CN114920252A - Chiral mesoporous silica nanoparticles and preparation and application thereof - Google Patents
Chiral mesoporous silica nanoparticles and preparation and application thereof Download PDFInfo
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- CN114920252A CN114920252A CN202210752305.2A CN202210752305A CN114920252A CN 114920252 A CN114920252 A CN 114920252A CN 202210752305 A CN202210752305 A CN 202210752305A CN 114920252 A CN114920252 A CN 114920252A
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- China
- Prior art keywords
- mesoporous silica
- chiral
- tartaric acid
- malic acid
- celecoxib
- Prior art date
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Abstract
The invention belongs to the field of pharmaceutical preparations, and particularly relates to chiral mesoporous silica nanoparticles, a preparation process thereof and application thereof in increasing solubility and oral absorption bioavailability of insoluble drugs. The invention takes a composition of chiral malic acid and 3-aminopropyltriethoxysilane as a chiral silane coupling agent, or a composition of chiral tartaric acid and gamma-mercaptopropyltrimethoxysilane as a chiral silane coupling agent, cetyl trimethyl ammonium bromide as a structure-directing agent, and tetraethoxysilane as a silicon source to synthesize the chiral mesoporous silica nanoparticles. The prepared malic acid or tartaric acid modified chiral mesoporous silica nanoparticles can be used for loading insoluble drugs, so that the solubility and the bioavailability of the insoluble drugs are improved.
Description
Technical Field
The invention belongs to the field of pharmaceutical preparations, and particularly relates to chiral mesoporous silica nanoparticles, a preparation process thereof and application thereof in increasing solubility and oral absorption bioavailability of insoluble drugs.
Background
Indomethacin, the name of Indometacin, is a classic and non-selective inhibitor of cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2), has anti-inflammatory, antipyretic and analgesic effects, and is available in the form of tablet, gel paste, suppository, etc. Indomethacin belongs to the BCS class ii drugs, i.e., low solubility, high permeability drugs. The main factor affecting the rate and extent of absorption of BCS class ii drugs in vivo is the dissolution capacity of the drug. From the chemical structure of indomethacin, indomethacin is an achiral drug.
Celecoxib, the British name is Celecoxib, the chemical name of the Celecoxib is 4- [5- (4-methylphenyl) -3- (trifluoromethyl) -1H-1-pyrazol-1-yl ] benzenesulfonamide, and the Celecoxib is a BCS II medicament mainly used for treating rheumatoid arthritis and osteoarthritis. Celecoxib inhibits prostaglandin production through selectively inhibiting cyclooxygenase-2 (COX-2), thereby achieving the effects of anti-inflammation and analgesia. From the chemical structure of celecoxib, celecoxib is an achiral drug.
Due to different stereo structures of chiral drugs, the chiral drugs may have great differences in the aspects of curative effect, safety, pharmacokinetics and the like in organisms with chiral environments, for example, the second-generation novel antihistamine drug levocetirizine is levorotatory form of cetirizine, and has smaller side effects and better bioavailability compared with dextrorotatory form and raceme.
Mesoporous Silica Nanoparticles (MSNs) are porous solid materials with inorganic silane structures, serve as drug carriers, and are deeply researched in the directions of drug controlled release, slow release, intelligent trigger release and the like. Because the mesoporous silica nanoparticle has the characteristics of stable skeleton structure, high specific surface area, no toxicity, good biocompatibility, biodegradability and the like, the mesoporous silica nanoparticle is often used as a carrier of a medicament. In addition, because the mesoporous silica nanoparticles contain abundant silanol groups, a new drug carrier material can be synthesized by a method of grafting functional groups, so that the mesoporous silica nanoparticles have great potential in the field of pharmaceutical preparations. The preparation of the chiral mesoporous silica nanoparticle and the use of the chiral mesoporous silica nanoparticle as a chiral carrier for entrapping achiral drugs, thereby improving the solubility and bioavailability of the drugs, is the direction of the research of medical technicians.
Disclosure of Invention
In order to overcome the defects of the prior art, the invention provides the chiral mesoporous silica nanoparticle, and the achiral medicine is coated by the chiral mesoporous silica nanoparticle, so that the solubility and the bioavailability of the medicine are improved.
The invention is realized by the following technical scheme:
the invention takes a composition of chiral malic acid and 3-aminopropyltriethoxysilane as a chiral silane coupling agent, or a composition of chiral tartaric acid and gamma-mercaptopropyltrimethoxysilane as a chiral silane coupling agent, cetyl trimethyl ammonium bromide as a structure-directing agent, and tetraethoxysilane as a silicon source to synthesize the chiral mesoporous silica nanoparticles.
Specifically, the preparation process of the chiral mesoporous silica nanoparticle comprises the following steps:
step 1: synthesizing a chiral silane coupling agent:
(1) respectively dissolving malic acid or tartaric acid in absolute ethyl alcohol;
(2) adding 3-aminopropyltriethoxysilane into anhydrous ethanol for dissolving malic acid, or adding gamma-mercaptopropyltrimethoxysilane into anhydrous ethanol for dissolving tartaric acid; stirring to obtain white precipitate, washing with absolute ethyl alcohol, centrifuging, and drying to obtain the chiral silane coupling agent.
Step 2: cetyl trimethyl ammonium bromide is dissolved in a mixed solution of redistilled water and absolute ethyl alcohol. Under the stirring of water bath at 25-30 ℃, ammonia water and chiral silane coupling agent are dissolved in the mixed solution. Then, ethyl orthosilicate is dropwise added into the mixed solution under vigorous stirring, and the mixed solution is stirred and then stands still.
And 3, step 3: and centrifuging the mixed solution after standing, and washing the obtained precipitate with water and alcohol in sequence. And drying the washed precipitate in a vacuum drying oven. Collecting white precipitate, dispersing in 0.01-0.02mol/l HCl-methanol solution, refluxing for 12 hours, centrifuging, washing with water, and drying to obtain the chiral mesoporous silica nanoparticles modified by malic acid or tartaric acid.
In the step 1, the malic acid is L-malic acid or D-malic acid; the tartaric acid is L-tartaric acid or D-tartaric acid;
the mass-volume ratio of the malic acid to the 3-aminopropyltriethoxysilane is as follows: 1: 1.5-1.7;
the mass volume ratio of the tartaric acid to the gamma-mercaptopropyltrimethoxysilane is as follows: 1: 1.2-1.4;
in the step 2, the volume ratio of redistilled water to absolute ethyl alcohol is 10-15: 3-5;
the mass volume ratio of the chiral silane coupling agent to the ammonia water is 1: 1.2-1.5;
the stirring speed is 600-1200 r/min.
The chiral mesoporous silica nanoparticles modified by malic acid or tartaric acid prepared by the invention are particles with the particle size of 50-1000nm, are in an amorphous state, and have the specific surface area of 50-250m 2 Per g, the pore diameter is 1-6nm, and the pore volume is 0.1-0.4cm 3 /g；
The chiral mesoporous silica nanoparticles modified by malic acid or tartaric acid prepared by the invention can be used for loading insoluble drugs, so that the solubility and the bioavailability of the insoluble drugs are improved.
The insoluble drug can be indomethacin, celecoxib, curcumin, praziquantel, nimesulide, carvedilol, nitrendipine and the like.
Wherein the mass ratio of the malic acid or tartaric acid modified chiral mesoporous silica nanoparticles to the insoluble drug is as follows: 2-6: 1.
further, the malic acid or tartaric acid modified chiral mesoporous silica nanoparticles are used for encapsulating insoluble drugs by an adsorption drug loading method.
