difference, and further prompts that the drug is loaded in the mesoporous of the material.

The invention passes through N₂Adsorption-desorption analysis method for MSN-NH₂The specific surface area, pore volume and pore diameter before and after drug loading were studied. FIG. 3 shows MSN-NH before drug loading₂The nitrogen adsorption-desorption isotherm is a typical IV-type adsorption isotherm, which shows the ordered mesoporous structure. Drug carrier MSN-NH obtained by BET method₂Specific surface area of 864.503m²Per g, pore volume of 0.894cm³(ii)/g; the pore size distribution curve obtained by the BJH method (figure 4) shows that MSN-NH₂Has a narrow pore size distribution with an average pore size of 1.7566 nm. MSN-NH₂The good mesoporous structure ensures the unique drug loading capability. Because the drug occupies the pore space of the mesoporous material, and MSN-NH₂In contrast, the drug-loaded sample MEQ @ MSN-NH₂Will decrease the specific surface area, pore volume and pore diameter, which is similar to MEQ @ MSN-NH₂The data of the nitrogen adsorption-desorption experiment (table 1) are consistent, which indicates that mequindox is actually loaded in the mesoporous pore canal of the carrier.

TABLE 1 structural parameters of nanoparticles MSN-NH2 and MEQ @ MSN-NH2

Samples MSN, MSN-NH₂And MEQ @ MSN-NH₂Is shown in the infrared spectrogram (see FIG. 5) at 1093cm^-1、799cm^-1、470cm^-1The absorption peaks of the vibration are respectively the absorption peaks generated by the asymmetric stretching vibration, the symmetric stretching vibration and the bending vibration of Si-O-Si and are positioned at 1632cm^-1The absorption peak is the characteristic peak of water molecules absorbed by MCM-41 type ordered mesoporous silicon and is positioned at 3436cm^-1The characteristic absorption of (A) is the bending vibration peak of silicon hydroxyl Si-OH and water molecule. The existence of the absorption peaks further proves the structure of the MCM-41 type ordered mesoporous silicon MSN; sample MSN-NH₂And MEQ @ MSN-NH₂There were also corresponding absorption peaks at all above positions, suggesting that neither amino functionalization of the sample MSN nor the subsequent covalent drug loading process caused a backbone change of the drug loaded material. In addition, sample MSN-NH compared to MSN₂At 1534cm^-1The new characteristic peak can be attributed to asymmetric bending shock absorption of N-H bond of primary amine, which indicates that the mesoporous material is successfully aminated. And MSN-NH before drug loading₂In comparison, sample MEQ @ MSN-NH₂Has an absorption peak of 1534cm^-1Displacement to 1552cm^-1The change can be attributed to the amino group on the surface of the nano-carrier and the carbonyl group in the mequindox molecule (the absorption peak is positioned at 1696 cm)^-1) Due to the formation of Schiff base covalent bonds.

The thermal stability of the samples can be evaluated by thermogravimetric analysis. The mesoporous material MSN has stable property at high temperature (figure 6) except desorption weight loss of volatile matters with low boiling points such as water, methanol and the like adsorbed in a desorption pore channel within 100 ℃, and the tiny weight loss is mainly attributed to degradation of a residual trace pore-forming agent CATB in the mesoporous pore channel; and sample MSN-NH₂And MEQ @ MSN-NH₂The obvious weight loss phenomenon exists in a high temperature area, and the similar thermal weight loss curve shape thereof implies that the drug molecules form prodrug molecules with the drug-loaded material in a covalent bond mode₂The characteristic of continuous weight loss at 300-550 ℃ is mainly attributed to the degradation of propylamino and residual trace pore-forming agent CATB in pore channels, and the weight loss above 550 ℃ is mainly attributed to the deep decomposition of modified methylene and trace pore-forming agent CATB on the mesoporous material. For sample MEQ@MSN-NH₂The tiny weight loss from 150 ℃ is mainly attributed to the fact that mequindox coupled on the mesoporous material starts to be slowly decomposed, the obvious weight loss at 300-550 ℃ is mainly attributed to skeleton decomposition of the mequindox connected with imino, and the weight loss above 550 ℃ is mainly deeply degraded by the mequindox skeleton₂In contrast, MEQ @ MSN-NH per unit mass₂The mass lost was much 5%, which is consistent with the total drug loading.