Furthermore, the chiral mesoporous silica nanoparticles modified by malic acid are used for loading indometacin, and the chiral mesoporous silica nanoparticles modified by tartaric acid are used for loading celecoxib.
When the malic acid modified chiral mesoporous silica nanoparticles are used for loading the indometacin, the mass ratio of the malic acid modified chiral mesoporous silica nanoparticles to the indometacin is as follows: 3-4: 1.
when the tartaric acid modified chiral mesoporous silica nanoparticles are used for loading celecoxib, the mass ratio of the tartaric acid modified chiral mesoporous silica nanoparticles to the celecoxib is as follows: 4-5: 1.
the method for loading indometacin on the chiral mesoporous silica nanoparticles through malic acid modification comprises the following steps:
step 1: dissolving indometacin in acetone to obtain indometacin acetone solution.
Step 2: and adding the malic acid modified chiral mesoporous silica nanoparticles into the indometacin acetone solution, sealing, shading and stirring, and drying the mixture in a vacuum drying oven.
And step 3: and washing the dried precipitate with a phosphate buffer solution with the pH value of 7.4, and drying in a vacuum drying oven to obtain the nano-composite material.
The method for preparing celecoxib loaded on chiral mesoporous silica nanoparticles by tartaric acid modification comprises the following steps:
step 1: dissolving celecoxib in absolute ethyl alcohol to obtain an absolute ethyl alcohol solution of celecoxib.
Step 2: adding tartaric acid modified chiral mesoporous silica nanoparticles into the anhydrous ethanol solution of celecoxib, sealing, shading and stirring, and placing the mixture in a vacuum drying oven for drying.
And step 3: washing the dried precipitate with distilled water, and drying in a vacuum drying oven to obtain the final product.
The method is characterized by respectively using a specific surface area and aperture analyzer (BET), a Differential Scanning Calorimetry (DSC), a Scanning Electron Microscope (SEM) and a Fourier infrared transform spectrum (FTIR) to respectively represent chiral mesoporous silica nanoparticles, malic acid modified chiral mesoporous silica nanoparticles loaded indometacin and tartaric acid modified chiral mesoporous silica nanoparticles loaded celecoxib.
In vitro release test is taken as a research method, and the in vitro release effect of the drug is examined by taking the accumulative release rate of the drug changing along with time as an evaluation index under the condition that phosphate buffer solution with pH value of 6.8 is taken as a dissolution medium.
Drug in vitro release experiments:
the model drug is indometacin group
A small cup method is adopted. Accurately weighing 5mg of indomethacin, and L-malic acid modified chiral mesoporous silica nanoparticle loaded indomethacin, D-malic acid modified chiral mesoporous silica nanoparticle loaded indomethacin and blank mesoporous silica nanoparticle loaded indomethacin with the same drug content. The resulting solutions were placed in 200ml of dissolution medium (pH 6.8 phosphate buffer). The experiment was carried out at 37 ℃ and 50 rpm. At preset time points (5min, 10min, 15min, 20min, 30min, 40min, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h) 5ml of sample was taken and 5ml of dissolution medium at 37 ℃ was replenished after each sampling to maintain a constant volume. After the sample was filtered through a 0.45 μm water-based microporous membrane, the absorbance was measured at a wavelength of 320nm, and the absorbance was substituted into a standard curve to calculate the cumulative release rate, thereby drawing a dissolution curve.
The second model drug is celecoxib group
A small cup method is adopted. Accurately weighing 5mg of celecoxib, L-tartaric acid modified chiral mesoporous silica nanoparticle loaded celecoxib with the same drug content, D-tartaric acid modified chiral mesoporous silica nanoparticle loaded celecoxib and blank mesoporous silica nanoparticle loaded celecoxib. Each of the solutions was put into 200ml of a dissolution medium (pH 6.8 phosphate buffer). The experiment was carried out at 37 ℃ and 100 rpm. At preset time points (5min, 10min, 15min, 20min, 30min, 40min, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 10h, 24h) 5ml of sample was taken and 5ml of dissolution medium at 37 ℃ was replenished after each sampling to maintain a constant volume. After the sample was filtered through a 0.45 μm water-based microporous membrane, the absorbance was measured at a wavelength of 254nm, and the absorbance was substituted into a standard curve to calculate the cumulative release rate, thereby drawing a dissolution curve.
The rat in-vivo circulating intestinal perfusion test is taken as a research method, the absorption rate constant of the drug indometacin within 3 hours and the absorption rate constant of the celecoxib within 12 hours are taken as evaluation indexes to investigate the absorption of the drug.
In vivo circulating intestinal perfusion test:
the model drug is indometacin group
12 male Wistar rats with the body weight of 200 +/-20 g are randomly and equally divided into four groups, namely an indomethacin group, an L-malic acid modified chiral mesoporous silica nanoparticle loaded indomethacin group, a D-malic acid modified chiral mesoporous silica nanoparticle loaded indomethacin group and a blank mesoporous silica nanoparticle loaded indomethacin group. Weighing about 1.35mg of indometacin and a drug-loaded carrier with the same drug content, respectively adding into 300ml of K-R solution containing 50mg of phenol red, and making into intestinal absorption test solution. Before the experiment, rats are fasted for 12 hours without water supply, anesthetized (5 ml/kg of 20% urethane) and fixed. Cutting abdominal cavity (about 3cm incision) along abdominal midline of rat, cutting a small opening at upper and lower ends of experimental intestinal canal, directly inserting one end of inlet rubber tube of constant temperature peristaltic pump into the incision at upper end, and tying with wire for connection, wherein one end of the inlet rubber tube is communicated with intestinal perfusate; one end of an outlet rubber tube of the constant-temperature peristaltic pump is inserted into a small opening at the lower end and is fastened by a wire for connection. And opening the constant-temperature peristaltic pump, slowly pumping the physiological saline with the temperature of 37 +/-0.5 ℃ into the intestinal tube, flushing the content in the intestinal tube, discharging the residual liquid in the intestinal tube by using air, and then closing the intestinal tube. After the normal saline is changed into the intestinal absorption test solution, a peristaltic pump is started, the balance is carried out for 10min at a constant flow rate (5mL/min), perfusion is carried out at 2.5mL/min, 3mL of a sample is absorbed from the intestinal absorption test solution, the sample is recorded as a sample measurement result at zero time, 3mL of K-R solution containing phenol red at 37 +/-0.5 ℃ is additionally added into the intestinal absorption test solution, then, the K-R solution containing phenol red is respectively added at set time points of 0, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5 and 3h, the sampling is carried out by the same method, the K-R solution containing phenol red at 37 +/-0.5 ℃ with the same volume is added by the same method, and the experiment is stopped after the constant temperature peristaltic pump circulates for 3 h. Measuring the peak area of indometacin with high performance liquid chromatograph, measuring the absorbance of phenol red with ultraviolet spectrophotometer, substituting into the standard curve, and calculating the logarithmic value and absorption rate constant of the residual drug amount.
(II) the model drug is celecoxib group
12 male Wistar rats weighing 200 +/-20 g are randomly and evenly divided into four groups which are respectively named as a celecoxib group, an L-tartaric acid modified mesoporous silica nanoparticle loaded celecoxib group, a D-tartaric acid modified mesoporous silica nanoparticle loaded celecoxib group and a blank mesoporous silica nanoparticle loaded celecoxib group. Weighing about 7.5mg of celecoxib and a drug-loaded carrier with the same drug content, and respectively adding the celecoxib and the drug-loaded carrier into 300ml of K-R solution containing 50mg of phenol red to prepare a test solution for intestinal absorption. Before the experiment, rats are fasted for 12 hours without water prohibition, anesthetized (5 ml/kg of 20% urethane) and fixed. Cutting abdominal cavity (about 3cm incision) along abdominal midline of rat, cutting a small opening at upper and lower ends of experimental intestinal canal, directly inserting one end of inlet rubber tube of constant temperature peristaltic pump into the incision at upper end, and tying with wire for connection, wherein one end of the inlet rubber tube is communicated with intestinal perfusate; one end of an outlet rubber tube of the constant-temperature peristaltic pump is inserted into a small opening at the lower end and is fastened by a wire for connection. And opening the constant-temperature peristaltic pump to slowly pump the physiological saline with the temperature of 37 +/-0.5 ℃ into the intestinal canal, flushing the content in the intestinal canal, discharging residual liquid in the intestinal canal by using air, and then closing the intestinal canal. After the normal saline is changed into the intestinal absorption test solution, a peristaltic pump is started, the balance is carried out for 10min at a constant flow rate (5mL/min), perfusion is carried out at 2.5mL/min, 3mL of a sample is absorbed from the intestinal absorption test solution, the sample is recorded as a sample measurement result at the zero moment, 3mL of K-R solution containing phenol red at 37 +/-0.5 ℃ is additionally added into the intestinal absorption test solution, then sampling is carried out at the set time points of 0, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3h, 4h, 5h, 6h, 8h, 10h and 12h respectively, the same volume of the K-R solution containing phenol red at 37 +/-0.5 ℃ is added in the same way, and the experiment is stopped after the constant-temperature peristaltic pump circulates for 12 h. And measuring the peak area of the celecoxib by using a high performance liquid chromatograph, measuring the absorbance of phenol red by using an ultraviolet spectrophotometer, and respectively substituting the absorbance into a standard curve to calculate the logarithmic value and the absorption rate constant of the residual drug.
The invention takes chiral malic acid and tartaric acid as chiral modification molecules for providing mesoporous silica nanoparticles, and the chiral malic acid and tartaric acid are respectively grafted on the mesoporous silica nanoparticles to construct the chiral mesoporous silica nanoparticles. Indometacin and celecoxib are respectively used as model drugs to construct a drug loading system, and the preparation process and the drug delivery advantages of the two chiral mesoporous silica nanoparticles are researched. The prepared chiral mesoporous silica nanoparticles have the advantages of reduced specific surface area and pore volume, and can better entrap insoluble drugs and improve the solubility and bioavailability of the insoluble drugs.
Drawings
FIG. 1 is an SEM image of mesoporous silica nanoparticles of examples 1-3;
a is a blank mesoporous silica nanoparticle; b is mesoporous silicon dioxide nano-particles modified by L-malic acid;
c is mesoporous silicon dioxide nano-particles modified by D-malic acid.
FIG. 2 is a specific surface area diagram and a pore size distribution diagram of the mesoporous silica nanoparticles of examples 1 to 3.
FIG. 3 is a DSC chart of indomethacin and mesoporous silica nanoparticles of examples 1-6.
FIG. 4 is an FTIR chart of indomethacin and mesoporous silica nanoparticles of examples 1-6.
FIG. 5 is a cumulative in vitro release profile of indomethacin and the mesoporous silica nanoparticles loaded with indomethacin of examples 4-6.
FIG. 6 is a graph showing the time-dependent change of the log value of the remaining dose of indomethacin in rat intestine loaded with mesoporous silica nanoparticles of examples 4 to 6.
FIG. 7 is an SEM photograph of mesoporous silica nanoparticles of examples 7-9;
a is a blank mesoporous silica nanoparticle; b is mesoporous silica nano-particles modified by L-tartaric acid;
c is the mesoporous silicon dioxide nano particle modified by D-tartaric acid.
FIG. 8 is a specific surface area diagram and a pore size distribution diagram of the mesoporous silica nanoparticles of examples 7 to 9.
FIG. 9 is a DSC of celecoxib, mesoporous silica nanoparticles of examples 7-12.
FIG. 10 is an FTIR chart of celecoxib, the mesoporous silica nanoparticles of examples 7-12.
Figure 11 is a celecoxib, celecoxib in vitro cumulative release profile of examples 10-12.
Figure 12 is a plot of the log of the amount of celecoxib remaining in the rat intestine versus time for celecoxib from examples 10-12.
Detailed Description
Example 1
Preparation of blank mesoporous silica nanoparticles
The preparation process comprises the following steps:
And 2, adding the ammonia water of the formula amount into the solution under the stirring of water bath at 25 ℃.
And 3, dropwise adding the tetraethoxysilane of the prescription amount into the solution under the condition of vigorous stirring (the rotating speed is 1200r/min), continuously stirring for 4 hours, and standing for 24 hours.
And 4, standing, centrifuging the solution, and washing the obtained precipitate with water and ethanol twice respectively. The washed precipitate was dried in a vacuum oven at 45 ℃.
And 5, collecting the dried precipitate, dispersing the precipitate in 400ml of 0.01mol/l HCl-methanol solution, refluxing for 12 hours, centrifuging, washing with water, and drying to obtain the blank mesoporous silica nanoparticles.
Fig. 1A shows that the prepared blank mesoporous silica nanoparticles are spherical nanoparticles with rough surfaces.
FIG. 2 shows that the specific surface area of the blank mesoporous silica nanoparticles is 458.16m 2 Per g, pore diameter of 2.2nm and pore volume of 0.451cm 3 /g。
FIG. 3 is a DSC of blank mesoporous silica nanoparticles showing that: no obvious endothermic peak, which indicates that the blank mesoporous silica nanoparticle is in an amorphous state.
The FTIR plot of the blank mesoporous silica nanoparticles of fig. 4 shows: 1078.0cm -1 Is the antisymmetric stretching vibration absorption peak of the Si-O-Si bond, 796.4cm -1 Is a symmetric stretching vibration absorption peak of the Si-O-Si bond, 468.6cm -1 Where is the bending vibration absorption peak of the Si-O bond. The result shows that the blank mesoporous silica nanoparticle is successfully synthesized.
Example 2
(1) Preparation of L-malic acid modified silane coupling agent
| L-malic acid | 2.4g |
| Anhydrous ethanol | 160ml |
| 3-aminopropyltriethoxysilane | 4ml |
(2) Preparation of L-malic acid modified mesoporous silica nano particle
The preparation process comprises the following steps:
And 2, adding the 3-aminopropyltriethoxysilane according to the prescription amount into the solution, and stopping stirring for 4 hours.
And 3, centrifuging the stirred reaction solution, and washing the precipitate with absolute ethyl alcohol for 2 times.
And 4, drying the washed white precipitate in a vacuum drying oven at 50 ℃ to obtain the L-malic acid modified silane coupling agent.
And 5, dissolving the prescription amount of hexadecyl trimethyl ammonium bromide into a mixed solution of 320ml of redistilled water and 96ml of absolute ethyl alcohol.
And step 6, sequentially adding the ammonia water and the 2.0g L-malic acid modified silane coupling agent into the mixed solution at the formula amount under the stirring of water bath at 25 ℃.
And 7, dropwise adding the ethyl orthosilicate according to the prescription amount into the solution under the condition of vigorous stirring, continuously stirring for 4 hours, and standing for 24 hours.
And 8, standing, centrifuging the solution, and washing the obtained precipitate with water and ethanol twice respectively. The washed precipitate was dried in a vacuum oven at 45 ℃.
And 9, collecting the dried precipitate, dispersing the precipitate in 400ml of 0.01mol/L HCl-methanol solution, refluxing for 12 hours, centrifuging, washing with water, and drying to obtain the L-malic acid modified mesoporous silica nanoparticles.