2.2MEQ @ MSN-NH2 drug loading and encapsulation efficiency

Formulation of taste masking Agents MEQ @ MSN-NH at a range of concentrations₂The absorbance of the artificial gastric juice solution is measured by an ultraviolet-visible spectrophotometer, and a standard curve is drawn according to the corresponding relation of concentration and absorbance. The Schiff base connecting bond between the nano carrier and the mequindox is destroyed by the artificial gastric juice to release the drug, the absorbance of the mequindox in the artificial gastric juice is measured, the concentration of the mequindox is calculated according to a standard curve, and then the concentration and the encapsulation rate are respectively 8.6% and 6.1% according to the formula of the encapsulation amount and the encapsulation rate.

2.3 taste masking agent MEQ @ MSN-NH₂In vitro Release study

FIG. 7 is a kinetic curve of release of mequindox from mesoporous materials under stimulation of simulated saliva and artificial gastric juice, and it can be known from the cumulative release curve that the drug is rapidly released in artificial gastric juice (pH 1.0), and the release amount within 30min exceeds the total drug loading amount, which negates 67%; in the simulated saliva (pH 6.6), the drug release rate is only 11% within 30min, and the drug release rate is as small as less than 9% within 5 min. In general, the retention time of the medicine in the oral cavity is shorter in the administration process, and the medicine release amount is smaller, so that the medicine is not rejected by the cultured animals due to the bitter taste of mequindox.

Discussion of 3

3.1 preparation of pH-sensitive mequindox nano taste-masking agent and taste-masking mechanism thereof

In the experiment, the MCM-41 type mesoporous silica nanoparticles are synthesized by taking Cetyl Trimethyl Ammonium Bromide (CTAB) as a template agent. Although mesoporous materials have been demonstrated to have good drug loadingHowever, the channel of the unmodified MCM-41 mesoporous material is always kept in an open state, and the medicine can enter a porous space and also can be freely released from a medicine storage chamber. In order to realize the selective release of mequindox in acid gastric juice, the invention uses 3-aminopropyl triethoxysilane to carry out amino functionalization on MCM-41 mesoporous nano-pore canals to prepare MSN-NH₂So that it immobilizes mequindox (MEQ @ MSN-NH) in the form of a Schiff base₂) Thereby achieving the purpose of taste masking.

Schiff bases are compounds containing methyleneamino group C ═ N, also known as imines. Although imines in which both substituents attached to the carbon atom are aliphatic hydrocarbon groups are unstable, imines in which one of the two substituents is an aryl group are stable and easy to prepare. As carbonyl in mequindox molecules is conjugated with aromatic rings, the method can couple mequindox to the mesoporous nano material in the form of Schiff base covalent bond by refluxing in methanol solution to form MEQ @ MSN-NH₂A nano prodrug. In a neutral oral environment, the stable Schiff base covalent system can block the release of the drug and play a role in taste masking; however, the acid-sensitive Schiff base reaches the stomach and can be hydrolyzed to release the drug.

3.2 taste masking agent MEQ @ MSN-NH₂In vitro Performance Studies

The bitter taste buds are mainly distributed at the root of the tongue, and the medicine is separated from the taste buds in the oral cavity to play a role in taste masking, which is one of the advantages of the medicine packaging technology. Taste evaluation is also an important step in the development of taste masking techniques. In order to overcome the sensitivity of different animals to drug bitter taste induction and the subjectivity of taste evaluation modes, the invention evaluates the taste masking effect of the mequindox nano prodrug by researching the release performance of the drug in simulated saliva and artificial gastric juice so as to ensure the reliability and the reproducibility of a conclusion.

Although the pH value of the digestive juice is influenced by various factors, the pH values of normal saliva and gastric juice are respectively 6.6-7.1 and 0.9-1.5, so that the pH values of simulated saliva and artificial gastric juice adopted by the invention are respectively 6.6 and 1.0, so as to ensure the reliability of evaluation.

Because the Schiff base formed by amino on the surface of the pore channel of the nano carrier material and the ketonic carbonyl on the mequindox is subjected to the stabilizing action of an aromatic ring on a drug molecule conjugated with the Schiff base, the imine bond can firmly restrict the mequindox in a mesoporous pore channel in neutral saliva without the chance of being induced by taste buds, and the purpose of taste masking is achieved. On the other hand, when the medicine is delivered to the acidic stomach from the oral cavity, the Schiff base which is pH value sensitive will be hydrolyzed by gastric acid, and the medicine can be released from the inside of the carrier material to realize the purpose of medicine transportation.

4 conclusion

The invention relates to a pH response type mequindox taste-masking nano prodrug prepared by coupling mequindox to an amino functionalized mesoporous nano material through an acid sensitive Schiff base. The preparation method of the mequindox taste-masking agent is simple, easy to operate and cheap and easily available in materials. The in vitro release research result shows that: the release rate of the nano-drug in simulated saliva within 5 minutes is only 8.7 percent of the total drug loading rate, so that the nano-drug has good taste masking performance; the drug can be rapidly released in the artificial gastric juice, 67 percent of the drug-loading rate can be released within 30min, and the release is basically finished within 24 hours, which shows the excellent drug delivery function. The taste of mequindox is masked through pH-response control, the problems of food refusal and the like of cultured animals caused by the contact of mequindox with taste buds in the oral cavity can be avoided, the water solubility of mequindox can be overcome, the absorption effect of medicaments is ensured, the action time of mequindox can be prolonged, and the defect of quick metabolism is overcome through slow release. Therefore, we reasonably believe that the taste masking system based on the pH-response mequindox nano prodrug has good application prospect.

Claims

1. A preparation method of mequindox taste-masking nano prodrug is characterized by comprising the following steps: the method comprises the following steps:

(1) synthesis of mesoporous nano material MSN

Sequentially adding 2.0g (5.48mmol) of CTAB and 7.0mL of 2mol/L NaOH solution into 960mL of distilled water, heating at 900r/min to raise the temperature of the solution to 80 ℃, dropwise adding 10mL (44.8mmol) of TEOS into the reaction mixed solution, changing the reaction mixture from colorless to blue and quickly into white emulsion in the dropwise adding process, continuously stirring at 900r/min for 2h after the dropwise adding is finished, cooling to room temperature, carrying out reduced pressure filtration to collect white precipitate, fully washing the precipitate with secondary distilled water and methanol in sequence, and drying at room temperature under reduced pressure to obtain 3.7g of MCM-41 type mesoporous nanomaterial CTAB @ MSN containing a template; in order to remove a CTAB template in a pore channel of a mesoporous material, 2.0g of the prepared CTAB @ MSN containing the template material is weighed and dispersed in 50mL of methanol, 1.0mL of concentrated hydrochloric acid is added, the reaction mixed solution is stirred and refluxed for 12 hours in a water bath kettle at 80 ℃, a centrifugally collected solid sample is dispersed in 50mL of methanol again, 1.0mL of concentrated hydrochloric acid is added, the reaction mixed solution is refluxed for 12 hours again, the centrifugally collected solid is fully washed and centrifuged by methanol, and the 1.26g of MCM-41 type white powdery mesoporous nano material MSN is obtained after normal temperature reduced pressure drying;

(2) synthesis of aminated mesoporous silicon nano material MSN-NH2

Dispersing 1.0g of mesoporous nano material MSN in 2mL of n-hexane, then adding 1.0mL of 3-Aminopropyltrimethoxysilane (APTES) into the suspension, stirring at normal temperature for 48h, fully washing a solid sample collected after centrifugation by using methanol, and centrifuging to obtain 1.08g of MCM-41 type white powdery aminated mesoporous silicon nano material MSN-NH₂；

(3) Synthesis of MEQ @ MSN-NH2

Respectively weighing 200mg of amino functionalized nano material MSN-NH₂And 300mg of mequindox in a round-bottom flask containing 30mL of methanol, heating and refluxing for 5h, concentrating under reduced pressure, fully washing the solid product with methanol to remove excessive mequindox, centrifuging to collect a solid sample, and drying under reduced pressure at normal temperature to obtain 211mg of pale yellow solid powder MEQ @ MSN-NH₂。