FIG. 1B shows that: the mesoporous silica nanoparticles modified with L-malic acid prepared in example 2 were spheroidal nanoparticles with a rough surface.
The results in FIG. 2 show that: the specific surface area of the mesoporous silica nanoparticles modified by the L-malic acid is 168.46m 2 G, pore diameter of 5.8nm and pore volume of 0.250cm 3 /g。
The DSC chart of the L-malic acid-modified mesoporous silica nanoparticle of fig. 3 shows that there is no significant endothermic peak, indicating that the L-malic acid-modified mesoporous silica nanoparticle is in an amorphous state.
The FTIR chart of the L-malic acid modified mesoporous silica nanoparticles of fig. 4 shows: 1076.0cm -1 Is the antisymmetric stretching vibration absorption peak of the Si-O-Si bond, 790.6cm -1 Is a symmetric stretching vibration absorption peak of the Si-O-Si bond, 460.9cm -1 At the bending vibration absorption peak of Si-O bond, 1639.1cm -1 The peak is the carbonyl stretching vibration absorption peak of amide, 3434.6cm -1 The position is a stretching vibration absorption peak of-OH, which shows that the mesoporous silica nanoparticle modified by the L-malic acid successfully realizes chiral modification.
Example 3
(1) Preparation of D-malic acid modified silane coupling agent
| D-malic acid | 2.4g |
| Anhydrous ethanol | 160ml |
| 3-aminopropyltriethoxysilane | 4ml |
(2) Preparation of D-malic acid modified mesoporous silica nano-particle
| Cetyl trimethyl ammonium Bromide | 3.0g |
| Redistilled water | 320ml |
| Anhydrous ethanol | 96ml |
| Ammonia water | 2.8ml |
| Tetraethoxysilane | 8ml |
| D-malic acid modified silane coupling agent | 2.0g |
The preparation process comprises the following steps:
And 2, adding the 3-aminopropyltriethoxysilane according to the prescription amount into the solution, and stopping stirring for 4 hours.
And 3, centrifuging the stirred reaction solution, and washing the precipitate for 2 times by using absolute ethyl alcohol.
And 4, drying the washed white precipitate in a vacuum drying oven at 50 ℃ to obtain the D-malic acid modified silane coupling agent.
And 5, dissolving the prescription amount of hexadecyl trimethyl ammonium bromide into a mixed solution of 320ml of redistilled water and 96ml of absolute ethyl alcohol.
And step 6, sequentially adding the ammonia water and the 2.0g D-malic acid modified silane coupling agent into the mixed solution at the temperature of 25 ℃ under the stirring of water bath.
And 7, dropwise adding the tetraethoxysilane of the prescription amount into the solution under the condition of vigorous stirring, continuously stirring for 4 hours, and standing for 24 hours.
And 8, standing, centrifuging the solution, and washing the obtained precipitate with water and ethanol twice respectively. The washed precipitate was dried in a vacuum oven at 45 ℃.
And 9, collecting the dried precipitate, dispersing the precipitate in 400ml of 0.01mol/l HCl-methanol solution, refluxing for 12 hours, centrifuging, washing with water, and drying to obtain the D-malic acid modified mesoporous silica nanoparticles.
Fig. 1C shows that the D-malic acid modified mesoporous silica nanoparticles prepared in example 3 are surface-roughened spheroidal nanoparticles.
The results in FIG. 2 show that: the specific surface area of the mesoporous silica nanoparticles modified by the D-malic acid is 184.38m 2 G, pore diameter of 2.8nm and pore volume of 0.197cm 3 /g。
The DSC diagram of the D-malic acid modified mesoporous silica nanoparticle in fig. 3 shows that there is no significant endothermic peak, indicating that the D-malic acid modified mesoporous silica nanoparticle is in an amorphous state.
The FTIR chart of the D-malic acid modified mesoporous silica nanoparticles in fig. 4 shows that: 1070.2cm -1 Is the antisymmetric stretching vibration absorption peak of the Si-O-Si bond, 796.4cm -1 Is a symmetric stretching vibration absorption peak of the Si-O-Si bond, 462.8cm -1 At the bending vibration absorption peak of Si-O bond, 1637.2cm -1 The peak is the carbonyl stretching vibration absorption peak of amide, 3436.5cm -1 The position is a stretching vibration absorption peak of-OH, which shows that the mesoporous silica nanoparticle modified by the D-malic acid successfully realizes chiral modification.
Physicochemical Properties of mesoporous silica nanoparticles of examples 1 to 3
| Examples | Specific surface area (m) 2 /g) | Pore size (nm) | Pore volume (cm) 3 /g) |
| 1 | 458.16 | 2.2 | 0.451 |
| 2 | 168.46 | 5.8 | 0.250 |
| 3 | 184.38 | 2.8 | 0.197 |
The results show that the spherical nanoparticles with rough surfaces are formed in the examples 1 to 3, no obvious endothermic peak exists, the mesoporous silica nanoparticles are in an amorphous state, the specific surface area of the mesoporous silica nanoparticles modified by the D-malic acid or the L-malic acid is obviously reduced, and the pore volume is reduced.
The silane coupling agents were prepared from L-lysine, D-lysine, L-leucine, D-leucine, L-tryptophan, D-tryptophan, L-phenylalanine, D-phenylalanine, L-threonine, D-threonine, L-isoleucine, and D-isoleucine, respectively, in accordance with the method of example 2.
The system before the reaction of the chiral silane coupling agent is in a solution state, and if particles are formed, the chiral micromolecules and the silane coupling agent are proved to react. However, the synthesis of the chiral silane coupling agent cannot obtain particles, i.e., the synthesis is unsuccessful.
The results show that: the chiral amino acid and 3-aminopropyltriethoxysilane as above cannot obtain a chiral silane coupling agent by the reaction process of the present invention.
Example 4
Preparation of blank mesoporous silica nanoparticle-loaded indomethacin of example 1
| Indometacin | 80mg |
| Acetone (II) | 4ml |
| Blank mesoporous silica nanoparticle | 240mg |
The preparation process comprises the following steps:
And 2, adding the blank mesoporous silica nanoparticles in the formula amount into the solution at room temperature, and sealing and stirring for overnight.
And 3, placing the mixture obtained in the step 2 in a vacuum drying oven at 40 ℃ for drying, washing the obtained precipitate with phosphate buffer solution with the pH value of 7.4, and then placing in the vacuum drying oven at 40 ℃ for drying to obtain the blank mesoporous silica nanoparticle loaded indometacin.
The DSC chart of indomethacin and blank mesoporous silica nanoparticle loaded indomethacin in fig. 3 shows that: the DSC chart of the indomethacin shows a distinct endothermic peak, which indicates that the indomethacin is in a crystalline state. In a DSC image of the blank mesoporous silica nanoparticle loaded with indometacin, no obvious endothermic peak exists, which indicates that the indometacin is successfully loaded in the pore canal of the blank mesoporous silica nanoparticle and exists in an amorphous state.
The FTIR plot of indomethacin and the blank mesoporous silica nanoparticle loaded indomethacin in fig. 4 shows that: 1589.0cm -1 And 1479cm -1 Two peaks appeared at the position are skeleton stretching vibration absorption peaks of benzene ring in indometacin structure, 833.0cm -1 The position is a characteristic absorption peak of para-substitution of a benzene ring. As can be seen from the figure, the absorption peak belonging to the benzene ring almost disappears, indicating that indomethacin is successfully loaded into the blank mesoporous silica nanoparticle.
Example 5
Preparation of L-malic acid modified mesoporous silica nanoparticle loaded indometacin
| Indometacin | 80mg |
| Acetone (II) | 4ml |
| L-malic acid modified mesoporous silica nanoparticle | 240mg |
The preparation process comprises the following steps:
And 2, adding the mesoporous silica nanoparticles modified by the L-malic acid in a prescription amount into the solution at room temperature, and sealing and stirring for overnight.
And 3, placing the mixture in a vacuum drying oven at 40 ℃ for drying, washing the obtained precipitate with a phosphate buffer solution with the pH value of 7.4, and then placing in the vacuum drying oven at 40 ℃ for drying to obtain the L-malic acid modified mesoporous silica nanoparticle loaded indometacin.
In fig. 3, the DSC chart of indometacin and L-malic acid modified mesoporous silica nanoparticle loaded indometacin shows that: the DSC chart of the indometacin shows a remarkable endothermic peak, which indicates that the indometacin is in a crystalline state. In a DSC image of the L-malic acid modified mesoporous silica nanoparticle loaded with the indometacin, no obvious endothermic peak exists, which indicates that the indometacin is successfully loaded into the pore channel of the L-malic acid modified mesoporous silica nanoparticle and exists in an amorphous state.
The FTIR chart of the indometacin and the L-malic acid modified mesoporous silica nanoparticle loaded indometacin in FIG. 4 shows that: 1589.0cm -1 And 1479cm -1 Two peaks appeared at the position are skeleton stretching vibration absorption peaks of benzene ring in indometacin structure, 833.0cm -1 The position is a characteristic absorption peak of para-substitution of a benzene ring. As can be seen from the figure, the absorption peak belonging to the benzene ring almost disappears, which indicates that the indomethacin is successfully loaded into the mesoporous silica nanoparticles modified by the L-malic acid.
Example 6
Preparation of D-malic acid modified mesoporous silica nanoparticle loaded indometacin
| Indometacin | 80mg |
| Acetone (II) | 4ml |
| D-malic acid modified mesogensPorous silica nanoparticles | 240mg |
The preparation process comprises the following steps:
And 2, adding the mesoporous silica nanoparticles modified by the D-malic acid into the solution at room temperature, and sealing and stirring the solution overnight.
And 3, placing the mixture obtained in the step 2 in a vacuum drying oven at 40 ℃ for drying, washing the obtained precipitate with a phosphate buffer solution with the pH value of 7.4, and then placing in the vacuum drying oven at 40 ℃ for drying to obtain the D-malic acid modified mesoporous silica nanoparticle loaded indometacin.
In fig. 3, the DSC chart of indometacin and D-malic acid modified mesoporous silica nanoparticle loaded indometacin shows that: the DSC chart of the indomethacin shows a distinct endothermic peak, which indicates that the indomethacin is in a crystalline state. In a DSC image of the D-malic acid modified mesoporous silica nanoparticle loaded with the indomethacin, no obvious endothermic peak exists, which indicates that the indomethacin is successfully loaded in the pore channel of the D-malic acid modified mesoporous silica nanoparticle and exists in an amorphous state.
The FTIR chart of indometacin and D-malic acid modified mesoporous silica nanoparticle loaded indometacin in fig. 4 shows that: 1589.0cm -1 And 1479cm -1 Two peaks appeared in the position are skeleton stretching vibration absorption peaks of benzene ring in indometacin structure, 833.0cm -1 The site is a characteristic absorption peak of para-substitution of a benzene ring. As can be seen from the figure, the absorption peak belonging to the benzene ring almost disappears, indicating that indomethacin is successfully loaded into the mesoporous silica nanoparticles modified by the D-malic acid.
Fig. 5 shows the in vitro cumulative release curves of indomethacin, indomethacin loaded on blank mesoporous silica nanoparticles, indomethacin loaded on L-malic acid modified mesoporous silica nanoparticles, and indomethacin loaded on D-malic acid modified mesoporous silica nanoparticles as follows: the release speed of the D-malic acid modified mesoporous silica nanoparticle loaded with indometacin is higher than that of indometacin, the release speed of the D-malic acid modified mesoporous silica nanoparticle loaded with indometacin is lower than that of the L-malic acid modified mesoporous silica nanoparticle loaded with indometacin and that of the blank mesoporous silica nanoparticle loaded with indometacin, and the release speed of the L-malic acid modified mesoporous silica nanoparticle loaded with indometacin is fastest.
In fig. 6, the curve showing the change of the logarithmic value of the residual drug amount of indomethacin, indomethacin loaded on the blank mesoporous silica nanoparticle, indomethacin loaded on the L-malic acid-modified mesoporous silica nanoparticle, indomethacin loaded on the D-malic acid-modified mesoporous silica nanoparticle in the rat intestine with time shows that: the absorption rate constant of indometacin is 0.000524, and the absorption rate per three hours is 12.86; the absorption rate constant of the blank mesoporous silica nanoparticle-loaded indometacin is 0.000535, and the absorption rate per three hours is 8.14; the absorption rate constant of the D-malic acid modified mesoporous silica nanoparticle loaded indometacin is 0.000236, and the absorption rate per three hours is 5.30; the absorption rate constant of the L-malic acid modified mesoporous silica nanoparticle loaded indometacin is 0.000643, and the absorption rate per three hours is 20.87. In four cases, namely indomethacin, blank mesoporous silica nanoparticle-loaded indomethacin, L-malic acid modified mesoporous silica nanoparticle-loaded indomethacin, and D-malic acid modified mesoporous silica nanoparticle-loaded indomethacin, the absorption rate constant of the blank mesoporous silica nanoparticle-loaded indomethacin is greater than that of indomethacin and D-malic acid modified mesoporous silica nanoparticle-loaded indomethacin, the absorption rate constant of the D-malic acid modified mesoporous silica nanoparticle-loaded indomethacin is the smallest, and the absorption rate constant of the L-malic acid modified mesoporous silica nanoparticle-loaded indomethacin is the largest.
The in vitro release results of the chiral mesoporous silica nanoparticle loaded with indomethacin obtained in examples 4 to 6 show that the release speed of the chiral mesoporous silica nanoparticle loaded with indomethacin obtained in example 5 is the fastest, because the amount of indomethacin in the L-malic acid modified mesoporous silica nanoparticle is greater in the amorphous state than in the blank mesoporous silica nanoparticle and the D-malic acid modified mesoporous silica nanoparticle.
The results of in vivo circulation intestinal perfusion tests of the chiral mesoporous silica nanoparticle-loaded indometacin obtained in examples 4 to 6 show that the absorption rate constant of the chiral mesoporous silica nanoparticle-loaded indometacin obtained in example 5, namely L-malic acid modified mesoporous silica nanoparticle, is the largest. According to the report, the absorption rate constant can be used for estimating the in vivo utilization speed and the drug effect speed of different preparations or different administration modes of a certain drug, and therefore, the transmembrane drug delivery effect of the blank mesoporous silica nanoparticle loaded with indometacin and the D-malic acid modified mesoporous silica nanoparticle loaded with indometacin is lower than that of the L-malic acid modified mesoporous silica nanoparticle loaded with indometacin. From the results, the L-malic acid modified mesoporous silica nanoparticle loaded indometacin has the best in-vitro drug release speed and the best absorption rate constant.
Example 7
Preparation of blank mesoporous silica nanoparticles
The preparation process comprises the following steps:
And 2, adding the ammonia water of the formula amount into the solution under the stirring of water bath at 25 ℃.
And 3, dropwise adding the tetraethoxysilane into the solution according to the formula amount under the condition of vigorous stirring (the rotating speed is 600r/min), continuously stirring for 4 hours, and standing for 24 hours.
And 4, standing, centrifuging the solution, and washing the obtained precipitate twice with water and ethanol respectively. The washed precipitate was dried in a vacuum oven at 45 ℃.
And 5, collecting the dried precipitate, dispersing the precipitate in 400ml of 0.01mol/l HCl-methanol solution, refluxing for 12 hours, centrifuging, washing with water, and drying to obtain the blank mesoporous silica nanoparticles.
Fig. 7A shows: the pore canal on the surface of the synthetic material is very compact.
The specific surface area diagram and the pore size distribution diagram of the blank mesoporous silica nanoparticles in fig. 8 show that: the specific surface area of the blank mesoporous silica nano-particles is 480.81m 2 G, pore diameter of 1.8nm and pore volume of 0.850cm 3 /g。
FIG. 9 shows that the DSC chart of the hollow mesoporous silica nanoparticles shows that there is no significant endothermic peak, indicating that the hollow mesoporous silica nanoparticles are in an amorphous state.
The FTIR plot of the hollow mesoporous silica nanoparticles of fig. 10 shows: 1070.3cm -1 Is the antisymmetric stretching vibration absorption peak of the Si-O-Si bond, 800.31cm -1 Is a symmetric stretching vibration absorption peak of the Si-O-Si bond, 460.9cm -1 Is the bending vibration absorption peak of the Si-O bond. The result shows that the blank mesoporous silica nanoparticle is successfully synthesized.
Example 8
(1) Preparation of L-tartaric acid modified silane coupling agent
| L-tartaric acid | 3.0g |
| Anhydrous ethanol | 160ml |
| Gamma-mercaptopropyl-trimethoxysilane | 4ml |
(2) Preparation of L-tartaric acid modified mesoporous silica nanoparticles
The preparation process comprises the following steps:
And 3, centrifuging the stirred reaction solution, and washing the precipitate for 2 times by using absolute ethyl alcohol.
And 4, drying the washed white precipitate in a vacuum drying oven at 50 ℃ to obtain the L-tartaric acid modified silane coupling agent.
And 5, dissolving the prescription amount of hexadecyl trimethyl ammonium bromide into a mixed solution of 320ml of redistilled water and 96ml of absolute ethyl alcohol.
And step 6, sequentially adding the ammonia water and the 2.0g L-tartaric acid modified silane coupling agent into the mixed solution according to the prescription amount under the stirring of water bath at 25 ℃.
And 7, dropwise adding the tetraethoxysilane into the solution according to the formula amount under the condition of vigorous stirring (the rotating speed is 600r/min), continuously stirring for 4 hours, and standing for 24 hours.
And 8, standing, centrifuging the solution, and washing the obtained precipitate twice with water and ethanol respectively. The washed precipitate was dried in a vacuum oven at 45 ℃.
And 9, collecting the dried precipitate, dispersing the precipitate in 400ml of 0.01mol/L HCl-methanol solution, refluxing for 12 hours, centrifuging, washing with water, and drying to obtain the L-tartaric acid modified mesoporous silica nanoparticles.
The SEM image of the L-tartaric acid modified mesoporous silica nanoparticles of FIG. 7B shows that the pores on the surface of the synthetic material are very dense.
The specific surface area diagram and the pore size distribution diagram of the L-tartaric acid modified mesoporous silica nanoparticle in fig. 8 show that: the specific surface area of the mesoporous silica nanoparticles modified by the L-tartaric acid is 225.53m 2 G, pore diameter of 2.0nm and pore volume of 0.310cm 3 /g。
The DSC chart of the L-tartaric acid-modified mesoporous silica nanoparticle in fig. 9 shows that there is no significant endothermic peak, indicating that the L-tartaric acid-modified mesoporous silica nanoparticle is in an amorphous state.
The FTIR plot of the L-tartaric acid-modified mesoporous silica nanoparticles of fig. 10 shows that: 1070.3cm -1 Is the antisymmetric stretching vibration absorption peak of the Si-O-Si bond, 800.31cm -1 Is a symmetric stretching vibration absorption peak of the Si-O-Si bond, 460.9cm -1 At the bending vibration absorption peak of Si-O bond, 1024.02cm -1 Is the absorption peak of the C-S-C stretching vibration, 3550.31cm -1 At a stretching vibration absorption peak of-COOH, 3436.53cm -1 The position is a stretching vibration absorption peak of-OH, which shows that the L-tartaric acid decorated mesoporous silica nanoparticle successfully realizes chiral modification.
Example 9
(1) Preparation of D-tartaric acid modified silane coupling agent
| D-tartaric acid | 3.0g |
| Anhydrous ethanol | 160ml |
| Gamma-mercaptopropyl-trimethoxysilane | 4ml |
(2) Preparation of D-tartaric acid modified mesoporous silica nanoparticles
| Cetyl trimethyl ammonium Bromide | 3.0g |
| Anhydrous ethanol | 96ml |
| Redistilled water | 320ml |
| Ammonia water | 2.8ml |
| Tetraethoxysilane | 8ml |
| D-tartaric acid modified silane coupling agent | 2.0g |
The preparation process comprises the following steps:
And 2, adding the gamma-mercaptopropyl trimethoxysilane with the formula amount into the solution, and stopping stirring for 4 hours.
And 3, centrifuging the stirred reaction solution, and washing the precipitate for 2 times by using absolute ethyl alcohol.
And 4, drying the washed white precipitate in a vacuum drying oven at 50 ℃ to obtain the D-tartaric acid modified silane coupling agent.
And step 5, dissolving the prescription amount of hexadecyl trimethyl ammonium bromide in a mixed solution of 320ml of redistilled water and 96ml of absolute ethyl alcohol.
And step 6, sequentially adding the ammonia water and the 2.0g D-tartaric acid modified silane coupling agent into the mixed solution according to the prescription amount under the stirring of water bath at 25 ℃.
And 7, dropwise adding the tetraethoxysilane into the solution according to the formula amount under the condition of vigorous stirring (the rotating speed is 600r/min), continuously stirring for 4 hours, and standing for 24 hours.
And 8, standing, centrifuging the solution, and washing the obtained precipitate twice with water and ethanol respectively. The washed precipitate was dried in a vacuum oven at 45 ℃.
And 9, collecting the dried precipitate, dispersing the precipitate in 400ml of 0.01mol/l HCl-methanol solution, refluxing for 12 hours, centrifuging, washing with water, and drying to obtain the D-tartaric acid modified mesoporous silica nanoparticles.
The SEM picture of the D-tartaric acid-modified mesoporous silica nanoparticles of fig. 7C shows that: the pore channels on the surface of the synthetic material are very compact.
The specific surface area diagram and the pore size distribution diagram of the D-tartaric acid-modified mesoporous silica nanoparticle of fig. 8 show that: the specific surface area of the D-tartaric acid modified mesoporous silica nanoparticle is 90.41m 2 G, pore diameter of 1.9nm and pore volume of 0.232cm 3 /g。
The DSC chart of the D-tartaric acid-modified mesoporous silica nanoparticle in fig. 9 shows that there is no significant endothermic peak, indicating that the D-tartaric acid-modified mesoporous silica nanoparticle is in an amorphous state.
The FTIR plot of the D-tartaric acid-modified mesoporous silica nanoparticles of fig. 10 shows that: 1070.3cm -1 Is the antisymmetric stretching vibration absorption peak of the Si-O-Si bond, 796.4cm -1 Is the symmetric stretching vibration absorption peak of Si-O-Si bond at 460.8cm -1 Is the flexural vibration absorption peak of Si-O bond at 3550.31cm -1 (ii) a stretching vibration absorption peak at-COOH of 3436.5cm -1 The position is a stretching vibration absorption peak of-OH, which shows that the D-tartaric acid modified mesoporous silica nanoparticle successfully realizes chiral modification.
Physicochemical Properties of mesoporous silica nanoparticles of examples 7 to 9
| Examples | Specific surface area (m) 2 /g) | Aperture (nm) | Pore volume (cm) 3 /g) |
| 7 | 480.81 | 1.8 | 0.850 |
| 8 | 225.53 | 2.0 | 0.310 |
| 9 | 90.41 | 1.9 | 0.232 |
The results show that the surface pore channels of the synthetic materials of examples 7-9 are very dense, have no obvious endothermic peak, and are in an amorphous state, and the specific surface area and pore volume of the mesoporous silica nanoparticles modified by D-tartaric acid or L-tartaric acid are obviously reduced.
Example 10
Example 7 preparation of celecoxib loaded on blank mesoporous silica nanoparticles
| Celecoxib | 40mg |
| Anhydrous ethanol | 4ml |
| Blank mesoporous silica nanoparticle | 200mg |
The preparation process comprises the following steps:
And 2, adding the blank mesoporous silica nanoparticles in the formula amount into the solution at room temperature, and sealing and stirring for overnight.
And 3, placing the mixture obtained in the step 2 in a vacuum drying oven at 40 ℃ for drying, washing the obtained precipitate with redistilled water, and placing in the vacuum drying oven at 40 ℃ for drying to obtain the blank mesoporous silica nanoparticle-loaded indometacin.
The DSC chart of the blank mesoporous silica nanoparticle loaded celecoxib of fig. 9 has no significant endothermic peak, which indicates that celecoxib is successfully loaded into the pores of the blank mesoporous silica nanoparticles and exists in an amorphous state. The DSC chart of the celecoxib shows that an obvious endothermic peak exists, which indicates that the celecoxib is in a crystalline state.
The FTIR plot of celecoxib in FIG. 10 shows 1589.12cm -1 And 1480.13cm -1 Is present atTwo peaks are the absorption peak of the skeleton stretching vibration of the benzene ring, 833.09cm -1 The position is a characteristic absorption peak of para-substitution of a benzene ring, 1120.44cm -1 Is the peak of C-F stretching vibration. In the infrared spectrogram of the blank mesoporous silica nanoparticle loaded celecoxib in fig. 10, the absorption peak belonging to the benzene ring and the absorption peak of C-F almost disappear, which indicates that the celecoxib is successfully loaded in the blank mesoporous silica nanoparticles.
Example 11
Preparation of L-tartaric acid modified mesoporous silica nanoparticle loaded celecoxib
| Celecoxib | 40mg |
| Anhydrous ethanol | 4ml |
| L-tartaric acid modified mesoporous silica nanoparticle | 200mg |
The preparation process comprises the following steps:
And 2, adding the mesoporous silica nanoparticles modified by the L-tartaric acid in the formula amount into the solution at room temperature, and sealing and stirring for overnight.
And 3, placing the mixture obtained in the step 2 in a vacuum drying oven at 40 ℃ for drying, washing the obtained precipitate with redistilled water, and placing the washed precipitate in the vacuum drying oven at 40 ℃ for drying to obtain the L-tartaric acid modified mesoporous silica nanoparticle loaded celecoxib.
The DSC profile of celecoxib in figure 9 shows a distinct endothermic peak indicating crystalline celecoxib. The DSC chart of the L-tartaric acid-modified mesoporous silica nanoparticle-loaded celecoxib of example 11 shows that there is no significant endothermic peak, indicating that celecoxib is successfully loaded into the channels of the L-tartaric acid-modified mesoporous silica nanoparticle and exists in an amorphous state.
The FTIR plot of celecoxib of figure 10 shows: 1589.12cm -1 And 1480.13cm -1 Two peaks appeared at the position are absorption peaks of skeleton stretching vibration of benzene ring, 833.09cm -1 The position is a characteristic absorption peak of para-substitution of a benzene ring, 1120.44cm -1 Is the peak of C-F stretching vibration. Example 11 is an infrared spectrum of the celecoxib loaded on the L-tartaric acid modified mesoporous silica nanoparticle, and it can be seen from the graph that the absorption peaks belonging to the benzene ring and the absorption peaks of C-F almost disappear, indicating that the celecoxib is successfully loaded on the L-tartaric acid modified mesoporous silica nanoparticle loaded celecoxib.
Example 12
Preparation of D-tartaric acid modified mesoporous silica nanoparticle loaded celecoxib
| Celecoxib | 40mg |
| Anhydrous ethanol | 4ml |
| D-tartaric acid modified mesoporous silica nanoparticle | 200mg |
The preparation process comprises the following steps:
And 2, adding the D-tartaric acid modified mesoporous silica nanoparticles into the solution at room temperature, and sealing and stirring for overnight.
And 3, placing the mixture obtained in the step 2 in a vacuum drying oven at 40 ℃ for drying, washing the obtained precipitate with redistilled water, and placing the washed precipitate in the vacuum drying oven at 40 ℃ for drying to obtain the D-tartaric acid modified mesoporous silica nanoparticle loaded celecoxib.
The DSC profile of celecoxib in figure 9 shows a distinct endothermic peak indicating crystalline celecoxib. The DSC chart of the D-tartaric acid-modified mesoporous silica nanoparticle-loaded celecoxib of example 12 has no significant endothermic peak, indicating that celecoxib is successfully loaded into the channels of the D-tartaric acid-modified mesoporous silica nanoparticle and exists in an amorphous state.
The FTIR plot of celecoxib in FIG. 10 shows 1589.12cm -1 And 1480.13cm -1 Two peaks appeared in the spectrum are the absorption peak of the skeleton stretching vibration of the benzene ring, 833.09cm -1 The position is a characteristic absorption peak of para-substitution of a benzene ring, 1120.44cm -1 Is the stretching vibration peak of C-F. Example 12 is an infrared spectrum of the celecoxib loaded on the D-tartaric acid-modified mesoporous silica nanoparticle, and it can be seen from the graph that the absorption peaks belonging to the benzene ring and the absorption peaks of C-F almost disappear, indicating that the celecoxib is successfully loaded on the D-tartaric acid-modified mesoporous silica nanoparticle loaded celecoxib.
In fig. 11, the in vitro cumulative release curves of celecoxib, blank mesoporous silica nanoparticle loaded celecoxib, L-tartaric acid modified mesoporous silica nanoparticle loaded celecoxib, and D-tartaric acid modified mesoporous silica nanoparticle loaded celecoxib indicate that: the release speed of the blank mesoporous silica nanoparticle loaded celecoxib is higher than that of celecoxib, and is lower than that of L-tartaric acid modified mesoporous silica nanoparticle loaded celecoxib and that of D-tartaric acid modified mesoporous silica nanoparticle loaded celecoxib. The L-tartaric acid modified mesoporous silica nanoparticle loaded celecoxib has the fastest release speed.
In fig. 12, the curve showing the change of the logarithmic value of the residual drug amount of celecoxib, blank mesoporous silica nanoparticle loaded celecoxib, L-tartaric acid modified mesoporous silica nanoparticle loaded celecoxib, D-tartaric acid modified mesoporous silica nanoparticle loaded celecoxib in rat intestine with time shows that: the absorption rate constant of celecoxib is 0.0033, and the absorption rate per 6 hours is 6.861; the absorption rate constant of the blank mesoporous silica nanoparticle-loaded celecoxib is 0.0038, and the absorption rate per 6 hours is 7.510; the absorption rate constant of the D-tartaric acid modified mesoporous silica nanoparticle loaded celecoxib is 0.0045, and the absorption rate per 6 hours is 9.11; the absorption rate constant of the L-tartaric acid modified mesoporous silica nanoparticle loaded celecoxib is 0.0055, and the absorption rate per 6 hours is 11.14. In the four of celecoxib, blank mesoporous silica nanoparticle loaded celecoxib, L-tartaric acid modified mesoporous silica nanoparticle loaded celecoxib and D-tartaric acid modified mesoporous silica nanoparticle loaded celecoxib, the absorption rate constant and the absorption rate per 6 hours of the D-tartaric acid modified mesoporous silica nanoparticle loaded celecoxib and the L-tartaric acid modified mesoporous silica nanoparticle loaded celecoxib are greater than the absorption rate constant and the absorption rate per 6 hours of the celecoxib and the blank mesoporous silica nanoparticle loaded celecoxib, and the absorption rate constant and the absorption rate per 6 hours of the L-tartaric acid modified mesoporous silica nanoparticle loaded celecoxib are the greatest.
The in vitro release results of the chiral mesoporous silica nanoparticle loaded celecoxib obtained in examples 10 to 12 show that the release speed of the chiral mesoporous silica nanoparticle loaded celecoxib obtained in example 11 is the fastest, because the amount of celecoxib in the L-tartaric acid modified mesoporous silica nanoparticle is more in the amorphous state than in the blank mesoporous silica nanoparticle and the D-tartaric acid modified mesoporous silica nanoparticle.
The results of the in-vivo circulation intestinal perfusion tests of the chiral mesoporous silica nanoparticle-loaded celecoxib obtained in examples 10 to 12 show that the absorption rate constant of the chiral mesoporous silica nanoparticle-loaded celecoxib in example 11, i.e., the L-tartaric acid modified mesoporous silica nanoparticle-loaded celecoxib, is the largest. The absorption rate constant represents the speed of the drug entering the systemic circulation from the absorption site, namely the proportionality constant between the absorption speed and the drug amount in the body, and is used for measuring the speed of the drug absorption. Therefore, the transmembrane drug delivery effect of the celecoxib loaded by the L-tartaric acid modified mesoporous silica nanoparticle is better than that of the celecoxib loaded by the D-tartaric acid modified mesoporous silica nanoparticle. In conclusion, the L-tartaric acid modified mesoporous silica nanoparticle loaded celecoxib is the best.
Claims (10)
1. A chiral mesoporous silica nanoparticle is characterized in that a composition of chiral malic acid and 3-aminopropyltriethoxysilane is used as a chiral silane coupling agent, or a composition of chiral tartaric acid and gamma-mercaptopropyltrimethoxysilane is used as the chiral silane coupling agent, hexadecyl trimethyl ammonium bromide is used as a structure directing agent, and tetraethoxysilane is used as a silicon source for synthesis.
2. The chiral mesoporous silica nanoparticle according to claim 1, wherein the preparation method comprises the following steps:
step 1: synthesizing a chiral silane coupling agent:
(1) respectively dissolving malic acid or tartaric acid in absolute ethyl alcohol;
(2) adding 3-aminopropyltriethoxysilane into anhydrous ethanol for dissolving malic acid, or adding gamma-mercaptopropyltrimethoxysilane into anhydrous ethanol for dissolving tartaric acid; stirring to obtain a white precipitate, washing with absolute ethyl alcohol, centrifuging, and drying to obtain a chiral silane coupling agent;
step 2: dissolving hexadecyl trimethyl ammonium bromide in a mixed solution of redistilled water and absolute ethyl alcohol, dissolving ammonia water and a chiral silane coupling agent in the mixed solution under the stirring of water bath at 25-30 ℃, then dropwise adding ethyl orthosilicate into the mixed solution under the vigorous stirring, and standing after stirring;
and step 3: centrifuging the mixed solution after standing, and sequentially washing the obtained precipitate with water and alcohol; and drying the washed precipitate in a vacuum drying oven, collecting a white precipitate, dispersing the white precipitate in an HCl-methanol solution, refluxing, centrifuging, washing with water, and drying to obtain the product.
3. The chiral mesoporous silica nanoparticle of claim 2,
in the step 1, the malic acid is L-malic acid or D-malic acid; the tartaric acid is L-tartaric acid or D-tartaric acid; the mass volume ratio of the malic acid to the 3-aminopropyltriethoxysilane is as follows: 1: 1.5-1.7; the mass-volume ratio of the tartaric acid to the gamma-mercaptopropyl-trimethoxysilane is as follows: 1:1.2-1.4.
4. The chiral mesoporous silica nanoparticle of claim 2,
in the step 2, the volume ratio of the redistilled water to the absolute ethyl alcohol is 10-15: 3-5; the mass volume ratio of the chiral silane coupling agent to the ammonia water is 1: 1.2-1.5; the stirring speed is 600-1200 r/min.
5. The chiral mesoporous silica nanoparticle of claim 2, wherein,
in step 3, the concentration of the HCl-methanol solution is 0.01-0.02 mol/l.
6. Use of the chiral mesoporous silica nanoparticles of any one of claims 1-5 in the preparation of a medicament for increasing the solubility or bioavailability of a drug.
7. The use of claim 6, wherein the drug is indomethacin, celecoxib, curcumin, praziquantel, nimesulide, carvedilol, nitrendipine.
8. The application of claim 6, wherein the mass ratio of the chiral mesoporous silica nanoparticles to the drug is as follows: 2-6: 1.
9. the application of claim 7, wherein the chiral mesoporous silica nanoparticles are malic acid modified chiral mesoporous silica nanoparticles, the drug is indomethacin, and the mass ratio of the chiral mesoporous silica nanoparticles to the indomethacin is as follows: 3-4: 1.
10. the application of claim 7, wherein the chiral mesoporous silica nanoparticles are tartaric acid modified chiral mesoporous silica nanoparticles, the drug is celecoxib, and the mass ratio of the chiral mesoporous silica nanoparticles to the celecoxib is as follows: 4-5: 1.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20110081416A1 (en) * | 2008-04-28 | 2011-04-07 | Formac Pharmaceuticals N.V. | Ordered mesoporous silica material |
| US20140200311A1 (en) * | 2011-06-29 | 2014-07-17 | Kyoeisha Chemical Co., Ltd. | (meth)allylsilane compound, silane coupling agent thereof, and functional material using the same |
| WO2021101468A1 (en) * | 2019-11-21 | 2021-05-27 | Cukurova Universitesi Rektorlugu | Method of producing nano-technological biomaterials alternative to blood with bonding of haemoglobin (hb), enzyme and drug |
| CN113562737A (en) * | 2021-07-29 | 2021-10-29 | 沈阳药科大学 | Mesoporous silica nanoparticle with adjustable chiral structure and preparation method and application thereof |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20110081416A1 (en) * | 2008-04-28 | 2011-04-07 | Formac Pharmaceuticals N.V. | Ordered mesoporous silica material |
| US20140200311A1 (en) * | 2011-06-29 | 2014-07-17 | Kyoeisha Chemical Co., Ltd. | (meth)allylsilane compound, silane coupling agent thereof, and functional material using the same |
| WO2021101468A1 (en) * | 2019-11-21 | 2021-05-27 | Cukurova Universitesi Rektorlugu | Method of producing nano-technological biomaterials alternative to blood with bonding of haemoglobin (hb), enzyme and drug |
| CN113562737A (en) * | 2021-07-29 | 2021-10-29 | 沈阳药科大学 | Mesoporous silica nanoparticle with adjustable chiral structure and preparation method and application thereof |
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| 王健鑫等: "手性介孔二氧化硅载体对***溶出行为的改善", 《实用药物与临床》, vol. 22, no. 12, pages 1299 - 1302 * |
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